WO2017019532A1 - Précurseur z (cpmp) pour traiter un déficit en cofacteur du molybdène type a - Google Patents

Précurseur z (cpmp) pour traiter un déficit en cofacteur du molybdène type a Download PDF

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Publication number
WO2017019532A1
WO2017019532A1 PCT/US2016/043639 US2016043639W WO2017019532A1 WO 2017019532 A1 WO2017019532 A1 WO 2017019532A1 US 2016043639 W US2016043639 W US 2016043639W WO 2017019532 A1 WO2017019532 A1 WO 2017019532A1
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patient
mocd
administering
cpmp
test
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PCT/US2016/043639
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English (en)
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Guenter Schwarz
Alex VELDMAN
Stephan ORTIZ
Jonathan MONTELEONE
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Alexion Pharmaceuticals, Inc.
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Publication of WO2017019532A1 publication Critical patent/WO2017019532A1/fr

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    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/688—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols both hydroxy compounds having nitrogen atoms, e.g. sphingomyelins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present disclosure relates to the use of cyclic pyranopterm monophosphate (cPMP, also known as molybdopterin derivative Precursor Z) for the treatment of diseases or disorders related to molybdenum cofactor deficiency (MoCD) type A.
  • cPMP cyclic pyranopterm monophosphate
  • MoCD molybdenum cofactor deficiency
  • Molybdenum cofactor deficiency is characterized by early, rapidly progressive, postnatal encephalopathy and intractable seizures, leading to severe disability and early childhood death. MoCD usually manifests during the first postnatal days with exaggerated startle reactions, alterations in muscle tone, lethargy, intractable seizures, and autonomic dysfunction.
  • brain imaging reveals global white matter and deep gray matter involvement, followed by rapidly evolving widespread subcortical necrosis. Multi cystic lesions appear within days, with subsequent brain atrophy and secondary microcephaly. Symptoms are predominantly- caused by sulfite toxicity due to a functional loss of sulfite oxidase, one of the
  • molybdenum cofactor-dependent enzymes in humans which also include xanthine oxidoreductase and aldehyde oxidase.
  • molybdopterin derivative precursor Z (cPMP) with molecular weight of 363 Da
  • the present disclosure provides a method of treating
  • Molybdenum Cofactor Deficiency (MoCD) Type A in a human patient in need thereof, the method comprising administering to the patient a pharmaceutically effective amount of cPMP:
  • the pharmaceutically effective amount is a dosage of from about 80 .ug/kg to about
  • the present disclosure provides a method of treating MoCD Type A in a human patient in need thereof! the method comprising administering to the patient a pharmaceutically effective amount of cPMP, or of a pharmaceutically acceptabl e salt thereof, at least once per day, wherein the pharmaceutically effective amount is a dosage of from about 300 ,ug/kg to about 1500 ⁇ tg/kg body weight per day, particularly from about 525 ⁇ ig/kg to about 1200 ⁇ g/kg body weight per day, wherein the administering is started prior to detection of cerebral lesions in the patient and/or prior to significant cerebral encephalopathy in the patient.
  • this disclosure provides a method of treating
  • Molybdenum Cofactor Deficiency (MoCD) type A in a human patient in need thereof the method comprising: a) determining the patient has encephalopathy or is at risk for encephalopathy, b) optionally conducting at least one test to diagnose the human patient as having MoCD; c) administering to the human a pharmaceutically effective amount of cPMP, or of a pharmaceutically acceptable salt thereof, at least once per day, wherein the pharmaceutically effective amount is a dosage of from about about 300 ug/kg to about 1500 m*/kg body weight per day, particularly from about 325 ,ug/kg to about 1200 &' ⁇ 3 ⁇ 4 body weight per day, particularly from 120 , ug/kg to about 320 ⁇ g/kg body weight per day; and d) conducting at least one test to diagnose the human patient as having MoCD type A, wherein if the human does not have MoCD type A, the administering ceases, wherein the administering is started prior to detection of cerebral lesions in the patient and/
  • the methods of this disclosure provide methods of treating MoCD type A in a human patient, wherein the patient is able to at least one of: feed orally at or before about three weeks of age, breathe unassisted by about one week of age; sit up unassisted at about 6 months of age, and sit up unassisted at about 12 months of age.
  • the methods of this disclosure provide methods of treating MoCD type A in a patient, where the patient survival is increased compared to untreated MoCD type A patients, wherein the increase is from about one day to about three years or more.
  • FIG. 1 shows molybdenum cofactor synthesis and its incorporation into the four known human molybdenum enzymes. Shown are the starting molecule (GTP), cyclic pyranopterin monophosphate (cPMP) and molybdopterin (MPT) as intermediates, as well as the proteins involved in individual synthetic steps: MOCS1A, MOCS I AB, MOCS2A, MOCS2B, and gephyrin (GPNH).
