Novartis Announces Partial Clinical Hold by FDA on Intrathecal Administration of Zolgensma for SMA

On October 30, Novartis announced that the U.S. FDA had partially placed a clinical hold on the intrathecal administration trials of AVXS-101. AveXis communicated the results of a small preclinical study to health regulatory authorities and clinical trial investigators; in this study, animal experiments showed mononuclear cell inflammation in the dorsal root ganglia (DRG), sometimes accompanied by degeneration or loss of neuronal cell bodies. The FDA’s partial hold does not affect the already marketed Zolgensma or the intravenous (IV) administration clinical trials of AVXS-101.

AveXis is investigating the intrathecal administration of AVXS-101 in patients with type 2 spinal muscular atrophy (SMA). The partial hold affected enrollment in the high-dose cohort of the STRONG trial, an ongoing, open-label, dose-comparison, multicenter study designed to evaluate the efficacy, safety, and tolerability of a single intrathecal dose of AVXS-101. Enrollment in the low- and mid-dose cohorts was previously completed, and interim results have been reported.

Prior to this announcement, on October 5, AveXis, a Novartis subsidiary, released the latest interim data from the Phase 1/2 STRONG study of intrathecal AVXS-101. The data showed that older patients with Type 2 spinal muscular atrophy (SMA) (aged ≥2 to <5 years) achieved a median increase in HFMSE score of 5.9 points from baseline, nearly twice the threshold for clinical significance, with a median follow-up duration of 9.3 months. This improvement exceeds the median HFMSE score increase of 4.2 points presented at the American Academy of Neurology Annual Meeting in May 2019. Half of the Type 2 SMA patients experienced a clinically meaningful improvement in motor function one month after treatment completion, defined as an increase in HFMSE score of ≥3 points from baseline. The Hammersmith Functional Motor Scale Expanded (HFMSE) is a widely used motor function scale in clinical practice and trials to assess physical capabilities and motor function in both non-ambulatory and ambulatory patients with Type 2 and Type 3 SMA.

STRONG Phase 1/2 Clinical Trial Data as of May 31, 2019:

The STRONG trial is an ongoing, open-label, dose-controlled, multicenter clinical study evaluating the efficacy, safety, and tolerability of a single intrathecal dose of AVXS-101 in patients with Type 2 spinal muscular atrophy (SMA) who have three copies of the SMN2 gene. All enrolled patients were able to sit but unable to stand or walk at the time of enrollment. Patients were stratified into two groups based on age at enrollment: one group comprising patients aged 6 months (inclusive) to under 2 years, and the other comprising patients aged 2 years (inclusive) to under 5 years. To date, 31 patients have been enrolled and received one of the following three doses: Dose 1 (6.0 × 10¹³ vg), Dose 2 (1.2 × 10¹⁴ vg), or Dose 3 (2.4 × 10¹⁴ vg). Data for Dose 3 were not disclosed at this conference. Three patients (out of 36 screened, representing approximately 8.3% of the total screened population) were excluded from enrollment due to excessively high anti-AAV9 antibody titers.

In the patient age group of 6 months or older (including 6 months) and younger than 2 years:

The primary endpoint of the pharmacodynamic study was the ability to stand unsupported for 3 seconds or longer (including 3 seconds).

The secondary endpoint of the pharmacodynamic study was achieving the ability to walk independently for five or more steps (including five steps), as assessed by the Bayley-III Gross Motor Milestone Scale.

Following treatment, the 16 subjects who received Dose 1 or Dose 2 achieved a total of 18 motor milestones; among them, two patients attained the ability to stand independently, and one of these two further achieved the ability to walk independently.

In the patient age group of 2 years and older (including 2 years) and under 5 years:

The primary endpoint of the pharmacodynamic study was the change in HFMSE score from baseline in enrolled patients.

The secondary endpoint of the pharmacodynamic study was achieving the ability to walk independently for five or more steps (including five steps), as assessed by the Bayley-III Gross Motor Milestone Scale.

Patients achieved clinically meaningful improvements in motor function over a median follow-up duration of 9.3 months, with a median increase of 5.9 points in HFMSE scores from baseline at the most recent follow-up.

In a response analysis, with observation starting one month after treatment initiation, half of the study participants (6 out of 12) achieved an increase in HFMSE score of at least 3 points.

Following treatment, the 12 patients who received Dose 2 achieved a total of four motor milestones, with one patient gaining the ability to walk with support.

