Classifications

• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• • 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 and pharmaceutical compositions for the treatment of FGFR3 -related chondrodysplasias.
• “Rare diseases” are diseases with a particularly low prevalence. In this manner, the European Union considers diseases to be rare when they affect not more than 5 per 10,000 persons (Rodwell and Ayme, 20l4a). As example, achondroplasia presents an estimated prevalence of 2.6 per 100,000 persons in EU (Orphanet, 2014). In this sense, rare diseases were defined for first time in EU Regulation (EC) N° 141/2000 ( Regulation (EC) N° 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products ).
• RTKs Receptor tyrosine kinases
• This RTKs type plays an essential role in the regulation of homeostasis of the cartilage e.g. chondrocyte differentiation, proliferation and apoptosis, and is required for normal skeleton development as well as regulation of both osteogenesis and postnatal bone mineralization by osteoblasts (UniProt, n.d.).
• Achondroplasia a nonlethal form of chondrodysplasia, is the most common type of dwarfism. It is mostly due to de novo mutation and has an autosomal dominant inheritance (Rousseau et ah, 1994; Di Rocco et ah, 2014).
• the mutation which produce an increase of FGFR3 function, affects many tissues, most strikingly the cartilaginous growth plate and bone in the growing skeleton, leading to a variety of manifestations and complications.
• FGFR3 signal transducer and activator of transcription 1
• MAPK mitogen activated protein kinase
• PLCy phospholipase C g
• PI3K-AKT phosphatidylinositol phosphate-3-kinaseserine/threonine kinase
• Cocoa ( Theobroma cacao ) is a major, economically important, international crop, which has been related to several nutritional benefits including high antioxidant capacity. These healthy properties have been associated with the phenolic fraction (Andujar et al., 2012; Cadiz-Gurrea et al., 2015).
• the main subclass of flavonoids found in cocoa is flavanols, particularly (epi)catechins monomers, and their oligomers, also known as procyanidins which range from dimers to decamers (Cadiz-Gurrea et ak, 2014).
• the present invention relates to methods and pharmaceutical compositions for the treatment of FGFR3 -related chondrodysplasias.
• the present invention is defined by the claims.
• the present invention relates to a method of treating a FGFR3-related chondrodysplasia in a patient in need thereof consisting in administering to the subject a therapeutically effective amount of a substantially pure (-)-epicatechin.
• the present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of a substantially pure (-)-epicatechin for use in a method of treating a FGFR3-related chondrodysplasia in a patient in need thereof.
• the term“FGFR3 -related chondrodysplasia” 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 after.
• the terms“FGFR3”, “FGFR3 tyrosine kinase receptor” and“FGFR3 receptor” are used interchangeably throughout the specification and refer to all of the naturally-occurring isoforms of FGFR3.
• 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 iso form 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);
• the FGFR3-related skeletal diseases are FGFR3-related chondrodysplasias and FGFR3-related craniosynostosis.
• the FGFR3- related skeletal osteochondrodysplasias correspond to an inherited or to a sporadic disease.
• the term“FGFR3 -related skeletal dysplasias” includes but is not limited to thanatophoric dysplasia type I, thanatophoric dysplasia type II, hypochondroplasia, achondroplasia and S ADD AN (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 corresponds to an inherited or to a sporadic disease.
• 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.
• 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.]).
• (-)-epicatechin has its general meaning in the art and refers to (2R,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol.
• the methods of producing or extracting (-)-epicatechin are well known to the skilled person.
• the term“substantially pure” refers to the total absence, or near total absence, of impurities, such as related-substance impurities.
• impurities such as related-substance impurities.
• a (-)- epicatechin composition is said to be substantially pure, there are either no detectable related- substance impurities, or if a single related-substance impurity is detected, it is present in an amount no greater than 0.1 % by weight, or if multiple related- substance impurities are detected, they are present in aggregate in an amount no greater than 0.6% by weight.
• the patient is administered with a pharmaceutical composition
• a pharmaceutical composition comprising the substantially pure (-)-epicatechin as active principle and at least one pharmaceutically acceptable excipient.
• active principle or“active ingredient” are used interchangeably.
• the active principle is used to alleviate, treat or prevent a medical condition or disease.
• pharmaceutically acceptable excipient it is understood a carrier medium which does not interfere with the effectiveness of the biological activity of the active ingredient(s) and which is not excessively toxic to the host at the concentration at which it is administered.
• Said excipients are selected, depending on the pharmaceutical form and the desired method of administration, from the usual excipients known by a person skilled in the art.
