CN116916907A - Triphenylcalcilytic compounds for the treatment of autosomal dominant hereditary hypocalcemia type 1 (ADH 1) - Google Patents

Triphenylcalcilytic compounds for the treatment of autosomal dominant hereditary hypocalcemia type 1 (ADH 1) Download PDF

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CN116916907A
CN116916907A CN202180077283.8A CN202180077283A CN116916907A CN 116916907 A CN116916907 A CN 116916907A CN 202180077283 A CN202180077283 A CN 202180077283A CN 116916907 A CN116916907 A CN 116916907A
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cltx
dose
daily
blood
subject
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S·布鲁斯
J·福克斯
R·萨尼-格罗索
A·科美利
A·斯里德哈
M·S·罗伯茨
M·T·柯林斯
R·I·伽弗尼
K·B·L·罗兹科
I·R·哈特雷
K·A·柏奏
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United States Government Represented By Secretary Of Health And Human Services
Kosilitix Therapy Co ltd
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United States Government Represented By Secretary Of Health And Human Services
Kosilitix Therapy Co ltd
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Priority claimed from PCT/US2021/050677 external-priority patent/WO2022060987A1/en
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Abstract

The present disclosure provides a method of treating autosomal dominant hereditary hypocalcemia type 1 (ADH 1) with a therapeutically effective amount of a compound of formula (I) (particularly CLTX-305), wherein the therapeutically effective amount of the compound increases the blood calcium concentration (ca) to a range of about 7.5mg/dL to about 10.5mg/dL, for example about 8.5mg/dL to about 10.5mg/dL. Also provided herein are methods of administering a therapeutically effective amount of a compound of formula (I) or CLTX-305 to treat autosomal dominant hereditary hypocalcemia type 1 (ADH 1) according to one or more dosing regimens.

Description

Triphenylcalcilytic compounds for the treatment of autosomal dominant hereditary hypocalcemia type 1 (ADH 1)
Cross-reference to related applications
The present application claims priority from U.S. provisional application No. 63/080165 filed on 18/9/2020 and U.S. provisional application No. 63/15977 filed on 10/3/2021, each of which is incorporated herein in its entirety for all purposes.
Statement regarding rights to application under federally sponsored research and development
Is not applicable.
Reference to "sequential list", table, or computer program list appendix submitted on optical disc
Is not applicable.
Technical Field
Autosomal dominant inherited hypocalcemia type 1 (ADH 1) is a rare systemic calcium homeostasis disorder caused by hypocalcemia due to activating mutations in the gene encoding the calcium sensitive receptor (CASR) (Hannan et al, human molecular genetics,2012, 21 (12), p.2768-2778; and Hofer et al, nature's: molecular cell lbiogy, 2003,4 (7), p.530-538). Calcium sensitive receptors (CaSR) play a dominant role in regulating systemic calcium homeostasis by controlling parathyroid hormone (PTH) secretion and urinary calcium excretion in response to changes in extracellular calcium concentration (Hofer et al, nature reviews: molecular cell biology,2003; and Gunn et al, ann Clin Biochem,2004, 41 (Pt 6): p.441-58). Negative allosteric modulators of CaSR (so-called calcification agents) may represent potential targeted therapies for ADH 1.
The incidence of ADH1 was uncertain and previously estimated to be about one-half of 70000 (Gunn et al, ann. Clin. Biochem., 2004) or 3.9 per 100000 (Dershem et al, the American Journal of Human Genetics,2020, 106, 1-14). According to any existing estimation, it meets applicable standards of other regulatory health authorities such as the United states food and drug administration and European drug administration, and is recognized as a rare disease by the National Institute of Health (NIH) rare disease research office (genetic and rare disease, (GARD) number: 2877) and the European rare disease Association (Orpha number: 428).
ADH1 is characterized by varying degrees of hypocalcemia, abnormally low levels of parathyroid hormone (PTH), hyperphosphatemia and low levels of magnesium, often accompanied by persistent hypercalcuria (Roszko et al, frontiers in Physiology,2016,7, p.458). The most common symptoms of hypocalcemia include paresthesia, muscle spasms, hand and foot twitches, mouth Zhou Mamu, and variable intensity, including the induction of seizures. Hypocalcemia may also manifest as laryngeal spasms, neuromuscular dysphoria, cognitive disorders, personality disorders, prolongation of superficial electrocardiogram QT intervals, which may be associated with increased risk of ventricular arrhythmias, electrocardiogram changes mimicking myocardial infarction and/or overt heart failure.
Hypocalcemia occurs in ADH1 patients primarily due to increased sensitivity of CaSR to extracellular ionized calcium, thereby inhibiting iPTH secretion and leading to 1,25- (OH) 2 Vitamin D (also known as 1, 25-dihydroxyvitamin D3; reducing calcium absorption in the intestine) and reduced levels of calcium reabsorption in the kidneys (leading to a relatively hypercalcemia). The increase in hypercalcemia is based on two mechanisms: PTH mediated reabsorption of calcium in the primary renal filtrate was reduced, while in the distal tubular, the mutated CaSR was hypersensitive to extracellular calcium concentration, with further reduction in calcium reabsorption. Furthermore, standard treatments for oral administration of calcium and calcitriol (e.g., 1, 25-dihydroxyvitamin D3) tend to potentiate hypercalcuria associated with long-term morbidity such as kidney stones, kidney calcification, and chronic kidney disease that can progress to renal failure (Khan et al, european journal of endocrinology,2018; and Li et al, clinical interventions in aging,2018, 13, p.2443-2452).
For this reason, a common approach to managing ADH1 is to balance the oral supplementation of calcium and calcitriol with the known high risk of kidney calcification, kidney stones and kidney failure (Roszko et al, frontiers in physiology, 2016). This means that healthcare providers must help patients find a regimen that can maintain the minimum serum calcium concentration that is compatible with symptomatic relief to minimize hypercalcemia. Thiazide diuretics are sometimes added to reduce the effects of calcium in the urine, but may lead to the risk of hypokalemia.
Experimental treatment of PTH (1-34) in ADH1 subjects was able to correct serum calcium but was unable to eliminate hypercalcuria (wine et al, the Journal of clinical endocrinology and metabolism,2012, 97 (2), p.391-399; wine et al, the Journal of pediatrics,2014, 165 (3), 556-63; and Gafni et al, journal of bone and mineral research,2015, 30 (11), p.2112-2118). Exogenous PTH (1-84) was approved for use in the orphan indication of hypoparathyroidism, but clinical studies supporting approved hypoparathyroidism patients excluded hypoparathyroidism patients due to calcium sensitive receptor mutations (Chomsky et al, world Journal of Surgery,2018, 42 (2), p.431-436; and Natpara product introduction).
Triphenylcalcilytic compounds refer to a class of compounds having calcium-sensitive receptor antagonism, as disclosed in U.S. patent No. 7304174, and are represented by the formula:
wherein R is 2 "is C 1-6 An alkyl group; r is R 4 "is methyl or cyclopropyl; r is R 6 "is a halogen atom or C 1-6 Alkyl, R 7 "is a hydrogen atom, a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or halogen C 1-6 An alkyl group, an optically active form thereof, a pharmaceutically acceptable salt thereof, or an optically active form of a salt thereof. In particular, the triphenylcalcilytic compound is represented by formula (I):
solvates, hydrates, pharmaceutically acceptable salts, or combinations thereof. In certain embodiments, the compound of formula (I) is CLTX-305 represented by the following formula:
previously, CLTX-305 (formerly JTT-305 or MK-5442) was developed by Nicotiana tabacum (JTI) and Merck (Merck) for the treatment of osteoporosis. Healthy volunteers and postmenopausal women with osteoporosis participated in a 1766 subject program, in which about 1280 people were exposed to JTT-305 in eight phase 1 and four phase 2 studies (including up to 52 weeks of exposure). While early data indicate potential net benefits for bone formation, late phase trials have failed to demonstrate efficacy at the endpoint of Bone Mineral Density (BMD) in postmenopausal osteoporosis women.
In the osteoporosis program, hypercalcemia is identified as a targeted but dose limiting side effect, as described below. Hypercalcemia constitutes a safety issue in the osteoporosis program, while an increase in blood calcium is considered as an indicator of the efficacy of the ADH1 program.
The compound of formula (I) or CLTX-305 may prove to be a unique therapy for the underlying pathogenesis of altered calcium homeostasis in ADH1 patients, in which case resetting the CaSR "set point" may normalize serum calcium while minimizing the need for oral calcium and calcitriol supplements and without increasing the risk of iatrogenic chronic hypercalcuria.
Accordingly, there is a need to develop CLTX-305 as a targeted therapy to treat hypocalcemia and calcium homeostasis disorders in chronic hypocalcemia patients due to activating mutations in the calcium sensitive receptor (CaSR).
Disclosure of Invention
In one aspect, the present disclosure provides methods of treating autosomal dominant hereditary hypocalcemia type 1 (ADH 1). The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound represented by formula (I):
or a solvate, hydrate, pharmaceutically acceptable salt, or combination thereof, wherein a therapeutically effective amount of the compound or the solvate, hydrate, pharmaceutically acceptable salt, or combination thereof increases blood calcium concentration (ca) to about 7.5 milligrams per deciliter (mg/dL) to about 10.5mg/dL, for example about 8.5mg/dL to about 10.5mg/dL.
In another aspect, the present disclosure provides a method of treating autosomal dominant hereditary hypocalcemia type 1 (ADH 1), wherein the method comprises administering to a subject in need thereof a compound represented by formula (I):
or a solvate, hydrate, pharmaceutically acceptable salt, or combination thereof, according to one or more dosing regimens including a first dosing regimen, a second dosing regimen, and/or a third dosing regimen,
wherein:
1) The first dosing regimen comprises administering a first therapeutically effective amount of the compound or the solvate, hydrate, pharmaceutically acceptable salt, or a combination thereof, wherein the first therapeutically effective amount increases blood calcium concentration (ca) to a maximum ca of about 10.5 milligrams per deciliter (mg/dL);
2) The second dosing regimen comprises administering a second therapeutically effective amount of the compound or the solvate, hydrate, pharmaceutically acceptable salt, or combination thereof, wherein the second therapeutically effective amount titrates the blood calcium concentration (ca) to a range of about 7.5mg/dL to about 10.5 mg/dL; and
3) The third dosing regimen comprises administering a third therapeutically effective amount of the compound or the solvate, hydrate, pharmaceutically acceptable salt, or combination thereof, wherein the third therapeutically effective amount maintains blood calcium concentration (ca) in the range of about 7.5mg/dL to about 10.5mg/dL for at least 12 weeks.
Drawings
Figure 1 shows the overall study design of a 2 b-stage open label dose range study evaluating the safety, tolerability and efficacy of CLTX-305 to maintain normal albumin corrected blood calcium (ca) in subjects with ADH 1-induced hypocalcemia.
Figure 2 shows an overview scheme of the 2b stage study.
Figure 3 shows the detailed protocol for cycles 1 and 2 (single and multiple incremental dose tests) of the study.
Fig. 4 shows a detailed scheme of study period 3.
Fig. 5 shows the dosing guidance algorithm for study period 1.
Fig. 6 shows the dosing guidance algorithm for study period 2.
Figures 7A-7D show normalized mineral steady state during study period 1: fig. 7A: blood calcium (mg/dL); fig. 7B: intact PTH (pg/mL); fig. 7C: blood phosphorus (mg/dL); fig. 7D:24h urinary calcium (mg/24 h).
Figure 8 shows the pharmacokinetic profile of CLTX-305 in humans during study period 1.
Figures 9A-9D show blood mineral levels and average levels of individual subjects 5 days after CLTX-305 administration: fig. 9A: blood calcium (mg/dL); fig. 9B: intact PTH (pg/mL); fig. 9C: blood phosphorus (mg/dL); fig. 9D: urine calcium (mg/day) for 24 hours.
Fig. 10A and 10B show a summary of the administration of oral CLTX-305 in cycles 1 and 2 of the study.
Detailed Description
I. Universal use
The present disclosure provides a method of treating autosomal dominant hereditary hypocalcemia type 1 (ADH 1) with a therapeutically effective amount of a compound of formula (I) (particularly CLTX-305), wherein the therapeutically effective amount of the compound increases the blood calcium concentration (ca) to a range of about 7.5mg/dL to about 10.5mg/dL, for example about 8.5mg/dL to about 10.5mg/dL. Also provided herein is a method of drug administration discovery for treating autosomal dominant hereditary hypocalcemia type 1 (ADH 1) with a therapeutically effective amount of a compound of formula (I) according to one or more dosing regimens (e.g., first, second and third dosing regimens). In particular, a therapeutically effective amount of a compound of formula (I) (e.g., CLTX-305) alleviates symptoms associated with hypocalcemia and minimizes hypercalcuria in ADH1 subjects.
II. Definition of
Unless specifically indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In addition, any method or material similar or equivalent to those described herein can be used in the practice of the present disclosure. For purposes of this disclosure, the following terms are defined.
"tablet" refers to solid pharmaceutical formulations with and without a coating. The term "tablet" also refers to a tablet having one, two, three or even more layers, wherein each of the above types of tablets may have no or one or more coatings. In some embodiments, the tablets of the invention may be prepared by roller compaction or other suitable means known in the art. The term "tablet" also includes mini-tablets, melt tablets, chewable tablets, effervescent tablets and orally disintegrating tablets. The tablet comprises CLTX-305 and one or more pharmaceutical excipients selected from one or more fillers, one or more binders, one or more glidants, one or more disintegrants, one or more surfactants, one or more binders and one or more lubricants. Optionally, a coating agent may also be included. To calculate the weight percent of the tablet formulation, the amount of coating agent is not included in the calculation. That is, the weight percentages reported herein are uncoated tablets.
By "pharmaceutically acceptable excipient" is meant a substance that facilitates administration of an active agent to a subject and absorption by the subject. Pharmaceutically acceptable excipients useful in the present disclosure include, but are not limited to, binders, fillers, glidants, disintegrants, surfactants, lubricants, coatings, sweeteners, flavoring agents, and colors. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.
"administration" refers to providing a treatment of a compound or form thereof to a subject, for example, by oral administration.
"patient" or "subject" refers to a living organism having or susceptible to a disease or disorder treatable by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, non-human primates (e.g., monkeys), goats, pigs, sheep, cattle, deer, horses, cows, rats, mice, rabbits, hamsters, guinea pigs, cats, dogs, and other non-mammals. In some embodiments, the subject is a human. In some embodiments, the subject is an adult (e.g., at least 18 years old). In some embodiments, the subject is less than 18 years old. In some embodiments, the subject is about 6 months to about 2 years old, about 2 years to about 5 years old, about 2 years to about 12 years old, about 2 years to about 16 years old, about 2 years to about 18 years old, about 5 years to about 12 years old, about 6 years to about 18 years old, about 12 years to about 18 years old, or any range therein.
"therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition that is useful in treating or ameliorating a defined disease or disorder, or that exhibits a detectable therapeutic or inhibitory effect. The exact amount will depend on The purpose of The treatment and will be determined by The clinician, pharmacist, etc. (see, e.g., lieberman, pharmaceutical Dosage Forms (vols.1-3,1992); lloyd, the Art, science and Technology of Pharmaceutical Compounding (1999); pickar, dosage Calculations (1999); and Remington: the Science and Practice of Pharmacy,20th Edition,2003,Gennaro,Ed., lippincott, williams and Wilkins).
"treatment", "treatment" and "treatment" refer to any indication of success in treating or ameliorating an injury, pathology or condition, including any objective or subjective parameter, such as alleviation; relief; alleviation of symptoms or making injury, pathology or condition more tolerant to the patient; degradation or slowing down of the decay; making the end point of the degradation less weak; improving physical or mental health of the patient. Treatment or amelioration of symptoms can be based on objective or subjective parameters; including physical examination, assays (e.g., analyzing a subject's fluid, such as blood, plasma, or urine), imaging analysis, neuropsychiatric examination, and/or psychiatric assessment.
"about" refers to a range of values that includes the stated value, which one of ordinary skill in the art would consider reasonably similar to the stated value. In some embodiments, the term "about" refers to within the standard deviation of using measurement methods generally acceptable in the art. In some embodiments, about represents a range extending to +/-10% of the specified value. In some embodiments, approximately represents a specified value.
"salt" refers to an acid or base salt of a compound of the present disclosure. Illustrative examples of pharmaceutically acceptable acid addition salts are inorganic (hydrochloric, hydrobromic, phosphoric, etc.) and organic (acetic, propionic, glutamic, citric, etc.) acid salts. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or the like. It will be appreciated that the pharmaceutically acceptable salts are non-toxic. Additional information regarding suitable pharmaceutically acceptable salts can be found in Remington's pharmaceutical sciences,17th ed., mack publishing company, easton, pa.,1985, incorporated herein by reference.
"solvate" refers to a compound provided herein or a salt thereof, further comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.
"hydrate" refers to a compound provided herein that complexes with water molecules or salts thereof. The compound of the present invention or a salt thereof may be complexed with 1/2 water molecules or 1 to 10 water molecules.
The content of the compounds of formula (I) in, for example, a tablet formulation is calculated on the basis of the normalized weight of the compounds of formula (I) on a salt-free and water-free basis, unless otherwise specified. That is, the salt and/or water content of the compound of formula (I) is not included in the calculation.
Unless otherwise specifically indicated, the CLTX-305 content in, for example, a tablet formulation is calculated based on the normalized weight of the compound of formula (I) in the form of the hemisulfate salt. The theoretical content of the compound of formula (I) in the tablet formulation on a salt-free and water-free basis can be calculated as follows: "content (or weight) =cltx-305×0.90 content (or weight) based on salt-free and water-free base of formula (I)". The actual content of the compound of formula (I) in the tablet formulation based on salt-free and water-free can be calculated from analytical certificate (CoA) (e.g. purity, water content, etc.) of CLTX-305. Thus, there may be a slight difference in the production of different batches of CLTX-305.
III method
In one aspect, the present disclosure provides methods of treating autosomal dominant hereditary hypocalcemia type 1 (ADH 1). The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound represented by formula (I):
Or a solvate, hydrate, pharmaceutically acceptable salt, or combination thereof, wherein a therapeutically effective amount of the compound or the solvate, hydrate, pharmaceutically acceptable salt, or combination thereof increases blood calcium concentration (ca) to a range of about 7.5mg/dL to about 10.5mg/dL, for example about 8.5mg/dL to about 10.5mg/dL.
For clinical laboratory evaluation, a typical reference range for human blood calcium concentration (cCa) is from about 8.5mg/dL to about 10.5mg/dL.
III-1: a compound of formula (I)
The compounds of formula (I) may be in the form of a pharmaceutically acceptable salt, a zwitterionic form or a neutral form, each optionally in the form of a solvate or hydrate.
In some embodiments, the pharmaceutically acceptable acid addition salt of the compound of formula (I) is represented by formula (Ia):
wherein HX is a pharmaceutically acceptable acid adduct.
Examples of acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monocarboxylic acid, phosphoric acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, monohydrogen sulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. In some embodiments, the compound of formula (I) is in the form of a sulfate salt. In some embodiments, the compound of formula (I) is in the form of a hemisulfate salt.
In some embodiments, the pharmaceutically acceptable base addition salt of the compound of formula (I) is represented by formula (Ib):
wherein M is a pharmaceutically acceptable cation of the base.
Base addition salts may be obtained by contacting the neutral form of the compound of formula (I) with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or the like. In some embodiments, the compound of formula (I) is its sodium salt.
In some embodiments, the compound of formula (I) is in the form of a zwitterion having formula (Ic):
in some embodiments, the compound of formula (I) is in neutral form.
In some embodiments, the compound of any one of formulas (I), (Ia), (Ib), and (Ic) is in the form of a solvate and/or hydrate. In some embodiments, the compound of any one of formulas (I), (Ia), (Ib), and (Ic) is in the form of a hydrate.
In some embodiments, the compound of formula (I) is in the form of a hemihydrate hemisulfate salt, CLTX-305, represented by the formula:
III-2: a subject
The subject may have one or more symptoms selected from the group consisting of: hypocalcemia, hypoparathyroidism, hypercalcuria, hyperphosphatemia, and/or hypomagnesemia. In some embodiments, the subject has hypocalcemia, hypoparathyroidism, hypercalcuria, hyperphosphatemia, hypomagnesemia, or a combination thereof. In some embodiments, the subject has hypocalcemia, hypoparathyroidism, hypercalcuria, hyperphosphatemia, or a combination thereof. In some embodiments, the subject has hypocalcemia. In some embodiments, the subject has hypoparathyroidism. In some embodiments, the subject has hyperphosphatemia. In some embodiments, the subject has hypercalcuria. In some embodiments, the subject has hypocalcemia and hypoparathyroidism. In some embodiments, the subject has hypocalcemia and hypercalcuria. In some embodiments, the subject has hypocalcemia, hypoparathyroidism, and hypercalcemia. In some embodiments, the subject has hypocalcemia, hypoparathyroidism, hypercalcuria and hyperphosphatemia. In some embodiments, the subject has hypocalcemia, hypoparathyroidism, hypercalcuria, hyperphosphatemia, and hypomagnesemia.
In some embodiments, the subject has an activating mutation in a calcium sensing receptor (CASR) gene.
In some embodiments, the subject does not have vitamin D deficiency prior to treatment with the compound of formula (I) (e.g., CLTX-305) or a form thereof. In some embodiments, the subject has a level of 25-hydroxy-vitamin D in the blood of at least about 25 nanograms per milliliter (ng/mL). In some embodiments, the subject has a level of 25-hydroxy-vitamin D in the blood of about 25ng/mL to about 60 ng/mL. In some embodiments, the subject has a level of 25-hydroxy-vitamin D in the blood of about 30ng/mL to about 60 ng/mL. In some embodiments, the subject has a level of 25-hydroxy-vitamin D in the blood of about 40ng/mL to about 60 ng/mL.
In some embodiments, the subject has or is taking calcitriol and/or an oral calcium supplement prior to administration of the compound of formula (I) (e.g., CLTX-305) or a form thereof. In some embodiments, the subject is instructed to stop taking calcitriol and/or oral calcium supplement prior to administration of the compound of formula (I) (e.g., CLTX-305) or a form thereof. In some embodiments, the subject is instructed to stop taking calcitriol prior to administration of the compound of formula (I) (e.g., CLTX-305) or a form thereof. In some embodiments, the subject is instructed to stop taking the oral calcium supplement prior to administration of the compound of formula (I) (e.g., CLTX-305) or a form thereof. In some embodiments, the subject is instructed to stop taking calcitriol on day 1, the day of admission to receive treatment with a compound of formula (I) (e.g., CLTX-305) or a form thereof, but continue to take oral calcium supplements. In some embodiments, the subject is not treated with calcitriol when treated with a compound of formula (I) (e.g., CLTX-305) or a form thereof. In some embodiments, the subject receives a calcium intake of at least about 1000 milligrams (mg) per day from a diet and/or supplement while being treated with a compound of formula (I) (e.g., CLTX-305) or a form thereof. In some embodiments, the subject receives at least about 1000mg of daily calcium intake from the diet and supplement while being treated with a compound of formula (I) (e.g., CLTX-305) or a form thereof.