  • GTP starting molecule
  • cPMP cyclic pyranopterin monophosphate
  • MPT molybdopterin
  • FIG. 2 shows clinical details and treatment characteristics of 16 infants with molybdenum cofactor deficiency (MoCD) treated with recombinantly-produced cPMP (rcPMP). Combined data for patients 1-11 and 12-16 are median (range).
  • FIG. 3 shows clinical severity scoring for patients with MoCD type A.
  • FIG. 4A shows urinary concentration (micromole per millimole creatinine) of S- sulfocysteine (normal controls ⁇ 9 micromole per millimole creatinine) for 1 1 patients with MoCD type A on rcPMP treatment during the fi rst two weeks of treatm ent.
  • FIG. 4B shows urinary concentration (micromole per millimole creatinine) of xanthine (normal controls ⁇ 38 micromole per millimole creatinine) for 1 1 patients with MoCD type A on rcPMP treatment during the first two weeks of treatment.
  • FIG. 4C shows urinary concentration (micromole per miliimoie creatinine) of urate (normal controls 820-2813 micromole per miliimoie creatinine) for 1 1 patients with MoCD type A on rcPMP treatment during the first two weeks of treatment.
  • FIG. 4D shows urinary S-sulfocysteine (SSC) normalization in patients during the first three months of treatment.
  • SSC urinary S-sulfocysteine
  • FIG. 4E shows long term monitoring of urinary SSC concentrations in patients #1-5, 7, and 9.
  • FIG. 4F shows long-term monitoring of urinary xanthine concentrations in patients #1-5, 7, and 9.
  • FIG. 5 shows a study profile for the observational prospective follow-up of 6 patients identified with MoCD in the neonatal period and treated with rcPMP on compassionate grounds.
  • FIG. 6A shows a representative axial T2 -weighted MRI brain image of patient
  • CSF cerebrospinal fluid
  • FIG. 7 shows clinical severity scores of the initial patients with MoCD type A treated with rcPMP from Examples 1 -3. Scores as described in Fig. 3.
  • FIG. 8 shows predicted mean (90% confidence interval) cPMP AUC (area under the curve) for the dosing regiment in pre-term and full-term neonates.
  • Molybdenum cofactor deficiency is a rare, life-threatening, autosomal recessive, inborn error of metabolism, characterized by disruption of the metabolic pathway for production of molybdenum cofactor (MoCo), resulting in a deficiency of activity of the three detoxifying enzymes, sulfite oxidase (SO), xanthine dehydrogenase, and aldehyde oxidase.
  • Molybdenum cofactor (MoCo) is synthesized by a complex biosynthetic pathway involving three steps, as shown in FIG. 1.
  • MoCD type A and type B are clinically indistinguishable, type C patients show additional lack of synaptic inhibition with a more severe progression than MoCD type A or type B.
  • Patients of all MoCD types may present with, e.g., elevation in exaggerated startle reactions, alterations in muscle tone (hypertonia, axial hypotonia, and/or limb hypertonia), lethargy, myoclonic twitching, intractable seizures, autonomic dysfunction, evolving brain edema and cysts, brain atrophy, enlargement of subarachnoid space and ventricles, loss of gray/white matter differentiation, abnormalities in feeding behavior, burst suppression or multifocal epileptic encephalogram, metabolic acidosis, and feeding difficulties.
  • a retrospective natural history review confirms a median survival of 36 months (Mechler, et al., Genetics in Medicine, (2015) 1-6).
  • the present disclosure provides safety and efficacy data for the complete prospectively monitored cohort of the first 16 neonates and infants with classical presentation of MoCD (1 1 with type A and f ve with type B), who received
  • the present disclosure provides data on the treatment of a neonate identified with MoCD type A, starting on day zero of life, with synthetic cPMP.
  • pharmaceutically acceptable salt is understood to include one or more stable, pharmaceutically acceptable, non-toxic counterions; particularly
  • mobdenum cofactor deficiency MoCo (molybdenum cofactor); MoCS (molybdenum cofactor synthesis); MRI (magnetic resonance imaging); MPT (molybdopterin); NaCl (sodium chloride); Na 2 HP0 4 (di sodium hydrogen phosphate); NaOH (sodium hydroxide); MR (nuclear magnetic resonance spectroscopy); cPMP or Precursor Z (cyclic pyranopterin monophosphate), SSC (S-sulfocysteine); , ug (microgram(s)); ⁇ - (microiiter(s)); ⁇ (micromoiar); rcPMP (recombinant cPMP).
