Rare Neurological Diseases: Spinal Muscular Atrophy and Huntington's Disease - Episode 19

Zolgensma and the START Trial for SMA

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Editor's note: this was filmed before the FDA approved Zolgensma.

Peter L. Salgo, MD: I’m assuming that families and patients like this drug.

Sika Dunyoh: Yes, yes.

Peter L. Salgo, MD: And they want this drug.

Sika Dunyoh: Absolutely.

Peter L. Salgo, MD: So if they hear of any roadblocks to this drug, they must go berserk.

Sika Dunyoh: Absolutely.

Peter L. Salgo, MD: What do you hear?

Sika Dunyoh: A lot of our patients don’t understand how decisions are made on the payer side, and so I think that doing more education for patients and caregivers to really understand how payers make decisions is a need that we’re seeing with our patients.

Peter L. Salgo, MD: Do the patients have to understand how insurance companies think? They just want their kid helped.

Sika Dunyoh: Well, I think that’s a valid argument. I do think that it would help reduce some of the frustration a bit if there is a bit more understanding.

Peter L. Salgo, MD: Really? Let me see how unfrustrating this is. Oh, the drug company, I understand that they won’t let my kid live. I’m not frustrated anymore. Why doesn’t that—

Sika Dunyoh: I understand what you’re saying. I think that for many families, hearing a no is a no, and when you need a yes, I don’t think it matters to some families. But I think that navigating insurance is an important skill that families who have rare diseases need to have.

Peter L. Salgo, MD: Let me translate a no, and you tell me whether I’m right. A no to an insurance company is no. We’ve done the cost analysis. It doesn’t make sense. A no to a family is death.

Sika Dunyoh: Absolutely.

Peter L. Salgo, MD: That’s what they hear. They don’t want to hear, “No, scientifically it doesn’t mean much. They say, “No? That’s my only hope.”

Sika Dunyoh: Yes. Their frustration and anger are valid. My sister had a rare disease, and she had challenges navigating insurance and finding physicians who were knowledgeable and getting access to treatments. So I understand as a caregiver the frustration personally. I think that knowledge is power, and I think being able to understand how to navigate insurance, how to talk to insurers, and how to talk to your provider to help them be your advocate is very important as a patient with a rare disease.

Peter L. Salgo, MD: All right, let’s change gears. If you thought this was expensive, we’re about to hit overdrive, I’m guessing. Because now we’ve got gene replacement therapy. I’m not even going to make a run at pronouncing this name. This is your job.

John Brandsema, MD: That’s fine.

Peter L. Salgo, MD: What is this called?

John Brandsema, MD: Zolgensma is the name now for this treatment, but it used to be called AVXS-101 because it was developed by a company called AveXis. The concept behind this therapeutic modality is to use a viral vector to deliver back the SMN1 gene that is missing in the patient. They use this viral vector to transduce this gene. It lives in the cell, not actually part of the DNA, but it is its own generating protein in the cell within the nucleus and gives back that SMN protein that you’re missing.

Peter L. Salgo, MD: This is scary but really exciting, right? Because you’re taking a virus, and you’ve altered the molecular material in the virus itself so that when it infects a cell and injects this molecular material, it doesn’t make new virus. What it does is it makes a gene in there that starts to make the chemical that these patients lack. As I understand it, and correct me if I’m wrong, it’s self-replicating. Once it’s in, and once it’s working, you’re not just treating a disease. Here comes the word that’s really amazing. You’ve cured the disease—this is a “c.”

John Brandsema, MD: What you’re trying to do is have continual expression of this particular genetic message that you’re trying to get across. The theory behind it is that it would only need to be delivered 1 time. So there’s a difference between something like nusinersen, where you’re looking at a lifetime of maintenance medication.

Maria Lopes, MD, MS: She’s smiling because it’s only 1 dose.

