1 2 aim

#apaperaday: Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS)

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Today’s pick is from @TheLancetNeuro by Mercuri et al on the phase 3 trial testing givinostat for the treatment of Duchenne. As you probably are aware, @US_FDA approved givinostat for Duchenne patients 6 and older last week. DOI: 10.1016/S1474-4422(24)00036-X

Givinostat is an HDAC inhibitor – see the #apaperaday from last Tuesday for more background information. Brief summary, givinostat could improve regeneration and reduce inflammation and fibrosis fat formation in mdx mice & a small group of Duchenne patients.

Here authors report the results of the phase 3 placebo-controlled double-blinded study, which involved 179 patients from 41 trial sites in 11 countries. Patients were enriched for a vastus lateralis (upper leg muscle) fat fraction between 5 and 30% (67%).

118 patients received givinostat and 61 placebo for 18 months. At the start of the trial, the baseline characteristics were the same for both groups. There was over 98% compliance with taking the treatment.

There were 25 treatment interruptions due to side effects: 19 for the givinostat group, lasting on average 4 weeks, and 6 in the placebo group lasting on average 7.5 weeks. For 50% in the givinostat group, the dose was adjusted, vs 11% in the placebo group.

The primary endpoint was the 4 stair climb, which reduced significantly less in the treatment group than the givinostat group (higher means getting worse in this graph). Note that the difference was apparent after 18 months, but not yet clear after 12 months.

For the secondary endpoints, there were often no significant changes, but there was a trend towards slower decline for the givinostat group for all endpoints: North Star Ambulatory Assessment, 6-minute walk distance, elbow and knee flexion force, and MRI fat fraction.

When combining all outcomes, a statistical analysis revealed that this combination (primary endpoint significant and trend for secondary endpoints) was very unlikely to be due to change. There were adverse events, most commonly diarrhea and vomiting.

It is known that givinostat can result in thrombocytopenia. Indeed, a reduction in platelets was seen in the givinostat group. For some, this led to an adjustment of treatment dose. Also, triglyceride levels increased in the givinostat group.

Authors discuss that both groups declined over the course of the trial, but that the givinostat group declined less. The 4 stair climb showed a 1.8 seconds difference. This may seem trivial and stair climbing not something you do the whole day. However…

count the number of times you have to do one step up or down and you will realize that being able to handle these better definitely makes an impact. The NSAA showed a 2 points difference, while this was not statistically significant (due to variability), it is clinically relevant.

Also, the MRI showed less increase in fat fraction, linking the quality of the muscle to the functional effects seen. Authors discuss that side effects were good and that overall the treatment was well tolerated.

When needed the dose can be adjusted without apparent effects on efficacy, but improved safety. Also, if needed, treatment breaks can be done. There were not significant effects seen for the secondary endpoints, but the trial was powered for the primary endpoint.

As discussed last Monday in #apaperaday it is difficult in a rare disease to power for more than a single endpoint due to heterogeneity and rareness. Authors discuss that no effects on heart and respiratory function in non-ambulatory patients have been assessed yet.

These trials are now ongoing and the real-world evidence can also start to be collected. Finally, authors outline that no female dystrophinopathy patients were included in the test and that the patients included were almost all White. So more work is to be done.

However, faced with the trial results I understand why FDA approved this drug for Duchenne: to date this is the most convincing set of results collected in a Duchenne trial (disclaimer that I consult for Italfarmaco; but also for many of the other companies in the space).