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With Zolgensma's approval of Novartis ZDA (NVS) for the treatment of spinal muscular atrophy (SMA) by the FDA last week, the field is poised for a duel between two rivals SMA treatments. Competition could reach far beyond the local competition between two isolated gene therapies for rare diseases. If there is always a winner, this could have long-term consequences for the future of gene therapy drug development and pricing.
With the approval of Zolgensma, he will face Spinraza, developed in partnership between Biogen (BIIB) and Ionis Pharmaceuticals (IONS). Spinraza and Zolgensma treat the same disease but in a different way. Let's talk about Spinraza first to understand how it works and from there, we can understand the main difference between the two drugs.
Spinraza is an antisense oligonucleotide (ASO), which binds to the genetic code of RNA and blocks the transcription of genes at that location. The result is an altered protein of the same genetic code, although manipulated. In particular, in the case of Spinraza, there are two relevant genes, SMN1 and SMN2. SMN1 normally codes for a complete NMS, but in SMA patients it is mutated and does not work. SMN2 is not affected but does not produce enough SMN protein due to a "stop" code just before transcription of a critical part of the gene encoding SMN. What the ASO does then is bind to and block this "stop" code, which allows the transcription to continue and produce a complete SMN protein from the functional SMN2 gene. So, basically, Spinraza blocks the stop code on the gene copy, causing transcription of the complete SMN protein from the remaining functional gene. The full explanation, for those interested, can be found here.
The advantage of Spinraza is that it can treat almost all cases of severe acute malnutrition. The disadvantage is that it does not solve the broken gene. This simply gives the body a new detour to bypass it. Spinraza must be a lifelong therapy with recurrent costs three times a year and a dose not to be missed or the disease may evolve. The cost of initial load injections is $ 750,000 the first year, followed by maintenance doses of $ 375,000 a year. There is not enough data yet to determine how long the drug remains effective overall and how long patients can continue to live on Spinraza, but treatment over a 10-year period would cost $ 4.125 million, to suppose that the price is never increased.
Zolgensma is different. It uses a viral vector to directly inject the genetic code into the defective neurons. Since the viruses are designed to inject genetic code into their target cells, Zolgensma uses a virus to do the same thing, with the exception of the virus that carries functional copies of the SMN1 gene. The virus injects the gene into the motor neuron cells, which then begin to produce the SMN protein themselves. The result is the healing of a unique treatment and the effective fixation of defective genes. It does not work all the time, but in cases where it works, here's how it's designed to work.
The advantage of this is obvious, requiring only a single treatment and no maintenance injection. At a price of $ 2.2125 million, this equates to about half the price of Spinraza over a 10-year period. The clinical data we have up to now confer an advantage on Zolgensma. 75% of patients in the high-dose cohort of a completed Phase I trial were able to sit unaided after 24 months and 2 patients were able to stand up and walk without help. The 12 patients in the high-dose cohort of this trial were alive after 24 months. The current phase III trial allowed 47.6% of patients to sit alone and 13 of 19 survived without ventilation for 14 months. With Spinraza, 23% of patients are still dead, which is similar to Zolgensma Phase III data, but only 40% responded to treatment with milestones. This was much better than the 0% placebo, but overall, Zolgensma seems to be more effective per dollar spent than Spinraza.
This is less clear when we subdivide clinical trials between presymptomatic and post-symptomatic patients. SA, author of Cranium Expert, did a good job on this, showing that in presymptomatic patients, 100% were able to sit unaided, compared to only 8% in patients who already had symptoms of ADS. This makes sense, because treatment before the symptoms means that you avoid the destruction of motor neurons. Cranium Expert shows that Spinraza has advantages in terms of efficacy compared to Zolgensma, but as we do not yet have data specifically pre-symptomatic Novartis, this is not a pure apple-to-apple comparison. If we assume that in presymptomatic patients, Zolgensma will work in the same way by rescuing the neurons before they are destroyed, Zolgensma will probably be more efficient from one apple to another, but we can not know it with certainty. Clearly, in order to determine if this is really bearish for Biogen and Ionis, we need apple apples data, although I suppose that, for presymptomatic patients, the results will be similar for both drugs and that Zolgensma will have a good price.
Zolgensma, however, has two major disadvantages. First, it does not apply to all SMA patients as some have an antibody against the virus used to transmit the genes. Novartis estimates that Zolgensma can be used to treat approximately 80% of patients with AMS, while Spinraza is close to 100%, at least in terms of applicability, if not actual effectiveness. The other disadvantage is that Zolgensma will be accompanied by a warning against serious liver damage. Spinraza does not contain a warning, but only an increased risk of bleeding and mild renal toxicity.
There is not enough data yet to determine which drug will be even better, so market performance will be fascinating in this case, and could mark a turning point in the types of gene therapies that will dominate the market. 'to come up. Will it act on Spinraza's "Rent-a-Gene" model that manipulates the existing genetic code but requires lifetime maintenance, or will it be the "Buy-a" model? -Gene "de Zolgensma who places a new genetic code in patients and corrects the problem problem with a treatment?
Until now, it seems to me that Zolgensma is more likely to win this battle. The efficiency is similar, but the cost is much lower, and no lifetime maintenance is required. The question of liver toxicity is to be monitored, although the incidence of hepatic toxicity during the trials was attenuated by prednisolone, a steroid that slows down inflammation. I do not believe that the boxed warning will pose a big problem, as SMA is a deadly disease and Zolgensma does not require follow-up treatment, which means that liver toxicity can probably be treated in the short term and overcome with steroids and probably won. t recurrent.
According to the clinical data we have to date, it seems to me that Zolgensma could begin to replace Spinraza in the market by becoming a front-line treatment, if only because it's so much less expensive and at least as effective. In case of antibody resistance, patients would obviously use Spinraza instead. But in the end, I think Zolgensma will pave the way for the "Buy-a-Gene" model, gaining in the long-term market and eventually becoming bearish relative to Biogen and Ionis and bullish to Novartis.
Disclosure: I / we have / we have no position in the actions mentioned, and we do not intend to initiate a position within the next 72 hours. I have written this article myself and it expresses my own opinions. I do not receive compensation for this (other than Seeking Alpha). I do not have any business relationship with a company whose shares are mentioned in this article.
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