Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/10—Antioedematous agents; Diuretics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the invention relates to a bradykinin (BK) B2-receptor antagonist having structural fomula (I) for use in prophylactic treatment of angioedema (AE) or in a method of treating AE, wherein said compound is at least once orally administered in a therapeutically effective dose to prevent, alleviate or treat AE symptoms.
• BK bradykinin
• This invention also provides a method of prophylactic treatment of a human patient suffering from AE or a method for on-demand treatment of a human patient who has experienced an acute AE attack, comprising orally administering to the human patient a therapeutically effective dose of at least 0.1 mg of the compound of formula (I) at least once to thereby alleviate or treat AE symptoms of the patient.
• Angioedema is an area of swelling of the lower layer of skin and tissue just under the skin or mucous membranes.
• the debilitating and often painful swelling may occur in the face, lips, tongue, limbs, genitals, gastrointestinal mucosa, urogenital region and airways.
• hives which are swelling within the upper skin. It is characterized by repetitive episodes of swelling, and onset is typically over minutes to hours. Predicting where and when the next episode of angioedema will occur is impossible. Patients may have one episode per month, but there are also patients who have weekly episodes or only one or two episodes per year.
• AE hereditary angioedema
• AAE acquired angioedema
• bradykinin- mediated non-histaminergic idiopathic angioedema idiopathic angioedema
• allergic angioedema idiopathic angioedema
• drug induced angioedema idiopathic angioedema
• HAE is a rare and potentially life-threatening genetic condition.
• HAE is an autosomal dominant disease, meaning that a defect in only one copy of the gene leads to symptoms and that it occurs at similar rates in both males and females. It is mainly caused by one or more mutations (inherited or spontaneous) in the SERPING 1 gene, which codes for the Cl -esterase inhibitor protein Cl -INH. Deficiency or malfunction of Cl -INH leads to uncontrolled synthesis and activity of plasma kallikrein and unconstrained BK production. Excessive BK production is recognized to be the key mediator of symptoms in patients with HAE and manifests as edema attacks, most commonly in the limbs, face, throat, lips, tongue, intestinal tract, urogenital region and airways.
• HAE patients with a deficiency in Cl -INH activity are classified as Type 1 or Type 2.
• Type 1 is the most common form and results in low levels of circulating Cl -INH
• Type 2 results in production of a low function protein.
• An additional form of HAE, called normal Cl -INH HAE can occur in patients with normal levels of Cl -INH for a variety of reasons including mutations in genes for Factor XII, plasminogen, angiopoietin-1 or kininogen-1.
• bradykinin-induced acute attacks of angioedema can occur idiopathically in individuals for which a hereditary cause has not yet been identified.
• Excessive amounts of BK can also be caused by increased circulation of estrogens, reduced Cl - INH levels due to underlying diseases, reduced elimination of BK, or through use of medications such as angiotensin-converting enzyme (ACE) inhibitors and tissue plasminogen activator (tPA).
• ACE angiotensin-converting enzyme
• tPA tissue plasminogen activator
• Cl -INH replacement products such as human plasma-derived Cl -INH concentrates (Berinert®, Cinryze®), which must be stored at 2°C to 25°C (36°F to 77°F), Cetor® or recombinant human Cl -INH (Ruconest®), the B2 receptor antagonist icatibant (Firazyr®), and the plasma kallikrein inhibitor ecallantide (Kalbitor®), which has been known to cause allergic reactions including anaphylaxis and must be administered by a doctor or nurse in a healthcare setting.
• Cl -INH replacement products such as human plasma-derived Cl -INH concentrates (Berinert®, Cinryze®), which must be stored at 2°C to 25°C (36°F to 77°F), Cetor® or recombinant human Cl -INH (Ruconest®), the B2 receptor antagonist icatibant (Firazyr®), and the plasma kallikrein inhibitor ecallantide (K
• Icatibant which must be administered by subcutaneous injection by a healthcare professional, is the only available B2 receptor antagonist indicated for treatment of acute HAE attacks Type 1 or Type 2 with Cl -INH deficiency.