  • the first day of life is considered to be day zero
  • the present application provides m ethods of treating or preventing a disease in a patient in need thereof.
  • the method comprises administering a pharmaceutically effective amount of cyclic pyranopterin monophosphate (i.e., cPMP or Precursor Z):
  • MoCD molybdenum cofactor deficiency
  • the present disclosure provides a method of treating
  • Molybdenum Cofactor Deficiency (MoCD) Type A in a human patient in need thereof, the method comprising administering to the patient a pharmaceutically effective amount of cPMP:
  • the pharmaceutically effective amount is a dosage of from about 80 .ug/kg to about 3000 ⁇ /kg body weight per day, particularly from about 120 ⁇ g/kg to about 320 ⁇ g/kg body weight per day.
  • the administering is started prior to detection of cerebral lesions in the patient. In certain embodiments, the administering is started prior to significant cerebral encephalopathy in the patient. In certain embodiments, the dosage is from about 240 ⁇ g/kg to about 320 ⁇ g/kg body weight per day. In certain embodiments, the dosage is from about 525 g/kg to about 1300 body weight per day.
  • the cPMP can be, for example, recombinant or synthetic.
  • the route of administration can be any route, for example, is at least one of intravenous (including intravenous infusion), oral, subcutaneous, intramuscular, and peritoneal route.
  • the patient can be any patient, including a neonate, and can be human.
  • the administering is started when a MoCD is suspected but not yet confirmed. In certain embodiments, the administering is started after a strongly positive sulfite dipstick test from a fresh urine sample of a symptomatic newborn baby,
  • the patient does not have encephalopathy in the brain at the start of administration, and does not have encephalopathy in the brain at about two years or more (e.g., about two to about four years) into cPMP treatment.
  • the lack of irreversible or cystic lesions in the brain can be determined by, for example, a brain scan, such as MRI.
  • this disclosure provides a method of treating
  • Molybdenum Cofactor Deficiency (MoCD) type A in a human patient in need thereof comprising: a) determining the patient has encephalopathy or is at risk for encephalopathy, b) optionally conducting at least one test to diagnose the human patient as having MoCD; c) administering to the human a pharmaceutically effective amount of cPMP, or of a pharmaceutically acceptable salt thereof, at least once per day, wherein the pharmaceutically effective amount is a dosage of from about 120 ( u,g/kg to about 320 ⁇ /kg body weight per day, or is a dosage from about about 525 to about 1300 ⁇ /kg body weight per day, and d) conducting at least one test to diagnose the human patient as having MoCD type A, wherein if the human does not have MoCD type A, the administering ceases.
  • MoCD Molybdenum Cofactor Deficiency
  • the administering is started prior to detection of cerebral lesions in the patient. In certain embodiments, the administering is started prior to significant cerebral encephalopathy in the patient. In certain embodiments, the dosage is from about 240 ⁇ ig/kg to about 320 ⁇ g/kg body weight per day. In certain embodiments, the administering is started prior to significant cerebral encephalopathy in the patient, and the dosage is from about 80 ⁇ g/kg to about 3000 ⁇ g/kg body weight per day. In certain embodiments, the administering is started prior to significant cerebral encephalopathy in the patient, and the dosage is from about 525 ⁇ g/kg to about 1300 ⁇ g/kg body weight per day.
  • the cPMP can be, for example, recombinant or synthetic, and may be any pharmaceutically acceptable said.
  • the route of administration can be any route, for example, is at least one of intravenous (including intravenous infusion), oral,
  • the route of administration is intravenous or oral.
  • the patient can be any patient, including a neonate, and can be human.
  • the at least one test can be a sulfite dipstick test, a brain scan, a urine test, a sulfite test, an SSC test, a xanthine test, or a urate test, in plasma or in urine.
  • the at least one test to diagnose the patient as having MoCD type A identifies at least one mutation on two alleles at a locus for MOCS1.
  • the at least one mutation can be identified in the patient, or can be identified in at least one parent or both parents of the patient, in certain embodiments, at least one of sulfite metabolite, urine S-sulfocysteine, thiosulfate, and xanthine level decreases in the human patient.
  • the administering is started when a MoCD is suspected but not yet confirmed.
  • the administering is started after a strongly positive sulfite dipstick test from a fresh urine sample of a symptomatic newborn baby.
  • the patient does not have encephalopathy in the brain at the start of administration, and does not have encephalopathy in the brain at about two years or more (e.g., about two to about four years) into cPMP treatment.
  • the lack of irreversible or cystic lesions in the brain can be determined by, for example, a brain scan, such as MRI.
  • the disease or disorder is not MoCD type B.
