Givinostat hydrochloride monohydrate for use in treating muscular dystrophy

Abstract

An improved method for treating muscular dystrophy in a patient is disclosed, comprising administering Givinostat hydrochloride monohydrate to a patient in need of such a treatment wherein the daily amount of Givinostat hydrochloride monohydrate which is administered to the patient depends on the body weight of the patient him / herself.

Description

[0001] Ref.: 24ST13IWO

[0002] Title

[0003] Givinostat hydrochloride monohydrate for use in treating muscular dystrophy

[0004] *****

[0005] The object of the present invention is an improved method for treating muscular dystrophy in a patient, comprising administering Givinostat hydrochloride monohydrate to a patient in need of such a treatment, wherein the daily amount of Givinostat hydrochloride monohydrate which is administered to the patient depends on the body weight of the patient to be treated.

[0006] State of the Art

[0007] Givinostat is a hydroxamic acid that acts as an inhibitor of Histone Deacetylase (HDAC) and exerts its action on the homonymous class I and II enzymes.

[0008] The chemical name of Givinostat is [6-(diethylaminomethyl)naphthalen-2- yl]methyl[4(hydroxycarbamoyl) phenyl]carbamate; Givinostat is also known as ITF2357 and it is normally used in the form of hydrochloride salt, in particular the hydrochloride monohydrate salt.

[0009] The chemical structure of Givinostat hydrochloride monohydrate is shown below:

[0010] US9421184 discloses a method for treating muscular dystrophy by administering

[0011] Givinostat hydrochloride, preferably Givinostat hydrochloride monohydrate. Ref.: 24ST13IWO

[0012] US9867799 discloses a method for treating muscular dystrophy by administering Givinostat hydrochloride, preferably Givinostat hydrochloride monohydrate, together with an anti-inflammatory agent, such as a steroid.

[0013] US2018311160 discloses an aqueous suspension comprising Givinostat and / or pharmaceutically acceptable salts and / or derivatives thereof, at least a wetting agent and / or at least a density-imparting agent.

[0014] Givinostat has been used in clinical trials for Muscular Dystrophies (Duchenne and Becker Muscular Dystrophies), for inflammatory diseases and for blood cancers (polycythemia vera, myelomas and lymphomas), including a Phase III study in Duchenne Muscular Dystrophy.

[0015] Mercuri et al., The Lancet, Vol. 3 April 2024, discloses the outcome of multicentre, randomised, double-blind, placebo-controlled, phase 3 trial, also referred to as Study 48. Eligible participants were ambulant, male, aged at least 6 years and had a genetically confirmed diagnosis of Duchenne muscular dystrophy. The purpose of the trial was aimed at evaluating the safety and efficacy of Givinostat hydrochloride monohydrate in the treatment of Duchenne muscular dystrophy. The dose was flexible, based on weight, and was reduced if not tolerated.

[0016] Definitions

[0017] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference; thus, the inclusion of such definitions herein should not be construed to represent a substantial difference over what is generally understood in the art. Ref.: 24ST13IWO

[0018] The term “physiologically acceptable excipient” herein refers to a substance devoid of any pharmacological effect of its own and which does not produce adverse reactions when administered to a mammal, preferably a human. Physiologically acceptable excipients are well known in the art and are disclosed, for instance in the Handbook of Pharmaceutical Excipients, sixth edition 2009, herein incorporated by reference.

[0019] The terms “comprising”, “having”, “including” and “containing” are to be construed open-ended terms (i.e. meaning “including, but not limited to”) and are to be considered as providing support also for terms as “consist essentially of”, “consisting essentially of”, “consist of” or “consisting of”.

[0020] The terms “consists essentially of”, “consisting essentially of” are to be construed as semi-closed terms, meaning that no other ingredients which materially affects the basic and novel characteristics of the invention are included (optional excipients may thus be included).

[0021] The terms “consists of”, “consisting of” are to be construed as closed terms.

[0022] The term “adverse reaction” means a decrease in platelets, diarrhea and / or an increase in triglycerides such as, for instance:

[0023] • platelet count <150 x 109 / L verified in two assessments one week apart;

[0024] • moderate or severe diarrhea;

[0025] • fasting triglycerides >300 mg / dL verified by two assessments one week apart.