• icatibant has been shown to provide a significantly faster onset of relief than placebo (2.0 h versus 19.8 h) (Lumry et al., Ann Allergy Asthma Immunol. (107), 529-537, 2011).
• Icatibant is recommended as a first-line treatment option for the treatment of acute HAE attacks in patients with HAE (Maurer et al., Allergy. (00), 1-22, 2018; DOI: 10.1111/all.13384).
• the currently approved prophylactic therapies for HAE include the Cl -INH replacement products such as intravenously administered Cinryze®; subcutaneously administered Haegarda®//Berinert® 2000/3000, which requires twice weekly injections; and the monoclonal antibody and plasma kallikrein inhibitor lanadelumab-flyo (sc Takhzyro®).
• Current treatment guidelines recommend against the use of the traditional oral medications for HAE, such as antifibrinolytics (tranexamic acid or epsilon aminocaproic acid), due to their limited efficacy (Stoppa-Lyonnet et al., N Engl J Med (317), 1-6, 1987; DOI: 10.1056/NEJM198707023170101).
• Attenuated androgens e.g. danazol, stanozolol, and oxandrolone
• danazol e.g. danazol
• stanozolol e.g. stanozolol
• oxandrolone e.g. danazol, stanozolol, and oxandrolone
• the use of attenuated androgens is limited by numerous safety issues, including seborrhea, altered libido, depression, fatigue, menstrual abnormalities, and masculinization.
• the present invention was made in view of the prior art and the needs described above, and, therefore, the present invention provides a compound having the structural formula (I) for use in prophylactic treatment of angioedema (AE) or in a method of treating AE, wherein said compound is at least once orally administered in a therapeutically effective dose to prevent, treat or alleviate AE symptoms.
• the present invention further provides the compound of formula (I) for use in the prophylactic treatment of angioedema (AE) or in a method of treating AE as mentioned above, wherein said use further comprises administering at least one additional therapeutic agent such as a CYP34A inhibitor.
• This invention also provides a method of prophylactic treatment of a human patient suffering from AE or a method for on-demand treatment of a human patient who has experienced an acute AE attack, comprising orally administering to the human patient in need thereof at least once a therapeutically effective dose of the compound of formula (I) to thereby prevent, alleviate or treat AE symptoms of the patient.
• This method of prophylactic or on-demand treatment may further comprise administering to the patient at least one additional therapeutic agent such as a CYP34A inhibitor.
• FIG. 1 Plasma levels of the compound of formula (I) observed in healthy volunteers under fasted conditions after oral administration of a single dose of from 1 to 22 mg of the compound. Graphs display mean including standard deviation bars.
• FIG. 1 Plasma levels of the compound of formula (I) observed in healthy volunteers under fasted condition and after a high caloric/high fat breakfast after oral administration of a single dose of 22 mg of the compound. Graphs display mean including standard deviation bars.
• Figure 3. Schematic Design of Bradykinin Challenge Study.
• Figure 4 Visualized pharmacokinetic profile of a single orally administered 12 mg dose of compound of formula (I) as determined in PK model.
• Figure 5 Visualized pharmacokinetic profile of a single orally administered 22 mg dose of compound of formula (I) as determined in PK model.
• Figure 7 A. Linear mean plasma concentration-time profiles of the compound of formula (I) (including standard deviation bars) after administration of a single 12 mg oral dose of the compound of formula (I) in the absence (Day 1) or presence (Day 7) of itraconazole* in healthy adult subjects.
• the present invention provides a compound having the structural formula (I): for use in prophylactic treatment of angioedema (AE) or in a method of treating AE, wherein said compound is at least once orally administered in a therapeutically effective dose to prevent, alleviate or treat AE symptoms.
