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Givinostat for Becker muscular dystrophy- A randomized, placebo-controlled, double-blind study

#apaperaday: Givinostat for Becker muscular dystrophy: A randomized, placebo-controlled, double-blind study

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Givinostat for Becker muscular dystrophy: A randomized, placebo-controlled, double-blind study

Today’s pick is by Comi et al in Frontiers In Neurology on the clinical trial with givinostat in Becker muscular dystrophy (BMD) patients. Doi: 10.3389/fneur.2023.1095121. BMD is caused by mutations that allow production of partially functional dystrophin. BMD is associated with progressive muscle wasting and loss of function. Duchenne MD (DMD) is caused by absence of dystrophin and is more severe (earlier onset and quicker progression).

However, even though DMD is the more severe type of dystrophinopathy, BMD is also a severe disabling disease. The severity varies between patients (age of symptom onset in childhood – midlife, progression fast or slower). Currently there is no therapy for BMD.

DMD and BMD have similar pathology: inflammation due to chronic muscle damage, replacement of muscle by fat and fibrosis and impaired regeneration. Thus, therapies that slow down DMD pathology should also work in BMD. Givinostat is an inhibitor of histone deacytelases (HDAC) and in DMD it has been shown to slow down fibrosis formation and to slow down disease progression on a functional level. Thus it makes sense to also do a clinical trial in BMD patients with givinostat.

A clinical trial was done with 51 patients, 44 of whom completed the trial. Patients were treated with high or low dose givinistat or placebo (1:1:1) for 12 months. Patients had a clinical and genetic diagnosis of BMD and were 18-65 years old.

The primary endpoint was fibrosis in histology. The placebo group had worse fibrosis at baseline. No change in increase in fibrosis was seen between placebo or givinostat treated patients after 12 months of treatment. Fat fractions measured by magnetic resonance imaging (MRI) showed no change for the givinostat treated patients, while for placebo there was an increase in fat fraction in the thigh and quadriceps.

Functional endpoints (MFM scores and 6 minute walk test) showed no change between baseline and 12 months, thus it was impossible to measure if there was a slower progression in the treated patients. Treatment was generally well tolerated. Givinostat doses were adjusted for 26 patients due to reduced platelet counts or increased triglyceride levels in blood. 3 patients stopped the trial due to adverse events, 1 due to platelet reduction (givinostat group), 2 due to high triglycerides (1 placebo, 1 givinostat)

Authors speculate in the discussion that generally it is assumed if something is effective in slowing down pathology in DMD, it should also be effective in BMD. But, in BMD it is more difficult to measure as the progression is slower & there is more variability between patients.

The variability was reflected in the baseline that differed between placebo and treatment groups for fibrosis and disease involvement. Authors suggest in the future stratification for e.g. MRI fat fraction might be needed. I think trials should also be longer than 12 months. Note that the DMD givinostat trial was 72 weeks – given that BMD progresses slower and one needs to show a decrease in disease progression it is not surprising no functional effect was seen in 12 months (52 weeks).

Authors explain that in the future it might be better to take the biopsy from the thigh muscle as MRI showed a slower increase in fat fraction for the thigh and not for the lower leg (biopsy location) for givinostat treated patients.

Even though the primary endpoint was not met, I would not want to conclude that the treatment does not work. More trials (longer and designed implementing the results provided by this first trial) are needed. However, kudos to authors and Italfarmaco for doing a trial in BMD!