[0026] The term “simultaneous, separate or sequential administration” herein refers to administration of the first and second compound at the same time or in such a manner that the two compound act in the patient’s body at the same time or administration of one compound after the other compound in such a manner to provide a therapeutic effect. In some embodiments the compounds are taken with a meal. In other embodiments, the compounds are taken after a meal, such as 30 Ref.: 24ST13IWO minutes or 60 minutes after a meal. In some embodiments, one compound is administered to a patient for a time period followed by administration of the other compound.

[0027] Figures

[0028] Figure 1 : Predicted AUC0-12 at Dose A by patients’ weight class prior to the conduct of Study 48.

[0029] Figure 2: Simulated AUC0-12 at Dose A by patients’ weight class based on the study 48 population pk model.

[0030] Figure 3: Simulated PLT levels at Dose A by patients’ weight class based on the Study 48 population pk / pd model.

[0031] Figure 4: Probability of dose reduction by starting dose and body weight class.

[0032] Figure 5: Comparing simulated Givinostat (steady state) auco-12 after starting dose (dose a) stratified by weight categories in subjects receiving the original 9-weight bands Givinostat dose regimen and the revised 4-weight bands Givinostat dose regimen.

[0033] Description of the invention

[0034] The present invention relates to a method for treating muscular dystrophy, comprising administering a starting dose of Givinostat hydrochloride monohydrate to a patient in need of such a treatment wherein: a. about 22.5 to about 27.5 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 10 kg to less than 20 kg; Ref.: 24ST13IWO b. about 31.5 to about 38.5 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 20 kg to less than 40 kg; c. about 45 to about 55 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 40 kg to less than 60 kg; d. about 54 to about 66 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 60 kg or more. According to a preferred embodiment of the invention: a. about 25 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 10 kg to less than 20 kg; b. about 35 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 20 kg to less than 40 kg; c. about 50 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 40 kg to less than 60 kg; d. about 60 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 60 kg or more.

[0035] In case of adverse reactions, the starting dosage disclosed above may be reduced as follows: a. about 18 to 22 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 10 kg to less than 20 kg; b. about 22.5 to 27.5 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 20 kg to less than Ref.: 24ST13IWO c. about 31.5 to 38.5 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 40 kg to less than 60 kg; d. about 40.5 to 49.5 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 60 kg or more.

[0036] According to a preferred embodiment of the invention, in case of adverse reactions the starting dosage is reduced as follows: a. about 20 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 10 kg to less than 20 kg; b. about 25 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 20 kg to less than 40 kg; c. about 35 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 40 kg to less than 60 kg; d. about 45 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 60 kg or more.

[0037] In case of persisting adverse reactions after the first dosage reduction, the dosage may be further reduced as follows: a. about 13.5 to 16.5 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 10 kg to less than 20 kg; b. about 18 to 22 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 20 kg to less than 40 kg; c. about 27 to 33 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 40 kg to less than 60 kg; Ref.: 24ST13IWO d. about 36 to 44 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 60 kg or more.

[0038] According to a preferred embodiment of the invention, in case of persisting adverse reactions after the first dosage reduction, the dosage is further reduced as follows: a. about 15 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 10 kg to less than 20 kg; b. about 20 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 20 kg to less than 40 kg; c. about 30 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 40 kg to less than 60 kg; d. about 40 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 60 kg or more.

[0039] According to a preferred embodiment of the invention, the muscular dystrophy is Duchenne, Becker or Limb Girdle muscular dystrophy.

[0040] According to a preferred embodiment of the invention, the patient is 6 years of age or older, more preferably he / she is 6 to 18 years old.

[0041] According to a preferred embodiment of the invention, Givinostat hydrochloride monohydrate is in crystal form.

[0042] According to a preferred embodiment of the invention, Givinostat hydrochloride monohydrate is administered in the form of a pharmaceutical composition comprising the same together with at least one physiologically acceptable excipient.