• the present inventions also provides methods using the compound of formula (I) in the prophylactic or on-demand treatment of AE.
• the AE is a bradykinin- mediated angioedema.
• a dose can be administered as a single dose or in a plurality of doses.
• the term "patient” or “subject” encompasses mammals.
• a patient as used herein is a mammal that has at least one symptom of a condition described herein (e.g. angioedema (AE)).
• AE angioedema
• the mammal is a human.
• treatment encompasses both disease-modifying treatment and symptomatic treatment, either of which may be prophylactic (i.e., before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms) or therapeutic (i.e., after the onset of symptoms, in order to alleviate, abate or reduce the severity and/or duration of at least one of the symptoms and/or prevent additional symptoms).
• Therapeutic treatment can, for example, be “acute treatment” or “on-demand treatment", where it is imperative to immediately halt the progression of the edema and alleviate the symptoms. This applies particularly to AE symptoms or episodes (acute AE attack(s)) affecting the larynx, which can cause death by suffocation if left untreated.
• terapéuticaally effective amount or dose means an amount of the compound of formula (I) that produces a result that in and of itself helps to heal, cure, alleviate, abate or reduce the severity and/or duration of at least one symptom associated with AE.
• prophylactic uses i.e. "prohylaxis”
• the compound of formula (I) is administered to a subject or patient susceptible to or otherwise at risk of a particular condition. Such an amount is defined to be a “prophylactically effective amount or dose.”
• Prophylactic treatments include administering to a patient who previously experienced at least one symptom of AE and is currently in remission, the compound of formula (I) in order to prevent a return of symptoms of AE.
• short-term prophylactic treatment or “short-term prohylaxis” refers to administration of the compound of formula (I) for a period of time before, and optionally after, exposure to trigger(s) that are likely to cause AE symptoms or AE attack(s), such as event(s) or procedure(s) including, but not limited to, anxiety, stress, minor trauma, surgery, medical or dental procedures and illnesses.
• trigger(s) that are likely to cause AE symptoms or AE attack(s) including, but not limited to, anxiety, stress, minor trauma, surgery, medical or dental procedures and illnesses.
• short-term prohylaxis includes the administration of at least one dose of the compound of formula (I) at least 30 minutes, at least 1 hour, at least 2 hours or at least 1 day prior to exposure to a trigger.
• one or more additional doses may be administered after exposure to the trigger.
• An option for short-term prophylaxis is to administer at least one dose of the compound of formula (I) for at least five days prior to exposure to a trigger, and to administer at least one further dose of the compound of formula (I) at least one, at least two days, at least three days or at last four days after exposure to the trigger.
• the compound of formula (I) is administered chronically, that is, for an extended period of time, including throughout the duration of the life of the patient or subject in order to ameliorate or otherwise control or limit symptoms associated with AE in a the patient or subject.
• the dose of drug being administered may be temporarily reduced or the interval between doses is extended or temporarily suspended for a certain length of time (i.e., a "drug holiday").
• a drug holiday can be between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 30 days or more than 30 days, a month, 2 months, 3 months, or 6 months.
• the dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
• unit dosage refers to physically discrete units suited as single administration dose for a subject to be treated, containing a therapeutically effective quantity of active compound in association with the required pharmaceutical carrier, e.g., a solution in a vial.
• the unit dosage can optionally comprise at least one, i.e. one or more, carrier substance, excipient and/or adjuvant.
• HAE hereditary angioedema
• AAE acquired angioe
• the compound, or a pharmaceutically acceptable salt, or solvate thereof for use according to any one of [4] to [10], wherein the compound, or a pharmaceutically acceptable salt, or solvate thereof, is administered at a dose that provides a C blood or blood plasma level of the compound of at least 10 ng/mL, at least 15 ng/mL, at least 20 ng/mL, at least 25 ng/mL, at least 30 ng/mL, at least 35 ng/mL, at least 40 ng/mL, at least 45 ng/mL or at least 50 ng/mL;
• the compound, or a pharmaceutically acceptable salt, or solvate thereof for use according to any one of [12] to [14] or [16], wherein the compound, or a pharmaceutically acceptable salt, or solvate thereof, is administered two times daily, wherein each dose comprises an amount of the compound equivalent to at least 0.