In some embodiments, the subject has been administered or is taking a thiazide diuretic prior to administration of a compound of formula (I) (e.g., CLTX-305) or a form thereof. In some embodiments, a subject who has taken or is taking a thiazide diuretic may be treated with a compound of formula (I) (e.g., CLTX-305) or a form thereof if the subject deactivates five (5) half-lives of the thiazide diuretic prior to commencing treatment with the compound of formula (I) (e.g., CLTX-305) or a form thereof and during treatment with the compound of formula (I) (e.g., CLTX-305) or a form thereof. In some embodiments, if the thiazine is used as an antihypertensive drug, an alternative therapy for treating hypertension may be provided. Examples of oral thiazide diuretics include, but are not limited to, chlorothiazide (Diuril), chlorthalidone, hydrochlorothiazide (Microzide), indapamide, and imidazolone. In some embodiments, the subject is not treated with a thiazide diuretic for 5 (5) half-lives prior to treatment with a compound of formula (I) (e.g., CLTX-305) or a form thereof. In some embodiments, the subject is not treated with a thiazide diuretic for a period of 5 (5) half-lives prior to treatment with a compound of formula (I) (e.g., CLTX-305) or a form thereof, wherein the thiazide diuretic is chlorothiazide (Diuril), chlorthalidone, hydrochlorothiazide (Microzide), indapamide, or metolapine. In some embodiments, the subject is not treated with a thiazide diuretic when treated with a compound of formula (I) (e.g., CLTX-305) or a form thereof. In some embodiments, the subject is not treated with a thiazide diuretic when treated with a compound of formula (I) (e.g., CLTX-305) or a form thereof, wherein the thiazide diuretic is chlorothiazide (Diuril), chlorthalidone, hydrochlorothiazide (Microzide), indapamide, or imidazolone.
In some embodiments, the subject has or is taking a CYP3A4 inhibitor (e.g., a strong CYP3A4 inhibitor such as clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir) prior to administration of a compound of formula (I) (e.g., CLTX-305) or a form thereof. In some embodiments, if clinically appropriate, a subject who has taken or is taking a CYP3A4 inhibitor should cease such treatment for at least 5 half-lives before and during treatment with a compound of formula (I) (e.g., CLTX-305) or a form thereof. In some embodiments, a subject treated with a CYP3A4 inhibitor (e.g., a potent CYP3A4 inhibitor) should maintain a stable dose throughout the course of treatment of a compound of formula (I) (e.g., CLTX-305) or a form thereof. In some embodiments, the subject is not treated with a CYP3A4 inhibitor (e.g., a strong CYP3A4 inhibitor such as clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and telanavir) for five (5) half-lives of the CYP3A4 inhibitor prior to treatment with the compound of formula (I) (e.g., CLTX-305) or a form thereof. In some embodiments, the subject is not treated with a strong CYP3A4 inhibitor for a period of five (5) half-lives of the strong CYP3A4 inhibitor prior to treatment with a compound of formula (I) (e.g., CLTX-305) or a form thereof, wherein the strong CYP3A4 inhibitor is clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or telanavir. In some embodiments, the subject is not treated with a CYP3A4 inhibitor (e.g., a strong CYP3A4 inhibitor such as clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and telanavir) while simultaneously treating with a compound of formula (I) (e.g., CLTX-305) or a form thereof. In some embodiments, the subject is not treated with a strong CYP3A4 inhibitor while being treated with CLTX-305, wherein the strong CYP3A4 inhibitor is clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, dar Luo Nawei, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or telanavir. In some embodiments, the subject is treated with a CYP3A4 inhibitor (e.g., a strong CYP3A4 inhibitor such as clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darifenacin Luo Nawei, indolonavir, lopinavir, nelfinavir, ritonavir, saquinavir, at a stable dose while being treated with a compound of formula (I) (e.g., CLTX-305) or a form thereof, in some embodiments, the subject is treated with a stable dose of a strong CYP3A4 inhibitor while being treated with a compound of formula (I) (e.g., CLTX-305) or a form thereof, wherein the strong CYP3A4 inhibitor is clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darifenacin Luo Nawei, indinavir, lopinavir, nelfinavir, saquinavir, or telangavir.
Further inclusion and exclusion criteria for subjects who may benefit from treatment with a compound of formula (I) (e.g., CLTX-305) or a form thereof, such as subjects who participate in a 2b phase open label dose range study, are described in example 5.
In some embodiments, the subject meets all inclusion criteria of 1) to 7) as described in example 5. In some embodiments, the subject meets all inclusion criteria of 1) to 7) as described in example 5, provided that the subject does not meet any of the exclusion criteria of 1) to 14) as described in example 5.
III-3 therapeutically effective amount/administration
In some embodiments, the therapeutically effective amount may be a total daily dose of no more than about 1800mg of the compound of formula (I) on a salt-free and water-free basis. In some embodiments, the therapeutically effective amount is a daily total dose of the compound of formula (I) of from about 9mg to about 1620mg, from about 9mg to about 1080mg, from about 9mg to about 810mg, from 9mg to about 540mg, or from about 9mg to about 324mg, on a salt-free and water-free basis, or any useful range therein.
In some embodiments, the therapeutically effective amount may be a total daily dose of no more than about 2000mg CLTX-305. In some embodiments, the therapeutically effective amount is a daily total dose of CLTX-305 of from about 10mg to about 1800mg, from about 10mg to about 1200mg, from about 10mg to about 900mg, from about 10mg to about 600mg, from about 10mg to about 360mg, or from about 30mg to about 180mg of CLTX-305. In some embodiments, the therapeutically effective amount is a total daily dose of about 10mg, 20mg, 30mg, 40mg, 60mg, 90mg, 120mg, 180mg, 360mg, 480mg, or 720mg CLTX-305. In some embodiments, the therapeutically effective amount is a total daily dose of about 10mg, 30mg, 60mg, 90mg, 120mg, 180mg, 360mg, 480mg, or 720mg CLTX-305. In some embodiments, the therapeutically effective amount is a total daily dose of about 10mg, 60mg, 90mg, 120mg, 180mg, 360mg, 480mg, or 720mg CLTX-305. In some embodiments, the therapeutically effective amount is a total daily dose of about 10mg, 60mg, 90mg, 120mg, 180mg, 360mg, or 480mg CLTX-305. In some embodiments, the therapeutically effective amount is a total daily dose of about 10mg, 60mg, 90mg, 120mg, 180mg, or 360mg cltx-305. In some embodiments, the therapeutically effective amount is a total daily dose of about 10mg, 60mg, 90mg, 120mg, or 180mg CLTX-305. In some embodiments, the therapeutically effective amount is a daily total dose of about 10mg, 30mg, 90mg, 120mg, or 180 mg.
In general, the compound of formula (I) or CLTX-305 may be administered orally. In some embodiments, the compound of formula (I) or CLTX-305 is administered orally. In some embodiments, the compound of formula (I) is administered orally. In some embodiments, CLTX-305 is administered orally. In some embodiments, the compound of formula (I) in a tablet formulation is administered orally. In some embodiments, CLTX-305 in the tablet formulation is administered orally.
In general, the compound of formula (I) or CLTX-305 may be administered one or more times per day (e.g., 2, 3, 4, or more times). In some embodiments, the compound of formula (I) or CLTX-305 is administered once, twice, three times, or four times per day. In some embodiments, the compound of formula (I) or CLTX-305 is administered once daily. In some embodiments, the compound of formula (I) or CLTX-305 is administered twice daily. In some embodiments, CLTX-305 is administered once, twice, three times, or four times per day. In some embodiments, CLTX-305 is administered once daily. In some embodiments, CLTX-305 is administered twice daily. In some embodiments, CLTX-305 is administered three times per day. In some embodiments, CLTX-305 is administered four times per day.
The compound of formula (I) may be in one or more dosage strength oral dosage forms wherein the compound of formula (I) is present in an amount of at least about 1mg, 5mg, 10mg, 20mg,30 mg,50 mg, 90mg,100mg,120mg,180mg,200mg,300mg,400mg or 500mg on a salt-free and water-free basis. In some embodiments, the oral dosage form is a tablet formulation of one or more dosage strengths. In some embodiments of the tablet formulation, the compound of formula (I) is present in an amount of 1 to 1000mg,1 to 750mg,1 to 500mg,1 to 250mg, 30 to 1000mg,30 to 750mg,30 to 500mg,30 to 200mg,30 to 180mg,30 to 120mg,30 to 90mg,50 to 1000mg,50 to 750mg,50 to 500mg,50 to 250mg,100 to 1000mg,100 to 750mg,100 to 500mg,100 to 250mg,200 to 1000mg,200 to 750mg,300 to 1000mg,300 to 750mg,300 to 500mg,400 to 1000mg,500 to 750mg,600 to 1000mg,5 to 250mg, or 5 to 100mg per tablet on a salt-free and water-free basis. In some embodiments of the tablet formulation, the compound of formula (I) is present in an amount of about 5mg, 10mg, 30mg, 60mg, 90mg,100mg,120mg, 150mg, 180mg,200mg, 250mg, 300mg,400mg, 500mg, 600mg, 700mg, 800mg, 900mg or 1000mg per tablet on a salt-free and water-free basis. In some embodiments of the tablet formulation, the compound is present in an amount of about 10mg, 30mg, 60mg, 90mg,100mg,120mg, 150mg, 180mg,200mg,300mg,400mg, 500mg or 700mg per tablet on a salt-free and water-free basis.
CLTX-305 may be an oral dosage form of one or more dosage strengths, wherein CLTX-305 is present in an amount of at least about 1mg, 5mg, 10mg, 20mg,30 mg,50 mg, 90mg, 100mg, 120mg, 180mg, 200mg, 300mg, 400mg, or 500mg. In some embodiments, the oral dosage form is a tablet formulation of one or more dosage strengths. In some embodiments of the tablet formulation, CLTX-305 is present in an amount of 1 to 1000mg,1 to 750mg,1 to 500mg,1 to 250mg, 30 to 1000mg,30 to 750mg,30 to 500mg,30 to 200mg,30 to 180mg,30 to 120mg,30 to 90mg,50 to 1000mg,50 to 750mg,50 to 500mg,50 to 250mg,100 to 1000mg,100 to 750mg,100 to 500mg,100 to 250mg,200 to 1000mg,200 to 750mg,200 to 500mg,300 to 1000mg,300 to 500mg,400 to 1000mg,400 to 750mg, 500 to 1000mg,500 to 750mg,600 to 1000mg,5 to 250mg, or 5 to 100mg per tablet. In some embodiments of the tablet formulation, CLTX-305 is present in an amount of about 5mg, 10mg, 30mg, 60mg, 90mg, 120mg, 180mg, 240mg, 300mg, 360mg, 420mg, 480mg, 540mg, 600mg, 660mg, or 720mg per tablet. In some embodiments of the tablet formulation, CLTX-305 is present in an amount of about 10mg, 30mg, 60mg, 90mg, 120mg, 180mg, 240mg, 360mg, or 720mg per tablet.
In some embodiments, CLTX-305 is administered twice daily to provide a total daily dose of no more than about 2000 milligrams of CLTX-305. In some embodiments, CLTX-305 is administered twice daily to provide a total daily dose of CLTX-305 of about 10mg to about 1800mg, about 10mg to about 1200mg, about 10mg to about 900mg, about 10mg to about 600mg, about 10mg to about 360mg, or about 30mg to about 180 mg. In some embodiments, CLTX-305 is administered twice daily to provide a total daily dose of about 10mg to about 360mg CLTX-305. In some embodiments, CLTX-305 is administered twice daily to provide a total daily dose of CLTX-305 of about 10mg, 20mg, 30mg, 40mg, 60mg, 90mg, 120mg, 180mg, 360mg, 480mg, or 720 mg. In some embodiments, CLTX-305 is administered twice daily to provide a total daily dose of CLTX-305 of about 10mg, 30mg, 60mg, 90mg, 120mg, 180mg, 360mg, 480mg, or 720 mg.
III-4: curative effect
As summarized in example 1 and detailed in examples 2-8, the stage 2b, open label dose range study can evaluate the safety, tolerability, and efficacy of CLTX-305 to maintain standardized albumin corrected blood calcium (ca) for subjects with hypocalcemia due to ADH 1.
Administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 may alleviate symptoms associated with hypocalcemia. In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 increases the blood calcium concentration (ca) to a range of about 7.5mg/dL to about 10.5mg/dL, for example about 8.5mg/dL to about 10.5mg/dL. In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 maintains a blood calcium concentration (ca) in the range of about 7.5mg/dL to about 10.5mg/dL, for example 8.5mg/dL to about 10.5mg/dL, for at least 12 weeks. In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 increases blood calcium concentration (ca) by at least about l mg/dL within the dosing interval. In some embodiments, administration of a therapeutically effective amount of CLTX-305 increases the blood calcium concentration (ca) to a range of about 7.5mg/dL to about 10.5mg/dL, for example about 8.5mg/dL to about 10.5mg/dL. In some embodiments, administration of a therapeutically effective amount of CLTX-305 maintains a blood calcium concentration (ca) in the range of about 7.5mg/dL to about 10.5mg/dL, for example about 8.5mg/dL to about 10.5mg/dL, for at least 12 weeks. In some embodiments, administration of a therapeutically effective amount of CLTX-305 increases blood calcium concentration (ca) by at least about 1mg/dL over the dosing interval.
In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 increases the intact parathyroid hormone (iPTH) in the blood to a clinical reference range, typically between about 15-65 picograms per milliliter (pg/mL). In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 increases the intact parathyroid hormone (iPTH) in the blood to peak levels of from about 150 to about 300 pg/mL. In some embodiments, administration of a therapeutically effective amount of CLTX-305 increases the intact parathyroid hormone (iPTH) in the blood to a peak level of from about 150 to about 300 pg/mL. In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 increases the intact parathyroid hormone (iPTH) in the blood to elevated levels of at least about 50 pg/mL. In some embodiments, administration of a therapeutically effective amount of CLTX-305 increases the intact parathyroid hormone (iPTH) in the blood to elevated levels of at least about 50 pg/mL. In some embodiments, the iPTH is maintained at an elevated level of at least about 50pg/mL for 1-12 hours. In some embodiments, the iPTH is maintained at an elevated level of at least about 50pg/mL for 6-12 hours. In some embodiments, the iPTH is maintained at an elevated level of at least about 50pg/mL for about 12 hours.
Administration of a therapeutically effective amount of a compound of formula (I) may minimize the extent of hypercalcemia. In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 reduces elevated urinary calcium levels. In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 reduces elevated urinary calcium levels within the dosing interval or over a 24 hour period. In some embodiments, administration of a therapeutically effective amount of CLTX-305 reduces elevated urinary calcium levels during the dosing interval or over a 24 hour period. In some embodiments, administration of a therapeutically effective amount of CLTX-305 decreases elevated urinary calcium levels over a 24 hour period. In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 increases urinary calcium clearance within the dosing interval or over a 24 hour period. In some embodiments, administration of a therapeutically effective amount of CLTX-305 increases urinary calcium clearance. In some embodiments, administration of a therapeutically effective amount of CLTX-305 increases urinary calcium clearance within the dosing interval or over a 24 hour period. In some embodiments, administration of a therapeutically effective amount of CLTX-305 increases urinary calcium clearance over a 24 hour period. In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 reduces the increased calcium/creatinine clearance to the normal range. In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 reduces the increased calcium/creatinine clearance to a normal range of less than about 0.02. In some embodiments, administration of a therapeutically effective amount of CLTX-305 reduces the increased calcium/creatinine clearance to a normal range of less than about 0.02.
Administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 minimizes the extent of hyperphosphatemia. In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 reduces blood phosphate levels to the normal range. In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 reduces blood phosphate levels to a normal range of about 2.5 to about 4.5 mg/dL. In some embodiments, administration of a therapeutically effective amount of CLTX-305 reduces blood phosphate levels to a normal range of about 2.5 to about 4.5 mg/dL.
Administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 may minimize the extent of hypomagnesemia. In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 increases blood magnesium levels to the normal range. In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 increases blood magnesium levels to a normal range of about 1.7 to about 2.2 mg/dL. In some embodiments, administration of a therapeutically effective amount of CLTX-305 increases blood magnesium levels to a normal range of about 1.7 to about 2.2 mg/dL.
Blood and urine samples can be taken to assess Pharmacokinetics (PK) and Pharmacodynamics (PD) of a subject (e.g., patient) treated with CLTX-305. In some embodiments, the following assessment is performed on the subject: 1) Pharmacodynamic endpoints measured over a period of up to 24 weeks (final visit); 2) Blood calcium-absolute level and baseline change from ca; 3) Urinary calcium clearance (partial excretion and total excretion for 24 hours); 4) Serum 1,25- (OH) 2 Vitamin D levels; 5) Magnesium, phosphate, creatinine of the blood sample; 6) pH of urine sample, magnesium, phosphate, sodium, potassium, creatinine, cAMP, citrate; 7) Collagen cross-linked C-terminal peptide (CTx), a marker of bone resorption; 8) Bone formation marker-blood procollagen type 1N-propeptide (P1 NP); 9) PK parameters: maximum plasma concentration (Cmax), reached(tmax) the time required, apparent terminal half-life (t 1/2), concentration versus time area under the curve (AUC) from time 0 to the last measurable time point (AUC (0-t)), AUC (0-24) from time 0 to 24 hours, extrapolated to infinity (AUC (0-inf)) after a single dose; and/or 10) steady state PK parameters: cmax, trough concentration (Ctough) and AUC (0-tau) over the dosing interval.
In some embodiments, the level of serum bone markers, 1, 25-hydroxyvitamin D, cAMP, albumin, potassium (K), creatine Kinase (CK), and/or creatinine in the blood of the subject is further assessed. Serum bone markers may be collagen cross-linked C-terminal peptide (CTx) and/or procollagen type 1N-propeptide (P1 NP). In some embodiments, the serum bone markers are blood collagen cross-linked C-terminal peptides (CTx) and/or blood procollagen type 1N-propeptides (P1 NP). In some embodiments, the serum bone markers are blood collagen cross-linked C-terminal peptide (CTx) and blood procollagen type 1N-propeptide (P1 NP).
In some embodiments, blood is collected at dosing intervals or over a period of about 24 hours. In some embodiments, blood is collected at dosing intervals or over a period of about 17 hours. In some embodiments, blood is collected over a dosing interval or over a period of about 17 hours, wherein Pharmacokinetic (PK) profiles, iPTH, serum bone markers (i.e., CTX, P1 NP), 1, 25-hydroxyvitamin D, cAMP, calcium (Ca), magnesium (Mg), phosphate (P), potassium (K), albumin, creatinine (Cr), or combinations thereof are assessed. In some embodiments, blood is collected over a dosing interval or over a period of about 13 hours, wherein Pharmacokinetic (PK) profiles are assessed. In some embodiments, blood is collected over a dosing interval or over a period of about 17 hours, wherein the iPTH is evaluated. In some embodiments, blood is collected over a dosing interval or over a period of about 13 hours, wherein serum bone markers (i.e., CTX and P1 NP) are evaluated. In some embodiments, blood is collected at dosing intervals or over a period of about 17 hours, wherein 1, 25-hydroxy-vitamin D and cAMP are evaluated. In some embodiments, blood is collected over a dosing interval or over a period of about 17 hours, wherein calcium (Ca), magnesium (Mg), phosphate (P), creatinine (Cr), and albumin are evaluated. In some embodiments, blood is collected over a dosing interval or over a period of about 13 hours, wherein potassium (K) and creatinine (Cr) are evaluated.
In some embodiments, the level of magnesium (Mg), phosphate (P), sodium (Na), potassium (K), creatinine (Cr), cAMP, and/or citrate, and/or ph of the urine in the subject's urine is further assessed.
In some embodiments, urine is collected during the dosing interval or during the 24 hour period. In some embodiments, urine is collected over an dosing interval or over a 24 hour period, wherein the levels of calcium (Ca), magnesium (Mg), phosphate (P), creatinine (Cr), and/or cAMP in the urine are measured; the pH value of urine; or a combination thereof. In some embodiments, urine is collected at 0 hours and 24 hours, wherein the level of calcium (Ca), magnesium (Mg), phosphate (P), sodium (Na), potassium (K), creatinine (Cr), and/or citrate in the urine; the pH value of urine; or a combination thereof.
In some embodiments, the subject is assessed by one or more tests including blood analysis, urine analysis, and/or hematology tests. Examples of such tests are described in tables 1, 2 and 3 of example 1. In some embodiments, blood and urine samples are arranged according to tables 4A-4C, 5, 6A-6C, and 7 of example 1.
In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 maintains blood calcium concentration (ca) in the range of about 8.5 to about 10.5mg/dL for at least 12 weeks without substantially adjusting the total daily dose. In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or CLTX-305 maintains blood calcium concentration (ca) in the range of about 8.5 to about 10.5mg/dL for at least 24 weeks without substantially adjusting the total daily dose.
III-5: dosing regimen method
In another aspect, the present disclosure provides a method of treating autosomal dominant hereditary hypocalcemia type 1 (ADH 1), wherein the method comprises administering to a subject in need thereof a compound represented by formula (I):
or a solvate, hydrate, pharmaceutically acceptable salt, or combination thereof, according to one or more dosing regimens including a first dosing regimen, a second dosing regimen, and/or a third dosing regimen,
wherein:
1) The first dosing regimen comprises administering a first therapeutically effective amount of the compound or the solvate, hydrate, pharmaceutically acceptable salt, or a combination thereof, wherein the first therapeutically effective amount increases blood calcium concentration (ca) to a maximum ca of about 10.5 milligrams per deciliter (mg/dL);
2) The second dosing regimen comprises administering a second therapeutically effective amount of the compound or the solvate, hydrate, pharmaceutically acceptable salt, or combination thereof, wherein the second therapeutically effective amount titrates the blood calcium concentration (ca) to a range of about 7.5mg/dL to about 10.5 mg/dL; and
3) The third dosing regimen comprises administering a third therapeutically effective amount of the compound or the solvate, hydrate, pharmaceutically acceptable salt, or combination thereof, wherein the third therapeutically effective amount maintains blood calcium concentration (ca) in the range of about 7.5mg/dL to about 10.5mg/dL for at least 12 weeks.
The 2b stage open label dose range study shown in figures 1 and 2 can evaluate the safety, tolerability and efficacy of CLTX-305 to maintain normal albumin corrected blood calcium (ca) in hypocalcemic subjects due to ADH 1. Efficacy of the study is described in section III-4. The study protocols for cycle 1 and cycle 2 (single and multiple incremental dose tests) are detailed in fig. 3, and the study protocol for cycle 3 is detailed in fig. 4.
The compounds of formula (I) are described in section III-1.
In some embodiments, the compound of formula (I) is in the form of a hemihydrate hemisulfate salt, such as CLTX-305, represented by the formula:
In some embodiments, the compound of formula (I) or CLTX-305 is administered orally. In some embodiments, CLTX-305 is administered orally. In some embodiments, CLTX-305 in the tablet formulation is administered orally.
This subject is described in section III-2.
In some embodiments, the subject has hypocalcemia, hypoparathyroidism, hypercalcuria, hyperphosphatemia, hypomagnesemia, or a combination thereof. In some embodiments, the subject has hypocalcemia, hypoparathyroidism, hypercalcuria, hyperphosphatemia, or a combination thereof. In some embodiments, the subject has hypocalcemia. In some embodiments, the subject has hypoparathyroidism. In some embodiments, the subject has hyperphosphatemia. In some embodiments, the subject has hypercalcuria. In some embodiments, the subject has hypocalcemia and hypoparathyroidism. In some embodiments, the subject has hypocalcemia and hypercalcuria. In some embodiments, the subject has hypocalcemia, hypoparathyroidism, and hypercalcemia. In some embodiments, the subject has hypocalcemia, hypoparathyroidism, hypercalcuria and hyperphosphatemia. In some embodiments, the subject has hypocalcemia, hypoparathyroidism, hypercalcuria, hyperphosphatemia, and hypomagnesemia.