[0043] According to an embodiment of the invention, the pharmaceutical composition may be administered by oral, sublingual, rectal, intravascular, intravenous, or subcutaneous route; preferably by oral route. Ref.: 24ST13IWO

[0044] According to an embodiment of the invention, the pharmaceutical composition is in a solid or a liquid form.

[0045] More in details, the solid form may be selected from the group consisting of powder, tablet, granulate, aggregate, compressed pill, coated pill, hard gelatin capsule, and gelatin capsule; the liquid form may be a suspension or a syrup.

[0046] According to an embodiment of the invention, the suspension may comprise at least a wetting agent and / or at least a density-imparting agent and / or at least a buffering agent and / or at least a suspending agent.

[0047] According to a preferred embodiment of the invention, the at least a wetting agent is a polyoxyethylene sorbitan fatty acid ester, poloxamer or a mixture thereof; the at least a density-imparting agent is sorbitol, sucrose or a mixture thereof; the at least a buffering agent is a phosphate buffer, citrate buffer, or tartrate buffer; the at least a suspending agent is tragacanth gum or xanthan gum.

[0048] According to a more preferred embodiment of the invention, the suspension essentially comprises Givinostat hydrochloride monohydrate, a polyoxyethylene sorbitan fatty acid ester, sorbitol, a tartrate buffer and tragacanth gum.

[0049] According to an embodiment of the invention, the method for treating muscular dystrophy, preferably Duchenne muscular dystrophy, that comprises administering Givinostat hydrochloride monohydrate according to the present invention, is associated with concomitant corticosteroid treatment; in particular, Givinostat hydrochloride monohydrate and the corticosteroid may be administered simultaneously, separately or sequentially. According to a preferred embodiment of the invention, Givinostat hydrochloride monohydrate is administered to ambulant patients.

[0050] Experimental section Ref.: 24ST13IWO

[0051] The dosing instructions devised for Study 48 were based on the following prior knowledge:

[0052] 1. Population pk analyses identified weight as the significant factor affecting Givinostat exposure. a. Lower weight — Higher Exposure b. Allometric Coefficient: 0.626

[0053] 2. Doses of 37.5mg BID and 25mg BID were efficacious in the Phase II study in boys 7 to <11 years of age and a weight <50kg. a. AUCO-12 at 37.5mg BID= 572±283 ng-h / mL (Mean±SD) b. AUCo-12 at 25mg BID= 337±128 ng-h / mL (Mean±SD)

[0054] 3. Threshold exposure for efficacy based on preclinical data: AUCo-12 of 150 ng-h / mL.

[0055] 4. Platelet (PLT) levels during treatment with Givinostat depend on platelet levels before treatment and on Givinostat exposures.

[0056] Flexible dosing instructions based on 9 different weight-based bands were devised for Study 48 to maximize efficacy. The starting dose (Dose A) targeted a similar exposure to that obtained with the highest dose of 37.5 mg BID in the phase II study (Study 43). Since a percentage of patients was predicted to have PLT reductions at this dose, a 33% dose reduction (Dose B) was allowed to ensure that patients would not drop out of the study in case the starting dose was not tolerated. Dose B was expected to give exposures like those obtained with the 25 mg BID dose in the phase II study. The 9 weight-based bands and the related doses A and B are shown in Table 1. Ref.: 24ST13IWO

[0057] Table 1 : Study 48 Treatment Regimen 1 b.i.d = twice daily.

[0058] * dose expressed as Givinostat hydrochloride monohydrate

[0059] Weight-based dose adjustments were defined to obtain similar AUC in all patients regardless of their baseline weight. Figure 1 shows the predicted AUC0-12 at Dose A by patients’ weight class prior to study 48 start.

[0060] Study 48 was not conducted on patients having a weight >10 and <12.5 kg or >70 kg. During a blinded safety review of haematological data on around 60 patients enrolled, it showed that approximately 50% to 60% of those subjects who had at least 8 weeks of treatment at Treatment Regimen 1 , had to reduce dose due to a decrease in platelet counts. This was higher than what predicted in PK-PD modelling of platelets. Therefore, the protocol was amended to change the starting dose to Dose B, which then allowed a 20% dose reduction (Dose C), whereas the patients who tolerated Dose A continued the treatment based on Dose A. Dose C was Ref.: 24ST13IWO expected to give efficacious exposures based on PK-PD modeling of preclinical data

[0061] (AUCo-12 of 150 ng-h / mL). The amended treatment regimen is shown in Table 2.

