US20220040175A1 - Infigratinib for treatment of fgfr3-related skeletal diseases during pregnancy - Google Patents

Infigratinib for treatment of fgfr3-related skeletal diseases during pregnancy Download PDF

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Publication number
US20220040175A1
US20220040175A1 US17/280,620 US201917280620A US2022040175A1 US 20220040175 A1 US20220040175 A1 US 20220040175A1 US 201917280620 A US201917280620 A US 201917280620A US 2022040175 A1 US2022040175 A1 US 2022040175A1
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fgfr3
treatment
infigratinib
bgj398
mutant
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Laurence Legeai-Mallet
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Assistance Publique Hopitaux de Paris APHP
Institut National de la Sante et de la Recherche Medicale INSERM
Fondation Imagine
Universite Paris Cite
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Assistance Publique Hopitaux de Paris APHP
Institut National de la Sante et de la Recherche Medicale INSERM
Universite de Paris
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Publication of US20220040175A1 publication Critical patent/US20220040175A1/en
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Assigned to UNIVERSITÉ PARIS CITÉ reassignment UNIVERSITÉ PARIS CITÉ CORRECTIVE ASSIGNMENT TO CORRECT THE PROPERTY NUMBERS PREVIOUSLY RECORDED AT REEL: 060390 FRAME: 0122. ASSIGNOR(S) HEREBY CONFIRMS THE CHANGE OF NAME. Assignors: Universite De Paris
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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
    • A61K31/33—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders

Definitions

  • the present invention relates to methods for treatment of FGFR3-related skeletal diseases during pregnancy.
  • Fibroblast growth factor receptors are a family of five receptor tyrosine kinases (RTKs) and are important regulators of skeleton development during endonchondral and membranous ossification throughout embryonic and postnatal development.
  • FGFR3 is expressed in both bone and cartilage and FGFR3 signaling regulates a variety of biological events during skeletal development.
  • FGFR3 gain-of-function mutations are responsible for a family of chondrodysplasias namely, achondroplasia (ACH) the most common form of dwarfism, a lethal form of dwarfism thanatophoric dysplasia (TD) as well as and hypochondroplasia (HCH).
  • ACH achondroplasia
  • TD lethal form of dwarfism thanatophoric dysplasia
  • HH hypochondroplasia
  • FGFR3 plays a significant role in growth plate cartilage, acting to inhibit both the rate of proliferation and the initiation of the chondrocyte hypertrophy.
  • NVP-BGJ398 Infigratinib (NVP-BGJ398) corrects pathological hallmarks of ACH and support it as a potential therapeutic approach for FGFR3-related skeletal diseases (Komla-Ebri, D., Dambroise, E., Kramer, I., Benoist-Lasselin, C., Kaci, N., Le Gall, C. & Kneissel, M. (2016). Tyrosine kinase inhibitor NVP - BGJ 398 functionally improves FGFR 3- related dwarfism in mouse model.
  • the present invention relates to methods for treatment of FGFR3-related skeletal diseases during pregnancy.
  • the present invention is defined by the claims.
  • the present invention relates to a method of treating a FGFR3-related skeletal disease in a fetus comprising administering to the pregnant subject an effective amount of Infigratinib.
  • the term “subject” denotes a mammal, such as a rodent, a feline, a canine, and a primate. Particularly, the subject according to the invention is a human. As used herein, the term “subject” encompasses “patient”.
  • FGFR3 FGFR3 tyrosine kinase receptor
  • FGFR3 receptor FGFR3 receptor
  • SEQ ID NO:1 An exemplary human amino acid sequence of FGFR3 is represented by SEQ ID NO:1.
  • the expressions “constitutively active FGFR3 receptor variant”, “constitutively active mutant of the FGFR3” or “mutant FGFR3 displaying a constitutive activity” are used interchangeably and refer to a mutant of said receptor exhibiting a biological activity (i.e. triggering downstream signaling), and/or exhibiting a biological activity which is higher than the biological activity of the corresponding wild-type receptor in the presence of FGF ligand.
  • a constitutively active FGFR3 variant according to the invention is in particular chosen from the group consisting of (residues are numbered according to their position in the precursor of fibroblast growth factor receptor 3 isoform 1-806 amino acids long-): a mutant wherein the serine residue at position 84 is substituted with lysine (named herein below S84L); a mutant wherein the arginine residue at position 248 is substituted with cysteine (named herein below R200C); a mutant wherein the arginine residue at position 248 is substituted with cysteine (named herein below R248C); a mutant wherein the serine residue at position 249 is substituted with cysteine (named herein below S249C); a mutant wherein the proline residue at position 250 is substituted with arginine (named herein below P250R); a mutant wherein the asparagine residue at position 262 is substituted with histidine (named herein below N262H); a mutant
  • FGFR3-related skeletal disease is intended to mean a skeletal disease that is caused by an abnormal increased activation of FGFR3, in particular by expression of a constitutively active mutant of the FGFR3 receptor, in particular a constitutively active mutant of the FGFR3 receptor as described above.
  • the term encompasses FGFR3-related chondrodysplasia and FGFR3-related craniosynostosis.
  • FGFR3-related chondrodysplasias include but are not limited to thanatophoric dysplasia type I, thanatophoric dysplasia type II, hypochondroplasia, achondroplasia and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans).
  • the FGFR3-related skeletal osteochondrodysplasia is caused by expression in the subject of a constitutively active FGFR3 receptor variant such as defined above.
  • the FGFR3-related chondrodysplasia is an achondroplasia caused by expression of the G380R constitutively active mutant of the FGFR3 receptor.
  • the FGFR3-related chondrodysplasia is a hypochondroplasia caused by expression of the N540K, K650N, K650Q, S84L, R200C, N262H, G268C, Y278C, S279C, V381E, constitutively active mutant of the FGFR3 receptor.
  • the FGFR3-related chondrodysplasia is a thanatophoric dysplasia type I caused by expression of a constitutively active mutant of the FGFR3 receptor chosen from the group consisting of R248C, S248C, G370C, S371C; Y373C, X807R, X807C, X807G, X807S, X807W and K650M FGFR3 receptors.
  • the FGFR3-related chondrodysplasia is a thanatophoric dysplasia type II caused by expression of the K650E constitutively active mutant of the FGFR3 receptor.
  • the FGFR3-related chondrodysplasia is a severe achondroplasia with developmental delay and acanthosis nigricans caused by expression of the K650M constitutively active mutant of the FGFR3 receptor.
  • the FGFR3-related craniosynostosis is Muenke syndrome caused by expression of the P250R constitutively active mutant of the FGFR3 receptor or Crouzon syndrome with acanthosis nigricans caused by expression of the A391E constitutively active mutant of the FGFR3 receptor.
  • Prenatal diagnosis of FGFR3-related skeletal diseases is routinely performed and typically includes ultrasound evaluation and confirmed by both genetic testing (i.e. DNA testing for mutations of FGFR3) using invasive diagnosis (e.g. amniocentesis or chorionic biopsy) or non-invasive prenatal diagnosis (NIPD) such as fetal DNA isolated from maternal blood.
  • genetic testing i.e. DNA testing for mutations of FGFR3
  • invasive diagnosis e.g. amniocentesis or chorionic biopsy
  • NIPD non-invasive prenatal diagnosis
  • treatment refers to both prophylactic or preventive treatment as well as curative, improving the patient's condition or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a “loading regimen”, which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at regular intervals, e.g., daily, weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]).
  • a “therapeutically effective amount” of the Infigratinib as above described is meant a sufficient amount to provide a therapeutic effect. It will be understood, however, that the total daily usage of the Infigratinib will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific polypeptide employed; and like factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the Infigratinib of the present invention is administered to the subject in the form of a pharmaceutical composition.
  • the Infigratinib may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.
  • pharmaceutically acceptable excipients such as a carboxylate, a carboxylate, a carboxylate, a carboxylate, a carboxylate, or adiluent, encapsulating material or formulation auxiliary of any type.
  • the active principle in the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
  • Infigratinib is orally or subcutaneously administered.
  • suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, as well as sublingual and buccal administration forms.
  • Infigratinib can be formulated into a composition in a neutral or salt form.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
  • Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine,
  • FIG. 1 (A-C) the measures of the upper limbs (humerus (A), ulna (B), radius (C)) showed a significant improvement of the length with BGJ398.
  • FIG. 2 (A-B) the measures of the lower limbs (femur (A), tibia (B)) showed an improvement of the length with BGJ398.
  • FGFR3-related chondrodysplasias encompass the most frequent chondrodysplasias (achondroplasia and hypochondroplasia) and Craniosynostoses (Muenke syndrome). All these osteochondrodysplasias are due to Fgfr3 germinal mutations, these Fgfr3 gain-of-function mutations impair the chondrogenesis and osteogenesis during the formation of the skeleton.
  • BGJ398 (4 mg/kg) subcutaneously in 5 pregnant mice at day E14.5 continuing daily through day 1 (after birth).
  • the pregnant mice received 5 injections of BGJ398 before delivery.
  • isofluorane inhalation was applied to the pregnant mice during 20 seconds before the subcutaneous injections. All the pups were analyzed at day 1 after birth. At necropsy, all the long bones were measured and embedded in paraffin and were submitted to histology and immunology.
  • the measures of the upper limbs showed a significant improvement of the length ( FIGS. 1A, 1B and 1C ).
  • the increase of the length of humerus, ulna, radius are +4.35%, +6.12%, 4.1% respectively.

