The executive vice president and chief research officer of the Muscular Dystrophy Association shared her reaction to the recent FDA approval of givinostat for Duchenne muscular dystrophy.
Sharon Hesterlee, PhD
Credit: Muscular Dystrophy Association
Duchenne muscular dystrophy (DMD), an X-linked disorder caused by mutations of the dystrophin gene, is the most common muscular dystrophy diagnosed during childhood.1 The condition results in a loss of functional dystrophin, part of the dystrophin–glycoprotein complex that assist with maintaining cell membrane integrity following mechanical stress after muscle contraction. The standard treatment for patients with DMD and delayed loss of muscle strength and function is systemic corticosteroids; however, they have unwanted adverse effects that often ensure dose reduction.
In recent news, the FDA approved givinostat (Duvyzat; Italfarmaco SpA), a proprietary histone deacetylase (HDAC) inhibitor, for patients living with DMD.2 The treatment is designed to inhibit HDACs, enzymes that prevent gene translation by changing the 3-dimensional folding of DNA in the cell. The supporting data for the approval comes from the phase 3 EPIDYS trial (NCT02851797), a large-scale study featuring 179 ambulant male individuals who were randomly assigned 2:1 to either oral givinostat or placebo for an 18-month treatment period. Of these, 120 boys formed the target population. Newly published in The Lancet Neurology, results showed a slower decline in givinostat-treated patients on the primary end point of climbing 4 stairs in comparison with placebo (difference, 1.78 seconds; P = .0345).1
In a new iteration of NeuroVoices, Sharon Hesterlee, PhD, executive vice president and chief research officer of the Muscular Dystrophy Association, discussed how the recent approval of givinostat impacts the landscape of treatment options for DMD. She also talked about the potential downstream effects of givinostat's approval for patients with DMD and other muscular dystrophies. Additionally, Hesterlee spoke about considerations that clinicians should bear in mind when prescribing givinostat to patients.
We're delighted to see another drug approved for Duchenne. I think we're starting to get a critical mass of options for patients, which is different from where we were 10 or 5 years ago when we didn't have many options for Duchenne.
The big thing is that now we have drugs that work in different pathways and different mechanisms. So, you can start to think about combining these drugs. The standard therapy, the gold standard for Duchenne, for many years has been corticosteroids, which are great but come with a lot of adverse effects. Last year, we had approved vamorolone (Agamree; Santhera Pharmaceuticals), which is a type of an alternative to steroids with less adverse effects but that works on certain pathways. The new drug, givinostat, works on different pathways. It's a different mechanism. You could imagine a scenario where you can start combining these drugs, and then you have the more complex biologics, exon skipping drugs, and even gene therapy now. The potential to combine different types of drugs that work in different ways might really start giving us significant benefits together. This is where breakthroughs have come in cancer and in AIDS as well as other areas where you've combined treatments, giving patients cocktails of drugs. It's starting to get us in that position where we can start doing that in Duchenne.
It's always great for families to have choices. Sometimes one drug is not the right choice for various reasons, it could be the adverse effect profile or other things. Even if you don't want to combine drugs, having the potential to have a choice. The other thing that's nice about givinostat is that it's not mutation specific effect. In theory, it's something that can be useful for Duchenne and Becker [muscular dystrophy], its mutation agnostic. You have a much wider audience of people who could take this drug, then can take some of the more specific genetic, biologic drugs. I think that's another good thing about it, its potential for widespread use. It might also even be potentially useful beyond Duchenne for some of the other muscular dystrophies.
There were some adverse effects described, I think they were generally mild and manageable. Like with any drug, you need to pay attention to the adverse effect profile and looking at combinations of drugs, you probably have a good idea of what other things patients are taking at the same time. I don't think there were any major red flags with the drug, but clinicians will be in a good position to judge that based on the label information.
The big thing we're waiting on now is to see if the gene therapy (SRP-9001) from Sarepta gets full approval. It was approved conditionally for a limited age range, and we should find out in a couple of months whether it will get an expanded approval. We're also looking out for readout of phase 3 data from the Pfizer gene therapy study, which is ongoing. Then, there are a whole range of exon skipping drugs that are in development, the second generation drugs that might be more effective that I am keeping an eye on, too. A lot going on in the Duchenne space is blown up, which is great because again, having options is good and having the ability to combine drugs is going to make a huge difference.
Gene therapy is coming into its own slowly. It's been a field that has been over 25 years in developing and now we're starting to see approvals. There's an approval in spinal muscular atrophy (SMA) marketed as Zolgensma (Novartis), which had remarkable effects. In Duchenne, the effects aren't quite as dramatic as what we've seen in SMA but they're measurable and appear beneficial. It could be that treating boys earlier might have an even greater effect. These are all questions that since it's early days, we don't know the answers to those. We're also starting to understand in a better way how to manage adverse effects for gene therapies, and looking at new vectors that we can dose at lower level to have less adverse effects.
The other thing we need to tackle with gene therapy is that after you've been treated, you're functionally immunized against that gene therapy vector. So, you can't be treated again. There are people working hard on this question, how do we retreat? Because it may be one and done it and it may not. We really don't know how long the benefits of gene therapy are going to last. It would be nice to have the ability to retreat patients. We're also working hard to figure out some people have preexisting antibodies to the vector and they're not eligible for gene therapy. How can we get around that? Those are some major focus areas for gene therapy and neuromuscular disease. Beyond that, the other thing that I know that we're interested in and have been investing in lately is nonviral gene therapy. Are there other ways to deliver genes to muscle tissue other than using a modified virus? It's always great to have different options.
There are always different things that can be addressed. I think a real focus that we all need to pay attention to in the field is, how do we rebuild muscle that's been lost? Most of the therapies that have been approved lately, even though they are fabulous, will likely slow down the loss of muscle. In gene therapy, you can't treat muscle that's not there. You're not putting genes in cells that don't exist. For patients who've already lost a lot of muscle mass, we need to start looking at ways to regenerate muscle. Unlike the nervous system, which has some regenerative capacity but is a little bit limited, muscle really can regenerate. We need to figure out how we can regenerate muscle and say that ‘just because you've lost that muscle doesn't mean there's nothing, we can do for you.’ I think that's the next push and that's a real unmet need, what do we do? There are plenty of patients living with muscle disease who already have lost a lot of function. I think our next focus is, how do we bring back that function
I think the potential for individual disease days is huge to raise awareness because rare disease and aggregate is not rare when you consider them all together. The chances that you know someone with a rare disease or high, the chances you know someone with a specific rare disease might be low. But overall, raising awareness is the first step to calling attention to an unmet need and focusing resources on that need. Any ability to participate in a particular disease day or general rare disease activities is helpful.
This approval is exciting because givinostat is the first HDAC inhibitor, a particular type of category drug, approved for DMD. Some other HDAC inhibitors are approved but primarily in the cancer space, so this is a new direction for these drugs. We're pleased to have been a part of this as we funded some foundational research in HDAC inhibitors in muscular dystrophy. It's gratifying to see yet another drug approved, where we felt like we played some role in that and we're excited that that option is available to patients now.
Transcript edited for clarity. Click here to view more NeuroVoices.