  • the term "patient” or "human patient” refers to a human.
  • a patient who has or is at risk for having MoCD, specifically type A may be identified by having parents of at least one already affected sibling, having at least one affected immediate family member (cousins, etc.), previously diagnosed by genetic or phenotypic testing.
  • At least one or both parents are identified as heterozygote carriers of at least one mutation at the locus on chromosome 6 for MOCS1.
  • a patient may have at least one mutation at the locus for MOCS1, e.g. including but not limited to mutations as identified in Reiss and Hahnewald, Human Mutation, 32(1): 10-18 (2011) and/or as identified in Leimkuhler et al., Human Genetics, 117(6): 565-570 (2005).
  • a patient may be identified by early signs of encephalopathy, blood levels of elevated sulfite, brain scans, urine tests (including but not limited to SSC, xanthine, and/or urate concentrations), and urine sulfite dipstick tests (i.e., a strongly positive sulfite dipstick test from a fresh postnatal urine sample).
  • a patient may be identified by genetic analyses in utero or following birth (e.g., immediately, one hour, one day, two days, three days, four days, five days, six days, one week, etc.). In some embodiments, the testing (whether phenotypic or genetic) is performed immediately following birth.
  • a patient may be identified by jerkiness, twitching, poor sucking, altered consciousness, and/or recurrent seizures following birth.
  • the patient is a neonate.
  • nonate refers to a newborn human child that was born (whether by vaginal or by caesarean delivery) less than about 4 weeks ago.
  • the neonate is from about zero days (birth date) to about 4 weeks old, from about two days to about 4 weeks old, from about three days to about 4 weeks old, from about four days to about 4 weeks old, from about five days to about 4 weeks old, from about six days to about 4 weeks old, from about 1 week to about 4 weeks old, from about 2 weeks to about 4 weeks old, or from about 3 weeks to about 4 weeks old.
  • the neonate is from about 1 day to about 1 week old, from about 2 days to about I week old, from about 3 days to about 1 week old, from about 4 days to about 1 week old, from about 5 days to about 1 week old, or from about 6 days to about one week old.
  • the neonate is less than about 1 week old.
  • the patient is treated on day zero, i.e., on the same day as the patient's birth.
  • provided herein is a method for treating a patient diagnosed with MoCD (e.g., MoCD type A), comprising administering to the patient a pharmaceutically effective amount of cPMP, or a pharmaceutically acceptable salt thereof.
  • a method for treating a patient presenting one or more symptoms of MoCD type A or a patient having an elevated risk of developing symptoms of MoCD type A and administering a pharmaceutically effective amount of cPMP, or a pharmaceutically acceptable salt thereof to a subject determined to have MoCD.
  • Such methods can include performing an assay (e.g., blood, urine, or cerebral scans) on the patient or on a sample provided from the patient, and identifying one or more symptoms of MoCD and/or diagnosing the patient as having MoCD,
  • Indicators of MoCD can include one or more of the gene or protein sequence variants (see, e.g., Table 2 in Reiss, J. and Hahnewald, R. Human Mutation 32(1): 10-18 (2011)).
  • the parents of a patient are tested for the presence of one or more gene or protein sequence variants associated with MoCD, particularly MoCD type A.
  • the patient is tested for one or more gene or protein sequence variants associated with MoCD, particularly MoCD type A.
  • the patient can be tested, for example, in utero, before birth, or following birth.
  • the patient is tested less than one hour following birth, less than two hours following birth, less than six hours following birth, less than 12 hours foliowing birth, less than 24 hours following birth, less than 3 days following birth, less than 5 days following birth, less than 10 days following birth, less than 20 days following birth, or less than 30 days following birth.
  • testing is performed foliowing birth by genetic testing of DNA extracted from blood or fibroblasts or other DNA sampling sources.
  • testing is performed prior to birth, via in utero amniotic sampling and/or chorionic villi sampling.
  • MoCD can also be diagnosed using phenotypic symptoms or indicators. For example, blood tests, urine tests, and/or cerebral scans can be performed to identify one or more abnormalities associated with MoCD in the patient.
  • S-sulfocysteine (SSC) is a non-enzymatic reaction product of cysteine and sulfite which is highly abundant in MoCD patient urine. Increased blood or urine levels of sulfite, S-sulfocysteine (SSC), and xanthine can be associated with MoCD in a patient.
  • Measurement of blood or urine levels of sulfite, SSC, and xanthine can be performed by direct dip-stick methods (e.g., sulfite) or HPLC methods as needed.
  • Neurological examinations measuring consciousness, quality of movements, feeding patterns, and seizure activity can be useful in diagnosing a patient with MoCD.