[0062] Table 2: Study 48 Treatment Regimen 2 b.i.d = twice daily.

[0063] * dose expressed as Givinostat hydrochloride monohydrate

[0064] The pharmacokinetic analyses using data from Study 48 confirmed body weight as the only significant factor impacting on Givinostat exposure. However, the allometric coefficient estimated was unexpectedly smaller (0.326 vs 0.626) than the one originally predicted. As a result, Givinostat exposures in Study 48 were surprisingly lower in patients with lower weights and higher in patients with higher weights (Figure 2).

[0065] Since PLT levels are correlated with Givinostat exposures and Givinostat exposures depended on patient’s weight, PLT levels decrease with increased patient’s weight (Figure 3). Ref.: 24ST13IWO

[0066] Therefore, the likelihood of a patient to complete the study on dose A, B or C depended not only on the starting dose but also on a patient’s weight. As shown in the following figure (Figure 4), heavier patients started at Dose A reduced the dose more frequently than lighter patients. Frequency of Dose B reduction to Dose C did not correlate with patient’s weight.

[0067] Pharmacometric analyses were thus conducted to evaluate a potential alternative dosing regimen that would reduce the weight bands from 9 to 4 and at the same time would ensure more similar exposures in patients with different weights. PK, PK-PD simulations were conducted for platelet count in 10,000 virtual pediatric patients, comparing the following dose regimens:

[0068] • The original 9-weight bands Givinostat dose regimen.

[0069] • The revised 4-weight bands Givinostat dose regimen, shown in table 3.

[0070] Table 3: 4-weight band Revised Dose Regimen

[0071] Dose Level Patient Weight (kg)

[0072] 10-20 20-40 40-60 > 60

[0073] Dose A, mg* b.i.d 25 35 50 60

[0074] Dose B, mg* b.i.d 20 25 40 50

[0075] Dose C, mg* b.i.d 15 20 30 40

[0076] * dose expressed as Givinostat hydrochloride monohydrate.

[0077] Starting with Dose A, the simulated platelet count information was used to determine the subsequent dose (Dose A, B or C) in each subject every 2 weeks until Month 18. Simulations were conducted under the assumption of non-time varying weight changes using with the software R version 4.2.0, package RxODE (v. 1.1.5).

[0078] The dose regimens were then compared in terms of: Ref.: 24ST13IWO

[0079] • Cmax and AUC after the first dose in various body weight groups.

[0080] • Maximum reduction in platelet count prior to first dose adjustment, and associated grade of platelet reduction.

[0081] • Proportion of subjects who are likely to continue on Dose A and those subjects needing dose modifications (A to B, A to B to C, etc.) until month 18.

[0082] Given the limited number of individuals in Study 48 with weight > 50 kg, subjects for the simulations were generated using age and body weight data (from 2 to 18 years of age) obtained from the NHANES database. PK-PD simulations were conducted with platelet assessment every 2 weeks. Each dose reduction was implemented directly after the first platelet assessment found below the threshold of 150 x 109 / L. Simulations were performed using the final models presented in the Report ITAL PMX GIVINOSTAT-3392 accounting for inter-individual variability. Residual variability was not included as part of the model-based simulations.

[0083] Results are presented for the following weight groups across both dosing regimens evaluated: 10 to 20 kg, 20 to 40 kg, 40 to 60 kg and > 60 kg.

[0084] Results

[0085] Results of the simulations across all dosing scenarios are presented and compared in Figure 5 and Tables 4 and 5. When comparing the 9-weight bands Givinostat dose regimen and the 4-weight bands Givinostat dose regimen, results of the simulations show that:

[0086] • The 4-weight bands Givinostat dose regimen surprisingly leads to similar exposures in the different weight bands.

