A preliminary Draft Evidence Report from the Institute for Clinical and Economic Review (ICER) says the investigational spinal muscular atrophy (SMA) treatment Zolgensma (onasemnogene abeparvovec-xxxx) could be more cost-effective than Spinraza (nusinersen) with a one-time price of $2 million.
However, ICER noted that more must be known regarding Zolgensma’s U.S. price and both therapies’ long-term benefits.
The report is open to public comment until Jan. 31. More information on how to submit comments and what type of information would be most useful can be found here.
Comments and their respective responses will be incorporated in the final evidence report, to be published by Feb. 21. This report will be subject to deliberation during a public meeting of the New England Comparative Effectiveness Public Advisory Council (CEPAC), on March 7 in Boston. Click here to register for the public meeting and its live webcast.
For the preliminary report, ICER, a nonprofit organization whose assessments increasingly influence medicines’ price negotiations in the U.S., spoke with patients and their families, clinicians, researchers, insurers, representatives from SMA patient advocacy groups, and the manufacturers of the two medicines.
The assessment — announced last August — compared the clinical effectiveness and economic impact of Zolgensma and Spinraza versus supportive care for SMA patients of all ages and types. It reviewed existing evidence while taking uncertainty and patient-centered considerations into account.
To analyze long-term cost-effectiveness, ICER used three models: one for symptomatic patients with SMA type 1, another for symptomatic patients with SMA types 2 or 3, and the third for presymptomatic SMA patients.
ICER calculated quality-adjusted life years (QALY) for both therapies, a measure in which their benefits in length of life are adjusted to reflect quality of life. One QALY equals one year of life in perfect health.
In an R&D and Investor update last November, Novartis said that its “one-time, potentially curative” gene therapy could be cost-effective at a list price of $4 million to $5 million. However, Zolgensma’s final price will be determined in negotiations with health plans, the company noted.
In its assessment, ICER estimated the potential therapy’s price at a lower benchmark — $2 million. This represents a cost of $240,000 per QALY in patients with symptomatic type 1 SMA, ICER said.
In a Dec. 20 Reuters story, ICER chief medical officer David Rind noted that although a good value usually lies within $100,000 to $150,000 per QALY, it can go higher for rare diseases such as SMA. Novartis said it would like comparisons against an ultra-rare threshold of $500,000 per QALY and against Spinraza, according to company spokesman Eric Althoff. “While a range of QALY thresholds were used, we believe cost-effectiveness assessments in SMA should be compared to currently available, chronic therapy and be assessed at the ultra-rare disease QALY threshold,” Althoff told Reuters.
Biogen’s Spinraza, the only approved therapy for all SMA types, carries a list price of $750,000 for the first year and about $375,000 per year thereafter. According to ICER’s preliminary estimate, Spinraza represents a cost of $728,000 per QALY (higher than Zolgensma’s) in presymptomatic patients.
“That is expensive by the way most people value things,” Rind told Reuters.
Reuters also reported that a Biogen spokeswoman said the draft report is “an incomplete representation of Spinraza’s value to patients and healthcare systems.” She told Reuters that comparing Spinraza’s treatment of nearly 6,000 patients to a group of 15 patients receiving Zolgensma in its pivotal Phase 1 trial (NCT02122952) was misleading and wrong.
Indeed, ICER addressed the number of patients treated with Zolgensma as a limitation for this cost-effectiveness comparison. “As in prior reports, we feel it is inappropriate for a therapy to appear cost-effective simply by offsetting costs of a recently introduced very expensive alternative. … Policymakers will have the results of the Zolgensma versus Spinraza modeling to support their own judgment of value,” the report stated.
Analyses of therapeutic efficacy were based on mortality, the need for permanent invasive ventilation, motor function, mobility, feeding support and other issues associated with SMA, as well as quality of life. As for safety, the report compared the frequency of serious adverse events (AEs), treatment-associated AEs, AEs leading to treatment discontinuation, and local reactions to infusions or injections of Spinraza or Zolgensma.
The report stated that both treatments provide substantial clinical benefit, as reflected in extended survival and improved motor function compared with SMA’s natural history or placebo. However, SMA type 1 babies were about a month older in Spinraza’s ENDEAR (NCT02193074) and CHERISH (NCT02292537) trials than in Zolgensma’s pivotal Phase 1 study, ICER noted.
The organization also expressed caution over insufficient clinical evidence for the two therapies. This includes narrow trial eligibility criteria precluding the generalizability of results (particularly in the case of Zolgensma) for patients with a different genetic profile or more severely ill, limited long-term safety (regarding repeated spinal tap injections of Spinraza) and efficacy data — such as how durable Zolgensma’s benefits are or how they affect presymptomatic patients — and the uncontrolled, open-label design of the START trial (NCT03421977) of Zolgensma. Evidence regarding benefits for patients with type 0 or type 4 SMA is also lacking, the report noted.
“Because SMA is a rare disease and the trials have short-term follow-up, the long-term effects of Spinraza or Zolgensma will take time to emerge,” ICER stated.
Also, age differences at treatment initiation as well as disease duration “limit our ability to adequately distinguish the net health benefit of Zolgensma versus Spinraza for infantile onset SMA,” ICER’s report said. “We therefore rate the evidence to be insufficient.” However, ICER noted that these conclusions may be updated in case additional safety and efficacy data become available.
The positive results of Zolgensma’s Phase 1 study were largely the basis of Novartis’ Biological License Application (BLA) to the U.S. Food and Drug Administration (FDA), seeking approval for Zolgensma — previously AVXS-101 — as a gene therapy for SMA type 1, the most common and severe form of the disease.
The FDA is currently reviewing the BLA, specifically covering intravenous delivery in infants up to 9 months old. A final decision is expected by May. Similar reviews are underway in Europe and Japan. Zolgensma was originally developed by AveXis, which was acquired by Novartis last year.
Zolgensma is designed to restore production of working and full-length SMN protein in motor neurons, which are specialized cells controlling muscle contraction, by delivering a functional copy of the SMN1 gene. SMA patients have a defective SMN1, leading to significantly lower levels of working SMN protein and loss of motor neurons, as well as muscle weakness and atrophy (shrinkage).
Spinraza is intended to boost the ability of the SMN2 gene to also generate full-length and functional SMN protein. Without Spinraza, most of the protein produced from SMN2 is unstable and shorter than usual.
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