John Brandsema, MD: OK. But there are questions about the level of expression that you’re going to have over the long term in different types of tissue. So SMA [spinal muscular atrophy] has a huge advantage in this in that the primary problem is the motor neuron. If you can get something in there that’s going to maintain, motor neurons aren’t dividing any longer. You have the motor neurons that you have for life right from birth, and they’re not a replicating cell. So if you have healthy expression of SMN in a motor neuron, it’s likely that that’s going to persist. But there are other tissues that also need SMN that are dividing, and once they divide, they’re not going to have that transduced vector in them anymore. This becomes much more of an issue in other disease targets, as well, that are using gene approaches.

Peter L. Salgo, MD: All right, I’m still going to stay excited.

John Brandsema, MD: Yes.

Peter L. Salgo, MD: There was the START trial, a phase 1 trial. What did that show?

John Brandsema, MD: This was a cohort of patients in Ohio. This has again been published in the New England Journal of Medicine. I think it included 15 total patients treated with gene transfer approach with this agent that again had very robust efficacy in terms of the response in terms of functional outcomes. None of these patients ended up needing significant amounts of respiratory support. The majority of them gained significant motor function over the follow-up period of the trial, again to the point of standing, walking, and so forth. These are again infantile-onset patients.

Peter L. Salgo, MD: Did I mention she was smiling?

John Brandsema, MD: Yeah. There’s been a more expansive trial in the infantile-onset population, and also these are IV [intravenous] delivered for the young babies. In older patients with type 2 SMA, there’s been an intrathecal trial that’s still in the research phase. The tolerability has been quite good. There was an issue with liver enzyme transaminase elevation, but this resolved with prednisone treatment around the delivery of the vector, and in general, it’s been well tolerated.

Peter L. Salgo, MD: This sounds really interesting. How much does it cost?

Maria Lopes, MD, MS: We don’t know yet.

Peter L. Salgo, MD: We don’t know yet. Do you?

John Brandsema, MD: No, I think it does not have its label yet, and so it hasn’t been officially announced.

Peter L. Salgo, MD: Let’s assume if it follows other gene therapies—if we’re going to make it a little bit or a lot bit—it’s on the lot bit side. On the other hand, it’s only once, right?

Maria Lopes, MD, MS: Well, that’s certainly exciting. Given the cost of the treatment we have today, which is ongoing, the ability if you really just give it once—that’s an if—then the question is, What is the durability of the effect? Is this indeed going to last 5 years, 10 years? No doubt that if it does, immediately we’re going to have the cost offsets…

Peter L. Salgo, MD: You’re not going to get a half-million-dollars-a-year drug cost. You may have a gabillion dollars once, but then nothing. Then maybe they get better. They require a lot less of other therapy. That’s kind of a win-win.

Maria Lopes, MD, MS: That’s exciting, yes, yes.

Peter L. Salgo, MD: Nice to be in medicine in this era, isn’t it?

Maria Lopes, MD, MS: It does require that you do have demonstrated durability.

Peter L. Salgo, MD: How do you define durability? You knew I was going there. Is it 5 years, 10 years, lifetime? Maybe you need a redose in what, 10 years? Is that good? Is that bad?

Maria Lopes, MD, MS: We don’t know any of those answers yet, right? We may also have other therapies, and then the question becomes, How do you sequence them? What do you allow in terms of combinations? So what if gene therapy isn’t actually a cure, then what is it that we are paying for? I think it brings back the notion that as more data evolve—and back to registries—but perhaps initially we need a new payment methodology because for the existing payment methodology in the United States, it’s not the payer who’s setting the price tag for a therapy. But that being said, whatever the price tag is.… We now have ICER [Institute for Clinical and Economic Review] as an independent body that has already ruled perhaps what that pricing should be. But independent of that, perhaps what we need is a payment methodology that pays over time to guarantee that you’re seeing the promised outcomes.

Peter L. Salgo, MD: Oh, so you amortize the cost.

Maria Lopes, MD, MS: Amortize the cost, exactly.

Peter L. Salgo, MD: Just as you amortize the benefit. It lasts a long time, and you can spread that out.