  • Electroencephalograms (EEGs) (measuring rhythmic elements and/or epileptiform discharges), brain imaging, and developmental testing using known procedures can also be used to determine whether encephalopathy or cerebral lesions are present in the patient.
  • Phenotypic symptoms and indicators may include, for example, improvement according to cognitive and/or motor scales from one or more accepted developmental scales, including Bayley Scale of Infant Development (BSID-III or Bayley- ⁇ ), improvement of quality of life (QoL), improvement in MRI severity (particularly cranial imaging), developmentally appropriate milestone attainment, appropriate increase in head circumference, or increase in survival rate.
  • BSID-III or Bayley- ⁇ Bayley Scale of Infant Development
  • QoL quality of life
  • improvement in MRI severity particularly cranial imaging
  • developmentally appropriate milestone attainment appropriate increase in head circumference, or increase in survival rate.
  • Successful treatment outcomes include but are not limited to at least one of improvement and/or lack of decline according to cognitive and/or motor scales from one or more accepted developmental scales, including Bayley Scale of Infant Development (BSID-III or Bayley-III), improvement of quality of life (QoL), improvement in MRI severity (particularly cranial imaging), developmental ly appropriate milestone attainment, appropriate increase in head circumference and growth, lack of brain necrosis, lack of brain cystic lesions on MRI imaging, lack of or decrease of seizures, decrease of dosing of anticonvulsive drugs, increase in survival rate, and improvement of life expectancy.
  • Bayley Scale of Infant Development BSID-III or Bayley-III
  • improvement of quality of life QoL
  • improvement in MRI severity particularly cranial imaging
  • developmental ly appropriate milestone attainment appropriate increase in head circumference and growth
  • lack of brain necrosis lack of brain cystic lesions on MRI imaging
  • lack of or decrease of seizures decrease of dosing of anticonvulsive drugs
  • increase in survival rate and improvement of life
  • the patient is able to at least one of feed orally at or before about three weeks of age; breathe unassisted by about one week of age; and/ or sit up unassisted at about 12 months of age.
  • the embodiments include where the patient is able to do one, two, or all three of these tasks.
  • a therapeutically effective amount of cPMP can include an amount (or various amounts in the case of multiple administrations) that improves the patient's chance of survival, increases the patient's survival rate, or increases the patient's life expectancy.
  • a disclosed method improves the life expectancy of a patient by any amount of time, including at least one day, at least one week, at least two weeks, at least three weeks, at least one month, at least two months, at least three months, at least six months, at least one year, at least 18 months, at least two years, at least 30 months, or at least three years, or the duration of treatment.
  • a patient may also be identified based on familial history (e.g., a sibling or close relative having MoCD or previously having tested positive for a MoCD type A mutation). Additional assays, non-limiting assays, and phenotypic symptoms that may be used in these methods are described herein. Additional assays are also known in the art.
  • the term "treating" or “treatment” refers to one or more of (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or
  • symptomatology of the disease conditi on or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease or reducing or alleviating one or more symptoms of the disease.
  • the method comprises administering to the patient a therapeutically effective amount of cPMP, or a pharmaceutically acceptable salt thereof.
  • therapeutically effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, or patient by a researcher, veterinarian, medical doctor or other clinician.
  • therapeutically effective amounts of cPMP will elicit improvements in the phenotypic markers of MoCD type A.
  • compound as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.
  • Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. All compounds, and salts thereof (e.g., pharmaceutically acceptable salts), can be found together with other substances such as water and solvents (e.g., hydrates and solvates).
  • the compound provided herein (i .e., cPMP) also includes tautomeric forms.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include, for example, ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system.
  • Tautomeric forms can be in equilibrium or stericaliy locked into one form by appropriate substitution.
  • cPMP may have the following tautomeric form:
  • cPMP or a pharmaceutically acceptable salt thereof, is substantially isolated.
  • the expression “substantially isolated” refers to a compound that is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds provided herein. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%o, at least about 97%>, or at least about 99% by weight of the compound provided herein, or pharmaceutically acceptable salt thereof.
  • stereochemistry of the stereocenter(s) present in the chemical structure As used herein, bonds symbolized by a simple line do not indicate a stereo-preference. Unless otherwise indicated to the contrary, chemical structures, which include one or more stereocenters, illustrated herein without indicating absolute or relative stereochemistry encompass all possible stereoisomenc forms of the compound ⁇ e.g., diastereomers and enantiomers) and mixtures thereof Structures with a single bold or dashed line, and at least one additional simple line, encompass a single enantiomeric series of all possible diastereomers.
  • cPMP When employed as a pharmaceutical, cPMP can be administered in the form of a pharmaceutical composition.
