Vamshi K. Rao, MD

As we embark on further research and therapies, the wonderful and positive message is that there are a lot of players involved. There are a lot of people thinking about this and dedicating an enormous amount of time. It is very heartfelt in everybody who I have met in the field, whether it be a great scientific mind like yourself, researchers who are in the trenches, or patient foundations. We could spend a lot of time discussing all that’s out there in different phases of development. But it would be fair to say that there are multiple angles, it’s a variable condition, it’s progressive, and we have to approach therapeutics with a lot of thought, without neglecting standard of care in the interim.

As people who care for these patients and think about the mechanisms of their disease, we have to constantly keep standard of care at the forefront so we can at least use what we have at this time—you alluded to steroids. We need to make sure we are keeping the child ready for whatever comes along so we can take them to a better place in their natural history, all the while diverging from what we know about natural history from our experience. I want our viewers know that there are ongoing treatment trials and drugs that are approved, but standard of care needs to continue. Dr Hoffman, as we conclude our session, what would you like to add to that?

That’s a terrific summary. I’d like to add this sense of optimism, too. Ten years ago, there were no clinical trials for Duchenne muscular dystrophy. Today, there are about 60 trials listed on clinicaltrials.gov. As you pointed out, the field of trying therapeutics in Duchenne muscular dystrophy has exponentially expanded, and that can only be viewed as very positive. But with that, participating in trials is so important. It’s a tremendous burden on patients and families, but we know and are so appreciative of the efforts of families, physicians, and sites, such as yours, that participate in clinical trials. Keeping that going will hopefully lead to effective therapies. That’s the only way to get there. It’s a really promising time. It’s a challenging disease, but I completely agree that the standard of care and keeping families engaged, hopefully in clinical trials as well, is critical to the future successes.

Thank you so much, Dr Hoffman. Your expertise and thoughtful way of approaching things is very helpful to this community. I thank all of you for watching this 

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Final thoughts from leading experts on the future of treating Duchenne muscular dystrophy and keeping standard of care in the forefront. 

Future of Treating DMD 

There’s a new kid on the block: casimersen. It’s an approved exon 45 skipping drug. It has a very similar mechanism of action in terms of the whole concept of a PMO [phosphorodiamidate morpholino oligomer] with the synthetic chain that skips through exon 45 amenable mutations. Administration is very similar. It’s proven to be very safe. It has also shown dystrophin production, leading to benefit. Like you said, it remains to be seen how efficacious it is over time in relation to real-world evidence or post-marketing.

With casimersen, we’re very happy that we now have another drug that targets a certain group of children, I believe in the 6% to 8% range. As you alluded to earlier, exon 51 amenable is around 10% to 12%. Both exon 53 and exon 45 are in the 6% to 8% range. Is there anything that caught your eye with casimersen that was different from the previous exon skipping drugs?

As you point out, it seems very similar. I was reading the FDA label yesterday, and the amount of drug-induced dystrophin, about 1%, is similar to the other Sarepta Therapeutics drugs. It seems that the delivery, dosing, and the 1% drug-related increases in dystrophin are all very similar between the 3 Sarepta drugs.

 Thank you for pointing that out. Again, I left the number out.

Recent approval of casimersen, its administration, efficacy, safety, and patient selection for treatment of Duchenne muscular dystrophy. 

Casimersen in the Clinical Setting 

We published a paper together on viltolarsen. Could you give us a few highlights about what we saw? I can start by saying that this was a phase 2 placebo study. The placebo was initially for 4 weeks, but then we switched everybody to treatment. There were 2 treatment arms: 40 mg/kg and 80 mg/kg. Could you tell us a little about what we saw in all the ways of measuring dystrophin that you beautifully alluded to before with the study for viltolarsen? What differences do you notice between viltolarsen and golodirsen when it comes to those numbers?

I’m sorry to force you to give us numbers.

 No, I’m fine with that as long as you interpret the numbers with your remarks, and specifically in terms of clinical benefit.

The viltolarsen studies looked at biopsies after 6 months of weekly treatment. There was very clear evidence that the drug was hitting its target. You could see the alternative splicing happening in the muscle very clearly. That translated into easily detectable dystrophin that was drug-induced. The FDA said in a public letter that the dystrophin data are very clear. The levels varied from patient to patient, generally from 1% to 10%, with a mean of about 6% normal levels. As we talked about earlier, you’d love to get up to about 10% of the abnormal dystrophin, but 6% is certainly getting there. If you look at clinical outcomes—it’s open-label, you can speak more to the clinical outcomes than I—it seems that patients were responding, at least compared to natural history studies.

There were significant improvements in clinical outcome, but a very small number of subjects. There were 16 subjects, 8 at each dose. These are not big studies, and they’re not powered for clinical benefit. Those in an accelerated approval have to be done post-marketing. In fact, the company, NS Pharma, Inc is doing a larger placebo-controlled study post-marketing with the major outcome of clinical benefit. That trial is not measuring dystrophin levels, because it is just for approval under an accelerated pathway. That’s good for the patients because you don’t want to take a lot of biopsies from the patients.

In terms of benchmarking viltolarsen to golodirsen, which is the Sarepta therapeutics drug, you can just look at how much dystrophin they’re making. What’s published in the FDA materials for golodirsen is about 1% drug-induced dystrophin, whereas for viltolarsen, the FDA documents and publications say about 6% increase in dystrophin. At first blush, it seems that the 6% is probably on average better than the 1%, but all these have to be borne out in clinical studies post-marketing. As I said before, we expect different patients to respond differently. You can’t directly equate a number of dystrophin with clinical improvement. You’re going to find some patients in whom 6% dystrophin has an enormous clinical benefit, and some in whom it may not show much.