In some embodiments, the subject has an activating mutation in a calcium sensing receptor (CASR) gene.
In some embodiments, the subject is free of vitamin D deficiency prior to treatment with CLTX-305. In some embodiments, the subject has a level of 25-hydroxy-vitamin D in the blood of at least about 25 ng/mL. In some embodiments, the subject has a level of 25-hydroxy-vitamin D in the blood of about 25ng/mL to about 60 ng/mL. In some embodiments, the subject has a level of 25-hydroxy-vitamin D in the blood of about 30ng/mL to about 60 ng/mL. In some embodiments, the subject has a level of 25-hydroxy-vitamin D in the blood of about 40ng/mL to about 60 ng/mL.
In some embodiments, the subject is not treated with calcitriol when treated with CLTX-305. In some embodiments, the subject receives at least about 1000mg daily calcium intake from the diet and/or supplement while being treated with CLTX-305. In some embodiments, the subject receives at least about 1000mg daily calcium intake from the diet and supplement while being treated with CLTX-305.
In some embodiments, the first dosing regimen comprises a total daily dose of at least about 10mg, 20mg, 30mg, 40mg, 60mg, 90mg, 120mg, 180mg, or 360mg CLTX-305. In some embodiments, the first dosing regimen comprises a total daily dose of at least about 30mg, 60mg, 90mg, 120mg, 180mg, or 360mg cltx-305. In some embodiments, the first dosing regimen comprises a total daily dose of about 30mg, 60mg, 90mg, 180mg, or 360mg cltx-305. In some embodiments, the first dosing regimen comprises a total daily dose of about 30mg, 90mg, or 180mg CLTX-305.
Typically, the first dosing regimen comprises an initial daily total dose of a small amount of CLTX-305 (e.g., about 10-30 mg). In some embodiments, the first dosing regimen comprises an initial daily total dose of about 30mg cltx-305.
Typically, CLTX-305 may be administered one or more times per day (e.g., 2, 3, or 4 times) during the first dosing regimen. In some embodiments, the first dosing regimen comprises administering CLTX-305 once a day for the first three days and then twice a day for two days.
In some embodiments, the first dosing regimen comprises administering CLTX-305 twice daily to provide a total daily dose of at least about 10mg, 20mg, 30mg, 40mg, 60mg, 90mg, 120mg, 180mg, or 360mg CLTX-305. In some embodiments, the first dosing regimen comprises administering CLTX-305 twice daily to provide a total daily dose of at least about 30mg, 60mg, 90mg, 120mg, 180mg, or 360mg CLTX-305. In some embodiments, the first dosing regimen comprises administering CLTX-305 twice daily to provide a total daily dose of CLTX-305 of about 30mg, 60mg, 90mg, 180mg, or 360 mg. In some embodiments, the first dosing regimen comprises administering CLTX-305 twice daily to provide a total daily dose of about 30mg, 90mg, or 180mg CLTX-305. In some embodiments, the first dosing regimen comprises a first period of one dosing per day and a second period of two dosing per day. In some embodiments, the first period of once-a-day dosing precedes the second period of twice-a-day dosing. In some embodiments, the total daily dose in the first period is the same as the total daily dose in the second period. In some embodiments, the total daily dose in the first period of time is different from the total daily dose in the second period of time.
The first dosing regimen may include one or more dose adjustments according to the subject's blood calcium concentration (ca) level, e.g., increasing or decreasing the total daily dose, whether or not the subject reaches a maximum ca of about 10.5 mg/dL. Or when the subject reaches a maximum ca of about 10.5mg/dL, the daily dosing frequency is increased (e.g., from once per day to twice per day) while maintaining the total daily dose. In some embodiments, the first dosing regimen comprises:
a1 Increasing the total daily dose when the blood calcium concentration (ca) is less than a maximum ca of about 10.5 mg/dL;
b1 Reducing the total daily dose when the blood calcium concentration (ca) reaches a maximum ca; and/or
c1 When the blood calcium concentration (ca) reaches the maximum ca, the daily dosing frequency is increased while maintaining the daily total dose.
The blood calcium concentration (ca) in the subject is determined after each of the one or more once daily doses and the one or more twice daily doses in order to determine whether to make one or more dose adjustments. In some embodiments, the blood calcium concentration (ca) is determined after each of one or more once daily doses and one or more twice daily doses. In some embodiments, the blood calcium concentration (ca) is determined after a once daily dose on days 1, 2, and 3 and a twice daily dose on days 4 and 5.
The total daily dose increases when the blood calcium concentration (ca) is less than the maximum ca of about 10.5 mg/dL. The daily total dose may be increased algorithmically (e.g., blood ca value, net increase in ca over the dosing interval, sustained increase in peak iPTH and/or iPTH) daily total dose according to the subject's parameters. In some embodiments, the daily total dose is increased by an algorithm as shown in fig. 5. In some embodiments, the daily total dose is increased by doubling the previous daily total dose (e.g., from 30mg to 60mg, from 60mg to 120mg, from 90mg to 180mg, etc.). In some embodiments, the daily total dose is increased by a factor of three (e.g., from 10mg to 30mg, from 30mg to 90mg, from 60mg to 180mg, from 90mg to 270mg, etc.) increase the previous daily total dose. In some embodiments, the daily total dose of CLTX-305 increases from about 30mg to about 60mg, from about 30mg to about 90mg, from about 30mg to about 120mg, from about 30mg to about 180mg, from about 10mg to about 20mg, from about 20mg to about 40mg, from about 60mg to about 90mg, from about 60mg to about 120mg, from about 90mg to about 180mg, or from about 180mg to about 360mg. In some embodiments, the daily total dose of CLTX-305 increases from about 30mg to about 60mg, from about 30mg to about 90mg, from about 30mg to about 120mg, from about 30mg to about 180mg, from about 10mg to about 20mg, from about 20mg to about 40mg, from about 60mg to about 90mg, from about 60mg to about 120mg, from about 90mg to about 120mg, or from about 90mg to about 180mg. In some embodiments, the daily total dose of CLTX-305 increases from about 30mg to about 60mg, from about 30mg to about 90mg, from about 90mg to about 120mg, or from about 90mg to about 180mg.
When the blood calcium concentration (ca) reaches a maximum ca of about 10.5mg/dL, the total daily dose is reduced. The daily total dose may be reduced algorithmically (e.g., blood ca value, net increase in ca over the dosing interval, sustained increase in peak iPTH and/or iPTH) based on the subject's parameters. In some embodiments, the daily total dose is reduced by an algorithm as shown in fig. 5. In some embodiments, the daily total dose is reduced to 2 (2/3) of the 3 th of the previous daily total dose (e.g., from 60mg to 40mg, from 90mg to 60mg, from 180mg to 120mg, etc.). In some embodiments, the total daily dose is reduced by half (1/2) of the total previous daily dose (e.g., from 60mg to 30mg, from 120mg to 60mg, from 180mg to 90mg, etc.). In some embodiments, the daily total dose is reduced to 1 (1/3) of the previous daily total dose (e.g., 30mg to 10mg, 90mg to 30mg, 180mg to 60mg, 270mg to 90mg, etc.). In some embodiments, the total daily dose of CLTX-305 is reduced from about 30mg to about 10mg, from about 40mg to about 20mg, from about 60mg to about 40mg, from about 90mg to about 60mg, from about 90mg to about 30mg, from about 120mg to about 90mg, from about 120mg to about 60mg, from about 180mg to about 120mg, from about 180mg to about 90mg, from about 180mg to about 60mg, or from about 360mg to about 180mg. In some embodiments, the total daily dose of CLTX-305 is reduced from about 30mg to about 10mg, from about 60mg to about 40mg, from about 90mg to about 60mg, from about 90mg to about 30mg, from about 180mg to about 120mg, from about 180mg to about 90mg, or from about 180mg to about 60mg.
When the blood calcium concentration (ca) reached a maximum ca of about 10.5mg/dL, the daily dosing frequency was increased while maintaining the daily total dose of CLTX-305. In some embodiments, the daily dosing frequency is increased from once a day to twice a day while maintaining the daily total dose of CLTX-305. In some embodiments, the daily dosing frequency is increased from once a day to twice a day while maintaining a total daily dose of CLTX-305 of about 30mg, 60mg, 90mg, 120mg, 180mg, or 360mg. In some embodiments, the daily dosing frequency is increased from once a day to twice a day while maintaining a total daily dose of CLTX-305 of about 30mg, 60mg, 90mg, 120mg, or 180mg.
In some embodiments, the first dosing regimen further comprises:
i) Selecting a minimum dose from one or more once-a-day doses, and administering said minimum dose twice a day, provided that the one or more once-a-day doses meet a criterion selected from the group consisting of:
i-1) blood calcium concentration (ca) increases by at least about 1mg/dL during the dosing interval;
i-2) blood calcium concentration (cCa) is maintained in the range of about 7.5 to about 10.5 mg/dL;
i-3) increasing the peak level of intact parathyroid hormone (iPTH) in the blood to about 150 to about 300 pg/mL; and
i-4) an increase in intact parathyroid hormone (iPTH) in the blood to an elevated level of at least about 50pg/mL, and for about 12 hours,
or alternatively
ii) selecting the highest dose among the one or more once-a-day doses, and administering the highest dose twice a day, provided that the one or more once-a-day doses do not meet any of the criteria i-1) to i-4; and the highest dose is tolerated in the subject.
In some embodiments, the lowest dose of the one or more once-a-day doses for twice-a-day dosing is about 30mg, 60mg, 90mg, 120mg, or 180mg cltx-305, provided that the one or more once-a-day doses meet any of the criteria of i-1 (to i-4). In some embodiments, the lowest dose of the one or more once-a-day doses for twice-a-day dosing is about 90mg or 180mg cltx-305, provided that the one or more once-a-day doses meet any of the criteria i-1) through i-4.
In some embodiments, the highest dose of the one or more once-a-day doses for twice-a-day dosing is about 30mg, 60mg, 90mg, 120mg, or 180mg cltx-305, provided that the one or more once-a-day doses do not meet any of the criteria of i-1) to i-4). In some embodiments, the highest dose of the one or more once-a-day doses for twice-a-day dosing is about 90mg or 180mg cltx-305, provided that the one or more once-a-day doses do not meet any of the criteria of i-1) to i-4).
The subject is assessed by blood and urine sampling during or at the end of the first dosing regimen. Blood and urine sampling schedules are described in section III-4. In some embodiments, blood and urine samples are arranged according to tables 4A-4C, 5, 6A-6C, and 7 of example 1.
In some embodiments, the second dosing regimen comprises a total daily dose of at least about 10mg, 20mg, 30mg, 40mg, 60mg, 90mg, 120mg, 180mg, 360mg, 480mg, or 720mg cltx-305. In some embodiments, the second dosing regimen comprises a total daily dose of at least about 10mg, 20mg, 40mg, 60mg, 120mg, 180mg, 360mg, 480mg, or 720mg cltx-305. In some embodiments, the second dosing regimen comprises a total daily dose of at least about 60mg, 120mg, 180mg, or 360mg cltx-305. In some embodiments, the second dosing regimen comprises a total daily dose of at least about 30mg, 90mg, 120mg, or 180mg cltx-305. In some embodiments, the second dosing regimen comprises a total daily dose of at least about 30mg, 90mg, or 180mg cltx-305. In some embodiments, the second dosing regimen comprises a total daily dose of about 40mg, 60mg, 120mg, 180mg, 360mg, 480mg, or 720mg cltx-305. In some embodiments, the second dosing regimen comprises a total daily dose of about 60mg, 120mg, 180mg, 360mg, 480mg, or 720mg cltx-305. In some embodiments, the second dosing regimen comprises a total daily dose of about 60mg, 120mg, 180mg, 360mg, 480mg, or 720mg cltx-305. In some embodiments, the second dosing regimen comprises a total daily dose of about 180mg or 360mg cltx-305.
Typically, the second dosing regimen comprises an initial daily total dose (e.g., about 10mg, 30mg, 60mg, 90mg, 120mg, 180mg, or 360 mg) of CLTX-305 calculated based on the daily total dose of the last day of the first dosing regimen. In some embodiments, the second dosing regimen comprises an initial daily total dose of about 10mg, 30mg, 60mg, 90mg, 120mg, 180mg, 360mg, 480mg, or 720mg cltx-305. In some embodiments, the second dosing regimen comprises an initial daily total dose of about 60mg, 90mg, 120mg, 180mg, 360mg, or 480mg cltx-305. In some embodiments, the second dosing regimen comprises an initial daily total dose of about 60mg, 90mg, 120mg, 180mg, or 360mg cltx-305.
Typically, CLTX-305 may be administered twice or more (e.g., 2, 3, or 4 times) per day during the second dosing regimen. In some embodiments, the second dosing regimen comprises administration of CLTX-305 at a daily dosing frequency of 2 to 4 times per day. In some embodiments, the second dosing regimen comprises administering CLTX-305 twice daily. In some embodiments, the second dosing regimen comprises administering CLTX-305 twice daily for five days.
In some embodiments, the second dosing regimen comprises administering CLTX-305 twice daily to provide a total daily dose of at least about 10mg, 20mg, 30mg, 40mg, 60mg, 90mg, 120mg, 180mg, or 360mg CLTX-305. In some embodiments, the second dosing regimen comprises administering CLTX-305 twice daily to provide a total daily dose of at least about 30mg, 60mg, 90mg, 120mg, 180mg, or 360mg CLTX-305. In some embodiments, the second dosing regimen comprises administering CLTX-305 twice daily to provide a total daily dose of about 30mg, 60mg, 90mg, 180mg, or 360mg CLTX-305. In some embodiments, the second dosing regimen comprises administering CLTX-305 twice daily to provide a total daily dose of about 30mg, 90mg, or 180mg CLTX-305. In some embodiments, the second dosing regimen comprises a first period of one dosing per day and a second period of two dosing per day. In some embodiments, the first period of once-a-day dosing precedes the second period of twice-a-day dosing. In some embodiments, the total daily dose in the first period is the same as the total daily dose in the second period. In some embodiments, the total daily dose in the first period is different from the total daily dose in the second period.
The second dosing regimen may include one or more dose adjustments or no dose adjustments depending on the subject's blood calcium concentration (ca) level, e.g., increasing or decreasing the daily total dose if the blood calcium concentration (ca) is not in the range of about 7.5 to about 10.5mg/dL, or maintaining the daily total dose when the blood calcium concentration (ca) is in the prescribed range. In some embodiments, the second dosing regimen comprises:
a2 Maintaining a total daily dose when the blood calcium concentration (ca) is maintained in the range of about 7.5 to about 10.5 mg/dL;
b2 Increasing the total daily dose when the blood calcium concentration (ca) is less than about 7.5 mg/dL; or (b)
c2 When the blood calcium concentration (ca) is greater than about 10.5mg/dL, the daily total dose is reduced.
The blood calcium concentration (ca) in the subject is determined after the first dosing regimen, before the second dosing regimen, or during the second dosing regimen. In some embodiments, the blood calcium concentration (ca) is determined after the first dosing regimen, before the second dosing regimen, or during the second dosing regimen. In some embodiments, the blood calcium concentration (ca) is determined after the first dosing regimen or after the initial two days of the second dosing regimen.
The daily total dose (e.g., initial daily total dose or adjusted daily total dose) of CLTX-305 may be maintained while the blood calcium concentration (ca) is maintained in the range of about 7.5 to about 10.5 mg/dL. The initial daily total dose may be the daily total dose on days 1 and 2. The adjusted daily total dose may be the daily total dose on day 3, day 4 and/or day 5. In some embodiments, the second dosing regimen maintains a daily total dose of CLTX-305 while the blood calcium concentration (ca) is maintained in the range of about 7.5 to about 10.5 mg/dL. In some embodiments, the second dosing regimen maintains an initial daily total dose of CLTX-305 while the blood calcium concentration (ca) is maintained in the range of about 7.5 to about 10.5 mg/dL. In some embodiments, the second dosing regimen maintains an adjusted daily total dose of CLTX-305 while the blood calcium concentration (ca) is maintained in the range of about 7.5 to about 10.5 mg/dL. In some embodiments, the second dosing regimen maintains an initial daily total dose of CLTX-305 on days 1 and 2 when the blood calcium concentration (ca) is maintained in the range of about 7.5 to about 10.5 mg/dL. In some embodiments, the second dosing regimen maintains a daily total dose of adjusted CLTX-305 on days 3, 4, and/or 5 when the blood calcium concentration (ca) is maintained in the range of about 7.5 to about 10.5 mg/dL.
When the blood calcium concentration (ca) is less than about 7.5mg/dL, the total daily dose is increased. The total daily dose may be increased algorithmically (e.g., blood ca value, net increase in ca over the dosing interval, peak iPTH, and/or sustained elevation of iPTH) according to the subject's parameters. In some embodiments, the total daily dose is increased according to the algorithm shown in fig. 6. In some embodiments, the daily total dose is increased by doubling the previous daily total dose (e.g., from 30mg to 60mg, from 60mg to 120mg, from 90mg to 180mg, etc.). In some embodiments, the daily total dose is increased by doubling the daily total dose up to the previous one (e.g., from 10mg to 30mg, from 30mg to 90mg, from 60mg to 180mg, from 90mg to 270mg, etc.). In some embodiments, the total daily dose of CLTX-305 increases from about 20mg to about 40mg, from about 40mg to about 60mg, from about 60mg to about 120mg, from about 120mg to about 180mg, from about 180mg to about 360mg, from about 360mg to about 480mg, or from about 480mg to about 720mg. In some embodiments, the daily total dose of CLTX-305 increases from about 30mg to about 60mg, from about 30mg to about 90mg, from about 10mg to about 20mg, from about 20mg to about 40mg, from about 60mg to about 120mg, from about 90mg to about 180mg, or from about 180mg to about 360mg. In some embodiments, the daily total dose of CLTX-305 increases from about 30mg to about 90mg, from about 60mg to about 120mg, from about 90mg to about 180mg, or from about 180mg to about 360mg. In some embodiments, the daily total dose of CLTX-305 increases from about 30mg to about 90mg, from about 90mg to about 180mg, or from about 180mg to about 360mg. In some embodiments, the daily total dose of CLTX-305 increases from about 30mg to about 90mg or from about 90mg to about 180mg.
When the blood calcium concentration (ca) is greater than about 10.5mg/dL, the total daily dose is reduced. The total daily dose may be reduced algorithmically (e.g., blood ca value, net increase in ca over the dosing interval, peak iPTH, and/or sustained elevation of iPTH) according to the subject's parameters. In some embodiments, the total daily dose is reduced according to the algorithm shown in fig. 6. In some embodiments, the daily total dose is reduced to 2 (2/3) of the 3 th of the previous daily total dose (e.g., from 60mg to 40mg, from 90mg to 60mg, from 180mg to 120mg, etc.). In some embodiments, the total daily dose is reduced by half (1/2) of the total previous daily dose (e.g., from 60mg to 30mg, from 120mg to 60mg, from 180mg to 90mg, etc.). In some embodiments, the daily total dose is reduced to 1 (1/3) of the previous daily total dose (e.g., 30mg to 10mg, 90mg to 30mg, 180mg to 60mg, 270mg to 90mg, etc.). In some embodiments, the total daily dose of CLTX-305 is reduced from about 40mg to about 20mg, from about 60mg to about 40mg, from about 120mg to about 60mg, from about 180mg to about 120mg, from about 360mg to about 180mg, or from about 480mg to about 360mg. In some embodiments, the total daily dose of CLTX-305 is reduced from about 30mg to about 10mg, from about 40mg to about 20mg, from about 60mg to about 30mg, from about 90mg to about 60mg, from about 90mg to about 30mg, from about 120mg to about 90mg, from about 120mg to about 60mg, from about 180mg to about 120mg, from about 180mg to about 90mg, from about 180mg to about 60mg, or from about 360mg to about 180mg. In some embodiments, the total daily dose of CLTX-305 is reduced from about 30mg to about 10mg, from about 90mg to about 60mg, from about 90mg to about 30mg, from about 180mg to about 120mg, from about 180mg to about 90mg, from about 180mg to about 60mg, or from about 360mg to about 180mg.
During or at the end of the second dosing regimen, the subject is assessed by blood and urine sampling. Blood and urine sampling schedules are described in section III-4. In some embodiments, blood and urine samples are arranged according to tables 4A-4C, 5, 6A-6C, and 7 of example 1.
In some embodiments, the third dosing regimen comprises a total daily dose of CLTX-305 of at least about 10mg, 20mg, 30mg, 40mg, 60mg, 80mg, 90mg, 120mg, 140mg, 180mg, 300mg, 360mg, 480mg, or 720 mg. In some embodiments, the third dosing regimen comprises a total daily dose of at least about 20mg, 40mg, 60mg, 120mg, 180mg, 360mg, 480mg, or 720mg CLTX-305. In some embodiments, the third dosing regimen comprises a total daily dose of at least about 60mg, 120mg, 180mg, or 360mg cltx-305. In some embodiments, the third dosing regimen comprises a total daily dose of at least about 30mg, 90mg, or 180mg cltx-305. In some embodiments, the third dosing regimen comprises a total daily dose of about 20mg, 40mg, 60mg, 120mg, 180mg, 360mg, 480mg, or 720mg cltx-305. In some embodiments, the third dosing regimen comprises a total daily dose of about 60mg, 120mg, 180mg, 360mg, 480mg, or 720mg cltx-305. In some embodiments, the third dosing regimen comprises a total daily dose of about 60mg, 120mg, 180mg, 360mg, 480mg, or 720mg cltx-305. In some embodiments, the third dosing regimen comprises a total daily dose of about 10mg, 20mg, 80mg, 140mg, or 300mg cltx-305.
Typically, the third dosing regimen comprises an initial total daily dose of CLTX-305 calculated based on the tolerised and/or effective total daily dose determined during the second dosing regimen. In some embodiments, the third dosing regimen comprises an initial daily total dose of CLTX-305 of about 10mg, 20mg, 30mg, 60mg, 80mg, 90mg, 120mg, 140mg, 180mg, 300mg, 360mg, 480mg, or 720 mg. In some embodiments, the second dosing regimen comprises an initial daily total dose of about 60mg, 90mg, 120mg, 180mg, 360mg, or 480mg CLTX-305. In some embodiments, the second dosing regimen comprises an initial daily total dose of about 60mg, 90mg, 180mg, or 360mg CLTX-305.
Typically, CLTX-305 may be administered twice or more (e.g., 2, 3, or 4 times) a day during the third dosing regimen. In some embodiments, the third dosing regimen comprises administration of CLTX-305 at a daily dosing frequency of 2 to 4 times per day. In some embodiments, the third dosing regimen comprises administering CLTX-305 twice daily. In some embodiments, the third dosing regimen comprises administering CLTX-305 twice daily for at least 24 weeks.
In some embodiments, the third dosing regimen comprises administering CLTX-305 twice daily to provide a total daily dose of at least about 10mg, 20mg, 30mg, 40mg, 60mg, 80mg, 90mg, 120mg, 140mg, 180mg, 300mg, 360mg, 480mg, or 720mg CLTX-305. In some embodiments, the third dosing regimen comprises administering CLTX-305 twice daily to provide a total daily dose of CLTX-305 of at least about 30mg, 60mg, 90mg, 120mg, 180mg, or 360 mg. In some embodiments, the third dosing regimen comprises administering CLTX-305 twice daily to provide a total daily dose of CLTX-305 of about 30mg, 60mg, 90mg, 180mg or 360 mg. In some embodiments, the third dosing regimen comprises administering CLTX-305 twice daily to provide a total daily dose of CLTX-305 of about 30mg, 90mg, or 180 mg. In some embodiments, the third dosing regimen comprises a first period of one dosing per day and a second period of two dosing per day. In some embodiments, the first period of once-a-day dosing precedes the second period of twice-a-day dosing. In some embodiments, the total daily dose in the first period is the same as the total daily dose in the second period. In some embodiments, the total daily dose in the first period of time is different from the total daily dose in the second period of time.