  • pharmaceutical composition As used herein, the expression "pharmaceutical
  • compositions comprises at least one compound, i.e., cPMP, or a pharmaceutically acceptable salt thereof, as a single compound or in a mixture, in combination with at least one excipient.
  • cPMP a pharmaceutically acceptable salt thereof
  • These compositions can be prepared as described herein or elsewhere, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be oral or parenteral. In some embodiments, administration is oral. In some embodiments, administration is parenteral.
  • parenteral admini stration includes intravenous, intraarterial, subcutaneous, peritoneal, intramuscular, or injection or infusion; or intracranial (e.g., intrathecal or intraventricular administration).
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • administration is selected from the group consisting of intravenous, oral, subcutaneous, intramuscular, and peritoneal
  • suitable excipients include, without limitation, lactose, dextrose, sucrose, sorbitol, raannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and raethyi cellulose.
  • the formulations can additionally include, without limitation, lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; flavoring agents, or combinations thereof.
  • the suitable excipient comprises at least one
  • pharmaceutically acceptable acid including but not limited to ascorbic acid, acetic acid, and citric acid, sodium salts including Na 2 HP0 4 -H 2 0, and hydroxide compounds including NaOH.
  • the active compound can be effective over a wide dosage range and is generally administered in a therapeutically effective amount.
  • the dosage of the compound, cPMP, or a pharmaceutically acceptable salt thereof, administered to a patient or individual is from about 80 ⁇ g kg patient body weight to about 320 ,ug/kg patient body weight, for example from about 100 ⁇ g/kg or about 120 ,ug/kg to about 320 ⁇ ig/kg, from about 200 ⁇ ig/kg to about 320 ⁇ ig kg, or from about 300 , ug/kg to about 320 .g/kg patient body weight.
  • the dosage of the compound, cPMP, or a pharmaceutically acceptable salt thereof, administered to a patient or individual is from about 120 ⁇ ig/kg to about 320 ⁇ ig/kg patient body weight. In some embodiments, the dosage of the compound, cPMP, or a pharmaceutically acceptable salt thereof, is from about 240 g/kg to about 320 ⁇ ig/kg patient body weight.
  • the dosage of the compound, cPMP, or a pharmaceutically acceptable salt thereof is from about 80 ,ug/kg to about 3000 ⁇ ig/kg patient body weight. In some embodiments, the dosage of the compound, cPMP, or a pharmaceutically acceptable salt thereof, is from about 300 to about 1300 m*/kg patient body weight.
  • the administration of the drug can be done by, for example, TV infusion and the dosage can be, for example, once per per day, twice per day, three times per day, or more often. In some embodiments, the administration is by IV infusion twice daily followed by once daily administration.
  • Recombinant cPMP (Examples 1-3) was obtained according to the method described in U.S. Patent No. 7,504,095 by Orphatec/Col bourne Pharmaceuticals GmbH. Recombinant cPMP was produced in 24 L expression cultures of E. coli and purified by two-step HPLC chromatography according to previously reported procedures, forming an amorphous solid upon freeze-drying (Santamaria-Araujo et al ., J. Biol Inorg. Chem., 2012, 17, 113-122.
  • the total solution was freeze-dried for 48 hours till an off-white powder was obtained.
  • the resulting powder was transferred into a 2 ml screw-cap polypropylene tube and washed three times with 1 ml Mi Hi Q water. In between each washing step, the tube was centrifuged at 13,000 rpm for 2 min and the supernatant was discarded. The washing steps were aimed to wash out remaining trace amounts of citric acid.
  • Endotoxin and microbiological assays providing acceptable results were performed by Chemical Analysis (Melbourne, Australia) or at EML (Surry Hills, Sydney, Australia).
  • Urine samples were diluted in water, 100- fold for samples having creatinine concentrations of 0.1 - 5 mmol L, or 200-fold for those above 5 mmol/L.
  • MoCD was suspected based on either symptoms or previous index cases in the family and initially diagnosed by demonstrating increased concentrations of sulfite, S- sulfocysteine (SSC), and xanthine, and decreased urate, as well as absence of urothione (the catabolic excretion product of MoCo) in body fluids. Every effort was made to start cPMP substitution as early as possible. Confirmatory diagnosis of MoCD type A or type B was confirmed through measurement of Compound Z (the cPMP oxidation product) concentration in pre-treatment urine, and by sequencing the MOCS1 and MOCS2 genes.