• the compound, or a pharmaceutically acceptable salt, or solvate thereof for use according to any one of [12] to [19], wherein the compound, or a pharmaceutically acceptable salt, or solvate thereof, is administered at a daily dose that provides a C blood or blood plasma level of the compound of at least 10 ng/mL, at least 15 ng/mL, at least 20 ng/mL, at least 25 ng/mL, at least 30 ng/mL, at least 30 ng/mL, at least 30 ng/mL, at least 35 ng/mL, at least 40 ng/mL, at least 45 ng/mL or at least 50 ng/mL;
• the compound, or a pharmaceutically acceptable salt, or solvate thereof for use according to any one of [1] to [22], wherein the compound, or a pharmaceutically acceptable salt, or solvate thereof, is administered as a unit dosage form that is selected from a solution, dispersion, suspension, and a solid oral dosage form;
• the compound, or a pharmaceutically acceptable salt, or solvate thereof for use according to any one of [1] to [23], wherein the compound, or a pharmaceutically acceptable salt, or solvate thereof, is administered in the form of a solid oral dosage form selected from a tablet, pill and capsule;
• the compound, or a pharmaceutically acceptable salt, or solvate thereof for use according to any one of [1] to [23], wherein the compound, or a pharmaceutically acceptable salt, or solvate thereof, is administered in the form of a solution, an oral dispersion, or an oral suspension;
• the compound for use according to [30], wherein the CYP3A4 inhibitor is selected from the group comprising itraconazole, clarithromycin, erythromycin, telithromycin, nefazodone, voriconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfmavir, ritonavir, saquinavir, tipranavir, cobicistat, troleandomycin, telaprevir, danoprevir, elvitegravir, mifepristone, mibefradil, LCL161, posaconazole, grapefruit juice DS, ceritinib, conivaptan, tucatinib, ribociclib, idelalisib and boceprevir, or a pharmaceutically acceptable salt, or solvate thereof;
• kits containing: (i) a pharmaceutical unit dosage composition comprising a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, or solvate thereof; and (ii) a pharmaceutical unit dosage composition comprising a therapeutically effective amount of a CYP3A4 inhibitor, or a pharmaceutically acceptable salt, or solvate thereof;
• bradykinin-mediated disorder is angioedema (AE);
• angioedema is hereditary angioedema (HAE), acquired angioedema (AAE), bradykinin-mediated non-histaminergic idiopathic angioedema, allergic angioedema, or drug-induced angioedema, or bradykinin-mediated angioedema of unidentified cause;
• HAE hereditary angioedema
• AAE acquired angioedema
• bradykinin-mediated non-histaminergic idiopathic angioedema allergic angioedema
• drug-induced angioedema or bradykinin-mediated angioedema of unidentified cause
• hereditary angioedema is type I HAE, type II HAE, or type III HAE, preferably type I HAE, type II HAE;
• treating or preventing HAE comprises reducing the frequency of HAE attacks, reducing the severity of HAE attacks, improving the quality of life, reducing or eliminating the need for additional standard of care treatments for HAE, reducing the need to discontinue other treatment due to HAE, or combinations thereof;
• preventing HAE comprises the prevention of recurrent attacks of HAE and the compound, or a pharmaceutically acceptable salt, or solvate thereof is administered daily at least once, at least twice, or at least three times;
• each dose comprises an amount of the compound equivalent to at least 0.1 mg, at least 0.5 mg, at least 1 mg, at least 2 mg, at least 5 mg, at least 10 mg, at least 20 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, or at least 100 mg; preferably an amount of the compound of 0. 1 to 100 mg, 1 to 90 mg, 2 to 80 mg, 3 to 70 mg, 4 to 60 mg or 5 to 50 mglO mg, at least 20 mg, at least 30 mg, at least 40 mg, or at least 50 mg;