The third dosing regimen may include a titration period and a maintenance period, each of which may last up to 12 weeks. Titration period involves one or more dose adjustments or no dose adjustments to bring the blood calcium concentration (ca) into the normal to low-normal range (e.g., about 7.5 to about 10.5 mg/dL). The maintenance period is to maintain a stable dose of stable normal to low-normal ca while avoiding hypercalcemia in the subject. In some embodiments, the third dosing regimen comprises a titration period. In some embodiments, the third dosing regimen comprises dropping a total dose of days while maintaining a blood calcium concentration (ca) in the range of about 7.5 to about 10.5 mg/dL. In some embodiments, the third dosing regimen comprises dropping a total dose of days while maintaining a blood calcium concentration (ca) in the range of about 8.5 to about 10.5 mg/dL. In some embodiments, the third dosing regimen comprises a maintenance period. In some embodiments, the third dosing regimen comprises maintaining a total daily dose while maintaining a blood calcium concentration (ca) in the range of about 7.5 to about 10.5 mg/dL. In some embodiments, the third dosing regimen comprises maintaining a total daily dose while maintaining a blood calcium concentration (ca) in the range of about 8.5 to about 10.5 mg/dL. In some embodiments, the third dosing regimen comprises maintaining a daily total dose while maintaining blood calcium concentration (ca) in the range of about 7.5 to about 10.5mg/dL and minimizing hypercalcemia in the subject. In some embodiments, the third dosing regimen comprises maintaining a daily total dose while maintaining blood calcium concentration (ca) in the range of about 8.5 to about 10.5mg/dL and minimizing hypercalcemia in the subject.
The third dosing regimen (e.g., titration period) may include one or more dose adjustments or no dose adjustments based on the blood calcium concentration (ca) level in the subject, e.g., increasing or decreasing the daily total dose if the blood calcium concentration (ca) is not in the range of about 7.5 to about 10.5mg/dL, or maintaining the daily total dose when the blood calcium concentration (ca) is within a specified range. In some embodiments, the third dosing regimen comprises:
a3 Maintaining a total daily dose when the blood calcium concentration (ca) is maintained in the range of about 7.5 to about 10.5 mg/dL;
b3 Increasing the total daily dose when the blood calcium concentration (ca) is less than about 7.5 mg/dL; or (b)
c3 When the blood calcium concentration (ca) is greater than about 10.5mg/dL, the daily total dose is reduced.
The blood calcium concentration (ca) in the subject is determined after the second dosing regimen, before the third dosing regimen, or during the third dosing regimen. In some embodiments, the blood calcium concentration (ca) is determined after the second dosing regimen, before the third dosing regimen, or during the third dosing regimen. In some embodiments, the blood calcium concentration (ca) is determined prior to or during the third dosing regimen. In some embodiments, the blood calcium concentration (ca) is measured during the third dosing regimen. In some embodiments, according to fig. 4, the blood calcium concentration (ca) is measured during the third dosing regimen at weeks 1-4, 6, 8, 12, 16, 20, and/or 24.
When the blood calcium concentration (ca) is maintained in the range of about 7.5 to about 10.5mg/dL, the daily total dose (e.g., the initial daily total dose or the adjusted daily total dose) of CLTX-305 may be maintained during the titration period. In some embodiments, the third dosing regimen maintains a daily total dose of CLTX-305 during the titration period while the blood calcium concentration (ca) remains in the range of about 7.5 to about 10.5 mg/dL. In some embodiments, the third dosing regimen maintains an initial daily total dose of CLTX-305 during the titration period while the blood calcium concentration (ca) remains in the range of about 7.5 to about 10.5 mg/dL. In some embodiments, the third dosing regimen maintains an adjusted daily total dose of CLTX-305 during the titration period while the blood calcium concentration (ca) remains in the range of about 7.5mg/dL to about 10.5 mg/dL.
When the blood calcium concentration (ca) is less than about 7.5mg/dL, the total daily dose is increased during the titration period. The total daily dose may be increased algorithmically according to subject parameters (e.g., blood ca value, body weight, age, sex, and/or other conditions). In some embodiments, the total daily dose during the drip period is increased according to an algorithm.
When the blood calcium concentration (ca) is greater than about 10.5mg/dL, the daily total dose is reduced during the titration period. The total daily dose may be reduced algorithmically according to subject parameters (e.g., blood ca value, body weight, age, sex, and/or other conditions). In some embodiments, the total daily dose increased during the titration period is reduced according to an algorithm.
During the third dosing regimen, the titration period can be extended to 12 weeks, after which each personalized dosing regimen is continued to maintain a stable dose, stable normal to low-normal ca, while avoiding hypercalcemia in the subject. Whether additional dose adjustments are required during maintenance may depend on potential factors associated with the time course of parathyroid function, intestinal calcium absorption, bone absorption and renal function changes, all of which are monitored. In some embodiments, the third dosing regimen during the maintenance period comprises one or more dose adjustments according to one or more parameters of parathyroid function, intestinal calcium absorption, bone absorption, and renal function.
The goal of the third dosing regimen is to reduce symptoms associated with hypocalcemia and hypercalcemia and minimize hypercalcemia in the subject. In some embodiments, the third dosing regimen reduces symptoms associated with hypocalcemia and hypercalcemia and minimizes hypercalcuria in the subject. In some embodiments, the third dosing regimen maintains blood calcium concentration (ca) in the range of about 7.5 to about 10.5mg/dL for at least 12 weeks. In some embodiments, the third dosing regimen maintains blood calcium concentration (ca) in the range of about 7.5 to about 10.5mg/dL for at least 24 weeks. In some embodiments, the third dosing regimen maintains blood calcium concentration (ca) in the range of about 8.5 to about 10.5mg/dL for at least 12 weeks. In some embodiments, the third dosing regimen maintains blood calcium concentration (ca) in the range of about 8.5 to about 10.5mg/dL for at least 24 weeks.
During the third dosing regimen, the subject does not take calcitriol, but if a minimum daily dietary intake of about 1000mg cannot be achieved and the subject suffers from persistent hypocalcemia, additional calcium supplements may be taken as needed. Titration of oral calcium supplements may be performed during the third dosing regimen, and may be up-or down-regulated based on achieving therapeutic goals for normal or low-normal ca without hypercalcuria. In some embodiments, the third dosing regimen further comprises administering an oral calcium supplement in addition to daily dietary calcium intake.
During or at the end of the third dosing regimen, the subject simultaneously takes blood and urine samples. Blood and urine sampling schedules are described in section III-4 and the number of weeks is noted as described in FIG. 4. In some embodiments, blood and urine samples are arranged according to tables 4A-4C, 5, 6A-6C, and 7 of example 1.
The subject may be assessed by one or more tests including blood analysis, urine analysis and/or hematology tests before, during and/or after any of the first, second and/or third dosing periods. Examples of such tests are described in section III-4, table 1, table 2 and Table 3 of example 1.
In some embodiments, the blood analysis includes analysis of iPTH, serum bone markers, 1, 25-hydroxyvitamin D, cAMP, phosphate (P), magnesium (Mg), potassium (K), albumin, creatinine (Cr), and/or Creatine Kinase (CK). In some embodiments, the serum bone markers are blood collagen cross-linked C-terminal peptide (CTx) and blood procollagen type 1N-propeptide (P1 NP).
In some embodiments, the blood analysis includes electrolytes (sodium, potassium, chlorine), calcium, magnesium, phosphorus, bicarbonate, glucose, blood Urea Nitrogen (BUN), creatinine, ALT, AST, alkaline phosphatase (ALP), LDH, amylase, lipase, uric acid, creatine Kinase (CK), total protein, albumin, total bilirubin, intact PTH, 25-hydroxyvitamin D,1, 25-dihydroxyvitamin D, CTx, and/or P1NP.
In some embodiments, urine analysis includes analysis of phosphate (P), magnesium (Mg), sodium (Na), potassium (K), creatinine (Cr), cAMP, citrate, and/or pH.
In some embodiments, urine analysis includes urine analysis including gravity, pH, protein, glucose, ketone, and/or blood, as well as analysis of cAMP, calcium, creatinine, magnesium, phosphorus, and/or citrate.
In some embodiments, the hematology test includes hemoglobin, hematocrit, whole blood count (CBC) including red blood cell count and index, HCT, hgb, white Blood Cell (WBC) count, platelet count and differential; and coagulation tests including PT, PTT and/or INR.
III-6: oral dosage form
The oral dosage form comprising the compound of formula (I) or CLTX-305 may be any oral dosage form comprising one or more pharmaceutically acceptable carriers and/or excipients. Oral formulations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets(s), gels, syrups, slurries, suspensions and the like, suitable for ingestion by a patient.
For preparing an oral dosage form comprising a compound of formula (I) or CLTX-305, the pharmaceutically acceptable carrier may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets (cachets), suppositories, and dispersible granules. The solid carrier may be one or more substances which may also be used as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details concerning formulations and administration techniques are well described in the scientific and patent literature, see, for example, the latest edition of the pharmaceutical science of Remington, mark publishing company, iston, pa. ("Lemington").
In powders, the carrier is a finely divided solid which is admixed with the finely divided active component. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in a suitable ratio and compacted in the shape and size desired.
Powders, capsules and tablets preferably contain 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, astragalus, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes, cocoa butter, etc. The term "formulation" is intended to include active compound formulations with encapsulating materials as carriers, which provide capsules in which the active ingredient, with or without other excipients, is surrounded by a carrier, which is thus bound thereto. Likewise, cachets (cachets) and lozenges are also included. Tablets, powders, capsules, pills, cachets (cachets) and lozenges can be used as solid dosage forms suitable for oral administration.
Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth gum; a low melting point wax; cocoa butter; a carbohydrate; sugars, including but not limited to lactose, sucrose, mannitol, or sorbitol, starches from wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropyl methyl cellulose or sodium carboxymethyl cellulose; and gums including acacia and tragacanth; and proteins including, but not limited to, gelatin and collagen. If desired, disintegrating or solubilizing agents can be added, such as cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate.
Dragee cores have a suitable coating, such as a concentrated sugar solution, which may also contain gum arabic, talc, polyvinyl pyrrolidone, carbomer gels, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to tablets or dragee coatings for product identification or to characterize the amount (i.e., dosage) of active compound. Pharmaceutical formulations of the dosage form may also be used orally, for example using push-in capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-in capsules may contain a compound of formula (I) or CLTX-305 in admixture with a filler or binder (e.g., lactose or starch), a lubricant (e.g., talc or magnesium stearate), and optionally a stabilizer. In soft capsules, the compounds of formula (I) or CLTX-305 may be dissolved or suspended in a suitable liquid, for example a fatty oil, liquid paraffin or liquid polyethylene glycol with or without stabilizers.
To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the compound of formula (I) or CLTX-305 is uniformly dispersed therein by stirring. The molten homogeneous mixture is then poured into a suitably sized mold and allowed to cool, thereby solidifying.
Formulations in liquid form include solutions, suspensions and emulsions, for example water or water/propylene glycol solutions.
Aqueous solutions suitable for oral administration may be prepared by dissolving the compound of formula (I) or CLTX-305 in water and adding suitable colorants, flavors, stabilizers and thickeners as desired. Aqueous suspensions suitable for oral use can be obtained by dispersing the finely divided active ingredient in water, for example natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia, and dispersing or wetting agents, for example naturally occurring phosphatides (for example lecithin), condensation products of alkylene oxides with fatty acids (for example polyoxyethylene stearate), condensation products of ethylene oxide with long-chain fatty alcohols (for example heptadecaethylene-hexadecanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (for example polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (for example polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, for example sucrose, aspartame or saccharin. The formulation may be adjusted based on osmotic pressure.
Also included are solid form preparations which are intended to be converted shortly before use into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These formulations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The oil suspension may be formulated by suspending a compound of formula (I) or CLTX-305 in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin) or in a mixture of these. The oil suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweeteners may be added to provide a palatable oral preparation, such as glycerin, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant (e.g., ascorbic acid). As an example of an injectable oil carrier, reference Minto, J.Pharmacol.exp. Ther.281:93-102,1997. Pharmaceutical formulations comprising a compound of formula (I) or CLTX-305 may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil or a mineral oil as described above, or a mixture thereof. Suitable emulsifying agents include naturally-occurring gums, for example gum acacia and gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitol monooleate, and condensation products of these partial esters with ethylene oxide, for example polyoxyethylene sorbitol monooleate. Emulsions may also contain sweetening and flavoring agents, such as syrup and elixir formulations. Such formulations may also contain a demulcent, a preservative or a colorant.
The oral dosage form comprising the compound of formula (I) or CLTX-305 may be any of the tablet formulations as disclosed in international patent application PCT/US2021/044295 filed on 8/3/1 of 2022, which is incorporated herein in its entirety for all purposes.
In some embodiments, the oral dosage form is a tablet formulation as described in International patent application No. PCT/US 2021/044295. The tablet formulation comprises:
a) A compound of formula (I), a solvate, a hydrate, a pharmaceutically acceptable salt, or a combination thereof; and
b) One or more pharmaceutically acceptable excipients selected from the group consisting of one or more fillers, one or more glidants, one or more disintegrants, one or more surfactants, one or more binders, one or more lubricants, and combinations thereof,
wherein the compound is present in an amount of at least about 12% by weight on a salt-free and water-free basis.
In some embodiments, the oral dosage form is a tablet formulation as a common mixed formulation of all dose strengths, as described in international patent application No. PCT/US 2021/044295. Common mixed tablet formulations include:
a) CLTX-305 represented by the following formula:
b) Seven or more pharmaceutically acceptable excipients including a first filler, a second filler, a glidant, a disintegrant, a surfactant, a binder, and a lubricant,
Wherein CLTX-305 is present in an amount of about 13% to about 30% by weight;
the first filler is mannitol;
the second filler is microcrystalline cellulose;
the glidant is colloidal silicon dioxide;
the disintegrating agent is croscarmellose sodium;
the surfactant is one or more sucrose fatty acid esters comprising sucrose palmitate;
the adhesive is hydroxypropyl methyl cellulose;
the lubricant is magnesium stearate; and
the ratio of the weight of the compound to the total weight of the seven or more pharmaceutically acceptable excipients is constant over two or more dosage strengths.
List of abbreviations
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V. examples
Example 1: stage 2b, open label dose range study-protocol abstract
1.1 summary of the study
The 2b stage open label dose range study was aimed at assessing CLTX-305 safety, tolerability and efficacy to maintain normal albumin corrected blood calcium (ca) in subjects with hypocalcemia due to ADH 1. The study included 2 queues and 3 cycles as shown in figure 1. Figure 2 illustrates an overview scheme of the 2b stage study. The detailed protocol of cycle 1 and cycle 2 (single and multiple incremental dose tests) of the study is shown in figure 3. The detailed scheme of study period 3 is shown in fig. 4.
Studies recruit up to 20 male or female subjects (up to 16 into the treatment phase) with autosomal dominant hereditary hypocalcemia type 1 (ADH 1) for evaluation.
In this study, 10mg, 30mg and 60mg of the active ingredient CLTX-305 were provided per oral tablet.
The estimated time from study start to group entry to complete data analysis was about 24 months. The total duration of study participation (including cycles 1,2 and 3) for each subject may be about 12 months, including 60 days from the screening visit to the beginning of study drug.
Research objective
Primary:
cycle 1 and cycle 2: single and multi-dose CLTX-305 was evaluated for safety and tolerability to ADH1 patients.
Cycle 3: CLTX-305 was evaluated for safety, tolerability, and efficacy in ADH1 subjects 24 weeks after dosing.
And (2) second-stage:
cycle 1 and cycle 2: the effect of CLTX-305 on increasing serum PTH levels in ADH1 subjects after single and multiple doses was evaluated.
Periods 1, & 2 and 3: 1) Assessing the Pharmacodynamic (PD) effect of CLTX-305 on blood calcium concentration; 2) Evaluation of PD Effect of CLTX-305 on calcium homeostasis related measures, including 1,25- (OH) 2 Vitamin D levels and urinary calcium excretion; 3) Assessing the effect of CLTX-305 on bone transition marker PD, including C-teoptide (CTx) and procollagen type 1N-propeptide (P1 NP); 4) Evaluating single and multiple increments Pharmacokinetic (PK) profile of dose CLTX-305 in ADH1 subjects.
Exploratory:
cycle 3: 1) Assessing the effect of CLTX-305 (encaleset) treatment on renal calcification/kidney stones in ADH1 participants; 2) The effect of CLTX-305 (encaleset) treatment on Bone Mineral Density (BMD) of ADH1 participants was evaluated.
Study endpoint
Primary:
periods 1,2 and 3: adverse Events (AEs), clinical safety laboratory tests, vital signs, electrocardiography (ECGs)
Cycle 3: albumin corrected blood calcium concentration (ca) and 24 hours urinary calcium excretion after up to 24 weeks of treatment with CLTX-305.
And (2) second-stage:
periods 1 and 2: blood concentration profile of iPTH over time (24 hours) after single and multiple administrations of CLTX-305.
Periods 1,2 and 3：
1) Pharmacodynamic endpoint (final visit) measured over a period of up to 24 weeks:
absolute level of calcemia-ca and change from baseline;
urinary calcium clearance (partial excretion and total excretion for 24 hours);
serum 1,25- (OH) 2 Vitamin D levels;
magnesium, phosphate, creatinine of the blood sample;
pH, magnesium, phosphate, sodium, potassium, creatinine, cAMP, citrate of urine samples;
collagen cross-linked C-terminal peptide (CTx), a marker of bone resorption; and
Bone formation marker-blood procollagen type 1N-propeptide (P1 NP);
2) PK parameters: maximum plasma concentration (Cmax), time to maximum plasma concentration (tmax), apparent terminal half-life (t 1/2), concentration versus time area under the curve (AUC) from time 0 to the last measurable time point (AUC (0-t)), AUC from time 0 to 24 hours (AUC (0-24)), AUC extrapolated to infinity after a single dose (AUC (0-inf)); and
3) Determination of steady-state PK parameters: cmax, trough concentration (Ctough) and AUC (0-tau) over the dosing interval.
Exploratory:
cycle 3: 1) Renal calcification and/or change in renal calculus from baseline to a predetermined point in time as assessed by renal ultrasound; and 2) changes in lumbar BMD, total hip BMD, femoral neck BMD, distal radius BMD, and total body BMD from baseline to a predetermined time point as assessed by dual energy x-ray absorption (DXA).
1.2 Activity timetable (SOA)
The event schedules for periods 1, 2 and 3 are shown in tables 1, 2 and 3, respectively.
Table 1: period 1 event schedule
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Abbreviations: adverse event = AE; albumin = Alb; alkaline phosphatase=alp; alanine aminotransferase = ALT; blood urea nitrogen = BUN; aspartic aminotransferase = AST; alkaline phosphatase=akphos; electrocardiogram = ECG; BID = twice daily; blood pressure = BP; calcium=ca; calcium-sensing receptor = CASR; chloride=cl; concomitant medication = con.med; creatinine=cr; dual energy x-ray bone densitometer = DXA; early Termination= (ET); treatment endpoint = EoT; follow-up = FU; follicle-stimulating hormone = FSH; glucose = Glu; heart rate = HR; hematocrit=hct; hemoglobin=hgb; lactate dehydrogenase=ldh; intact parathyroid hormone = iPTH; magnesium=mg; national institutes of health clinical center = NIHCC; parathyroid hormone = PTH; phosphate=po 4 The method comprises the steps of carrying out a first treatment on the surface of the Phosphorus=p; potassium=k; pharmacodynamics = PD; pharmacokinetic = PK; prothrombin time/prochrombin time = PT/INR; red cell count = RBC; thromboplastin in the case of thromboplastinM=ptt; serious adverse event = SAE; QD = once per day; total bilirubin = Tbili; triglyceride=tg; white blood cell count = WBC; fertility women = WOCBP
1. Screening access by NIH clinical center.
2. If the subjects either stopped the study (ET) prematurely or stopped taking CLTX-305 (EoT), then a correlation evaluation was performed, the previous medication regimen was resumed, the FU laboratory was scheduled for 1-2 days, and FU calls were made within 30±7 days after the last dose of CLTX-305.
3. The out-patient laboratory examination includes collecting Cr, ca, alb, mg, PO blood on day 7 or day 8 after discharge from NIH CC on day 6 4 iPTH and PK samples.
4. Including CaSR mutation analysis (if not recorded).
5. Safety laboratory-chemistry (Na, K, cl, bicarbonate, glu, BUN, cr, alb, total protein, ca, mg, PO 4 iPTH,25-OH vitamin D, cholesterol, TG, AST, ALT, tbili, alk phos, LDH, amylase, lipase, uric acid), hematology (RBC, hemoglobin (Hgb), hct, RBC index, WBC, differential), coagulation (PT/PTT/INR), urine analysis. HIV, viral hepatitis panel, is only performed at screening visit.
6. The height was measured only at the time of screening.
7. Vital signs include automatic cuff measurement of supine or sitting Blood Pressure (BP), heart Rate (HR) and respiratory rate, acquired every 8 hours during hospitalization. The screening will be performed once for orthostatic blood pressure and heart rate, once daily in cycle 1.
8. Calcitriol was stopped on day 1 during admission.
9. On days 1, 2 and 3, subjects received CLTX-305 according to the dosing algorithm. On days 4 and 5, subjects received BID doses based on days 1-3.
10. Screening urine 24 hours at visit and 10-14 days prior to day 1 dosing(Ca，Mg，PO 4 Cr, na, K, citrate, pH).
11 The outpatient laboratory examinations on days 14-10 include: blood Cr, calcium, albumin, magnesium, phosphate and 25-OH vitamin D.
12. The interview laboratory test of the outpatient laboratory will be at a screening visit time prior to cycle 1>And carried out in the group of 21 days.
13. After the last dose of CLTX-305, the subject restored the previous outpatient routine treatment regimen prior to discharge.
14. Telephone contact: should be done on days 9 to 11, or after calcium results. PI/researchers reviewed the results with the subjects.
15. Telephone contacts: 30+ -7 days after the last administration of CLTX-305 in cycle 1 to examine Adverse Event (AEs)/adverse reaction (Con) drugs
Table 2: period 2 event schedule
Abbreviations: adverse event = AE; albumin = Alb; alkaline phosphatase=alp; alanine aminotransferase = ALT; blood urea nitrogen = BUN; aspartic aminotransferase = AST; alkaline phosphatase=akphos; electrocardiogram = ECG; BID = twice daily; blood pressure = BP; calcium=ca; calcium-sensing receptor = CaSR; chloride=cl; concomitant medication = con.means; creatinine=cr; dual energy x-ray bone densitometer = DXA; early Termination= (ET); end of treatment = EoT; follow-up = FU; follicle stimulating hormone = FSH; glucose = Glu; heart rate = HR; hematocrit=hct; hemoglobin=hgb; lactate dehydrogenase=ldh; intact parathyroid hormone = iPTH; magnesium=mg; national institutes of health clinical center = NIHCC; parathyroid hormone =PTH; phosphate=po 4 The method comprises the steps of carrying out a first treatment on the surface of the Phosphorus=p; potassium=k; pharmacodynamics = PD; pharmacokinetic = PK; prothrombin time/prochrombin time = PT/INR; red cell count = RBC; thromboplastin time = PTT; serious adverse event = SAE; QD = once per day; total bilirubin = Tbili; triglyceride=tg; white blood cell count = WBC; fertility women = WOCBP
1 Subjects in cohort 2 were screened for access at NIH CC. The subject may complete the screening visit as an outpatient or overnight at NIH CC. Cohort 1 subjects did not require rescreening assessment. Subjects who completed screening visits in weeks may choose to stay overnight in NIH CC within a few days before the beginning of cycle 2 (day 1).