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US17/280,620 2018-09-28 2019-09-27 Infigratinib for treatment of fgfr3-related skeletal diseases during pregnancy Abandoned US20220040175A1 (en)

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EP18306275.1 2018-09-28
EP18306275 2018-09-28
PCT/EP2019/076241 WO2020065034A1 (fr) 2018-09-28 2019-09-27 Infigratinib pour le traitement de maladies du squelette associées à fgfr3 pendant la grossesse

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US20230241061A1 (en) * 2020-06-11 2023-08-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of fgfr3-related cognitive deficit
CN116887822A (zh) * 2020-12-18 2023-10-13 奎德治疗学股份有限公司 治疗软骨发育不全的方法
WO2023117879A1 (fr) * 2021-12-20 2023-06-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'un inhibiteur de la tyrosine kinase de fgfr3 pour le traitement des troubles de réparation et de formation d'os liés au fgfr

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US20160051549A1 (en) * 2011-12-12 2016-02-25 Institut National De La Sante Et De La Recherche Medicale (Inserm) Antagonist of the fibroblast growth factor receptor 3 (fgfr3) for use in the treatment or the prevention of skeletal disorders linked with abnormal activation of fgfr3

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WO2013088191A1 (fr) * 2011-12-12 2013-06-20 Institut National De La Sante Et De La Recherche Medicale (Inserm) Antagoniste du récepteur 3 du facteur de croissance des fibroblastes (fgfr3) à utiliser dans le traitement ou la prévention de troubles squelettiques liés à une activation anormale du fgfr3

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US20160051549A1 (en) * 2011-12-12 2016-02-25 Institut National De La Sante Et De La Recherche Medicale (Inserm) Antagonist of the fibroblast growth factor receptor 3 (fgfr3) for use in the treatment or the prevention of skeletal disorders linked with abnormal activation of fgfr3

Non-Patent Citations (4)

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Title
Jin M, et al. A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the lethal phenotype of mice mimicking human thanatophoric dysplasia. Hum Mol Genet. 2012 Dec 15;21(26):5443-55. (Year: 2012) *
M. Jin et. al. (A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the lethal phenotype of mice mimicking human thanatophoric dysplasia. Hum Mol Genet. 2012 Dec 15;21(26):5443-55. (Year: 2012) *
Matsushita et. al. (M. Matsushita et al. Maternal administration of meclozine for the treatment of foramen magnum stenosis in transgenic mice with achondroplasia. J Neurosurg Pediatr. 2017 Jan;19(1):91-95. (Year: 2017) *
Matsushita M, Mishima K, Esaki R, Ishiguro N, Ohno K, Kitoh H. Maternal administration of meclozine for the treatment of foramen magnum stenosis in transgenic mice with achondroplasia. J Neurosurg Pediatr. 2017 Jan;19(1):91-95. (Year: 2017) *

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WO2020065034A1 (fr) 2020-04-02
JP2022502408A (ja) 2022-01-11
EP3856187A1 (fr) 2021-08-04

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