It is reported that all participants in the STRONG study experienced at least one treatment-emergent adverse event (TEAE). Among them, 13 subjects (43% of the total) were assessed by investigators as having TEAEs related to the treatment. Serious TEAEs occurred in 13% of the total participants (n=4). A total of 7 serious TEAEs (one each) were reported in these 4 patients, namely influenza, pneumonia, respiratory syncytial virus infection, elevated ALT (alanine aminotransferase), elevated AST (aspartate aminotransferase), increased serum alkaline phosphatase (AKP), and respiratory failure. The elevations in ALT and AST (occurring in the same patient) were deemed treatment-related. However, no subject discontinued participation in the trial due to serious TEAEs, and no deaths were reported.

On the other hand, Novartis stated that this suspension does not affect Zolgensma (AVXS-101), which was launched on May 25, 2019, or the clinical trials of intravenous (IV) administration of AVXS-101. Furthermore, AveXis announced that it has completed a comprehensive review of all available human safety data to date, and no changes in sensory-related adverse reactions have been observed in either intrathecal administration of AVXS-101 or Zolgensma administration. AveXis is collaborating with health authorities to confirm further guidance for clinical investigators. AveXis remains confident that the overall benefit-risk profile for treating patients is favorable and will continue to advance the clinical research of intravenous AVXS-101. Novartis and AveXis also reaffirmed their commitment to the research and development of gene therapies for spinal muscular atrophy (SMA). Meanwhile, efforts are underway to communicate with the FDA to resume dosing in the intrathecal clinical trials of AVXS-101 as soon as possible.

Since its inception, Zolgensma has been met with both high expectations and acclaim, while simultaneously facing ongoing controversy. On May 24 of this year, the U.S. Food and Drug Administration (FDA) approved Zolgensma as a one-time gene therapy for the treatment of spinal muscular atrophy (SMA). Its hefty price tag has drawn significant industry attention: $2.125 million per dose, equivalent to approximately RMB 14.687 million. According to Novartis’ third-quarter financial report, the drug generated sales as high as $160 million within just four months of its market launch.

However, behind the impressive performance lies a multitude of doubts. In August this year, it was reported that Novartis made changes to the preclinical data related to animal studies submitted to the FDA and failed to notify the FDA in a timely manner, which drew severe criticism from the agency. Nevertheless, this "production issue" is unrelated to the data falsification scandal; it primarily pertains to manufacturing problems and the associated production facilities.

Novartis spokesperson Eric Althoff stated that the Committee for Medicinal Products for Human Use (CHMP) of the European Union would inspect Zolgensma’s manufacturing facilities in December of this year, with a decision on approval expected in the first quarter of 2020. Japan is also scheduled to make its decision in the first half of next year. The Novartis spokesperson did not specify the exact issues raised by regulatory authorities in these countries, but indicated that the concerns primarily centered on production and CMC (Chemistry, Manufacturing, and Controls). Consequently, the approval of Zolgensma has been delayed in both the EU and Japanese markets.

But regardless of external opinions, Novartis has remained optimistic about Zolgensma. To address pricing concerns and accelerate market access, the company proposed a payment model whereby reimbursement is contingent upon the drug achieving its promised therapeutic efficacy, with the option of installment payments. On one hand, Wall Street analysts project full-year sales to exceed $2 billion. On the other hand, analysts at JPMorgan hold a different view, arguing that, based on a survey of 26 physicians treating spinal muscular atrophy (SMA), the proportion of SMA patients receiving this gene therapy is too small, suggesting that the product may struggle to generate over $1 billion in “sustainable revenue.”

In reality, the pressure facing Novartis’ Zolgensma stems not only from current public opinion or “scandals,” but also from the need to take measures to counter the “threat” posed by Biogen’s Spinraza. Market research indicates that approximately half of Zolgensma patients discontinued treatment in favor of Spinraza during the third quarter. Meanwhile, risdiplam, an oral therapy under development by Roche and PTC Therapeutics, is emerging as a dark horse “sweeping” the market.

References:

[1] Novartis announces AVXS-101 intrathecal study update. Retrieved 2019-10-30,from

https://ml-eu.globenewswire.com/Resource/Download/7735ec74-9341-4041-a287-e1afae3b8b9f

Sources: Huihui Yaoka, FDA Official Website, Yiyao Shijian, Jike Yaowen

Responsible Editor: Sanqi

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