2 If the subjects either stop the study (ET) in advance or stop taking CLTX-305 (EoT), a correlation evaluation is performed, the previous medication regimen is resumed, and the FU laboratory is scheduled within 1-2 days. Subjects received an out-patient laboratory examination (see footnote 10) about 1-2 days after the discharge of the NIHCC. PI/field staff should contact subjects within 3-5 days to review test results and provide guidance regarding clinical management as they transition to previous clinical care providers. Alternatively, the subject may be on NIH CC overnight to complete the assessment.
3 Including CaSR mutation analysis (if not recorded).
4 Safety laboratory-chemistry (Na, K, cl, bicarbonate, glu, BUN, cr, alb, total protein, ca, mg, PO 4 iPTH,25-OH vitamin D, cholesterol, TG, AST, ALT, tbili, alkphos, LDH, amylase, lipase, uric acid), hematology (RBC, hgb, hct, RBC index, WBC, diff), coagulation (PT/PTT/INR), urine analysis. Unless repeated measures are clinically taken, HIV, viral hepatitis teams and iron screening can only be performed at screening visit.
5 The height was measured only at the time of screening.
6 Vital signs include automatic cuff measurement of supine or sitting Blood Pressure (BP), heart Rate (HR) and respiratory rate, during hospitalization Collected every 8 hours. The screening will be performed once for orthostatic blood pressure and heart rate, once daily for cycle 2.
7 Calcitriol was discontinued on day 1 during admission.
8 Initial dose of CLTX-305BID based on the results of cycle 1 (day 1 and day 2). If calcium is not increased to the normal range, the CLTX-305 dose will be increased by 3-5 days. On day 5, subjects will take frequent PK/PD samples over 24 hours.
9 24 hour urine was screened 14 to 10 days prior to day 1 dosing (Ca, mg, PO 4 Cr, na, K, citrate, pH
10 For queues 1 and 2: the out-of-office laboratory examinations from day 14 to day 10 prior to admission include: blood Cr, ca, alb, mg, PO 4 25-OH vitamin D, hematology (RBC, hgb, hct, RBC index, WBC)
11 The interview laboratory test of the outpatient laboratory will be at a screening visit time prior to cycle 2>In 21 days of human performance.
12 After the last dose of CLTX-305, CLTX-305 supplies were dispensed prior to discharge for subjects continuing cycle 3.
13 ET and EoT-the last FU call should occur within 30±7 days of the last day of CLTX-305 administration in cycle 2.
14 ECG evaluation: day 1, 3 and 5, 3 hours.+ -. 30min (AM) after each administration
Table 3: period 3 activity schedule
Abbreviations: adverse event = AE; albumin = Alb; alkaline phosphatase=alp; polypropylene (C)Amino acid aminotransferase = ALT; blood urea nitrogen = BUN; aspartic aminotransferase = AST; alkaline phosphatase=alk Phos; electrocardiogram = ECG; BID = twice daily; blood pressure = BP; calcium=ca; calcium-sensing receptor = CaSR; chloride=cl; concomitant medication = con.means; creatinine=cr; c-terminal peptide = CTX; dual energy x-ray bone densitometer = DXA; early Termination= (ET); end of treatment = EoT; follow-up = FU; follicle stimulating hormone = FSH; glucose = Glu; heart rate = HR; hematocrit=hct; hemoglobin=hgb; lactate dehydrogenase=ldh; intact parathyroid hormone = iPTH; magnesium=mg; national institutes of health clinical center = NIHCC; parathyroid hormone = PTH; phosphate=po 4 The method comprises the steps of carrying out a first treatment on the surface of the Phosphorus=p; potassium=k; pharmacodynamics = PD; pharmacokinetic = PK; procollagen type 1N-propeptide=p1np; prothrombin time/prochrombin time = PT/INR; red cell count = RBC; thromboplastin time = PTT; serious adverse event = SAE; QD = once per day; total bilirubin = Tbili; triglyceride=tg; white blood cell count = WBC; fertility women = WOCBP
1 If the subject stops the study (ET) in advance or stops taking CLTX-305 (EoT), the subject will be asked to return to NIH CC for ET/EoT access assessment and to return to unused CLTX-305 as soon as possible before each regimen of cycle 3 is completed. The subject should be resumpted with an outpatient regimen of oral calcium and active vitamin D. Subjects will conduct FU activity as described in table and footnote 2, and will then conduct a safe FU call for 30 ± 7 days.
2 All subjects will obtain the following out-patient laboratory evaluations after the last dose of CLTX-305 and after restarting their previous oral calcium and active vitamin D regimen: blood Cr, ca, alb, mg, PO 4 . Follow-up (FU) calls should be made within 3-5 days to review laboratory results and receive guidance regarding their ADH1 clinical management as they transition to the previous clinical care provider.
3 Unscheduled access: laboratory evaluations were performed after dose adjustment or evaluation or AE follow-up, where clinically indicated procedures would be performed.
4 The current CLTX-305 dose and calcium dosing regimen, any modifications and reasons for the modifications were recorded.
5 Outpatient assay: blood samples for clinical laboratory (Na, cl, bicarbonate, K, BUN, cr and including Alb, ca, mg, PO 4 iPTH, CTX and P1 NP).
6 Height was measured only at week 24/last visit or ET visit.
7 Vital signs include automatic cuff measurement of supine or sitting Blood Pressure (BP), heart Rate (HR) and respiratory rate.
8 Key physical examination: body weight measurements at all visits.
9 Safe laboratory-chemistry (Na, K, cl, bicarbonate, glu, BUN, cr, alb, total protein, ca, mg, PO) collected in NIH CC visit 4 25-OH vitamin D, cholesterol, TG, AST, ALT, tbili, alkphos, LDH, amylase, lipase, uric acid), hematology (RBC, hgb, hct, RBC index, WBC, diff), coagulation (PT/PTT/INR).
10 CLTX-305 was managed and recorded during the NIHCC access/internal PK/PD collection date.
11 See tables 4A-4C: PD measurements and non-dense sampling days at time points and table 7: sample collection was studied.
12 See table 4A: PK time points used a non-dense sampling day schedule.
13 See table 4A: during NIHCC visit, see time interval for urine collection for calculation of partial excretion rate and 24 hour urine Ca, mg, PO 4 Cr, cAMP, citrate, na, K, pH.
14 Ca, mg, PO urine from 20 week clinic for 24 hours 4 Cr, na, K, citrate, pH. Participants who either stopped taking CLTX-305 (encaleet) (EoT) or opted not to continue into LTE before completing cycle 3 for each regimen will collect 24 hours urine in a 30±7 day follow-up.
1.3 pharmacokinetic, pharmacodynamic and urine sampling times
The pharmacokinetic, pharmacodynamic and urine sampling times are detailed in tables 4A-4C, table 5, table 6A-6C and table 7 to show the different dense samplings of study periods 1-3.
Table 4A: non-dense BID sampling days-cycle 1: day 4 (BID dose) and cycle 3: PK/PD sampling days
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1 PK for cycle 3 was collected only at 24 weeks; and +30min time points table 4B was collected only at 24 weeks of cycle 3: non-dense BID sampling days (if CLTX-305 dose. Ltoreq.180 mg BID) -cycle 2: day 1,2,3 and 4
1 Urine was only run at cycle 2 (day 1) for 15min
Table 4C: non-dense BID sampling days (if CLTX-305 dose >180mg BID) -cycle 2: day 3 and day 4
Table 5: dense sampling days for QD dosing-cycle 1: day 1,2,3
1 Urine was only run in cycle 1 (day 1) for 15min
Table 6A: dense sampling days for QD dosing-cycle 1: day 5
Abbreviations: time relative to = TRT
Table 6B: dense sampling days for BID dosing (if CLTX-305 dose >180mg BID) -cycle 2: day 5
Abbreviations: time relative to = TRT
Table 6C: dense sampling days for BID dosing (if CLTX-305 dose. Ltoreq.180 mg BID) -cycle 2: day 5
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Abbreviations: time relative to = TRT
Table 7: study sample collection time points for cycles 1 and 3-cycle 1: day 1 and day 4, and cycle 3: week 8, 16 and 24
Example 2:2b phase, open label dose range study-introduction
2.1 pharmacokinetics and product metabolism
CLTX-305 (non-proprietary name: encalaeret, molecular formula (C) 29 H 33 ClFNO 4 ) 2 ·H 2 SO 4 ·H 2 O, molecular weight 1144.15) were formulated as 10, 30 and 60mg round white film coated tablets for current clinical trials. Active agents inhibit CaSR, IC by allosteric modulation 50 86.2+6.2nM (in a cell-based assay of 2mM extracellular calcium). In humans, two major glucuronic acid metabolites (M1 and M3) are present.
M1(IC 50 >3000 nM) is inactive, whereas M3 (IC) 50 67.3+6.6 nM) active.
CLTX-305 is rapidly absorbed in humans (t max Median 1.5hr (range 0.75-3h at maximum single dose or at steady state). Elimination half-life after single administration (t 1/2 ) About 6.5 hours, and 11-14 hours in steady state (14 days). In the fasted state, plasma CLTX305 concentrations increased in dose proportion over the dose range (5, 10, 15, 30, 50 and 100 mg) without significant food effects. CLTX-305 had minimal accumulation in postmenopausal women in japan after two weeks of once daily (QD) dosing. Based on non-clinical data, fecal excretion is the primary route of elimination. In humans, unchanged CLTX-305 and its metabolites are excreted in small amounts in urine (total amount of parent and metabolite <5％)。
The two major glucuronic acid metabolites exhibit similar pharmacokinetics to the parent drug, M1 median t max About 2 hours. M3 median t max About 1.5 hours. For M1 (inactive), the concentration in plasma is about 2-fold higher than the concentration of the parent drug; for M3 (active) concentrations were lower (10% compared to the parent). Neither M1 nor M3 showed long lasting elimination.
No significant age-related or ethnic differences were observed in CLTX-305 pharmacokinetics (american population versus japanese subjects). AUC and C in women max Values may be about 37% and 30% higher, but these differences are not significant when considering body weight. Liver and kidney damage studies have not been performed.
In a drug interaction study, co-administration with ketoconazole (an effective CYP3A4 inhibitor) resulted in C max Increase about 1.67 times, AUC 0-24 About 2-fold increase, while the effect on M1 and M3 is slightly smaller.
2.2 efficacy of CLTX-305 in previous clinical trials
In previous osteoporosis development programs, a dose-related increase in endogenous serum parathyroid hormone (PTH) and calcium (Ca) was observed in subjects that assumed CaSR to function normally (i.e., healthy volunteers and postmenopausal women osteoporosis). In healthy postmenopausal women, repeated doses of CLTX-305 of 15 or 20mg resulted in a sustained elevation of Intact PTH (iPTH) within 3-4 hours after a single daily administration. The stimulation of the iPTH was consistent after 6 and 12 months of daily dosing, with no evidence of a rapid response. The CLTX-305 dose in phase 2 study was limited to 15mg once daily (QD) to minimize hypercalcemia.
Chronic once daily doses of up to 15mg, albumin corrected blood calcium (ca) levels reached plateau in long-term trials in postmenopausal women with normal systemic calcium homeostasis (normal CaSR sensitivity), with up to 30% of subjects with elevated blood calcium beyond the upper limit of the laboratory reference range. This hypercalcemia is asymptomatic, can be altered by reducing calcium/vitamin D supplementation, and/or can be alleviated after cessation of CLTX-305 administration. In the program of CLTX-305 for the treatment of osteoporosis in postmenopausal women, no Serious Adverse Events (SAEs) associated with hypercalcemia or hypocalcemia were observed.
In summary, a large amount of data from previous osteoporosis development projects suggests that CLTX-305 is associated with a dose-proportional increase in peak serum iphh levels in subjects likely to express wild-type CaSR, with a duration of iphh elevation less than 8-12 hours, but with a chronic daily oral dose of 15mg or more of cga elevation.
2.3 Risk/benefit assessment
Known potential risk
CLTX-305 is generally well tolerated in humans during chronic treatments up to 12 months or more. In the previous osteoporosis development program, CLTX-305 was administered to more than 1300 healthy men and postmenopausal women; no particular safety issues or signs were found when administered acutely to 100mg and chronically to 15mg qd. In addition to the known adverse events, CLTX-305 did not observe a significant pattern of Adverse Events (AEs), indicating intolerance or evidence of toxicity (target or off-target), targeted pharmacological effects that stimulated endogenous PTH hormone release and dose-related hypercalcemia (in normal parathyroid subjects) were as described above.
The most common adverse events reported in early trials included constipation, headache, dizziness, nausea, vomiting, abdominal pain, back pain and dermatitis, as well as increased blood calcium concentrations. In the larger phase 2 trial, no frequency differences occurred in these adverse events, and in this trial, there was no specific adverse event pattern, nor apparent differences in AE of system, organ, and category (except differences in calcium levels) between CLTX-305 group and placebo or comparative group.
Comprehensive QT studies in healthy subjects showed that prolongation of QTc was clinically insignificant after a single oral dose of CLTX-305 up to 100mg at any examined time point.
In preclinical safety and toxicology studies, the dose limiting effect of CLTX-305 is related to the mechanism-based elevation of serum calcium concentration and the effect on calcium homeostasis. In contrast, no off-target or other tissue or organ specific toxicity was found.
It is not clear whether CLTX-305 would have an effect on pregnancy or breast feeding in humans. According to the results of reproductive toxicity studies performed in rabbits, CLTX-305 may have potential teratogenic effects in humans, with an increased incidence of skeletal abnormalities (sternal fusion) in fetuses of 30mg/kg and beyond. Currently, women with fertility (WOCBP) will be approved to receive pregnancy tests for screening and interval throughout the trial and are required to use contraceptive measures and agree to avoid pregnancy during experimental treatment.
There is currently no approved replacement therapy for the ADH1 population to maintain blood calcium levels in the normal or low-normal range, other than oral calcium and active vitamin D supplements. Activating mutations in CASR lead to inadequate response of the isth to low blood calcium levels, and thus these patients were low calcium when not treated. The goal of the treatment is to increase blood calcium concentration sufficiently to improve/eliminate symptoms and improve function and health. Current oral supplement therapy is challenged by the frequency of use of calcium and active vitamin D and the pill burden, and iatrogenic complications associated with high calcium urine (caused by increased total calcium load). These complications of current treatments generally include kidney calcification, progressive renal insufficiency, and may lead to renal failure. CLTX-305 therapy is explored as a potential alternative or adjunct therapy to maintain blood calcium levels while minimizing hypercalcuria.
In the up-dosing and dose discovery components of cycles 1, 2 and 3, the participants may experience fluctuations in their blood calcium levels, including the likelihood of hypocalcemia and/or hypercalcemia. The long-term risk of such fluctuations in CLTX-305 is not expected to be greater than the risk of current treatments, but such fluctuations may be more frequent in the initial dose escalation/dose discovery portion of the clinical study. This clinical study aims to minimize the risk of undesirable fluctuations in blood calcium and related serum chemistry: in dose discovery cycles 1 and 2, the subject will be under supervision of frequent monitoring of blood calcium levels multiple times per day, and may be under treatment of hypocalcemia or hypercalcemia as desired, while determining an effective dose of CLTX-305. Prior to entering outpatient cycle 3, each subject was assessed for evidence of an effective dose of individualized CLTX-305 during hospitalization. During cycle 3, the subject continued to take the combination of the calcium supplement and the personalized CLTX-305 starting dose and will re-evaluate and dose titrate at least weekly based on the results of the outpatient laboratory monitoring and the telephone contact with the survey site staff. The outpatient method of adjusting dosages and regimens is similar to current practice of optimizing conventional therapies using oral calcium and active vitamin D.
Other risks and potential discomfort associated with frequent blood and urine sampling procedures during cycle 1 and cycle 2 are illustrated in informed consent, and include medical history, physical examination, renal ultrasound and evaluation of EKG in a supervised indoor environment. During testing, multiple blood and urine collections, blood drawing and/or intravenous catheter placement will occur with known common risks (discomfort, bruising), with less risk of complications, including syncope (typically a vasovagal response to vision or needle insertion) or inflammation at the site of insertion (including potential pain and swelling) and potential infection. If these occur, they will be treated.
Based on all evidence obtained so far, other organ-specific or poorly safe signals that may be of clinical interest have not been found. Clinical trials in new target populations of ADH1 patients will closely assess the relevant effect of dose on calcium homeostasis and employ routine safety monitoring (see section 5.3 of IB for details regarding CLTX-305 safety data).
Known potential benefits
There is currently no clear CLTX-305 benefit to the target population of ADH 1-induced hypocalcemia patients. In vitro and in vivo studies have shown that preclinical data, including mouse models, indicate that calcium-dissolving agents, including CLTX-305, may shift sensitivity of ADH 1-mutated CaSR to "normal", resulting in normalization of blood calcium levels. In a preliminary study directed to humans with ADH1, a research calcium-dissolving agent was demonstrated to dose-dependently stimulate PTH, associated with a short-lived inhibition of urinary calcium excretion, although the doses and time tested may be insufficient to demonstrate a clear change in serum calcium levels (Roberts et al, journal of bone and mineral research: american society of bone and mineral research, official journal, 2019).
Potential risk and benefit assessment
Taken together, both preclinical and available clinical data support the further clinical development of CLTX-305 as a potential therapy for ADH1 molecular deficiency. Current therapeutic criteria include oral calcium and active vitamin D supplements, which are complicated by increased susceptibility of CaSR to exogenous calcium, which results in excessive urinary calcium excretion with small increases in blood calcium. This increased urinary calcium excretion occurs because, due to changes in CaSR function in the parathyroid gland, the level of iPTH is suboptimal and, due to excessive stimulation of CaSR in the distal tubular, both lead to increased urinary calcium loss and are associated with chronic complications of renal function. CLTX305, as a calcium-dissolving agent, can inhibit CaSR to facilitate achieving and maintaining therapeutic goals of standardized blood calcium concentrations while also avoiding or minimizing hypercalcuria.
One challenge facing the clinical development of CLTX-305 is that the dose of CLTX-305 effective for ADH1 patients may be higher than the dose previously determined to increase blood calcium in extensive clinical experience in normal parathyroid subjects (postmenopausal women in previous osteoporosis projects). If no specially designed clinical trial is performed, the effective CLTX-305 dose for ADH1 patients cannot be determined. The currently proposed clinical trial is aimed at utilizing conventional early drug development methods, including single and multiple incremental doses, while utilizing previous safety exposure data to address important issues of dose response, acute safety and tolerability, and clear proof of concept as to how much CLTX-305 can normalize blood calcium in ADH1 subjects.
This study was aimed at minimizing the known potential risks (as described above) while maximizing the dose range studied to increase the likelihood of establishing CLTX-305 as a definitive proof of concept for the potential utility of the treatment of hypocalcemia in ADH1 patients.
Example 3: stage 2b, open label dose range study-target and endpoint
Table 8: target and endpoint
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Example 4:2b phase, open label dose range study-study design
4.1 general design
This is a single point, open label, dose-range study aimed at assessing the safety, tolerability and efficacy of CLTX-305 to maintain normal albumin corrected calcium (ca) in subjects with hypocalcemia due to ADH 1. The study consisted of 2 queues and 3 cycles as depicted in figure 2.
Two main queues are planned:
queue 1: a maximum of 8 subjects (a minimum of 5) were initially enrolled in cycle 1 (hospitalization) after which they could return to participating in cycle 2 (hospitalization, at least 8 weeks apart). Subjects who completed cycle 2 were eligible to enter cycle 3 (outpatient) for up to 24 weeks of CLTX-305 dosing.
Queue 2: a maximum of 8 additional subjects (a minimum of 5) entered cycle 2 (hospitalization) directly. The initiation of queue 2 will be based on an evaluation of the accumulated data from queue 1. Queue 2 subjects completing cycle 2 were eligible to enter outpatient cycle 3 (outpatient) for up to 24 weeks of CLTX-305.
Subjects in both cohorts completing cycle 2 were eligible to enter cycle 3. The dose of outpatient CLTX-305 will be determined from examination of individual dose response data for cycle 1 and/or cycle 2 based on determining well-tolerated BID doses with preliminary evidence of effectiveness. During the outpatient period (cycle 3), the subject will make the necessary additional personalized dose titration based on the safety data and the results of critical therapeutic measures.
Period 1 and period 2 of the study are detailed in fig. 3. Period 3 of the study is detailed in fig. 4.
Cycle 1: the hospitalization period, which includes 5 dosing days, during which the subject will receive a once-daily (QD) dose escalation of 3 days, followed by a twice-daily (BID) dose for 2 days at the individualized test dose of CLTX-305.
Cycle 2: during hospitalization of the inpatients, including 5 dosing days, the subject will receive BID doses of CLTX-305 based on individual responses from cycle 1 (for subjects who completed cycle 1) or review of pooled data from cycle 1 (for subjects who were not previously exposed to CLTX305, entered into cohort 2 of cycle 2). Initial dose, dose level 1 (DL 1) will be administered under ca monitoring for 2 days (48 hours). Participants will either titrate the encalaeret dose up or down depending on the ca level, the dose may be increased if ca remains below the lower normal limit, and the dose may be decreased if ca is greater than or equal to the upper normal limit. The final test day (day 5) will include frequent blood and urine sampling to collect 24-hour PK/PD curves after at least 3 consecutive days of dosing (at DL1 or DL 2).
Cycle 3: CLTX-305 was administered out-patient for up to 24 weeks. Subjects who completed cycle 2 will continue to self-administer CLTX-305 at the initial BID dose based on their tolerance and response to BID dosing during cycle 2. Initial titration will control symptoms and continuously monitor efficacy endpoints (mainly ca and urinary calcium excretion) based on the needs of each subject, with the aim of optimizing ca in the normal range while minimizing hypercalcemia. The subject will not take calcitriol, but if a minimum daily dietary intake of about 1000mg cannot be achieved and the subject suffers from persistent hypocalcemia, additional calcium supplements may be taken as needed. Titration of oral calcium supplements will be guided by the survey point during the clinic and can be titrated up or down depending on whether normal or low-normal ca is reached without the therapeutic goal of hypercalcemia. In cycle 3, the titration period will be extended to 12 weeks, after which each personalized dosage regimen will continue to be administered to maintain a stable dose, stable normal to low-normal ca, while avoiding hypercalcemia. The need for additional dose adjustments may depend on potential factors related to the time course of parathyroid function, intestinal calcium absorption, bone absorption and renal function changes, all of which will be monitored.
4.2 scientific principles of research design
Current clinical trials aim to test CLTX-305 in the dosage range of once and twice daily dosing to determine the ability of calcium dissolving agents to increase blood calcium in ADH1 patients.