• the additional therapeutic agent is a CYP3A4 inhibitor, or a pharmaceutically acceptable salt, or solvate thereof; preferably a CYP3A4 inhibitor selected from the group comprising itraconazole, clarithromycin, erythromycin, telithromycin, nefazodone, voriconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, cobicistat, troleandomycin, telaprevir, danoprevir, elvitegravir, mifepristone, mibefradil, LCL161, posaconazole, grapefruit juice DS, ceritinib, conivaptan, tucatinib, ribociclib, idelalisib and boceprevir,
• the CYP3A4 inhibitor is selected from the group comprising itraconazole, clarithromycin, erythromycin, telithromycin, nefazodone, voriconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, cobicistat, troleandomycin, telaprevir, danoprevir, elvitegravir, mifepristone, mibefradil, LCL161, posaconazole, grapefruit juice DS, ceritinib, conivaptan, tucatinib, ribociclib, idelalisib and boceprevir, or a pharmaceutically acceptable salt, or solvate thereof.
• the compound of formula (I) for use in the prophylaxis or treatment of AE, or in the methods of prophylactic or on-demand treatement of AE attacks, according to the present invention is associated with numerous advantages when compared to known therapeutics for the trreatment of AE in general and treatment of HAE, especially acute HAE in particular.
• Advantages of the present invention in comparison to the sole currently available BK B2 receptor antagonist icatibant, which is administered by subcutaneous injection include, for example, higher species selectivity, superior potency, superior pharmacological activity (prolonged efficacy), increased patient convenience due to oral availability (no injection needed), and significantly reduced treatment burden (fewer administrations, lower doses, exclusion of injection-site reactions).
• bradykinin (BK) was purchased from Bachem Bioscience (Torrance, CA) and icatibant from Phoenix Pharmaceuticals (Burlingame, CA).
• the compound of formula (I) was prepared as described in WO 2019/101906 and, where necessary, under Good Manufacturing Practice (GMP) regulations.
• GMP Good Manufacturing Practice
• a qualified person performed the final release of the study drug, i.e. the compound of formula (I), according to Directive 2003/94/EC annex 13; and study drug labels contained information to meet the applicable regulatory requirements.
• Trial medication was packed, labelled and released under the responsibility of the pharmacist of the clinical site in accordance with GMP practice guidelines, International Conference on Harmonization (ICH), Good Clinical Practice (GCP) and applicable local laws/regulations.
• Other compounds and drugs used in the trials were commercially available, obtained from the respective manufacturer or an official supplier, and used in accordance with the protocol and the manufacturers ’ summary of product characteristics (SPCs).
• AUCinf / AUC AUC from time 0 to infinite time, calculated as AUCiast + Ci as z , where Ci as t is the last observed measurable (non-below-quantification limit) concentration; extrapolations of more than 20% of the total AUC are reported as approximations; b.i.d. twice daily
• T dosing interval ti/2 apparent terminal elimination half-life calculated as 0.693//, z ; tiag time period between the time of dosing and the time of the first measurable (non-BQL) concentration tmax actual sampling time to reach the maximum observed analyte concentration.
• Vz/F apparent volume of distribution calculated as dose/(X z * AUC x ,).
• the bradykinin B2 receptor is well known for its species selective pharmacology (Paquet et al., Br. J. Pharmacol. (126), 1083-1090, 1999 (DOI: 10.1038/sj.bjp.0702403); Burgess et al., Br. J. Pharmacol. (129), 77-86, 2000 (DOI: 10.1038/sj.bjp.0703012)).