• the pharmaceutical composition of the present invention does not comprise a second active principle. Accordingly, in some embodiments, the pharmaceutical composition of the present invention is not a Theobwma cacao extract as described in WO 2016046375. In some embodiments the pharmaceutical composition does not comprises an amount of flavonols, sweroside, and hexenyl 5 xylopyranosyl glucopyranoside. In some embodiments, the pharmaceutical composition of the present invention does not comprise an amount of procyanidin, catechin, cinchonain and derivatives thereof.
• the pharmaceutical composition does not comprises an amount of 3,4-N-phenylpropenoyl-L- aminoacid or derivative thereof chosen from /V-caffeoyl-L-aspartate, L-Aspartic acid, A/-[3- (4-hydroxyphenyl)-l - oxo-2-propenyl], L-Aspartic acid, A/-[3-(4-hydroxy-3-methoxyphenyl)- 1 -oxo-2- propenyl], trans-clovamide (A/-[(2E)-3-(3,4-dihydroxyphenyl)-l -oxo-2-propen-l - yl]- 3-hydroxy-L-tyrosine), deoxyclovamide (A/-[(2E)-3-(3,4-dihydroxyphenyl)-l -oxo-2- propen-l -yl]-L-tyrosine) and derivatives thereof.
• the pharmaceutical composition of the present invention does not comprise a compound selected from the group consisting of quercetin, quercetin glucuronide, quercetin hexose, quercetin arabinoside and isomers thereof and/or said at least one procyanidin, catechin, cinchonain and derivative thereof chosen from proanthocyanidin A, (epi)catechin, (epi)catechin dimer hexose, arabinopyranosyl- (epi)catechin-(epi)catechin, (epi)gallocatechin, (epi)catechin glucopyranoside, catechin diglucopyranoside, cinchonain I, (epi)catechin tetramer, (epi)catechin pentamer, (epi)catechin hexamer, (epi)catechin methyl dimer, (epi)catechin ethyl dimer, procyan
• the pharmaceutical composition does not comprises an amount of procyanidin B; (epi)catechin tetramer; (epi)catechin pentamer; hexenyl xylopyranosyl glucopyranoside; (epi)catechin dimer hexose; arabinopyranosyl- (epi)catechin-(epi)catechin; - procyanidin C; - proanthocyanidin A; (epi)catechin ethyl dimer; quercetin; quercetin hexose; - cinchonain I; procyanidin A; and sweroside.
• a “therapeutically effective amount” of the substantially pure (-)-epicatechin 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 substantially pure (-)-epicatechin 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.
• FIGURES are a diagrammatic representation of FIGURES.
• FIG. 3 (A, B, C). BPC of eleven obtained fractions from PC Sep-Pak fraction by HPLC-ESI-TOF-MS.
• Figure 7 Representative data of treatments of TD human chondrocyte lines using FGF2 (lOOng/ml) and fraction 5 (lOOpg/ml). p* 0.0212
• Figure 8 Representative data of treatments of ACH human chondrocyte lines using FGF2 (lOOng/ml) and fraction 5 (lOOpg/ml). p** 0.0038
• Figure 9 Representative picture of femurs treated with fraction 5 (lOpg/ml).
• Figure 10 Graphic representation of femur length and % of growth of the femurs treated with F5 (lOpg/ml).
• FIG. 1 Representative picture of femurs treated with (-)-epicatechin (lOpg/ml).
• Figure 12 Graphic representation of femur length and % of growth of the femurs treated with (-)-epicatechin (lOpg/ml).
• Figure 13 Graphic representation of femur length and % of growth of the femurs treated with (-)-epicatechin (lpg/ml).
• Diethyl ether and methanol for extraction were purchased from Fisher (Fisher Scientific Co., Fair Lawn, NJ), ethyl acetate from Lab-Scan (Gliwice, Sowinskiego, Tru), ethanol and acetone from AnalaR Normapur (VWR International, Inc., Darmstadt, Germany) and dimethyl sulfoxide (DMSO) was purchased from Panreac (Barcelona, Spain) for analytical assays (-)-epicatechin was purchased from Sigma-Aldrich (St Louis, MO, USA). Water was purified by a Milli-Q system from Millipore (Bedford, MA, USA). Deuterated solvents such as dimethylsulfoxide were purchased from Eurisotop (France). For NMR analysis, the sample was dissolved in dimethylsulfoxide-d6 and transferred in an oven-dried 5 mm NMR tube for spectral analysis.