[0087] • Dose reductions occur within the first 3 months, consistent with the findings of the PK-PD analysis of Study 48 where platelets reduction plateaus within the first 6 to 8 weeks of treatment. Ref.: 24ST13IWO

[0088] • Due to the dose reduction rules, all patients converge to similar Givinostat exposures irrespective of the starting dosing conditions. This is consistent with the behavior observed in Study 48.

[0089] • Overall, the number of dose reductions are similar compared to the original 9- weight bands Givinostat dose regimen, though, of note, the proportion of patients requiring no dose reduction was numerically higher for the 4-weight bands Givinostat dose regimen compared with the original 9-weight bands Givinostat dose regimen (Table 5).

[0090] Notes: Boxes are the 25thand 75thPls, the line is the geometric mean, and whiskers are the 5th and 95th Pls of the steady state AUC within the dosing interval. The dark green line is the preclinical target AUCss within the dosing interval (150 ng.h / mL, corresponding to a daily AUC of 300 ng.h / mL); green areas correspond to the exposure range of Study 48.

[0091] Ref.: 24ST13IWO

[0092] Table 4: Simulated Percentage of Subjects With Different Grades of Thrombocytopenia Stratified by Weight Categories in Subjects Receiving the Original 9-weight bands Givinostat dose regimen and the 4-weight bands Givinostat dose regimen Ref.: 24ST13IWO

[0093] Table 5: Simulated Proportion of Dose Reductions Stratified by Weight Categories in Subjects Receiving the Original 9-weight bands Givinostat dose regimen and the 4-weight bands Givinostat dose regimen

[0094] In summary, the 4-weight-band Givinostat dosing regimen surprisingly leads to exposures and proportions of dose reductions in the simulated pediatric DMD population that are comparable to the dosing instructions included in Study 48. The 4-weight-band Givinostat dosing regimen provides a means to simplify the dose regimen, decrease the likelihood of dose reductions due to platelet count reductions in the heavier weight bands (> 40 kg), and still achieve exposures equivalent to those observed in Study 48.

Claims

Ref.: 24ST13IWOClaims1 . Givinostat hydrochloride monohydrate for use in treating muscular dystrophy, characterized in that: a. about 22.5 to about 27.5 mg of Givinostat hydrochloride monohydrate is administered to a patient twice daily if his or her body weight is 10 kg to less than 20 kg; b. about 31 .5 to about 38.5 mg of Givinostat hydrochloride monohydrate is administered to a patient twice daily if his or her body weight is 20 kg to less than 40 kg; c. about 45 to about 55 mg of Givinostat hydrochloride monohydrate is administered to a patient twice daily if his or her body weight is 40 kg to less than 60 kg; d. about 54 to about 66 mg of Givinostat hydrochloride monohydrate is administered to a patient twice daily if his or her body weight is 60 kg or more.

2. Givinostat hydrochloride monohydrate for use according to claim 1 , wherein: a. about 25 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 10 kg to less than 20 kg; b. about 35 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 20 kg to less than 40 kg; c. about 50 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 40 kg to less than 60 kg;Ref.: 24ST13IWO d. about 60 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 60 kg or more.

3. Givinostat hydrochloride monohydrate for use according to any one of the preceding claims wherein, in case of adverse reactions, the dosage is reduced as follows: a. about 18 to 22 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 10 kg to less than 20 kg; b. about 22.5 to 27.5 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 20 kg to less than 40 kg; c. about 31.5 to 38.5 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 40 kg to less than 60 kg; d. about 40.5 to 49.5 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 60 kg or more.

4. Givinostat hydrochloride monohydrate for use according to any one of the preceding claims wherein, in case of adverse reactions, the dosage is reduced as follows: a. about 20 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 10 kg to less than 20 kg;Ref.: 24ST13IWO b. about 25 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 20 kg to less than 40 kg; c. about 35 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 40 kg to less than 60 kg; d. about 45 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 60 kg or more.