Current studies aim to confirm the utility of the calcium-dissolving agent CLTX-305 in treating hypocalcemia due to ADH1 by allosteric antagonism of the mutant CaSR in these patients. The study was aimed at determining the lowest effective dose, steady state pharmacokinetic/pharmacodynamic (PK/PD) relationship and/or maximum tolerated dose in the target population of established ADH 1. Such data would be established during hospitalization periods 1 and 2, producing personalized doses, providing information for the initial dose of out-patient exposure during period 3. The initial outpatient administration can be further titrated with an oral calcium supplement in order to optimize blood calcium without calcitriol while minimizing urinary calcium excretion.
Due to the orphan nature of ADH1, and the rarity of the subjects participating in the clinical trial, sponsors believe that it is reasonable to extend the study to outpatient cycle 3 based on the expectation that cycles 1 and 2 of cohorts 1 and 2 will determine an individualized and reasonably average effective amount.
4.3 dose rationality
Current studies suggest that the first administration starts with 30mg of CLTX-305 in the new target population of ADH1 subjects. This dose has previously been demonstrated to be safe and well tolerated in non-ADH 1 subjects (i.e., humans not carrying variants that drive the pathogenic function of ADH 1) and is clearly associated with increased plasma iPTH and increased ca. It is expected that this may be an ineffective or least effective dose in ADH1, thus representing a logical starting dose based on dose escalation and dose discovery. Details regarding the PK/PD relationship of CLTX-305 in parathyroid subjects assuming normal CaSR function.
Using the single increment and multiple increment dose paradigm, the study will investigate the PK-PD relationship of CLTX-305 in ADH1 subjects. Since ADH1 is an orphan disease, few potential subjects are identified, and since good safety data was provided in previous development programs, we propose personalized dose escalation in a cohort of about 16 subjects. It is not predicted what average dose of CLTX-305 will lead to an increase in calcium in ADH1, but it is expected that the dose may need to be increased from 30mg to at least one log. The supervised hospitalization at cycles 1 and 2 will allow dosing according to safety and tolerability and closely monitor evidence of efficacy according to changes in the iphh and ca of each subject. Increasing the dosage of ca within 1-5 days, e.g., >1mg/dL, would establish clear proof of concept for CLTX-305 as a potential treatment for ADH 1. The dose associated with hypercalcemia will establish an upper limit or maximum tolerated dose.
Given that cycles 1 and 2 are designed to determine the individual effective doses and potentially the upper limit of CLTX-305, these results should help to select an initial outpatient dose, possibly a lower dose, and provide information for the initial method of outpatient dose adjustment and optimization during cycle 3.
Cycle 3 is intended to identify individualized chronic doses. Due to the time frame differences in PTH effects (relatively immediate limitation of calcium loss in urine, followed by an increase in endogenous 1,25- (OH) 2 The effect of vitamin D on GI absorption, and ultimately mobilizing bone calcium), chronic outpatient doses may be lower than those shown to be acutely effective. Dose response curves for iPTH stimulation and ca elevation of cycles 1 and 2 may also provide information for current updated PK-PD models based on non-ADH 1 subjects (Cabal et al, journal of bone and mineral research, 2013, 28 (8), pages 1830-1836). Taken together, the personalized subject data and the sustained cumulative data for all subjects should aid in rational out-patient dosing and titration.
Example 5: stage 2b, open label dose range study-study population
A. Inclusion criteria
The subjects met the following inclusion criteria during the screening process:
1) Being able to understand and sign written informed consent or agreements must be obtained before the study procedure begins;
2) Age is more than or equal to 16 years old;
3) Postmenopausal women were allowed to participate in the study:
a) Women are considered postmenopausal women to have no fertility if they have a natural (spontaneous) amenorrhea for at least 12 months before the study begins and have appropriate clinical characteristics (e.g., age-appropriate, history of vasomotor symptoms), or have undergone surgical bilateral ovariectomy (with or without hysterectomy), or tubal ligation. In the case of ovariectomy alone, women should be considered to be non-fertility only if their reproductive status is confirmed by a follow-up hormone level assessment.
4) Body Mass Index (BMI) of 18.5 to<39 kg/m 2 ；
5) Having an activating mutation of the CASR gene;
6) A subject receiving a thiazide diuretic therapy may be included in the study if he would like and be able to deactivate the thiazide drug for at least 5 half-lives before starting to use CLTX-305 and during the study treatment. When thiazines are used as antihypertensive agents, alternative therapies will be provided; and
7) Subjects receiving treatment with strong CYP3A4 inhibitors (including clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, dar Luo Nawei, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, telanavir) were refractory to at least 5 half-lives during screening before starting CLTX-305. Subjects who must continue to use strong CYP3A4 inhibitors may still be enrolled if they can take the drug at a stable dose throughout the course of the trial.
8) Subjects receiving magnesium or potassium citrate supplement treatment should begin discontinuing treatment from day 1 of cycle 1 and cycle 2 and may require discontinuing treatment at cycle 2.
B. Exclusion criteria
Subjects meeting any of the following criteria during the screening process were not eligible for study participation:
1) A history of PTH1-84 or 1-34 treatment within the first 3 months;
2) History of hypocalcemia onset in the past 3 months;
3) Blood 25-OH vitamin D level <25ng/mL;
a) If the subject had 25-OH vitamin D levels <25ng/mL in the blood at the time of screening, then cholecalciferol or ergocalciferol supplements would be taken. Once the 25-OH vitamin D level >25ng/mL, the subject will be eligible to continue into the treatment phase of the study.
4) Researchers believe that abnormal laboratory values may make subjects unsuitable for study participation;
5) Glomerular filtration rate (eGFR) estimated using CKD-EPI<25mL/min/1.73m 2 (for the case of<Subjects 18 years old will calculate Schwartz equation);
6) 12 leads resting Electrocardiogram (ECG) had clinically significant abnormalities;
7) Screening for a subject positive for serological detection of hepatitis b surface antigen (HbsAg), hepatitis c antibody, hepatitis a immunoglobulin M (IgM) or Human Immunodeficiency Virus (HIV) virus at visit;
8) Male hemoglobin (Hgb) <13g/dL, female <12g/dL;
9) Pregnant or lactating (lactating) women, wherein pregnancy is defined as the state of the female after conception until termination of pregnancy, confirmed by positive serum hCG laboratory tests;
10 Fertility women, defined as all women who are physiologically capable of pregnancy, unless they use a high-efficiency contraceptive method during the administration period and within 3 months after cessation of study treatment. The high-efficiency contraceptive method comprises the following steps:
complete abstinence (when this corresponds to the subject's preferred and usual lifestyle). Periodic abstinence (e.g., calendar, ovulation, co-thermogenesis, post-ovulation methods) and withdrawal are unacceptable contraceptive methods.
Female sterilization (surgical double sided ovariectomy with or without hysterectomy already performed) or tubal ligation at least six weeks prior to receiving study treatment. In the case of ovariectomy alone, the reproductive status of females is only confirmed by a follow-up hormone level assessment.
Male sterilization (at least 6 months prior to screening). For female subjects in the study, the vasectomy male partner should be the only partner for that subject.
A combination of (a+b or a+c, or b+c) of:
a) The use of oral, injectable or implantable hormonal contraceptive methods or other forms of hormonal contraception have considerable efficacy (failure rate < 1%), such as hormonal vaginal rings or transdermal hormonal contraception.
b) An intrauterine device (IUD) or an intrauterine device (IUS) is placed.
c) Barrier method for contraception: condoms or occlusive caps (diaphragms or cervix/domes) with spermicidal foams/gels/films/creams/pessaries.
11 Sexually active men, unless they use the condom for intercourse during CLTX-305 (study medication) and three months after the last study medication administration and during active participation in the study, do not give birth to children from the first CLTX-305 dose of cycle 1, cycle 2 (cohort 2) until cycle 3 ends. A vasectomy male must also use a condom to prevent study drug delivery by semen.
12 Allergy to any active substance or excipient of CLTX-305;
13 Screening for a history of drug or alcohol dependence within 12 months prior to visit;
14 History of thyroid or parathyroid surgery;
15 Currently engaged in other drug studies; and
16 One year from the start of the study group to the last dose of study medication, is reluctant to avoid donation within 12 weeks prior to screening visit.
C. Incorporation of a weaknesses participant
Subjects between 16 and 18 years of age may participate in this study. Older teenagers have the ability to provide sufficient consent in the fortified phase 2a study, the benefit of which is still uncertain. Older children are excluded because of the strong surgical procedures and uncertain clinical benefit.
Example 6:2b phase, open label dose range study-study intervention
6.1 study intervention management
During cycle 1, subjects from cohort 1 will take CLTX-305QD and BID with water as per the method, as described in example 7.
During cycle 2, subjects from cohorts 1 and 2 will take CLTX-305BID with water as described in example 7.
During cycle 3, subjects entering cohorts 1 and 2 of cycle 3 will be discharged home to continue taking CLTX-305BID with water, as described in example 7.
6.1.1 study intervention description
The study drug (IMP) CLTX-305 will be provided in the form of a white film coated tablet containing 10, 30 and 60mg dose strength of the active ingredient enceallet.
CLTX-305 would be provided in the form of bottled 10mg,30mg and 60mg tablets.
6.1.1 administration and administration
CLTX-305 administration in ADH1 subjects was determined based on previous experience of acute and chronic CLTX-305 administration in the osteoporosis program project, including exposure for up to 1 year mainly in postmenopausal women assuming normal CaSR function. The recommended initial dose in ADH1 is 30mg, as this dose has been shown to lead to acute elevation of ca in subjects with true parathyroid glands without ADH1 mutations. Based on the pilot human study data of the relevant calcium-dissolving agent NPSP795 (Roberts et al, bone and mineral research: journal of the american society of bone and mineral research, 2019), which also studied the highest dose known to lead to calcium elevation in normal parathyroid subjects, but not in ADH1 subjects, we expected that the 30mg initial dose might be ineffective or inefficient, but represented a reasonable initial dose that has proven safe and previously well tolerated.
Because of the comprehensive safety databases present in previous osteoporosis development projects, including safety exposure for 12 months or longer, the current first ADH1 study will include repeated dosing, dose escalation and dose individualization of individual ADH1 participants over time. Similar to crossover design, dose escalation in subjects should reduce variability and improve accuracy of dose/response modeling compared to methods that may use separate parallel or sequential cohorts. Up to 16 subjects should be viable and can characterize the average dose-exposure-response curves of individuals and groups as well as the proof of concept of ca elevation. Our method is preferred because the super-orphan nature of the disease makes conventional parallel group dose discovery infeasible.
CLTX-305 will be tested in once daily doses and twice daily doses. In the previous osteoporosis program project, CLTX-305 was administered once daily, which was believed to stimulate a transient increase in the secretion of the ips levels (spike) within 2 hours, and a second low plateau level of ips (still elevated compared to baseline) at doses of 30mg and above for up to 12 hours. Although PK (drug exposure) and PD (elevated levels of iPTH) lasted less than 24 hours, evidence of some increase in valley ca (measured 24 hours after the last administration) suggests that once-daily dosing and once-daily dose escalation should be tested in ADH1 subjects.
CLTX-305 (enceateret) may be administered within 30 minutes before a meal. In the previous phase 1 trial, dietary administration was associated with adequate systemic absorption, rapid increases in the plasma level of iPTH, but PTHC compared to fasted max Slightly lower (see the manual of the researchers for detailed information and results regarding phase I trials). The recommendation of administration within 30 minutes before meals was chosen as an example of ADH1 administration because, unlike the osteoporosis program, ADH1 patients were not targeted to maximize PTH Cmax, but to promote full day iPTH levels above baseline, sufficient to raise blood cCa levels to the normal range. However, it is expected that twice daily dosing may result in lower iPTH levels C over the course of 24 hours than once daily dosing max And more stable iPTH levels. This protocol was intended to test this hypothesis by performing a once-and twice-daily dose escalation in cycle 1 and a twice-daily dose escalation in cycle 2.
An overview and general description of the intervention (CLTX-305 administration) study strategy is presented below. Additional details regarding the dose, protocol and titration algorithm/instructions for each cycle can be found in example 7 and figures 5 and 6.
Cycle 1 (single increment dose escalation and BID PK/PD profile) -cohort 1
In cycle 1, eligible cohort 1 subjects were enrolled into NIH CC after completion of the screening test. On days 1-3 of admission, cohort 1 subjects will receive a single daily administration of CLTX-305 and a regimen prescribed dose escalation from an initial dose of 30mg on day 1 to a maximum dose of 180mg on day 3. Based on the personalized response to the QD dose escalation, the personalized dose of CLTX-305 will be selected for BID dosing on days 4 and 5.
Day 1, 2 and 3 (QD dose escalation): up to 8 subjects (at least 5) will receive a single dose, dose escalating treatment 3 days prior to period 1 admission. Morning doses will be administered on days 1, 2 and 3, respectively, with frequent blood and urine sampling for PK/PD measurements over 24 hours. CLTX-305 will be administered within 30 minutes before breakfast. If the dose escalation is limited due to tolerance or hypercalcemia, the researcher may negotiate with the sponsor to choose to discontinue the pre-specified dose escalation. In this case, the researcher may negotiate with the sponsor to choose to repeat the last well-tolerated dose on days 2 and 3, or titrate as appropriate.
Dose escalation will continue on days 1, 2 and 3 without temporary flushing, as the previously extensive PKPD data supports minimal drug accumulation within 24 hours of once-a-day dosing (see manual of researchers for details). Similarly, when CLTX-305 is administered once a day, it is expected that the level of iPTH does not remain elevated for 24 hours after administration. However, any carryover effects that may occur should not confuse the goal of demonstrating an acutely effective dose of CLTX-305. For any given subject, a ca value >10.5mg/dL during the dosing interval will indicate that the subject has reached the highest dose of CLTX-305, and no further dose escalation will be required. In this case, the investigator, after negotiating with the sponsor, may choose to repeat the last well-tolerated dose on the remaining QD test days (e.g., day 2 and day 3) as appropriate. A detailed example of the dose and titration modification based on the ca response is shown in fig. 5.
Day 4 and day 5 (BID dose escalation): based on the individual PD response of each subject to QD dose escalation, a personalized dose of CLTX-305 will be selected for BID dosing on days 4 and 5 d. CLTX-305 will be once a day in the morning and once a night within 30 minutes before breakfast and dinner. The dose selected should be based on the response of each subject to ca and/or PTH levels during the previous QD dosing period (days 1-3). A BID dosing guidance algorithm based on individual response to QD dosing in cycle 1 is presented in fig. 5.
Cycle 2 (BID dose) -queues 1 and 2
In cycle 2, qualified cohort 1 subjects who have completed cycle 1 may return NIH to cycle 2 after at least 8 weeks. After all cohort 1 subjects completed cycle 1 and analyzed the data, the sponsor would open the registration of cohort 2 subjects. Eligible cohort 2 subjects may enter cycle 2 directly after completion of the screening and consent process according to the protocol. In cycle 2, all subjects will begin CLTX-305BID dosing within 30 minutes before breakfast and dinner on days 1 and 2. The ca concentration will often be monitored throughout cycle 2 and the CLTX-305 dose up-or down-regulated as needed to achieve the target of normal ca concentration. The 24 hour PK/PD curve for CLTX-305 will be evaluated on day 5. A coaching algorithm for initiating and titrating BID dosing during cycle 2 is presented in fig. 6.
Period 3 (queue 1 and queue 2) -outpatient administration
In cycle 3, as described in more detail in example 7, the initial outpatient dose of CLTX-305 will be personalized based on the results from hospitalization cycles 1 and/or 2. Period 3 will include a titration period of about 12 weeks and a maintenance period of about 12 weeks, with the total exposure time of the outpatient to CLTX-305 being about 24 weeks. Titration will be performed by researchers of NIH in planned or unplanned telephone contact visits, based on assessment of blood and urine calcium results, with clinical chemistry results of ca, mg, phosphorus being reviewed in NIH CC visits (approximately every 8 weeks) with the aim of optimizing CLTX-305 doses without calcitriol, targeting normal ca and phosphorus concentrations, avoiding symptoms of hypocalcemia or hypercalcemia, and minimizing the extent of hypercalcemia. Oral calcium supplements may be used on a daily basis with a minimum dietary intake of at least 1000mg as desired.
Dose limiting toxicity
The goal of current studies in ADH1 subjects is to increase ca concentration, including determining doses that are capable of bringing ca out of the normal range. It is important to determine whether allosteric modulators of CaSR are capable of causing hypercalcemia in patients with CaSR activating mutations. The study was aimed at monitoring the increase in ca in a closely monitored and expert setting familiar with acute treatments and interventions when necessary. In previous osteoporosis projects, hypercalcemia determined by laboratory testing was confirmed as dose limiting in putative thyroid normal subjects without CASR mutations, but it is notable that laboratory hypercalcemia was not significantly associated with hypercalcemia symptoms; these events were detected in routine laboratory monitoring and managed by either suppressing or lowering CLTX-305 dose.
Another inherent study objective is to evaluate the safety and tolerability of different doses and regimens, including characterizing dose-limiting adverse events, determining the maximum dose associated with acceptable safety risks, and determining the dose that can be effective to increase or maintain stable normal ca concentrations.
According to previous experience of osteoporosis programs accumulated in human clinical tests, no specific safety signal or adverse event of acute or chronic CLTX-305 administration was found. In a healthy postmenopausal population of women receiving up to 12 months of treatment, dose limiting hypercalcemia is the only signal required to limit chronic doses to 15mg once a day. Since there is no particularly expected adverse event profile or expected dose limiting toxicity in humans, safety monitoring of CLTX-305 will be based on established methods and principles. Based on adverse event monitoring, protocols of security laboratories, vital signs, physical examination and EKGs specify that safety measures are to be evaluated during hospitalization periods 1 and 2. For any individual subject, the experience of adverse events will be assessed and recorded according to the guidelines given in example 7, and appropriate measures will be taken for study drug administration according to the discretion and assessment of the investigator.
It is expected that ADH1 subjects will require higher doses of CLTX-305 to see comparable changes in ca than previously tested normally functioning CaSR subjects, and thus current protocols prescribe potential dose increases above 100mg, including acute doses that may be >400mg, to determine effective doses in new CaSR dysfunctional target populations where increased ca represents efficacy, rather than safety side effects.
The recommended initial dose for ADH1 subjects was 30mg, which was well tolerated in healthy normal volunteers without specific safety signs, but was also rapidly effective in increasing cCa. This dose is expected to be ineffective or inefficient in increasing ca in ADH1 subjects. Thus, based on the safety and efficacy of the known ca, 30mg CLTX-305 represents a reasonable initial dose for this first ADH1 test. Furthermore, CLTX-305 was acutely safe and well tolerated in the range of 5-100mg (approximately 10-fold range) in non-ADH 1 subjects. Initial phase 1, a single incremental dose trial in healthy persons assuming normal CaSR function was designed to be escalated to 400mg CLTX-305; however, based on increasing ca concentration, the highest dose of 100mg was determined. It was assumed that the highest dose in CaSR-functioning persons was chosen to be 100mg to avoid excessive ca elevation and was safely used as the highest dose in phase I full QTc studies.
Notably, while ADH1 patients may exhibit a right-shift dose response compared to healthy non-ADH 1 people, no biological theory is expected to be significantly steeper in the dose response profile of ADH1 patients. It is therefore important to plan the appropriate dose increase in this first ADH1 trial to demonstrate the calcium enhancement. The range of planned doses explored by QDs in ADH1 subjects included the range of 30 to 180mg (approximately 6-fold range). If a higher dose is required to confirm efficacy for ca, dose escalation will continue, but shift to the BID regimen specified in more detail in the algorithm/guidelines in example 7.
In previous osteoporosis programs, hypercalcemia adverse events were asymptomatic and determined from periodic laboratory evaluations. The dose limiting threshold for the ca level after CLTX-305 administration was designated as part of the dosing and titration algorithm in example 7. In summary, subjects who reached ca >10-10.5mg/dL (in cycle 1) and ca >10mg/dL (in cycle 2) after dosing will not go to higher CLTX-305 doses during dose escalation in cycle 1 or 2. During the dose escalation of cycle 1, the dose of subjects with ca values between 10-10.5mg/dL was increased by only 30mg. Subjects reaching ca >10-10.5mg/dL in cycle 1 and >10mg/dL in cycle 2 will maintain or reduce their dose, with final frequent sampling as appropriate.
Dose modification
For general principles based on dosing and titration limitations for toxicity or hypercalcemia, see above. For detailed information on the dose guidance algorithm for each cycle, please see example 7.
Dose adjustment dose modification should be based on the ca threshold >10-10.5mg/dL in cycles 1 and 2 according to the guidelines/algorithm prescribed by the protocol described in example 7. Likewise, titration for outpatient cycle 3 will be based primarily on periodic assessment of ca, and ca >10mg/dL also requires dose modification. In cycle 3, the dose modification may include a decrease in CLTX-305 and/or a change in oral calcium supplementation regimen.
Drug management
During periods 1 and 2 of hospitalization for NIH CC stay, on the day of once-a-day CLTX-305 administration, the subject will receive a dose in the morning that can be taken with about 8 ounces of water 30 minutes before breakfast. On the day of twice-a-day CLTX-305 administration, the subject would receive one dose in the morning, a second dose in the evening, and may take about 8 ounces of water within 30 minutes before breakfast and dinner.
During cycle 3, the researcher/prescribing personnel would instruct the subject to take one dose of CLTX-305 in the morning and the second dose in the evening. It is recommended, but not required, to take the dose within 30 minutes of breakfast and dinner.
6.2 preparation/processing/storage/liability
Acquisition and accountability
The on-site research pharmacist or commissioner will keep an accurate record of CLTX-305 received by the sponsor, including the date and quantity received. In addition, an accurate medication treatment record will be maintained that specifies the amount of medication to be administered to each subject, the date of the dispense, and the number of any returns. The manifest record must be available for review at any time, and a copy of the record will be provided to the sponsor at the end of the study. After the study is completed, the on-site study pharmacist or commission will provide the sponsor with a complete CLTX-305 liability record.
Formulation, appearance, packaging and label
CLTX-305 will be provided in the form of white film coated tablets containing 10, 30 and 60mg doses of the active ingredient enceateret.
The tablets contained the following excipients: mannitol, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, sucrose fatty acid ester, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol and titanium oxide.
Product storage and stability
The sponsor will provide the drug supply to the research center. CLTX-305 would be stored at controlled room temperature between 20 ℃ and 25 ℃ allowing for offset between 15 ℃ and 30 ℃ in bottles provided by sponsors.
In cycle 1 and cycle 2, all subjects received only CLTX-305 assigned and managed by NIH CC survey field personnel. After the final CLTX-305 accountability is completed, all unused CLTX-305 must be returned to the sponsor or destroyed in the field under the sponsor's approval. If unused CLTX-305 is not returned to the sponsor, the sponsor must be provided with proof of destruction.
In cycle 3, CLTX-305 will be administered to the subject to allow for outpatient BID self-administration at an individualized starting dose between NIH CC visits to allow for dose up-titration by the investigator as appropriate. If desired, other CLTX-305 (encaleret) may be mailed to the subject according to standard NIH CC pharmacy procedures. The subject will return unused CLTX-305 on each assigned NIH CC visit, which will be checked for accountability and compliance estimation. The subject must return unused CLTX-305 to the NIHCC at the next visit. CLTX-305 accountability will be performed by NIH pharmacists or delegates. After the final CLTX-305 accountability is completed, any unused CLTX-305 must be returned to the sponsor or destroyed in the field under the approval of the sponsor and following NIH procedures. If unused CLTX-305 is not returned to the sponsor, the sponsor must be provided with proof of destruction.
