Zolgensma will still be the first $1B gene therapy

October 31, 2019
beautiful cell with blue background

By Anthony Davies

Say what you will about Novartis; it’s always interesting over there by the Rhine. It’s been a rollercoaster of news about Zolgensma lately—from the timing of the data manipulation reporting…to the excellent 3Q earnings…to Japan and the EU’s manufacturing concerns.

And, of course, there’s the loudest news of the day: a clinical hold on the Zolgensma trial in children over two years of age. This news comes a scant six months after U.S. FDA approval for younger patients. How is this likely to play out?

First, let’s recap the reason for the cessation of testing the therapy over a certain age, even though no children in the trial suffered nerve inflammation. Older children receive the therapy via a spinal injection, versus an intravenous injection in the youngest patients. It is starting to appear as if the trouble is due to dose-limiting toxicity concerns similar to those acknowledged by Jim Wilson—a great-granddaddy of our emerging gene therapy field—when he resigned from the Scientific Advisory Board of Solid Biosciences in 2018.

Wilson’s concern came with the unexpected triggering of an innate immune response in gene-therapy dosing (in non-human primates). Options to counteract the response could eventually look like treatments to suppress inflammation (think: corticosteroids) or to temporarily weaken a patient’s immune response (think: immune modulating treatments).

But, for the time being, and in a field young enough to have not yet pushed the boundaries of dose-limiting toxicity, the possibility of an immune-system-triggered rejection makes the dosage limit a very real factor.

To quote Jim Wilson’s interview in Forbes, these limitations may require us to “select diseases in which the unmet need is so significant that it would justify the risks.”

That is, opportunely, a precise description of Spinal Muscular Atrophy (SMA), Zolgensma’s target.

It’s possible, then, that we will eventually see Zolgensma simply becoming more valuable for a more closely-targeted market even if the milder type 2 SMA remains out of reach (thus limiting Zolgensma’s initial reach). Given that the therapy doesn’t reverse the progression of the disease but instead stops it in its tracks, it is a more attractive solution for children not affected by this pause in testing.

In other words, an economic model for Zolgensma success is likely to take into account the classic push-pull between incidence and prevalence. As Denise Roland astutely notes, if newborn screening takes hold (resulting over time in much higher incidence and much lower prevalence), it could eventually bump nearly all affected children into the under-two-years category: the category best served by Zolgensma.

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