Italfarmaco Provides Update on Advanced-Stage Clinical Development Program with Givinostat in Duchenne Muscular Dystrophy

-- The Interim data from EPYDIS Phase 3 trial shows that the trial is NOT FUTILE and the Independent Data Monitoring Committee recommends trial continuation --

-- Blinded re-estimation of study sample size allows reduction of total number of subjects to be enrolled --

-- Analyses of long-term study with Givinostat suggest a delay in disease progression --

MILAN, Italy I April 27, 2020 I The Italfarmaco Group provided today an update on the clinical development program of Givinostat, its proprietary histone deacetylase (HDAC) inhibitor, in Duchenne Muscular Dystrophy. The company announced that an Independent Data Monitoring Committee (IDMC) has recommended the continuation of the trial based on the interim imaging analysis, which showed a lower muscle fat infiltration with Givinostat compared to the placebo group after 12 months of treatment. In a related update to the trial, the Company also announced that a blinded sample size re-estimation supports a reduction in the number of patients required to be enrolled in the Phase 3 trial. Finally, the Company showed that data analysed from a long-term follow-up of the previously reported Phase 2 study in DMD suggest that addition of Givinostat to steroid treatment delays disease progression when compared to published natural history data.

Paolo Bettica, MD, PhD, Chief Medical Officer at the Italfarmaco Group commented, “The interim data from our Phase 3 trial and the updated long-term study results with Givinostat are both very encouraging. We have currently enrolled 160 boys in the Phase 3 trial and with the re-estimation of the sample size reducing the number of boys in the study to 169, Italfarmaco could close enrollment in the trial as early as July 2020 with the final analysis of the results expected in 2022”.

The EPYDIS Phase 3 clinical trial is a randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of Givinostat in patients with DMD. As defined by the study protocol, an interim futility analysis was conducted on the trial by an Independent Data Monitoring Committee to evaluate the effect of Givinostat in DMD patients compared to placebo control. The first 50 patients randomized in the ‘in-target’ group treated for 12 months were subjected to a non-invasive imaging method called Magnetic Resonance Spectroscopy (MRS), which is used to accurately and reproducibly measure muscle fat fraction (MFF) in the vastus lateralis (VL) muscle of the thigh. Fat infiltration in these muscles is a characteristic of disease progression in DMD patients and makes this assessment a valuable objective endpoint to assess the efficacy of Givinostat. The results showed that the mean change of VL MFF from baseline to 12 months of treatment in the Givinostat-treated patients was lower than that of the placebo group, suggesting that the disease progression was slower in Givinostat-treated patients.

The sample size re-estimation conducted on blinded data showed that the variability of the 4 Stair Climb (4SC) change after 18 months was much smaller than what was originally expected. This reduction allows Italfarmaco to lower the sample size of the study while maintaining full statistical power. Based on this analysis, the total number of patients to be randomized in the study is now 169 instead of 242.

Prof. Eugenio Mercuri, Professor of Paediatric Neurology at the Catholic University, Rome, Italy, commented on this analysis, “The interim analysis, together with the positive histology results of the Phase 2 study, are both good signals suggesting Givinostat’s potential beneficial effect in DMD boys. We look forward to near-term completion of the study enrollment and remain hopeful that the imaging result will be supported by functional data, in order to confirm Givinostat’s ability to slow-down disease progression.”

The Company also conducted new follow-up analyses* with the DMD patients in the on-going, long-term extension of the previously reported Phase 2 trial. The preliminary results showed a delay in disease progression in patients who were treated with Givinostat and steroids for more than 6 years when compared to published results from the natural history study by The Cooperative International Neuromuscular Research Group (CINRG). The mean age of loss of ambulation in DMD subjects treated with Givinostat on top of corticosteroids is 15.20 years compared to the one in the CINRG study, which was 13.40 years. Moreover, the yearly rate of decline of two respiratory parameters, Forced Vital Capacity % Predicted (FVC%) and Peak Expiratory Flow % Predicted (PEF%), is 2.3% and 0%, respectively, in DMD subjects treated with Givinostat and corticosteroids. This contrasts with the 4 to 6% yearly rate of decline of these parameters, which has been shown in natural history studies of a patient population comparable to the Givinostat cohort.

*The results of these analyses are not published yet.

About Givinostat

Givinostat is an investigational drug discovered through Italfarmaco’s internal research and development efforts in collaboration with Lorenzo Puri (SanfordBurnhamPrebys Medical Research Institute, San Diego, formerly Santa Lucia Foundation, Rome) and his team, and partnerships with Telethon and Parent Project aps. It is being evaluated for safety and efficacy for the treatment of Duchenne- and Becker- Muscular Dystrophy. Givinostat inhibits histone deacetylases (HDACs). HDACs are enzymes that prevent gene translation by changing the three-dimensional folding of DNA in the cell. Studies show that Duchenne patients have higher than normal HDAC levels, which may prevent muscle regeneration, and also trigger inflammation. In the company’s clinical study in DMD boys aged seven to less than 11 years, Givinostat was observed to slow disease progression, significantly increase muscle mass and reduce the amount of fibrotic tissue. Givinostat treatment also significantly reduced muscle tissue necrosis and fatty replacement, two additional parameters related to disease progression (Bettica et al., Neuromuscular Disorder 2016).

About Italfarmaco Group

Italfarmaco is a specialty pharmaceutical company engaged in the discovery, development, manufacturing and marketing of branded prescription and nonprescription products in more than 60 countries on 5 continents. Italfarmaco’s research and development expertise is best demonstrated through its HDAC inhibitor development programs, addressing new therapeutic treatments of specialty and rare diseases. Through both marketed drugs and compounds in development, Italfarmaco is dedicated to serving patients whose needs remain largely unmet.

SOURCE: Italfarmaco

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