6.3 measures to minimize the bias: randomization and blind method
Is not applicable. This is an open label study.
6.4 study of intervention compliance
For hospitalization periods 1 and 2, cltx-305 would be managed and recorded by the field staff. The time of CLTX-305 administration will be recorded in the appropriate generic report format. A researcher or prescribing person will schedule oral study medication at the site of investigation to ensure compliance with the study medication. In outpatient cycle 3, the subject will self-manage CLTX-305 and should be given instructions in terms of dose, dose time and meal time. For CLTX-305 management, please refer to the following sections: "drug administration". During each study visit and phone contact, the field staff will review and record compliance (e.g., record missed doses), and review and record any dose changes.
6.5 concomitant therapy
At the time of screening, the NIH investigator will specifically ask each subject for all concomitant drug use and record the drug, dose and time of use in the appropriate CRF. Typically, on-site staff will monitor, record and manage all concomitant medications during hospitalization at the time of admission and throughout the course of the study.
All subjects will be instructed to stop taking calcitriol on day 1, the day of admission, but continue with the oral calcium supplementation regimen. Throughout the treatment period, the subject will obtain at least 1,000mg of total daily calcium from the diet and supplements.
A subject receiving a thiazide diuretic may be enrolled in the study if he would like to and be able to discontinue the thiazide for 5 half-lives before starting CLTX-305 and during the study treatment. When thiazines are used as antihypertensive agents, alternative therapies will be provided.
Subjects receiving treatment with strong CYP3A4 inhibitors (including clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, dar Luo Nawei, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, telanavir) should have at least 5 half-lives during screening before starting CLTX-305 and during study treatment if clinically appropriate. Otherwise, subjects receiving strong CYP3A4 inhibitor treatment should remain at a steady dose throughout the trial.
Example 7:2b phase, open label dose range study-study evaluation
7.1 treatment period
7.1.1 cycle 1 (single increment dose escalation and BID PK/PD Profile) -cohort 1
For subjects with screening access >21 days prior to starting study drug, an outpatient laboratory test will be performed 10-14 days prior to admission to conduct a blood and urine chemistry test for examination by NIH researchers.
All subjects will be instructed to stop taking calcitriol on day 1, the day of admission, but continue the oral calcium supplementation regimen until admission.
First day (admission): eligible subjects in cohort 1 will enter NIH CC one day prior to administration of cycle 1.
Day 1, 2 and 3 (QD dose escalation): up to 8 subjects (at least 5) will receive single dose, ascending dose treatment 3 days prior to admission. Morning doses of 30, 90 and 180mg will be administered on days 1, 2 and 3, respectively, with frequent blood and urine sampling for 24 hours to make PK/PD measurements (detailed information and time points on PK/PD analysis, as in tables 4A-4C, table 5, and table 6A-6℃ Cltx-305 will be administered with water within 30 minutes before breakfast if dose increase is limited due to tolerance or hypercalcemia, the investigator may choose to repeat the last well-tolerated dose on days 2 and 3 after negotiating with the sponsor, or to make down-titration as needed (for dose guidance algorithms, see below).
Day 4 and day 5 (BID dose escalation): based on the individual PD response of each subject to QD dose escalation, a personalized dose of CLTX-305 will be selected for BID dosing on days 4 and 5. CLTX-305 will be once a day in the morning and once a night within 30 minutes before breakfast and dinner. The dose selected should be based on the response of each subject to ca and/or PTH levels during the previous QD dosing period (days 1-3). The researcher, after negotiating with the sponsor, may choose 90 or 180mg BID (total daily dose of 180 and 360mg, respectively), but will make decisions based on the following criteria for each subject;
the lowest dose that results in an increase of cCa of 1mg/dL during the dosing interval, or the lowest dose that maintains cCa within the normal range without exceeding the upper limit of the reference range during the dosing interval
And/or:
peak iPTH 150-300pg/mL and/or
iPTH level is continuously increased by ≡50pg/ml (ideally up to 12 hours)
If a single QD dose for a given subject does not meet the criteria described above, the researcher should select the highest well-tolerated QD dose and start the dose from day 4 morning and recommend dosing once in the morning and at night within 30 minutes before the meal.
During BID dosing on days 4 and 5, ca and isth will be monitored and PK/PD blood and urine samples are often taken. The time points and the details of the measurements for the day 5 PK/PD samples are specified in tables 6A-6C. The total blood volume collected during cycle 1 for each subject will be about 524mL. If the subject's body weight is low (adult <50kg or adolescent <55 kg), the blood collection will decrease to stay within the range of 10.5mL/kg/8w (adult) and 9.5mL/kg/8w (pediatric) of the NIH guidelines. The last dose of study medication will be performed at night on day 5.
Fig. 5 shows a schematic representation of dose modification based on the above guidance.
Day 6 (discharge): after collection of PK/PD blood samples in the morning on day 6, all subjects will resume their previous conventional treatment regimen. On day 6, the ca levels will be monitored throughout the day. This time can be extended if additional monitoring or treatment (e.g., stabilized calcium) is required prior to discharge.
Outpatient tests performed on days 7-8 of cycle 1 (expected to be about 24-48 hours after discharge from the NIH clinical center) are preferably collected at NIHCC. If not, subject's contact information will be provided to sponsor signed medical service facility where the subject allowsSamples were collected at home at the time agreed to by both parties. The collected blood sample will be evaluated for CLTX-305 concentration and blood calcium, magnesium, phosphate, 1,25- (OH) 2 Vitamin D and PTH. This would allow us to evaluate both calcium homeostasis and to obtain the final PK sample when the concentration of CLTX-305 was diluted after cycle 1. Samples assuming a half-life of CLTX-305 in steady state of about 10-14 hours, the PK samples will represent the time point between 40-70 hours after the last dose of CLTX-305 (administered at night on day 5). Telephone contact will be made for review with survey site personnel on days 9-11 or once there is a calcium result.
To characterize the pre-study blood calcium status and changes associated with experimental intervention, this protocol will rely on frequent measurement of albumin corrected blood calcium concentrations. The tests will be conducted according to the specifications of the national institutes of health clinical center laboratory (Besseda, malyland). The main indicator of whether the blood calcium level is normal or not will be based on correction of serum or plasma albumin, the formula of which is: corrected calcium (ca) =total measured calcium (mg/dL) +0.8 (4-albumin (g/dL)) or total measured calcium (mmol/L) +0.2 (4-albumin (g/dL)), it is recognized that total calcium reported in SI units (mmol/L) can be converted to conventional units (mg/dL) by multiplying by 4. Given that albumin levels in the subjects of the group are expected to be normal and stable, the measurement of total calcium and ca may be similar throughout the course of the study. Ionized calcium assays will also be provided at the NIH clinical center survey site and can be measured in the event of severe hypocalcemia or in the event of any doubt about the accuracy of the ca measurement. The collection of the ionized calcium is determined by expert researchers on a case-by-case basis according to clinical conditions.
7.1.2 cycle 2 (BID dose) -queues 1 and 2
For cohort 1, subjects will receive an outpatient laboratory blood and urine chemistry test 10-14 days prior to entry into NIH CC. For cohort 2 subjects who were screened for access more than 21 days prior to the start of study drug, blood and urine chemistry checks will be performed 10-14 days prior to admission. The results will be reviewed by NIH researchers.
All subjects will be instructed to stop taking calcitriol on day 1, the day of admission, but continue with the oral calcium supplementation regimen.
First day (admission): eligible subjects will enter the NIH clinical center one day prior to dosing.
Cohort 1-subjects in cohort 1 who completed cycle 1 will be scheduled to return to cycle 2 (to restore blood volume and hematocrit levels) after at least 8 to 12 weeks. BID doses will be personalized based on each subject's previous response to CLTX-305 during cycle 1.
The first 7 subjects completing cycle 2CLTX-305-201 and entering cycle 3 had a broad CLTX-305 dose requirement from 10mg to 180mg BID once a day, indicating that CLTX-305 (encaleret) dosing was highly individualized. As a result, all remaining subjects in cycle 2 will receive an initial CLTX-305 90mg BID dose of at least 3-4 doses to assess safety, tolerability and ability to modulate ca levels. The CLTX-305 dose will be up-or down-regulated as needed to keep the ca level below 10mg/dL and blood phosphorus level above the normal lower limit. The dose will be adjusted in 10, 30 or 60mg increments depending on the available CLTX-305 (encalelet) tablet strength. On day 5, frequent sampling test days will be performed, with additional continuous blood and urine sampling to assess 24-hour PK/PD profile.
If DL1 is insufficient to raise or maintain cCa within normal reference ranges within 48 hours, the dose will be increased to dose level 2 (DL 2) BID on days 3, 4 and 5, including frequent sampling test day (day 5), and additional continuous blood and urine sampling is performed to assess the 24-hour PK/PD profile. 6A-Table 6C specifies details of PK/PD time points during the 5 th day frequent sampling period. The total blood volume collected during cycle 2 for each subject will be about 458mL. If the subject's body weight is low (adult <43kg or adolescent <48 kg), the blood collection will decrease to stay within the range of 10.5mL/kg/8w (adult) and 9.5mL/kg/8w (pediatric) of the NIH guidelines. If at any time the CLTX-305 dose is associated with hypercalcemia (ca >10 mg/dL), the dose should be reduced to a lower dose level.
Dose titration embodiments based on these simple rules are shown in fig. 6:
queue 2-queue 2 will begin after queue 1 completes cycle 1 and has reviewed PD dose responses. The subject will receive an initial CLTX-305 90mg BID dose of at least 3-4 doses to assess safety, tolerability and ability to modulate ca levels. The CLTX-305 (encealeret) dose will be titrated up or down as needed to keep the ca level below 10mg/dL and the blood phosphorus level above the normal lower limit. The dose will be adjusted in 10, 30 or 60mg increments depending on the available CLTX-305 (encalelet) tablet strength.
The subject will take the final dose of study medication at night on day 5. After the final continuous PK/PD blood sampling in the morning of day 6, all subjects completing cycle 2 were eligible to participate in cycle 3, receiving the same BID dose (or lower) of CLTX-305 in the outpatient setting. Subjects entering cycle 3 will be discharged from the NIH clinical center at doses determined by the investigator to be effective and tolerated by everyone during cycle 2.
If the subject does not participate in cycle 3, the subject will resume his previous conventional outpatient treatment regimen on day 6 prior to discharge.
To characterize the pre-study blood calcium status and changes associated with experimental intervention, this protocol will rely on frequent measurement of albumin corrected blood calcium concentrations. The tests will be conducted according to the specifications of the national institutes of health clinical center laboratory (Besseda, malyland). The main indicator of whether the blood calcium level is normal or not will be based on correction of serum or plasma albumin, the formula of which is: corrected calcium (ca) =total measured calcium (mg/dL) +0.8 (4-albumin (g/dL)) or total measured calcium (mmol/L) +0.2 (4-albumin (g/dL)), it is recognized that total calcium reported in SI units (mmol/L) can be converted to conventional units (mg/dL) by multiplying by 4. Given that albumin levels in the subjects of the group are expected to be normal and stable, the measurement of total calcium and ca may be similar throughout the course of the study. Ionized calcium assays will also be provided at the NIH clinical center survey site and can be measured in the event of severe hypocalcemia or in the event of any doubt about the accuracy of the ca measurement. The collection of the ionized calcium is determined by expert researchers on a case-by-case basis according to clinical conditions.
7.1.3 cycle 3 (queue 1 and queue 2) -out-patient administration
Cycle 3 will include a titration period of about 12 weeks and a maintenance period of about 12 weeks, with the total exposure time of the outpatient to CLTX-305 being about 24 weeks. In cycle 3, the initial outpatient dose of cltx-305 will be based on the results of hospitalization cycles 1 and 2. The outpatient titration will be performed by NIH researchers with the aim of optimizing CLTX-305 doses without calcitriol, targeting normal ca and phosphorus concentrations, while minimizing the need for calcium supplements, avoiding symptoms of hypocalcemia or hypercalcemia, and minimizing the extent of hypercalcemia. If blood cCa level >10.5mg/dL, NIH researchers can consider maintaining the CLTX-305 (encaleet) dose and restarting at a lower CLTX-305 (encaleet) dose after blood cCa drops to <10 mg/dL. Oral calcium supplements may be used as desired above a minimum initial intake of at least 1000mg per day.
Study visits included NIH hospitalization every 8 weeks for PK/PD assessments, safety assessments, and recording AEs and concomitant medications. During titration and maintenance, subjects will be contacted by telephone according to the regimen to review the results of the out-patient laboratory blood and urine evaluations, confirm the sufficiency of the current study medication regimen (including supplements), query for hypo/hypercalcemia symptoms, and evaluate AE. The total blood volume collected by each subject over 24 weeks during cycle 3 was about 540mL.
7.1.4 follow-up and early termination
Subjects will receive follow-up 30±7 days after the last study drug administration to assess AE.
If the subject stops participating in the study or terminates the study prematurely, the same procedure as in example 1 should be followed: 1.2 all Early Termination (ET) security assessments listed in the activity schedule.
When subjects stop or exit taking study medication, they will revert to the previous outpatient oral calcium and active vitamin D regimen to address their potential ADH1 problem and maintain ca blood levels upon return to the previous clinical care provider. The subjects will be instructed to receive an outpatient laboratory blood calcium test within 1-3 days after discontinuing study medication and send these results to the NIH investigator for review. The researcher should be in communication with the subject to review the calcium blood results and suggest optimizing their clinic clinical management.
7.2 evaluation of efficacy
7.2.1 pharmacokinetic and pharmacodynamic blood sampling
All PK blood samples were analyzed by CRO signed by the sponsor. All PD blood samples will be managed by the NIH laboratory. Details of sample handling and treatment are provided in the study procedure manual. The acquisition times of these samples are detailed in example 1: 1.2.
The key efficacy assessment is the concentration of ca over time.
For a list of PK/PD and security analytes in blood and urine, see 7.4.3.
7.2.2 timing intervals and 24 hour urine
The acquisition times of these samples are detailed in tables 1, 2, 3, 4A-4C and 6A-6C of example 1.
7.2.3 samples for genetic/genomic analysis
For subjects in CASR who have no previously recorded activating mutations or affected first-order relatives (relevant literature collected and archived in the subject's study folder), diagnosis of ADH1 will be confirmed by genetic testing at screening.
If the subject's CASR mutation is not confirmed at the time of screening, a blood sample will be collected for somatic analysis of the CASR gene.
If pathogenic variations in CASR are not identified, additional tests of other inherited forms of parathyroid dysfunction may be provided to the subject.
No additional gene detection is required as part of the protocol.
7.3 Security and other assessment
Physical examination
At the times detailed in the activity schedule of example 1, the subject will receive a complete Physical Examination (PE) that will be completed by a physician or properly trained health professional. Any abnormal physical examination findings that are considered clinically significant (i.e., associated with symptoms and/or requiring medical intervention) will be recorded as AEs.
Vital signs
Vital signs will be assessed according to the times and details specified in the activity schedules of table 1, table 2 and table 3 of example 1. Any abnormal vital sign that is considered clinically significant (i.e., associated with symptoms and/or requiring medical intervention) will be recorded as an AE.
Clinical laboratory assay
Blood and urine samples for clinical laboratory testing will be collected at the times detailed in the activity schedule of example 1. At the time of screening, samples will be collected at the NIH clinical center. Other tests during screening can be performed at an outpatient laboratory in the vicinity of the subject. All laboratory checks (PD and safety) of treatment cycles 1 and 2 will be measured at the NIH clinical center.
Outpatient tests performed on days 7-8 of cycle 1 (expected to be about 24-48 hours after discharge from the NIH clinical center) are preferably collected at NIH CC. If this is not possible, the subject's contact information will be provided to the sponsor's contracted healthcare facility, where the subject allows, to schedule the sample collection at home at the time of the two parties ' consent. The collected blood sample will be evaluated for CLTX-305 concentration and blood calcium, magnesium, phosphate, 1,25- (OH) 2 Vitamin D and PTH. This would allow us to evaluate both calcium homeostasis and to obtain final PK parameters when CLTX-305 concentration was diluted after cycle 1. Assuming a half-life of CLTX-305 in steady state of about 10-14 hours, the PK samples would represent the time point between 40-70 hours after the last dose of CLTX-305 (administered at night on day 5). Will be on days 9-11 or will be contacted by telephone for review with the survey site personnel once there is a calcium result.
Laboratory tests for outpatient cycle 3 will include outpatient laboratory blood sampling tests for calcium and calcium-related analytes, including safety laboratory tests.
Researchers will evaluate the clinical significance of values outside of the laboratory provided reference range.
The samples will be collected, processed and stored according to the instructions provided in the laboratory manual.
A researcher or qualified assistant researcher will review the clinical significance of all laboratory results. Any laboratory result deemed clinically significant (i.e., associated with signs and symptoms and/or requiring medical intervention) will be recorded as AE.
Electrocardiogram
The standard 12-lead ECG will be evaluated at the times specified in the activity schedule of example 1. After 5 minutes of rest, the electrocardiogram will be performed in the supine position. The researcher or qualified assistant researcher will review all of the clinical significance of the ECG interpretation and interval time measurement. Any ECG interpretation deemed clinically significant (i.e., associated with symptoms and/or requiring medical intervention) will be reported as AE.
Dual energy x-ray absorption (DXA))
According to the activity program of example 1, bone densitometry of the spine, hip, distal radius and whole body was performed by DXA during weeks 24 of cycle 1 and 2, cycle 3.
The study involved radiation exposure at screening visit and one DXA scan performed at week 24 of cycle 3. Such radiation exposure is not necessary for healthcare and is used only for research purposes. The participants in this study will receive far less radiation than the dose guidelines established by the NIH radiation safety committee for pediatric (less than 500mrem per year) or adult (less than 5000mrem per year) study subjects. The participants obtained an effective dose of less than 2 millirem from participation in this study. The protocol has been approved by the radiation safety committee.
7.4 adverse events and serious adverse events
All adverse events were reported according to the study protocol.
7.4.1 events of particular interest
ADH1 hypocalcemia
The primary goal of CLTX-305 treatment of ADH1 subjects was to increase serum calcium levels. Hypocalcemia is not an expected side effect of CLTX-305 treatment, but it is a complication of the underlying disease being treated. Thus, hypocalcemia may develop when underlying disease treatment is inadequate and may occur due to under-dosing or missing of a particular effective drug.
Current research involves reducing the dose of current maintenance drugs or suspending use altogether (i.e., oral calcium supplements and calcitriol) to facilitate dose discovery of CLTX-305 and possibly establish clinical proof of concept. In these cases, there is a risk that the subject may experience symptoms of hypocalcemia before an effective dose of CLTX-305 is reached. To mitigate this risk, research designs first emphasize safety. All changes in oral maintenance medications and CLTX-305 dosing will be performed in the first two phases with participants residing in the clinical center, measuring blood calcium multiple times per day, and closely monitored by a health professional with personal experience in caring for ADH 1. In addition to these precautions, monitoring and capture of events suggestive or consistent with hypocalcemia will be examined as AE of particular concern, as described below.
Evaluation of blood calcium concentration
To characterize the pre-study blood calcium status and changes associated with experimental intervention, this protocol will rely on frequent measurement of albumin corrected blood calcium concentrations. The tests will be conducted according to the specifications of the national institutes of health clinical center laboratory (Besseda, malyland). The main indicator of whether the blood calcium level is normal or not will be based on correction of serum or plasma albumin, the formula of which is: corrected calcium (ca) =total measured calcium (mg/dL) +0.8 (4-albumin (g/dL)) or total measured calcium (mmol/L) +0.2 (4-albumin (g/dL)), it is recognized that total calcium reported in SI units (mmol/L) can be converted to conventional units (mg/dL) by multiplying by 4. Given that albumin levels in the subjects of the group are expected to be normal and stable, the measurement of total calcium and ca may be similar throughout the course of the study. Ionized calcium assays will also be provided at the NIH clinical center survey site and can be measured in the event of severe hypocalcemia or in the event of any doubt about the accuracy of the ca measurement. The collection of the ionized calcium is determined by expert researchers on a case-by-case basis according to clinical conditions.
HypocalcemiaIs an adverse event of (a): symptomatic and asymptomatic
Adverse events consistent with hypocalcemia will be classified as symptomatic or asymptomatic and their severity assessed, with a range of clinical manifestations being recognized. Symptomatic hypocalcemia will be based on identifying symptoms consistent with hypocalcemia, such as hand, foot or lip numbness/tingling, muscle cramps/twitches, other weakness or dizziness and/or new or worsening anxiety, including anger or depression and neurocognitive signs of confusion/hallucinations, with laboratory evidence of ca decline. When blood calcium levels are checked to confirm calcium status, relevant symptoms will be recorded. The Case Report Forms (CRFs) of symptomatic hypercalcemia as AE of particular interest will capture detailed information for each hypercalcemia event including, but not limited to, symptoms, concomitant ca concentrations, contributors, treatments, solutions and measures related to study drug.
Based on a threshold defining ca <7mg/dL, asymptomatic hypocalcemia will also be captured as an AE of particular interest. Since ca levels are often sampled throughout hospitalization, asymptomatic low ca outcomes will be determined during routine ca monitoring.
Clinical evaluation and treatment of hypocalcemia
The severity of symptoms of hypocalcemia ranges from asymptomatic to life threatening. Appropriate treatments and actions with respect to study drugs and/or other interventions (e.g., emergency calcium supplementation) will be based primarily on clinical assessment of severity and acuity. Cases of hypocalcemia (if any) in this trial are expected to be controlled by supportive care.
Different patients may have different sensitivities to low calcium levels, but one advantage of performing this initial safety and proof of concept trial at NIH is that expert researchers have a wealth of experience in managing these patients and specific historical knowledge about the clinical process and management of many members of the prospective cohort to be studied. Researchers conducting this study have accumulated and institutional experience in caring for these patients for decades, including management of underlying disease-induced hypercalcemia. This includes managing outpatient oral calcium and calcitriol regimens based on outpatient laboratory monitoring and symptom assessment to ensure patient function, health and quality of life experience.
Suitable assessments may include continuous ca measurements, initial and follow-up EKG as appropriate based on clinical assessments (e.g., bradycardia) and/or whether ca <7 mg/dL.
At the discretion of the NIH investigator's expert, the step intervention would include standard measures such as oral calcium and/or calcitriol supplements for mild-moderate events (see below). In cases where hypocalcemia is not resolved or exacerbated, and there are more acute clinical manifestations including worsening of neurocognitive deficits, seizures, hand and foot twitches, hypotension or cardiac dysfunction, appropriate emergency interventions will be made on site according to the standard of care, including intravenous calcium gluconate, as described below.
Adding oral calcium supplement and/or calcitriol
Since all subjects were orally administered at least 1000mg of elemental calcium per day throughout the trial period, additional supplemental oral calcium supplements in the range of 1,000-2,000mg could be administered as needed, with close follow-up to ca. The short-term requirement of a calcium supplement and/or 1-2 doses of calcitriol (the doses being based on the previously known sensitivity of each subject and the dose of the outpatient calcitriol, if known, e.g. possibly in the range of 0.5-2 mcg) results in stable calcium levels without interfering with the on-schedule dose increase, especially if required on days 1 and 2 before an effective dose of CLTX-305 has been reached. At the discretion of the investigator, more severe or long-term hypocalcemia without response to oral supplements may require premature termination of the study period. If calcium levels are unstable and evidence of clinically significant hypocalcemia suggests that further dosing is not possible during the study, CLTX-305 dosing is discontinued and the subject can resume the previous outpatient calcium and calcitriol regimen and discharge after stabilization and follow-up closely. These subjects may be eligible to return to a repeat study period or a next study period following the protocol, as determined by the researcher and sponsor.