5. Givinostat hydrochloride monohydrate for use according to any one of claims 3 or 4 wherein, in case of persisting adverse reactions after the first dosage reduction, the dosage is further reduced as follows: a. about 13.5 to 16.5 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 10 kg to less than 20 kg; b. about 18 to 22 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 20 kg to less than 40 kg; c. about 27 to 33 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 40 kg to less than 60 kg; d. about 36 to 44 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 60 kg or more.Ref.: 24ST13IWO6. Givinostat hydrochloride monohydrate for use according to any one of claims 3 or 4 wherein, in case of persisting adverse reactions after the first dosage reduction, the dosage is further reduced as follows: a. about 15 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 10 kg to less than 20 kg; b. about 20 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 20 kg to less than 40 kg; c. about 30 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 40 kg to less than 60 kg; d. about 40 mg of Givinostat hydrochloride monohydrate is administered to the patient twice daily if his or her body weight is 60 kg or more.

7. Givinostat hydrochloride monohydrate for use according to any one of the preceding claims, wherein said muscular dystrophy is Duchenne muscular dystrophy.

8. Givinostat hydrochloride monohydrate for use according to any one of the preceding claims, wherein said muscular dystrophy is Becker muscular dystrophy.

9. Givinostat hydrochloride monohydrate for use according to any one of the preceding claims, wherein said muscular dystrophy is Limb Girdle muscular dystrophy.

10. Givinostat hydrochloride monohydrate for use according to any one of the preceding claims, wherein said patient is 6 years of age or older.Ref.: 24ST13IWO11 . Givinostat hydrochloride monohydrate for use according to any one of the preceding claims, wherein said patient is 6 to 18 years old.

12. Givinostat hydrochloride monohydrate for use according to any one of the preceding claims, wherein it is administered in the form of a pharmaceutical composition comprising the same together with at least one physiologically acceptable excipient.

13. Givinostat hydrochloride monohydrate for use according to claim 11 , wherein said pharmaceutical composition is administered by oral, sublingual, rectal, intravascular, intravenous, or subcutaneous route, preferably by oral route.

14. Givinostat hydrochloride monohydrate for use according to any one of claim 11 or 12, wherein said pharmaceutical composition is in a solid or a liquid form.

15. Givinostat hydrochloride monohydrate for use according to claim 13, wherein said solid form is selected from the group consisting of powder, tablet, granulate, aggregate, compressed pill, coated pill, hard gelatin capsule, and gelatin capsule.

16. Givinostat hydrochloride monohydrate for use according to claim 13, wherein said liquid form is a suspension or a syrup.

17. Givinostat hydrochloride monohydrate for use according to claim 15, wherein said suspension comprises at least a wetting agent and / or at least a densityimparting agent and / or at least a buffering agent and / or at least a suspending agent.

18. Givinostat hydrochloride monohydrate for use according to any one of claims 15 or 16, wherein said suspension comprises at least a wetting agent, at least a density-imparting agent, at least a buffering agent and at least a suspending agent.Ref.: 24ST13IWO19. Givinostat hydrochloride monohydrate for use according to any one of claims 16 or 17, wherein said at least a wetting agent is a polyoxyethylene sorbitan fatty acid ester, poloxamer or a mixture thereof; said at least a densityimparting agent is sorbitol, sucrose or a mixture thereof; said at least a buffering agent is a phosphate buffer, citrate buffer, or tartrate buffer; said at least a suspending agent is tragacanth gum or xanthan gum.

20. Givinostat hydrochloride monohydrate for use according to any one of claims16 to 18, wherein said suspension essentially comprises Givinostat hydrochloride monohydrate, a polyoxyethylene sorbitan fatty acid ester, sorbitol, a tartrate buffer and tragacanth gum.21 . Givinostat hydrochloride monohydrate for use according to any one of the preceding claims, wherein Givinostat hydrochloride monohydrate is in crystal form.

22. Givinostat hydrochloride monohydrate for use according to any one of the preceding claims, wherein it is administered together with a corticosteroid.

23. Givinostat hydrochloride monohydrate for use according to claim 22, wherein Givinostat hydrochloride monohydrate and said corticosteroid are administered simultaneously, separately or sequentially.

24. Givinostat hydrochloride monohydrate for use according to any one of the preceding claims, wherein said patient is ambulant.

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