Gene Therapy, R&D

New Zolgensma data suggest comparable efficacy to Spinraza — analysts

As Novartis awaits the FDA decision on its spinal muscular atrophy (SMA) gene-therapy, Zolgensma, the company that developed the treatment for the rare, deadly inherited disorder, AveXis, presented data snapshots from ongoing trials on Sunday, prompting analysts to suggest that the one-shot therapy was looking comparable to Biogen’s approved Spinraza.

In the ongoing late-stage STR1VE study, designed to evaluate the efficacy and safety of a one-time IV infusion of Zolgensma in patients with SMA Type 1 who are <6 months of age, data showed patients continued to show event-free survival well above normal historical controls, AveXis suggested at the American Academy of Neurology annual meeting.

SMA causes muscle weakness and progressive loss of movement, triggered by a genetic deterioration in the nerve cells connecting the brain and spinal cord to the body’s muscles. Babies with type 1 rarely survive beyond the first few years of life, while most children with type 2 survive into adulthood. Types 3 and 4 don’t usually affect life expectancy. The Swiss drugmaker has suggested a price of $4 -$5 million for Zolgensma, which it acquired via its $8.7 billion takeover of AveXis.

Another significant update was the snapshot from the STRONG study, which is evaluating the intrathecal delivery of Zolgensma in patients with SMA Type 2. Patients were stratified into two groups based on age at time of dosing: patients who are ≥6 months but <24 months, and patients who are ≥24 months but <60 months. The primary efficacy outcome for patients in the first group is the ability to stand without support ≥3 seconds; the main goal for the second group is a change in Hammersmith Functional Motor Scale-Expanded (HFMSE) score from baseline. Since dosing, 22 motor milestones in 10 patients have been achieved across Dose A and Dose B, including two patients who gained the ability to stand independently, one of whom went on to walk alone, and one patient who gained the ability to walk with assistance. The median duration of follow-up was 6.5 months and all 30 patients are alive.

“The average age at enrollment in STRONG was 17 months…these results are challenging to interpret or compare with the Spinraza data since the Biogen/Ionis study enrolled patients who were slightly older (3 years at baseline). Thus, we believe the most comparable datapoint is efficacy on the HFMSE, which was the primary endpoint in Biogen/Ionis’ Spinraza trial. On this measure, AVXS-101 produced a mean 4.2 point improvement at a median follow up time of 7.5 months; by comparison, Spinraza generated a ~3 point improvement at 9 months in the Phase III CHERISH study. The magnitude of these improvements are obviously very close to one another, and when we think about STRONG/CHERISH designs and the recruited trial populations, the balance of confounding variables probably favors the STRONG study a little, underlying our conclusion that the efficacy of gene therapy and Spinraza are probably pretty similar,” Stifel analysts wrote in a note.

Evercore ISI’s Umer Raffat suggested that in the second group, although Zolgensma appears to kick in faster, both the gene-therapy and Biogen’s $BIIB Spinraza plateau at the same. But, there is one crucial caveat — the patients in AveXis trial seemed to have lower HFMSE scores to begin with, he wrote.

Overall, no treatment-emergent deaths have been presented in the new data, he noted. Roughly two weeks ago, AveXis disclosed that one of the infants in the STR1VE-EU study died from an infection, and authorities are investigating whether Zolgensma played a role in the death. Although regulatory bodies are expected to be accommodating for safety issues when it comes to a potential once-and-done treatment for the lethal disease, competition absent these safety concerns could certainly temper adoption.

The AveXis data “looks competitive and like a viable option for patients, including new intrathecal dosing for Type 2, etc, and beyond just infants (where gene therapy is most competitive to start). We think FDA approval and a fairly ‘broad label’ could be coming for Novartis as soon as this week. Our doc survey suggests more than 1/3 of patients could opt for this; hence, Biogen estimates may be too high for Spinraza,” Jefferies analysts wrote in a note.

PTC Therapeutics $PTCT and Roche’s oral SMA therapy, risdiplam, will likely be taken to the FDA for review  later this year for a broad population, and could be on the market by the end of 2020, they added.

“Bottom line — we could see a 1/3, 1/3, 1/3 split of market over time,” Jefferies analysts said. Doctors suggest gene therapies “could be 30-33% share of new SMA Type I-III patients over time. An estimated 20-25% could look to switch from Spinraza to gene therapy (depends on weight of patient). 2) Similarly, docs suggest 1/3 share for oral risdiplam, too, after 3-5 years; 3) Commentary by docs suggests an even split of opinions on the market as well — from oral pills ‘very appealing’ and ‘game changer’ and ‘especially attractive for teens/adults’ to other therapies need more data and likely combo,” citing their survey.

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