Venous calcium supplement
In the case of severe hypocalcemia, the NIH clinical center has facilities for advanced supportive treatment including venous replacement, oxygen supplementation, continuous ECG monitoring and bedside ionized calcium monitoring (if needed). Intravenous calcium may be administered according to clinical instructions.
Example 8: stage 2b, open label dose range study-statistical considerations
All analysis details will be provided in the formal Statistical Analysis Program (SAP).
Statistical hypothesis
All data will be analyzed descriptive and no hypothesis testing will be performed.
Sample size determination
The sample size of up to 8 subjects in cycle 1 (cohort 1) and up to 8 other subjects in cycle 2 (cohort 2) are consistent with conventional first human single and multiple incremental studies (SAD and MAD) that typically recruit 8-10 subjects per dose group, with the incremental based on safety and tolerability.
The sample size of the current study is not based on statistical tests on formal power assumptions. Proposed clinical trials represent the re-use of CLTX-305, with extensive exposure and safety data from previous osteoporosis programs, for improved single and multiple escalation dose studies in new ADH1 patient target populations. However, the different experimental calcium-dissolving agents recently published NPSP795 (Reberts et al, 2019) reported preliminary evidence of a dose response to iPTH in ADH1 subjects, with a sample size of 5 persons. The authors speculate that, although known test doses may significantly increase the iPTH in non-ADH 1 subjects, a greater dose is required to stimulate PTH in ADH1 subjects to adequately observe the increase in ca. The current protocol aims to explore a broad range of potential doses of safety and tolerability, however, if an effective dose is reached, the proposed sample size of about 16 subjects may be sufficient to confirm a clear proof of concept of the iPTH and/or ca.
Human for analysisGroup of
Safety crowd: all subjects receiving at least one dose of study drug
PK population: all subjects who received at least one dose of study drug and had enough PK samples to be able to calculate PK parameters for CLTX-305.
PD population: all subjects had PD data.
Statistical analysis
All analysis details will be provided in the formal Statistical Analysis Program (SAP).
Demographics and other baseline characteristics
Demographic and other baseline characteristics will be summarized by treatment.
Security analysis
Where appropriate, the safety and tolerability parameters will be summarized using descriptive statistics. All security data will be provided in the data list.
AE will be encoded using the med dra dictionary. The incidence of AE (TEAE) per treatment burst will be summarized in terms of system organ category, preferred terminology and treatment assignment. Multiple AEs for the same preferred term will be calculated once in each subject. Concomitant medication will be encoded using the WHO medication dictionary with generic terms and Analytical Treatment Chemistry (ATC) codes and summarized under ATC codes, WHO medication generic names and treatment methods. The reasons for terminating treatment prematurely will be summarized and listed illustratively in terms of treatment allocation and access. The safety laboratory examination results, vital signs and 12-lead ECG will be summarized and listed descriptively according to treatment assignments and visits. The values at the predetermined time points and the change in the baseline will be summarized. Laboratory data will be listed and values and baseline changes at each visit will be summarized. Additional checklists will be provided for the treatment of emergency laboratory abnormalities.
AE (classified under preferred terms) occurring during treatment will be considered TEAE if not present before the first dose CLTX-305 or if present before the first dose CLTX-305 but of increased severity during treatment. If more than 1 AE were reported before the first dose CLTX-305 and coded as the same preferred term, the AE with the greatest severity would be used as a benchmark against the AE that is also coded as the preferred term and occurs during that period. AE occurring more than 30±7 days after the last dose of CLTX-305 will not be counted as TEAE.
Pharmacokinetic analysis
PK parameters will be calculated for each subject and summarized as treatment. Only subjects with enough data to calculate each PK parameter will be included in the summary of each PK endpoint.
Pharmacodynamic analysis
PD parameters will be calculated for each subject and summarized in terms of treatment method. Only subjects with enough data to calculate each PD parameter will be included in the analysis.
Metaphase analysis
Due to the open label study design and the quantitative laboratory analytes used to derive PK and PD endpoints, both sponsors and NIH researchers will be able to conduct joint periodic data reviews continuously throughout the study.
Before cycle 2 begins, single and multi-dose (QD and BID) responses to cycle 1 will be reviewed for safety, tolerability, and impact on iPTH and ca.
Example 9: study period 1/results of queue 1
Six adults with ADH1 due to four different activation variants of CASR were studied in a continuous, three-cycle, 2 b-phase, open-label, dose-range study of the calcium-dissolving agent encalelet (CLTX-305) according to the protocol of examples 1-8. The study of cycle 1 cohort 1 is summarized in fig. 2. The calcium, magnesium and calcitriol supplements were discontinued at the beginning of cycle 1, subjects received daily doses of increased encalelet (30 mg,90mg,180 mg) for 3 consecutive days, then 120mg or 180mg twice daily on days 4 and 5, with frequent blood and urine sampling.
Subject characteristics: subject' sThe baseline characteristics are summarized in table 9.
Table 9: baseline characteristics of the subject
ECG QTcB = electrocardiogram Bazett (Bazett) corrected Q-T interval;
* Measurements (mean ± standard deviation) taken on day 1 prior to dosing; and
CASR variant (n): C131Y (2), P221L (2), A840V (1), E604K (1).
Pharmacodynamics, pharmacokinetics, efficacy, safety and tolerability
Six subjects received the following doses of CLTX-305: day 1: 30mg (QD); day 2: 90mg (QD); day 3: 180mg (QD); day 4: 180mg (BID); and day 5: 180mg (BID), except that one subject received a second dose of 120mg on day 5.
Average baseline PTH was 3.4+ -4.5 pg/mL (average+ -SD; nl 10-65); during the administration of encaleret, PTH increased rapidly and dose-dependently with an average level of 64.8.+ -. 49.6pg/mL 24 hours by day five. Albumin corrected blood calcium (ca) increased from baseline 7.6±0.6mg/dL (nl 8.4-10.2) to a 24 hour average of 9.0±0.5mg/dL on day 5. Phosphorus was reduced from baseline 4.5.+ -. 0.7mg/dL (nl 2.3-4.7) to a 24 hour average of 2.9.+ -. 0.5mg/dL on day 5. Magnesium increased from baseline 1.6.+ -. 0.4mg/dL (nl 1.6-2.6) to a 24 hour average of 2.0.+ -. 0.5mg/dL on day 5. On days 4 and 5, the ADH1 subjects remained largely within normal ranges for blood calcium, phosphorus and magnesium. When subjects were routinely treated, 24 hours urinary calcium was elevated at screening visit (436±255 mg/day, nl < 250-300) and decreased to 63±127 mg/day on day 5 with increasing encalaeret dose. During the administration of enceallet, urinary calcium excretion became normal in 3 subjects, while 3 subjects were undetectable. As shown in table 10, encaaert was well tolerated and no serious adverse events were reported.
Table 10: adverse Event (AE) summary, n (%)
Subjects suffering from serious adverse events 0(0％
Subjects with adverse events 5(83％)
Mild and mild 5(83％
Medium and medium 0(0％)
Severe severity of 0(0％)
Number of adverse events 9
Mild and mild 9(100％)
Medium and medium 0(0％)
Severe severity of 0(0％)
As shown in fig. 7A-7D, mineral steady state was normalized [ mean ± SD ] during period 1 of the study. FIG. 7A shows blood calcium levels (mg/dL); FIG. 7B shows the complete PTH level (pg/mL); FIG. 7C shows phosphorus levels (mg/dL); FIG. 7D shows the urinary calcium level (mg/24 hours) for 24 hours.
As shown in fig. 8, the pharmacokinetic profile of CLTX-305 indicated a proportional increase in plasma exposure dose [ mean ± SD ] during study period 1.
Blood mineral levels and averages of individual subjects after 5 days of CLTX-305 are shown in fig. 9A-9D. FIG. 9A shows blood calcium levels (mg/dL); FIG. 9B shows the complete PTH level (pg/mL); FIG. 9C shows blood phosphorus levels (mg/dL); fig. 9D shows 24 hours urinary calcium levels (mg/day). (The representation shows the value on day 4, whereas the value on day 5 is not available. * Values below the quantitative limit of measurement are plotted as "0". )
Conclusion(s): enceaeret (CLTX-305) is well tolerated when orally administered once or twice daily for 5 days, with no serious adverse events reported. Consistent changes in blood and urine mineral measurements from baseline provided preliminary proof of concept data, CLTX-305 may be an effective treatment for ADH 1. By day 5, blood calcium, PTH and phosphate have generally recovered to normal and remained within normal ranges. Urinary calcium excretion was normal or undetectable in all subjects with CLTX-305 and hypercalcemia.
Example 10: study period 2/results of queue 2
Another 7 subjects with ADH1 were studied as described in the previous examples. Table 11 summarizes the baseline characteristics of these subjects.
Table 11: baseline characteristics of the subject
ECG QTcB = electrocardiogram Bazett (Bazett) corrected Q-T interval;
* Measurements taken on day 1 (mean ± SD) prior to administration of cycle 1 or cycle 2; and
CASR variant (n): C131Y (2), P221L (2), E604K (1), A840V (3), F788C (1), T151M (1), Q245R (1), I692F (1), E228K (1).
Fig. 10A and 10B show a summary of dosing for study periods 1 and 2. As shown in fig. 10B, cycle 2 is characterized by personalized dose titration.
As shown in table 12, encaleret was well tolerated in cycle 2, with no serious adverse events reported.
Table 12: adverse Event (AE) summary, n (%)
Blood mineral levels after CLTX-305,5 days of administration in cycle 2 are consistent with those shown in fig. 9A-9D.
Conclusion: among 13 participants, the average blood calcium and 24-hour urinary calcium excretion after cycle 1 and cycle 2 correction by enceaerts were normalized. During periods 1 and 2, average PTH increased and phosphate decreased to the normal range. The personalized BID dose of cycle 2 resulted in a reduction in the average dose on day 5 compared to cycle 1. Enceaeret was well tolerated with no serious adverse event reports when administered once or twice daily over 5 days. Continued improvement in mineral homeostasis suggests that encaaert may be an effective treatment for ADH 1. In this 2b phase study, the outpatient assessment of Encealeet was still in progress.
Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be understood by those skilled in the art that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. The present application should predominate if there is conflict between the instant application and the references provided herein.

Claims (56)

1. A method of treating autosomal dominant hereditary hypocalcemia type 1 (ADH 1), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by formula (I):
or a solvate, hydrate, pharmaceutically acceptable salt, or combination thereof, wherein the therapeutically effective amount of the compound, or the solvate, hydrate, pharmaceutically acceptable salt, or combination thereof, increases blood calcium concentration (ca) to a range of about 7.5 milligrams per deciliter (mg/dL) to about 10.5 mg/dL.
2. The method of claim 1, wherein the compound is in the form of a hemihydrate hemisulfate salt, such as CLTX-305 of formula (Ia):
3. The method of claim 1 or 2, wherein the subject has hypocalcemia, hypoparathyroidism, hypercalcuria, hyperphosphatemia, and/or hypomagnesemia.
4. The method of any one of claims 1 to 3, wherein the subject has an activating mutation in a calcium sensitive receptor (CASR) gene.
5. The method of any one of claims 1 to 4, wherein the level of 25-hydroxy-vitamin D in the blood of the subject is at least about 25 nanograms per milliliter (ng/mL).
6. The method of any one of claims 1 to 5, wherein the subject is not treated with calcitriol.
7. The method of any one of claims 1 to 6, wherein the subject receives at least about 1000mg daily calcium intake from a diet and/or supplement.
8. The method of any one of claims 1 to 7, wherein the therapeutically effective amount is a daily total dose of CLTX-305 from about 10mg to about 1800mg, from about 10mg to about 1200mg, from about 10mg to about 900mg, from about 10mg to about 600mg, or from about 10mg to about 360 mg.
9. The method of claim 8, wherein the therapeutically effective amount is a total daily dose of CLTX-305 of about 10mg, 20mg, 30mg, 40mg, 60mg, 80mg, 120mg, 140mg, 180mg, 300mg, 360mg, 480mg, or 720 mg.
10. The method of any one of claims 1 to 9, wherein the compound of formula (I) or CLTX-305 is administered orally.
11. The method of any one of claims 1 to 10, wherein the compound of formula (I) or CLTX-305 is administered once, twice, three times or four times per day.
12. The method of claim 11, wherein the compound of formula (I) or CLTX-305 is administered twice daily.
13. The method of any one of claims 1 to 12, wherein the therapeutically effective amount of the compound of formula (I) or CLTX-305 increases blood calcium concentration (ca) by at least about lmg/dL within the dosing interval.
14. The method of any one of claims 1 to 13, wherein the therapeutically effective amount of the compound of formula (I) or CLTX-305 increases the intact parathyroid hormone (iPTH) in the blood to a peak level of from about 150 picograms per milliliter (pg/mL) to about 300 pg/mL.
15. The method of any one of claims 1 to 14, wherein the therapeutically effective amount of the compound of formula (I) or CLTX-305 increases the intact parathyroid hormone (iPTH) in the blood to elevated levels of at least about 50 pg/mL.
16. The method of claim 15, wherein the iPTH is maintained at an elevated level of at least about 50pg/mL for 1-12 hours.
17. The method of claim 16, wherein the iPTH is maintained at an elevated level of at least about 50pg/mL for about 12 hours.
18. The method of any one of claims 1 to 17, wherein the pH of magnesium (Mg), phosphate (P), sodium (Na), potassium (K), creatinine (Cr), cAMP, and/or citrate and/or urine in the urine of the subject is further assessed.
19. The method of any one of claims 1 to 18, wherein the therapeutically effective amount of the compound of formula (I) or CLTX-305 maintains a blood calcium concentration (ca) in the range of about 7.5mg/dL to about 10.5mg/dL for a period of at least 12 weeks without substantially adjusting the total daily dose.
20. The method of any one of claims 1 to 19, further comprising administering an oral calcium supplement in addition to daily calcium intake.
21. A method of treating autosomal dominant hereditary hypocalcemia type 1 (ADH 1), the method comprising administering to a subject in need thereof a compound represented by formula (I):
or a solvate, hydrate, pharmaceutically acceptable salt, or combination thereof, according to one or more dosing schedules including a first dosing schedule, a second dosing schedule, and/or a third dosing schedule,
Wherein:
1) The first dosing regimen comprises administering a first therapeutically effective amount of the compound or the solvate, hydrate, pharmaceutically acceptable salt, or combination thereof, wherein the first therapeutically effective amount increases blood calcium concentration (ca) to a maximum ca of about 10.5 milligrams per deciliter (mg/dL);
2) The second dosing regimen comprises administering a second therapeutically effective amount of the compound or the solvate, hydrate, pharmaceutically acceptable salt, or combination thereof, wherein the second therapeutically effective amount titrates the blood calcium concentration (ca) to a range of about 7.5mg/dL to about 10.5 mg/dL; and
3) The third dosing regimen comprises administering a third therapeutically effective amount of the compound or the solvate, hydrate, pharmaceutically acceptable salt, or combination thereof, wherein the third therapeutically effective amount maintains blood calcium concentration (ca) in the range of about 7.5mg/dL to about 10.5mg/dL for at least 12 weeks.
22. The method of claim 21, wherein the compound of formula (I) is in the form of a hemihydrate hemisulfate salt, CLTX-305, represented by the formula:
23. the method of claim 21 or 22, wherein the compound of formula (I) or CLTX-305 is administered orally.
24. The method of any one of claims 21 to 23, wherein the subject has hypocalcemia, hypoparathyroidism, hypercalcuria, hyperphosphatemia and/or hypomagnesemia.
25. The method of any one of claims 21 to 24, wherein the subject has an activating mutation in a calcium sensitive receptor (CASR) gene.
26. The method of any one of claims 21 to 25, wherein the level of 25-hydroxy-vitamin D in the blood of the subject is at least about 25 nanograms per milliliter (ng/mL).
27. The method of any one of claims 21 to 26, wherein the patient is not treated with calcitriol.
28. The method of any one of claims 21 to 27, wherein the patient receives at least about 1000mg daily calcium intake from a diet or supplement.
29. The method of any one of claims 21 to 28, wherein the first dosing regimen comprises a daily total dose of CLTX-305 of at least about 10mg, 20mg, 30mg, 40mg, 60mg, 80mg, 90mg, 120mg, 140mg, 180mg, 300mg or 360 mg.
30. The method of claim 29, wherein the first dosing regimen comprises an initial daily total dose of about 30mg CLTX-305.
31. The method of any one of claims 21 to 30, wherein the first dosing regimen comprises administration of CLTX-305 at a daily dosing frequency of 1 to 4 times per day.
32. The method of claim 31, wherein the first dosing regimen comprises administration of CLTX-305 once daily for the first three days and then twice daily for two days.
33. The method of any one of claims 21 to 32, wherein the first dosing regimen comprises:
a1 Increasing the total daily dose when the blood calcium concentration (ca) is less than a maximum ca of about 10.5 mg/dL;
b1 Reducing the total daily dose when the blood calcium concentration (ca) reaches said maximum ca; and/or
c1 When the blood calcium concentration (ca) reaches the maximum ca, the daily dosing frequency is increased while maintaining the daily total dose.
34. The method of claim 33, wherein the blood calcium concentration (ca) is measured after each of one or more once daily doses and one or more twice daily doses.
35. The method of claim 34, wherein the total daily dose is increased from about 30mg to about 60mg, from about 30mg to about 90mg, from about 10mg to about 20mg, from about 20mg to about 40mg, from about 60mg to about 90mg, from about 60mg to about 120mg, from about 90mg to about 180mg, or from about 180mg to about 360mg CLTX-305.
36. The method of claim 34, wherein the total daily dose is reduced from about 30mg to about 10mg, from about 40mg to about 20mg, from about 60mg to about 30mg, from about 90mg to about 60mg, from about 90mg to about 30mg, from about 120mg to about 90mg, from about 120mg to about 60mg, from about 180mg to about 120mg, from about 180mg to about 90mg, from about 180mg to about 60mg, or from about 360mg to about 180mg CLTX-305.
37. The method of claim 34, wherein the daily dosing frequency is increased from once daily to twice daily while maintaining a total daily dose of CLTX-305 of about 30mg, 60mg, 90mg or 180mg.
38. The method of any one of claims 21 to 37, wherein the first dosing regimen further comprises:
i) Selecting a minimum dose from one or more once-a-day doses and administering said minimum dose twice a day, provided that the one or more once-a-day doses meet a criterion selected from the group consisting of:
i-1) blood calcium concentration (ca) increases by at least about 1mg/dL during the dosing interval;
i-2) blood calcium concentration (cCa) is maintained in the range of about 7.5 to about 10.5 mg/dL;
i-3) increasing the intact parathyroid hormone (iPTH) in the blood to a peak level of from about 150pg/mL to about 300 pg/mL; and
i-4) an increase in intact parathyroid hormone (iPTH) in the blood to an elevated level of at least about 50pg/mL, and for about 12 hours,
or alternatively
ii) selecting the highest dose among the one or more once-a-day doses, and administering the highest dose twice a day, provided that the one or more once-a-day doses do not meet any of the criteria i-1) to i-4; and the highest dose is tolerable in the subject.
39. The method of any one of claims 21 to 38, wherein the second dosing regimen comprises a daily total dose of CLTX-305 of at least about 10mg, 20mg, 40mg, 60mg, 80mg, 120mg, 140mg, 180mg, 300mg, 360mg, 480mg, or 720 mg.
40. The method of claim 39, wherein the second dosing regimen comprises an initial daily total dose of CLTX-305 of about 10mg, 20mg, 30mg, 60mg, 80mg, 90mg, 120mg, 140mg, 180mg, 300mg, 360mg, 480mg, or 720 mg.
41. The method of any one of claims 21 to 40, wherein the second dosing regimen comprises administering CLTX-305 at a daily dosing frequency of 2 to 4 times per day.
42. The method of claim 41, wherein the second dosing regimen comprises administering CLTX-305 twice daily for 5 days.
43. The method of any one of claims 21 to 42, wherein the second dosing regimen comprises:
a2 Maintaining the daily total dose while blood calcium concentration (ca) is maintained in the range of about 7.5mg/dL to about 10.5 mg/dL;
b2 Increasing the total daily dose when the blood calcium concentration (ca) is less than about 7.5 mg/dL; and/or
c2 When the blood calcium concentration (ca) is greater than about 10.5mg/dL, the daily total dose is reduced.
44. The method of claim 43, wherein the blood calcium concentration (ca) is measured after the first dosing regimen or after the initial two days of the second dosing regimen.
45. The method of claim 44, wherein the total daily dose is increased from about 20mg to about 40mg, from about 40mg to about 60mg, from about 60mg to about 120mg, from about 120mg to about 180mg, from about 180mg to about 360mg, from about 360mg to about 480mg, or from about 480mg to about 720mg of CLTX-305.
46. The method of claim 44, wherein the total daily dose is reduced from about 40mg to about 20mg, from about 60mg to about 40mg, from about 120mg to about 60mg, from about 180mg to about 120mg, from about 360mg to about 180mg, or from about 480mg to about 360mg of CLTX-305.
47. The method of any one of claims 21 to 46, wherein the third dosing regimen comprises a daily total dose of CLTX-305 of at least about 10mg, 20mg, 40mg, 60mg, 80mg, 120mg, 140mg, 180mg, 300mg, 360mg, 480mg, or 720 mg.
48. The method of claim 47, wherein the third dosing regimen comprises an initial daily total dose of CLTX-305 of approximately 10mg, 20mg, 40mg, 60mg, 80mg, 120mg, 140mg, 180mg, 300mg, 360mg, 480mg or 720 mg.
49. The method of any one of claims 21 to 48, wherein the third dosing regimen comprises administration of CLTX-305 at a daily dosing frequency of 2 to 4 times per day.
50. The method of claim 49, wherein the third dosing regimen comprises administering CLTX-305 twice daily for at least 24 weeks.
51. The method of any one of claims 21 to 50, wherein the third dosing regimen comprises titrating the daily total dose while maintaining the blood calcium concentration (ca) in the range of about 7.5mg/dL to about 10.5 mg/dL.
52. The method of claim 51, wherein the third dosing regimen comprises:
a3 Maintaining the daily total dose when the blood calcium concentration (ca) is in the range of about 7.5mg/dL to about 10.5 mg/dL;
b3 Increasing the total daily dose when the blood calcium concentration (ca) is below about 7.5 mg/dL; and/or
c3 When the blood calcium concentration (ca) is greater than about 10.5mg/dL, the daily total dose is reduced.
53. The method of any one of claims 21, 47-52, wherein the third dosing regimen reduces symptoms associated with hypocalcemia and hypercalcemia and minimizes hypercalcuria in the subject.
54. The method of any one of claims 21, 47-53, wherein the third dosing regimen maintains the blood calcium concentration (ca) in the range of about 7.5mg/dL to about 10.5mg/dL for at least 24 weeks.
55. The method of any one of claims 21, 47-53, wherein the third dosing regimen further comprises administering an oral calcium supplement in addition to daily calcium intake.
56. The method of any one of claims 21 to 55, wherein the subject is assessed by one or more tests comprising blood analysis, urine analysis and/or hematology tests.
CN202180077283.8A 2020-09-18 2021-09-16 Triphenylcalcilytic compounds for the treatment of autosomal dominant hereditary hypocalcemia type 1 (ADH 1) Pending CN116916907A (en)

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