June 26, 2021 / Clinical Trials

Italfarmaco Announces Topline Data from Phase 2 Trial with Givinostat in Patients with Becker

This afternoon at PPMD’s Virtual Annual Conference, Italfarmaco shared Phase II Study results from the Givinostat trial in patients with Becker. They also issued a press release below. Although they did not meet the primary endpoint, the company reports that MRI data showed that Givinostat counteracted muscle deterioration and will continue to study it as a potential treatment for Becker. The safety profile of Givinostat was in line with previous studies and no serious safety concerns were observed. Based on the results, the company plans to meet with regulatory authorities to discuss future development plans for Givinostat in adults with Becker.

Read the Announcement from Italfarmaco

MILAN–(BUSINESS WIRE)–Italfarmaco Group announced today topline data from its proof-of-concept Phase 2 trial with Givinostat, the company’s proprietary histone deacetylase (HDAC) inhibitor, in 51 adult males with Becker Muscular Dystrophy (BMD). The study was designed to evaluate the effect of Givinostat in BMD, building on the experience developed in Duchenne Muscular Dystrophy. Based on this experience, change in total fibrosis in the muscle biopsy was selected as the primary endpoint of the study and change in fat fraction and contractile CSA using quantitative Magnetic Resonance Imaging (MRI) as key secondary endpoints. Givinostat did not show significant difference in the primary endpoint compared to placebo. However, significant difference from placebo in MRI of muscles in the whole thigh as well as quadriceps confirmed the ability of Givinostat to counteract muscle deterioration in the treated BMD patients. The safety profile of Givinostat in BMD was in line with previous studies and no serious safety concerns were observed. Based on the overall results, the Company plans to meet with US and EU regulators to discuss the next development steps for Givinostat in adults with BMD. The topline data was presented by Paolo Bettica on June 26, 2021, at the virtual Parent Project Muscular Dystrophy (PPMD) Annual Conference.

“Becker Muscular Dystrophy is a debilitating rare disease with no treatment currently available. We are very encouraged by the significant difference in muscle fat infiltration between the two groups after 12 months, indicating a beneficial effect of Givinostat in delaying muscle deterioration. These, as well as other measures, support the further development of Givinostat in BMD and we will evaluate the best path forward in discussion with the regulatory bodies,” said Paolo Bettica, MD, PhD, Chief Medical Officer at the Italfarmaco Group. “We will continue to analyze the data to understand better the lack of meeting the primary endpoint, which could be attributed to high variability and imbalances of baseline histology parameters between cohorts, and lack of progression within the 12 months of study duration.”

Dr. Bettica added: “Although this clinical trial in BMD was a stand-alone study, the study further confirms the ability of Givinostat to prevent downstream pathogenic effects due to dystrophin genetic defects, which was already seen in young boys with Duchenne Muscular Dystrophy.”

The Phase 2 trial investigating Givinostat in BMD patients was a randomized, double-blind, placebo-controlled study (ClinicalTrials.gov: NCT03238235). In total, 51 patients between the ages of 19 and 61 years were randomized in a 2:1 ratio and treated with an oral suspension of Givinostat or placebo twice per day for a period of 12 months. Of the patients enrolled in the study, 30 out of 34 in the Givinostat group and 17 out of 17 in the placebo group completed the trial and were included in the analysis. Two patients had to withdraw from the trial due to the occurrence of an adverse event, which was resolved, and two patients were not able to travel back to the trial site due to the Covid-19 pandemic and had to be withdrawn.

Overview of Clinical Results

Primary Endpoint: Muscle tissue fibrosis was selected as the primary endpoint to assess the efficacy of Givinostat based on the previous experience in Duchenne Muscular Dystrophy. Tissue biopsies taken at the end of 12 months from the biceps muscle in the upper arm to determine the change from baseline in total muscle tissue fibrosis (%), did not show a change over the 12 months of treatment in both groups with no difference between the Givinostat-treated group and the placebo group.

Secondary Endpoints:

Fat infiltration: A key secondary endpoint was the change from baseline of fat infiltration of muscles in the whole thigh and the quadriceps using MRI. The imaging results revealed no change of fat infiltration in the Givinostat-treated population while an increase in fat infiltration was observed in the placebo group over the study timeframe of 12 months with a significant difference between the groups. Fat infiltration in these muscles is a characteristic of disease progression in BMD patients and the data suggests that Givinostat treatment can prevent such disease progression.

Contractile and total thigh muscle cross-sectional area (CSA): The Givinostat-treated patient cohort did not demonstrate changes in the muscle contractile CSA, whereas the placebo group showed a reduction in contractile CSA after 12 months indicating a progression of muscle atrophy in the placebo group that was prevented by Givinostat.

Functional tests: Several functional tests administered, including time function tests and the 6-minute walking test did not show changes over time in both groups with no difference between Givinostat and placebo. However, the Standing and Transfer Domain of the Motor Function Measure (MFM) scale showed a significant decline in the 12 months of the study with a difference between the Givinostat and placebo groups close to significance (p=0.06) at the end of the study, suggesting a functional benefit with Givinostat treatment.

Safety: No serious Adverse Events (AE) or death occurred during the course of the trial. The initial dose of Givinostat (≈70 mg twice daily) according to the trial protocol was changed to ≈50 mg twice daily in the amended protocol to reduce the occurrences of any Treatment Emergent Adverse Events (TEAE). Similar to what previously observed, the most frequent TEAE were diarrhea, platelet decrease and triglyceride increase. No other safety concerns were observed; Givinostat treatment continues to show a good safety profile.

Giacomo Comi, MD, Professor of Neurology at the University of Milan and Principal Investigator of the study commented, “BMD is a milder form of muscular dystrophy manifesting later in life in many patients as a result of slow disease progression. Clinical variability is a recognized feature of this disorder. The lack of significant change in some parameters with Givinostat treatment could have been related to the protocol-defined timeframe of 12 months. BMD patients remain an underserved population with only very limited treatment options, and I am encouraged to see a positive trend towards clinical benefit with Givinostat treatment. I look forward to continuing our investigation of Givinostat to define its full potential for patients with BMD.”

Krista Vandenborne, PhD, Professor and Chair of the Department of Physical Therapy at the University of Florida added, “The non-invasive method of MRI imaging allows us to analyse a range of important parameters in determining disease progression in muscular dystrophy. The highly significant correlations between MRI and function/strength at baseline suggests that reduced muscle degeneration will translate into a functional benefit in due course with continued treatment.”

“Individuals with Becker Muscular Dystrophy develop damaged muscle cells over time and due to the lack of the proper functioning of a protein called dystrophin in these cells, they fail to repair themselves effectively and muscle function is declining in the long term. I am encouraged to see the initial effect of Givinostat in counteracting this,” said Erik Niks, MD, Neurologist at Leiden University Medical Centre.

Italfarmaco is also investigating the effect of Givinostat treatment in patients with Duchenne Muscular Dystrophy (DMD) in a Phase 3 trial (ClinicalTrials.gov: NCT02851797). DMD, although genetically similar to BMD, is a more severe form of muscular dystrophy and differs significantly in terms of disease pathophysiology. The topline results of this Phase 2 trial in BMD support further development of Givinostat in the adult population with BMD.

The study was funded by Italfarmaco SpA and Regione Lombardia, Grant 231836, as part of the European Regional Development Fund (ERDF) of the Regional Operational Program (ROP) 2014− 2020.

Read full press release.

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