That’s a very important point. You could have dystrophin levels that are lower with a higher benefit, and higher with a lower benefit. That connection is very difficult to make. I can tell you from personal experience that talking to families about numbers and clinical outcomes is a very nuanced conversation.

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Viltolarsen phase II study data is discussed as well as a comparison of viltolarsen to golodirsen for treatment of Duchenne muscular dystrophy. 

Viltolarsen Phase II Study  

 Let‘s switch gears to something very positive going on in the field: the availability of exon skipping treatments. As we all know, the first treatment to be approved was an exon 51 skipping agent, which was later christened as eteplirsen. We subsequently had approval for 2 drugs that are exon 53 skipping agents: golodirsen and viltolarsen. Very recently, the exon 45 skipping drug casimersen was approved. Can you talk a little about exon skipping? You alluded to it earlier, but can you talk a little about the differences of these different agents? At the synthetic level, what is the difference between these agents and their backbones?

Sure. Exon skipping is a fascinating area of therapeutics. It’s one of the first drugs meant to help the gene fix itself. It’s a small snippet—about 20 bases of sequence—that’s delivered IV [intravenously]. It goes all the way into the nuclei of the muscle. As the dystrophin gene is transcribing from DNA to RNA and then to protein, it binds to the RNA. In Duchenne muscular dystrophy, the gene is inactive. It’s trying to make RNA, but its RNA is nonfunctional. This snippet comes in and basically splices and helps repair the RNA to make it like in Becker muscular dystrophy, where it can make dystrophin. The real-time fixing of the gene mutation as it’s being transcribed and translated is fascinating. It’s also fascinating that it works to some extent, because getting those oligonucleotides through the bloodstream, throughout the muscle, and to all the nuclei and RNAs is a tour de force.

As you mentioned, there are 4 drugs. That’s because you have to tailor the drug for the gene’s mutation. To fix the mutation, you can’t use any generic place in the gene. You have to target exactly where that patient’s mutation is. Right next to it, the drug helps fix it or skip over the mutation, which is why it’s called exon skipping. About 10% of kids with Duchenne muscular dystrophy have mutations that are amenable to exon 51 skipping, or the eteplirsen drug. The other 90% don’t, because their mutations are not amenable. Likewise, 8% or 10% of patients have mutations that are amenable to exon 45, with another 10% amenable to exon 53. These different drugs target different subsets of patients who have Duchenne muscular dystrophy.

 Let’s start by talking about one of these drugs. As we look at these drugs, these synthetic oligonucleotides, the way the body eliminates them is through the renal system. Safety-wise, one of the things we are all looking for is to monitor renal function, although most of these trials haven’t shown a serious effect on the renal system, particularly the kidney. Overall, these drugs have been very safe. They have been tolerated well. Most of the safety signals have been at the level of adverse events rather than serious adverse events. There have been no deaths reported. Needless to say, these exon skipping drugs are very safe. All of them are administered IV weekly. There is a lot of work going on to see how they can be altered so they don’t have to be administered every week. Once a month would be wonderful in terms of patient compliance and overall convenience.

As we think about these drugs, let’s look at the 2 exon 53 skipping drugs: viltolarsen and golodirsen. Based on the clinical trial data, what differences have you seen in what the publications have shown? You and I have been intimately involved in the exon 53 viltolarsen study. What is the difference between golodirsen and viltolarsen?

Your description is very accurate. A lot of the drug hits the kidney and is excreted right away. A very small fraction ends up actually hitting the gene target in the muscle or the messenger of any target. There’s so much room for improving this, as you outlined. The drug load to the kidney is significant because it is so rapidly excreted.

We say it’s a snippet of DNA or RNA, but interestingly, it’s a different chemistry called morpholino chemistry. It is not biological per se. It’s a highly modified chemistry. If you look at it at first blush, it looks like DNA/RNA with the bases and ribose backbone. But the ribose backbone is replaced with a completely alien structure called a morpholine ring. That turns out to be a huge advantage because the body does not see it as something biological, or worst-case scenario, as a virus. Most of our exogenous DNA or RNA coming at us is a virus, and our body freaks out and wants to get rid of it as soon as it can. These morpholinos do not invoke any antiviral or innate immunity and they’re not metabolized. They stay intact, which is good. But then the body says, “This is just garbage, let’s get it out in the kidney,” and that’s why it ends up in the kidney.

Any efforts to try to keep targeting, to get more into the muscle and have it stay there longer, are really important. There are lots of efforts underway to try to do that. Even how it gets into the muscle is interesting. It seems to be brokered by macrophages. The macrophages may take it up to try to protect the body, and then in remodeling dystrophic muscle, degeneration/regeneration, seems to release it back into the muscle. There’s a recent publication on that. It’s all very complicated with a lot of room for improvement.

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A review of exon skipping agents, their function, mechanism of action, and the different drugs used in clinical practice to treat Duchene muscular dystropy.    

Vamshi K. Rao, MD

Articles

Future of Treating DMD

Casimersen in the Clinical Setting

Viltolarsen Phase II Study

Exon Skipping Agents Used in DMD