• the antagonist potency of the compound of formula (I) in cells expressing B2 receptors from human, cynomolgus monkey, dog, rat, and mouse was determined as described in Lesage et al., Front. Pharmacol. 11:916; DOI: 10.3389/fphar.2020.00916.
• the Kb value (nM) of the compound of formula (I) to antagonize BK activation of the cynomolgus monkey B2 receptor was found to be in the same range as for the human B2 receptor (1.42 nM versus 0.15 nM).
• the compound of formula (I) was however more than 1000-fold less potent in antagonizing the rat B2 receptor, more than 3000-fold less potent towards the mouse B2 receptor, and 18,000-fold less potent towards the dog B2 receptor.
• icatibant showed a more or less stable antagonist potency across species (3.19 nM (human B2 receptor); 4.06 nM (cynomolgus monkey B2 receptor); 5.6 nM (rat B2 receptor); 4.40 nM (mouse B2 receptor) and 30.7 nM (dog B2 receptor).
• the compound of formula (I) is devoid of intrinsic agonist activity.
• the compound of formula (I) has a higher species selectivity, and is about 20 times more potent at human B2 receptor than the sole currently available BK B2 antagonist icatibant.
• the objective of the study was to compare and assess the systemic exposure of the test compounds in vivo after a single oral administration in the cynomolgus monkey, in particular oral exposure and dose-proportionality in exposure.
• the Test Facility for the study was Charles River Laboratories France Safety Assessment SAS, 329 Impasse du Domaine Rozier, Les Oncins, 69210 Saint-Germain-Nuelles, France.
• the Test Facility is AAALAC accredited and the study design was reviewed and approved by the ethical committee of the Test Facility as per the standard document “Singe Dose unique_2015juillet02 CEA”.
• the study design was in general compliance with the following animal health and welfare guidelines:
• test compounds were the compound of formula (I) and compound A, ( )-/V-(l-(3-chloro- 5-fluoro-2-((2-methyl-4-(l-methyl-l/f-l,2,4-triazol-5-yl)quinolin-8-yloxy)methyl) phenyl) ethyl)- 2-(difluoromethoxy)acetamide having the following structure:
• test compounds were administered to three non-naive male monkeys via oral gavage (po) at 1 mg/kg, 5 mL/kg and 10 mg/kg, 5 mL/kg.
• the vehicle for the oral doses used was 25% HPPCD (Kleptose HPB, parenteral grade, Roquette) in a 10-mM phosphate buffer (NaiHPO-i, pH 7 for 1 mg/kg and pH 2 or 3 for 10 mg/kg formulation), and the dose concentration was 0.2 mg/mL for the 1 mg/kg and 2 mg/mL for the 10 mg/kg formulation.
• HPPCD Kelptose HPB, parenteral grade, Roquette
• NaiHPO-i 10-mM phosphate buffer
• the assessment of the general health status was based on morbidity/mortality, clinical observations, detailed clinical/physical examinations and body weight.
• the test compounds did not adversely affect the general health status or the body weight gain of the animals throughout the study period.
• pharmacokinetic blood samples were
• the systemic exposure to the test compounds after oral administration was found to be doseproportional over the dose range of 1 to 10 mg/kg in all animals for both test compounds.
• significant differences between the test compounds were found for the maximal observed mean plasma concentration (Cmax (ng/mL)) and the area under the curve extrapolated to infinity (AUC(O-inf) (ng*h/mL)).
• Cmax maximal observed mean plasma concentration
• AUC(O-inf) ng*h/mL
• the compound was very rapidly absorbed and reached peak plasma levels within 30 to 60 minutes after dosing in all subjects under fasted conditions.
• the systemic exposure was dose proportional with a mean ti/2 ranging from 3.5 to 5.6 h between doses.
• Plasma levels for the compound reached therapeutic efficacious threshold concentration within 15 min for all doses and were maintained for approximately 12 h with doses of 12 mg and 22 mg.