  • SSC S- sulfocysteine
  • xanthine decreased urate
  • urothione the catabolic excretion product of MoCo
  • Recombinant cPMP infusions typically started at a daily dose of 80 ( u,g/kg body weight in the first 11 patients (#1-7 and #12-15). This dose was extrapolated from a dose that most effectively abolished symptoms and lethality in a mouse model (Schwarz et al., Hum. Mol Gen. 2004, 13. 1249-1255) and was adjusted and administered using a standardised treatment protocol derived from successful treatment of the initial case (Veldman et al., Pediatrics, 2010, 125, el249-e!254).
  • rcPMP aqueous stock solution (dissolved in 30 mmol/L citrate buffer, pH 3.0) was neutralized by NaOH and phosphate-buffered saline.
  • frozen pre-formulated and neutralized aqueous rcPMP solution was used as described herein. Frozen aqueous solutions were thawed and intravenously administered through a 0,22 um filter line.
  • Biochemical efficacy was determined using urinary SSC as a marker for sulfite oxidase activity and urinary xanthine and urate for xanthine oxidoreductase activity. During the first 90 days of treatment, samples were collected daily to determine treatment response and to inform dose adjustment. Samples were then collected every week or every two weeks.
  • Clinical efficacy was assessed daily for the first two weeks, at least weekly during the first three months, and regularly thereafter by clinical and neurological examination, which recorded consciousness, quality of movements, feeding pattern, and seizure activity.
  • a scoring system ranging from 0 (asymptomatic) to 12 (severe encephalopathy) was developed to quantify clinical symptoms.
  • the total score (obtained by combining scores from 0-2 for each tested indication) ranges from 0 (asymptomatic) to 12 (severely compromised) according to FIG. 3.
  • Electroencephalography, brain imaging, and developmental testing were done as clinically indicated.
  • Pati ent #8 was scored at 7 days of age, prior to ECMO and haemodialysis for sulfite detoxification; rcPMP treatment was started 4 days later. Patient #1 1 had rcPMP treatment discontinued after 5 days, and patient surviving. EEG, brain imaging, and developmental testing were performed as clinically indicated. Results are shown in FIG. 7,
  • Clinical adverse events were mostly related to intercurrent diseases such as airway infections. Seven of the eight patients on long-term rcPMP treatment suffered from at least one episode of pneumonia, and two patients (#4, #5) required short-term mechanical ventilation. Two patients temporarily suffered from mild asthma (#3, #4), and three from infantile eczema (#2, #3, #4). One patient (#6) was diagnosed with oral leukoplakia and mild left ventricular myocardial hypertrophy two weeks into treatment, unlikely related to rcPMP and not requiring intervention. Patient #3 was diagnosed with asymptomatic cholelithiasis during the third year. All patients on long-term treatment had permanent central venous access surgically inserted, and experienced one or more serious line-related complications such as site infection, septicaemia, or rupture.
  • MoCD type A patients on long-term treatment The parents of patient #6 decided to abandon treatment after 111 days and the patient was lost to follow-up.
  • Patient #2 exhibited significant cerebral lesions via MRI prior to rcPMP treatment, had been treated late and suffered from severe disability. When the patient became terminally ill from aspiration pneumonia, treatment was reevaluated. Recombinant cPMP was discontinued after 446 days, and patient #2 eventually succumbed to respiratory failure. Both patients #6 and #2 had shown a complete biochemical response and partial clinical improvement regarding seizure control, feeding pattern, and behavior.
  • cPMP Recombinant cPMP is well -tolerated and safe in treatment of neonates and infants suffering from MoCD type A and type B. Neither tachyphylaxis nor any serious adverse drag reaction were observed over a period of up to five years. Long-term daily intravenous infusions however may be challenging for patients, their families and health care systems and they may carry a risk of bacteriemia and severe infection. Serious adverse events unsurprisingly arose from the frequent and long-term use of central venous lines. The industrial large-scale synthesis of cPMP may allow the further development of safer and more cost-effective and convenient administration routes.
  • MoCD can cause prenatal symptoms such as facial dysmorphism and, rarely, intrauterine brain malformations and connatal microcephaly (Carmi-Nawi, N. et al., J Child Neurol. 26:460-64 (2010)).
  • Patient #5 started convulsing within one hour after birth. Only one of the patients was born mildly microcephalic and none was encephalopathic immediately after birth. Their rapid postnatal deterioration supports the notion that fetal sulfite could potentially be cleared through transplacental transport or maternal metabolism in utero (Sie, SD et al., J Inherit Metab Dis 2010 33(suppl 3):401 - 07).
  • MoCD type A has become a treatable disease. Restoration of molybdenum cofactor-dependent enzyme activities with rcPMP before the onset of significant encephalopathy results in good long-term developmental outcomes. Later treatment alleviates symptoms. The possibility of MoCD type A needs to be urgently explored in every neonate presenting with altered consciousness or recurrent seizures to avoid any delay in rcPMP substitution, and to ensure maximize possible treatment benefit.