• a concentrated T. cacao extract was used in this study (Molteoleder, Spain).
• the polyphenols from whole cocoa matrix were analytically characterized using a solution of cocoa extract of 10 mg/mL in DMSO.
• a solution stock of 0.1 g/mL was prepared by dissolving the appropriate amount of cacao extract in DMSO. The sample was sonicated for 5 min, vortexed for 1 min, and then centrifuged for 5 min at 7700 g before the cartridges purification.
• a solution stock of 75 mg/mL was prepared by dissolving the PC fraction of Cl 8 Sep-Pak cartridges in DMSO. The sample was sonicated for 5 min, vortexed for 1 min, and then centrifuged for 5 min at 7700 g before the semi-preparative HPLC analysis.
• T. cacao and isolated fractions were analytically characterized using an Agilent 1200 series rapid-resolution LC system (AgilentTechnologies, Palo Alto, CA, USA) equipped with a binary pump, an autosampler and a diode-array detector (DAD).
• the HPLC system was coupled to a time-of-flight (TOF) mass spectrometer (Bruker Daltonics, Bremen, Germany) equipped with an electrospray ionization (ESI) interface (model G1607A from Agilent Technologies, Palo Alto, CA).
• TOF time-of-flight
• ESI electrospray ionization
• T. cacao extract prepared as describe above in sample preparation section was fractionated by Waters Cl 8 Sep-Pak cartridges following the method describe by Sun et al. (Sun et al., 2006) and Monagas et al. (Monagas et al., 2003) with some modifications. Five different fractions were obtained: phenolic acids (PA fraction), monomeric and oligomeric flavan-3-ols (PC fraction), polymeric proanthocyanidins (PP fraction), monomers (MN fraction) and oligomers (OL fraction).
• PA fraction phenolic acids
• PC fraction monomeric and oligomeric flavan-3-ols
• PP fraction polymeric proanthocyanidins
• MN fraction monomers
• OL fraction oligomers
• the compounds from the T. cacao and fractions were separated following the method described by Cadiz-Gurrea et al. (Cadiz-Gurrea et al., 2014) with this modifications: the HPFC system was coupled to a TOF mass spectrometer equipped with an ESI interface operating in negative ion mode using a capillary voltage of +3.5 kV.
• the other optimum values of the source parameters were: drying gas temperature, 200 °C; drying gas flow, 10 L/min; and nebulizing gas pressure, 2.3 bar. The detection was performed considering a mass range of 50-1200 m/z.
• the samples were injected in triplicate to ensure the repeatability of the analysis.
• NMR spectra was recorded at 293 ⁇ 0.1 K on a Bruker Avance III 600 spectrometer operating at a proton frequency of 600.13 MHz using a 5 mm QCI quadruple resonance pulse field gradient cryoprobe.
• the sample was measured, without rotation and using 8 dummy scans prior to 128 scans.
• TOCSY 1H-1H total correlation spectroscopy
• HSQC 1H-13C heteronuclear single quantum coherence
• HMBC 1H-13C heteronuclear multiple bonds coherence
• the HMBC spectrum was recorded with the same parameters used in the HSQC spectra except for 37729.71 Hz of spectral width in F 1.
• the coupling constant for HSQC experiment was fixed to 145 Hz whereas HMBC experiment was obtained using fixed coupling constants of 145 and 8 Hz (long range).
• the F5 from cocoa extract was evaluated in vitro using chondrocyte lines expressing human FGFR3 gain-of-function mutations.
• the cells were depleted during 24 hours, we tested various concentrations (50, 100, 200 Lig/m 1 ) of F5 from cocoa.
• the cocoa fraction was added in the medium then the cells were stimulated with a ligand of the receptor FGF2 (Fibroblast Growth Factor).
• FGF2 Fibroblast Growth Factor
• the levels of phosphorylated Erkl/2 and Erkl/2 were measured using the Li-Cor technology and Imager.
• BSA Sigma
• cocoa F5 or (-)-epicatechin (Sigma-0394-05-90) or DMSO (as control) at a concentration of 10 and 30 Lig/ml.
• the left femur was cultured in supplemented medium and compared with the right one cultured in control medium. The bone length was measured at the beginning (before treatment) and at the end of time course.
• Fgfr3 +/+ and Fgfr3 Y367C/+ mice were determined by PCR of tail DNA as previously described (Pannier et al., Biochim Biophys Acta, 1792: 140-147, 2009). All experimental procedures and protocols were approved by the Animal Care and Use Committee.