• Observed plasma levels of the compound of formula (I) in cohorts under fasted conditions are shown in Fig. 1.
• a comparison of plasma levels of the 22 mg dose cohort under fasted condition and the 22 mg cohort with HCHF breakfast is shown in Fig. 2.
• the compound of formula (I) was safe and well tolerated when administered orally up to single doses of 22 mg. No adverse event was reported as serious, no premature withdrawals due to an adverse event occurred, and no severe adverse event was reported. In addition, no clinically relevant fluctuations of blood pressure and no orthostatic hypotension linked to the compound of formula (I) occurred. The overall incidence of adverse events was similar between the placebo groups and the groups receiving the compound of formula (I). Treatment-related adverse events were reported for three subjects who received the compound of formula (I) (12 or 22 mg), all within the gastrointestinal system and of mild severity: upper abdominal pain, vomiting, and nausea. There were no apparent trends or dose-related changes in hematology, clinical chemistry, vital signs, or ECG. Details of the safety evaluation are summarized in Table 2 below.
• PD Pharmacodynamics
• BK challenge model which involves the demonstration of the inhibition of BK-mediated diastolic blood pressure drop and heart rate increase by administering BK to healthy subjects at specific intervals after administration of the compound.
• the bradykinin challenge is a validated surrogate assessment that was reviewed and approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for phase I clinical trials in the development of icatibant.
• FDA U.S. Food and Drug Administration
• EMA European Medicines Agency
• the clinical dose of icatibant established with the BK challenge has demonstrated successful resolution of HAE attacks in randomized clinical trials and over 10 years of clinical experience with icatibant.
• Schematic design of the BK challenge study is shown in Fig. 3.
• BK Inhibition of BK was assessed in the BK challenge (Fig. 3) with single doses of 12 and 22 mg of the compound of formula (I).
• the compound (12 and 22 mg) was administered orally (p.o.) to 16 healthy volunteers.
• BK was injected intravenously prior to oral administration of the compound, i.e. BK predosing challenge, and at 1, 4, 8, 12 and 24 hours after oral administration (dosing) of the 12 and 22 mg single dose, respectively.
• BK injections were administered to induce cardiovascular responses in the volunteers. The cardiovascular responses were monitored, and blood samples were drawn over 24 hours for PK assessment.
• the PD outcome variables were measured from 5 min before until 5 min after each BK bolus.
• Dampened BK-induced effects are closely associated with successful therapeutic outcome for icatibant (Leach et al., Icatibant Duration of Action During Bradykinin Challenge, JACI (129), AB222 (2012); https://www.jacionline.org/article/S0091-6749(l l)02076-8/fulltext); FDA Office of Clinical Pharmacology Review Firazyr®, Application Number 0221500rigls000 (2011); https://www.accessdata.fda.gOv/drugsatfda_docs/nda/2011/022150Origls000ChemR.pdf), the sole BK antagonist currently available.
• PK/PD analysis using the same approach as in the icatibant evaluation was conducted.
• changes of BK responses induced by the compound of formula (I) were evaluated with a nonlinear mixed-effect PK/PD model.
• PK was analyzed using a two-compartment body model with first-order oral absorption and a lag time; results are shown in Table 4.
• For the PK/PD model a simple Emax-model with a direct link was utilized.
• the EC50 and EC85 values estimated for each PD response associated with the BK challenge are shown in Table 5 below.
• the composite average shows an EC50 of 2.4 ng/mL and an EC85 of 13.8 ng/mL for the compound of formula (I).
• the free plasma concentration associated with said EC50 value of 2.4 ng/mL is 170 pM, a potency that is in line with the antagonist potency of the compound of formula (I) at recombinant and endogenous human B2 receptors (150 and 350 pM, respectively).
• the intrinsic PD potency of the compound of formula (I) at the K B2 receptor was found to be about 25-fold higher than that of icatibant (8.9nM).