  • a patient was identified prior to birth by a combination of prenatal genetic testing and medical history (deceased affected sibling) as having MoCD type A.
  • a predelivery brain MRI and ultrasound 33 weeks, 5 days) showed very minor abnormalities, for example, mild dysmorphic signs manifested by hypertelorism; very mild hypoplasia of the cerebellar hemispheres, potentially the result of increased retro-cerebellar fluid spaces, mild thickening of the cavum septum peilucidum (CSP), but otherwise, no abnormal findings, and no cysts, cystic lesions, or ischemic or edematous signs.
  • CSP cavum septum peilucidum
  • Synthetic cPMP was manufactured according to previously published methods, i.e. WO 2012/1 12922.
  • the initial dose of synthetic cPMP was administered via intravenous syringe pump at a rate of 1.5ml/minute approximately 2 hours post delivery (day zero) at a concentration of 525 ⁇ /kg body weight (concentration 0.5mg/ml).
  • the second dose was administered (525 ⁇ /3 ⁇ 43 ⁇ 4) about 21 hours after the initial dose.
  • the patient experienced episodes of apnea that were possibly due to seizure activity and required intubation. Feeding was supplemented via nasogastric tube (10-20cc each feeding) in addition to oral feedings because oral feeding was insufficient.
  • the breathing tube was able to be removed on day 2, and no seizures were observed after the first day.
  • the daily dosing of cPMP will be increased to about 1000 ⁇ g/kg; at six months the daily dosing will be increased to about 1200 ,ug/kg, and at nine months the daily dosing will be increased to about 1300 ⁇ ig/kg and maintained at this dose.
  • An MRI will be performed regularly and will show no cystic lesions and no cerebral encephalopathy.
  • the renal maturation factor was calculated by inserting gestational age into the Rhodin equation (Rhodin, M.M., et al., Pediatr. Nephrol. 24: 67-76 (2009)).
  • Age-specific PK parameters were calculated using estimated population parameters (available from, for example, the World Health Organization and/or the Centers for Disease Control), the renal maturation factor, and body weight. Then AUC was calculated for doses ranging from 100 to 2,000 , ug/kg in increments of 100 ⁇ ig/kg.
  • the dose achieving an AUC matching the NOAEL was determined using linear interpolation between the available doses.
  • Table 2 illustrates the dosing nomogram for neonates bom at 34 weeks gestational age to achieve NOAEL and Table 3 illustrates the dosing nomogram for neonates born at 40 week gestational age (full term) to achieve NOAEL.
  • the patients and the treatment success will be evaluated by previously described testing, including but not limited to, Bayley-III, QoL evaluations, cranial imaging, MRI, increase in survival, increase in lifespan, etc, particularly compared to untreated patients with MoCD type A. Patients will be able to sit up unassisted by 12 months, or be able to sit up unassisted by about 6 months.

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Abstract

L'invention concerne des méthodes d'utilisation de la pyranoptérine monophosphate cyclique (cPMP) pour le traitement de maladies ou de troubles chez les êtres humains associés à un déficit en cofacteur du molybdène (MoCD) type A, dans lesquelles au moins une fois par jour l'ingrédient actif est administré à une dose spécifique.
PCT/US2016/043639 2015-07-24 2016-07-22 Précurseur z (cpmp) pour traiter un déficit en cofacteur du molybdène type a WO2017019532A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7504095B2 (en) 2004-01-29 2009-03-17 Technische Universitaet Braunschweig Method for obtaining precursor Z and use thereof for the production of a means for therapy of human molybdenum cofactor deficiency
WO2012112922A1 (fr) 2011-02-18 2012-08-23 Alexion Pharmaceuticals, Inc. Procédés de synthèse de dérivés z de précurseur de molybdoptérine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7504095B2 (en) 2004-01-29 2009-03-17 Technische Universitaet Braunschweig Method for obtaining precursor Z and use thereof for the production of a means for therapy of human molybdenum cofactor deficiency
WO2012112922A1 (fr) 2011-02-18 2012-08-23 Alexion Pharmaceuticals, Inc. Procédés de synthèse de dérivés z de précurseur de molybdoptérine

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ALEX VELDMAN ET AL: "Successful Treatment of Molybdenum Cofactor Deficiency Type A With cPMP", PEDIATRICS, AMERICAN ACADEMY OF PEDIATRICS, vol. 125, no. 5, 1 January 2010 (2010-01-01), pages e1249 - e1254, XP009192092, ISSN: 0031-4005, DOI: 10.1542/PEDS.2009-2192 *
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