• mice IgGl anti-y-tubulin (Sigma-Aldrich #T6557, 1 : 1000) and rabbit anti-Arll3b (Proteintech #177111-AR, 1 :500).
• Cells were washed with PBS, and then incubated with goat anti-mouse IgGl coupled with AlexaFluor 488 (Life Technologies, 1 : 1000) and goat anti-rabbit coupled with AlexaFluor 647 (Life Technologies, 1 : 1000) secondary antibodies for 2h at room temperature in the dark. Samples were extensively washed and mounted with a solution of DAPI-Fluoromount G (SouthemBiotech) containing DAPI (4’, 6’- diamidino-2-phenylindole) for nuclear staining.
• DAPI-Fluoromount G SouthemBiotech
• Image acquisition were captured using a Spinning disk confocal microscope.
• the system is composed by a Yokogawa CSU-X1 spinning disk scanner coupled to a Zeiss Observer Zl inverted microscope and controlled by Zen Blue software.
• Tile images were acquired with a Plan Apochromat 63x oil immersion objective (NA 1.46) through a Hamamatsu Orca Flash 4.0 sCMOS Camera.
• All confocal experiments showing PC length was acquired in same conditions using slice thickness of 0.20mhi and a pixel size of 60nm.
• Post-treatment analyses were performed with FIJI (Fiji Is Just ImageJ; NIH) and Imaris v8.3 software (Bitplane).
• FIJI Fiji Is Just ImageJ; NIH
• Imaris v8.3 software (Bitplane).
• We next measured in 2D the PC lengths by IMARIS software (
• the Figure 1 showed the different profiles (base peak chromatograms and characterized compounds), which were obtained by Sep-Pak C 18 cartridges.
• This proposed method permitted separating phenolic compounds from the whole T. cacao extract into various different fractions, which were less complex, enabling their use in order to achieve pure fractions of interested compounds.
• eleven fractions were obtained by combination of solid phase extraction by Sep-Pak Cl 8 cartridges and semi-preparative HPLC isolation in order to obtain purified fractions of monomeric and oligomeric PAs (Figure 2).
• the composition of each one was established by the detailed HPLC-ESI-TOF-MS ( Figure 3 A, B and C).
• F5 was selected as a candidate for the biological experiments in achondroplasia model.
• Figure 4 showed the 1 H spectra in DMSO-d6 for F5 where the most abundant compound corresponded to (-)-epicatechin ( Figure 5).
• Table 1 contains the 1 H and 13 C NMR data obtained in this work for (-)-epicatechin in F5 from cacao sample.
• the identification of similar substances as (+)-catechin and (-)- epicatechin was carried out on the basis of the spectroscopic data of aliphatic protons H-3(C) and H-2(C).
• High values of the coupling constant 3 / 2, 3 (8-10 Hz) indicate the presence of (+)catechin, whereas 3 / 2, 3 values round 2 Hz or broad singlet demonstrated the presence of (-)- epicatechin in our cacao fraction.
• F5 has been evaluated for a concentration of 10 pg/ml. The percentage of femur growth was more important in Fgfr3 Y367(/+ mice than in the Fgfr3 +/+ mice. F5 significantly increased the length of the Fgfr3 Y367C/+ femurs comparing to Fgfr3 +/+ femurs ( Figure 9). F5 did not impair the growth of the Fgfr3 +/+ femurs ( Figure 10).
• the immunohistological analyses showed a slight modification of the collagen type X expression in proximal and distal femurs treated with F5.
• the analyses of the both proximal and distal femur did not show obvious modification of the epiphysis size.
• collagen type X was not modified in proximal and distal femurs, while the expressions of FGFR3 and Sox9 were strongly decreased in proximal and distal femurs. Interestingly, the phosphorylated Erkl/2 expression was slightly decreased in proximal and distal femurs treated with (-)-epicatechin.
• Figure 14 showed a graphical representation of length of the average primary cilium Fgfr3 Y367C/+ chondrocytes with and without (-)-Epicatechine treatment (h>100).
• the data represent mean+S.E.M., two-tailed unpaired t-test. ns, not significant; *p ⁇ 0.05, ***p ⁇ 0.00l, ****p ⁇ 0.000l .
• n is the number of primary cilium measured
• N is the number of cultured chondrocytes analyzed
• A is the average of the length of the primary cilium.
• the addition of (-)-epicatechin leads to an elongation of primary cilium.
• Orphanet 2014. Prevalence of rare diseases : Bibliographic data. Orphanet Rep. Ser. 1-

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