• the data also allows a comparison of the expected therapeutic performance of the compound of formula (I) with that of icatibant. It has been shown for icatibant that the therapeutic response to an acute HAE attack wanes after approximately 6 hours. This is also the time point when icatibant concentrations drop below therapeutic levels due to the short half-life (1.4h) of the drug. More precisely, it was shown for the approved 30 mg dose of icatibant that icatibant plasma concentration has a 75% probability of being 50% effective (i.e. to be above EC50) for at least 6.5 hours and a 50% probability of being 85% effective (i.e. to be above ECss) for 5.5 hours.
• the investigated doses (12 and 22 mg, respectively) of orally administered compound of formula (I) exceed the duration of effect reported for 30 mg subcutaneously injected icatibant considerably. Due to the longer half-life of the compound of formula (I), the compound of formula (I) stays above the therapeutic targets for much longer than icatibant.
• the 12 mg oral dose of the compound of formula (I) showed rapid absorption and then stayed above EC50 for 10-12 hours and above ECss for 7 hours, suggesting that this dose is at least as effective as a 30 mg s.c. injection of icatibant. Duration of effect for the higher 22 mg oral dose was approximately twice as long, and thus equivalent to two icatibant injections 6 h apart.
• a randomized, double-blind, placebo-controlled single ascending dose study was performed to examine the safety, tolerability, and PK of single ascending oral doses of 22, 33, and 50 mg of the compound of formula (I) in healthy volunteers after a standard caloric meal, and a single oral dose of 40 mg of the compound of formula (I) was tested in healthy volunteers under fasting conditions.
• the compound of formula (I) Over the investigated dose range from 22 to 50 mg (factor 2.27 increase) after a standardized breakfast, the compound of formula (I) showed dose-proportional PK with a 2.37-fold and 2.39- fold increase for mean Cmaxand AUCo-24h, respectively.
• Administration of the compound of formula (I) after a standardized breakfast resulted in 40-50% decrease in Cmax, but AUCinf did not show a significant change compared to administration under fasting conditions.
• Ci2h and C2411 plasma concentration for the compound of formula (I) was higher under fed conditions, which is indicative of favorable effects in prophylactic treatment.
• An open-label, single sequence crossover drug-drug interaction trial was performed to evaluate the effect of multiple doses of itraconazole, a potent CYP3A4 inhibitor, at steady-state on the PK of a single dose of the compound of formula (I) in healthy subjects.
• the trial was carried out to evaluate the safety and tolerability of the compound of formula (I) alone and in combination with multiple doses of the CYP3 A4 inhibitor itraconazole in healthy adult subjects. Thirteen healthy subjects were enrolled and completed the study.
• Plasma concentrations of the compound of formula (I) were determined predose and over a 48- hour evaluation period after dosing of the compound of formula (I) on Days 1 and 7. Trough plasma concentrations of itraconazole were determined by taking predose plasma samples on Days 4 - 7, to document exposure to itraconazole. It was found that the mean itraconazole predose plasma concentration (Ctrough) levels increased gradually from Day 4 (386 ⁇ 82.2 ng/mL) to Day 7 (597 ⁇ 178 ng/mL). Similar observations were made for the mean hydroxyitraconazole predose plasma concentration (Ctrough) levels, which increased gradually from Day 4 (730 ⁇ 93.5 ng/mL) to Day 7 (1187 ⁇ 213 ng/mL). These values are consistent with the previously published data of Hardin et al. (Pharmacokinetics of itraconazole following oral administration to normal volunteers; Antimicrob Agents Chemother. 32(9): 1310-1313, 1988).
• duration of effect of the compound of formula (I) is significantly improved in the presence of a CYP3A4 inhibitor compared administration of the compound alone.
• This longer duration of effect of the compound of formula (I) is highly advantageous in therapeutic application as it can markedly reduce treatment burden of patients in that frequency of administrations and/or dose can be drastically lowered.

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