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Two New Treatments for Spinal Muscular Atrophy May Be Clinically Effective, But Are They Cost-Effective?
An Independent Watchdog Agency Does the Math



Article In Brief

An independent watchdog group said two emergent therapies for spinal muscular atrophy are not cost-effective but that does not mean neurologists should not prescribe them. The agency does not assess what the drug is worth for an individual patient or family; it considers the cost-effectiveness of drugs from a societal perspective.

In terms of clinical effectiveness, two new treatments for patients with type 1 spinal muscular atrophy (SMA) get a big thumbs-up from a self-appointed watchdog on drug pricing. But neither therapy—nusinersen (Spinraza), approved in 2016, and onasemnogene abeparvovec (Zolgensma), anticipated for approval in May—can be considered cost-effective.

In fact, nusinersen needs a price cut of at least 80 percent to be called cost-effective. And, while onasemnogene abeparvovec has not yet been priced, drug maker Novartis has suggested a price that is millions of dollars out of line for the clinical benefit that it has demonstrated to date.

That's the finding of an evaluation by the Institute for Clinical and Economic Review (ICER), an independent nonprofit organization that has assigned itself a big task: Sort out the evidence for emerging therapies and weigh it against the breathtaking prices being placed on drugs.

Although the SMA therapies are way overpriced, that does not mean neurologists should not prescribe the drugs or that insurers should not pay for them, ICER spokesman David Whitrap said. Rather, ICER's aims to call attention to the fact that, in many cases, the prices being charged for drugs do not reflect an independent assessment of their worth.

ICER doesn't purport to say what a drug is worth for an individual patient or family; it considers the cost-effectiveness of drugs from a societal perspective.

“The purpose of our reports is not to assign a price above which access should be denied,” Whitrap, ICER's vice president of communications and outreach, said in an email. “Instead, our goal is to help all stakeholders understand what an appropriate price should be.”

[The principal investigators of the major trials for both therapies did not respond to Neurology Today's requests for commentary on the ICER report.]

What ICER Found on SMA

The ICER review found, among other findings, that there is high-quality evidence that nusinersen benefits children with type 1 SMA, and it appears to benefit presymptomatic SMA, although data have not yet been published to support that. Moreover, based on the results of a very small trial, onasemnogene abeparvovec, a gene therapy, appears to provide a large benefit to these patients via a one-time treatment. But the data—based on the treatment of 12 infants—is much more limited than that for nusinersen so head-to-head comparison is not possible. There is also moderate evidence that nusinersen provides at least a small benefit to patients with later-onset SMA; no data to assess the effectiveness of onasemnogene abeparvovec in presymptomatic patients or those with later-onset disease, and the long-term effectiveness and safety are not known for either therapy.

A Value-Based Price Benchmark

ICER uses a cost-effectiveness methodology to create what it calls a “value-based price benchmark” that reflects a treatment's benefits for patients over their lifetime. [For more on how it arrives at that benchmark, see “Policy & Practice-How the Institute for Clinical and Economic Review Assesses Cost-Effectiveness” on page TK.]

For nusinersen, that is between $72,000-$130,000 for the first year of treatment and between $36,000-$65,000 for each year thereafter. Currently Biogen's list price for the drug is $750,000 for the first year and $375,000 in subsequent years.

For onasemnogene abeparvovec, ICER's price benchmark is between $310,000-$900,000 for the single treatment. That's a far cry from $4 million or $5 million, which, according to Reuters' report of a conference call with investors, is Novartis' idea of a cost-effective price for the drug.

ICER is hoping that its view will influence the drug's manufacturer to adjust its thinking. “Novartis has a real opportunity here to demonstrate both scientific and ethical leadership by setting a launch price closer to this value-based range,” Whitrap said. “If we want to make the coming wave of gene therapies affordable to patients and the health system, we need to be mindful of the precedent and structure being established right now.”

The Drugs Assessed

SMA, the foremost genetic cause of death for infants, is caused by a mutation in the survival motor neuron gene 1 (SMN1) which, in a healthy person, produces a protein that affects muscle control.

Nusinersen is an antisense oligonucleotide that targets another gene—SMN2—so that it creates more functional SMN protein. It is administered into the fluid around the spine with four loading doses over 63 days and maintenance doses every four months thereafter.

Onasemnogene abeparvovec (known as AVXS-101 before it was rebranded as Zolgensma) is a gene therapy that delivers a copy of SMN to supplement the defective SMN1. It is being studied as a one-time intravenous administration. The FDA granted onasemnogene abeparvovec designations as both a “breakthrough therapy” and a fast track therapy to speed it through the approval process.

Because onasemnogene abeparvovec has not yet been priced, ICER used $2 million as a “placeholder” price for its cost-effectiveness analysis. At that price, using ICER's calculations, onasemnogene abeparvovec would be more cost-effective than nusinersen.

Perspectives from Neurologists

That takeaway does not sit right with David Michelson, MD, lead author of the AAN's evidence review for nusinersen, published last fall. In his view, drawing any conclusions from the onasemnogene abeparvovec trial, which included only 12 patients, is “extremely tenuous.”

“And the data used to forecast effectiveness of the two different drugs are based on very different populations in a disease that changes by the day,” said Dr. Michelson, a child neurologist at Loma Linda University Health. “Even a one-week difference in the average age of the patients involved could be very significant.”

He thinks ICER's process for comparing the relative value of treatments is worthwhile, but in this case, there may not be sufficient data to make a valid comparison.

“Because there is so much difference between the two trials, I see a lot of what ICER started with and extrapolated to the nth degree as a very uneven playing field,” he said. “I'm not happy that people will come away with such a strong impression of the difference in the effectiveness and cost-effectiveness of the two drugs.”

Nusinersen Use To Date

Until nusinersen, there was no disease-modifying treatment for SMA. Although the long-term prognosis and function of patients receiving the drug is not yet known, nusinersen is redefining the natural history of the disease, according to the AAN evidence review published in 2018 in Neurology.

“The discovery and approval of nusinersen is fundamentally altering the landscape of SMA diagnosis and treatment,” Dr. Michelson and his co-authors wrote in their review.

Now that there is treatment available, the federal government in July added SMA to its official list of recommendations for newborn screening. Since then, 20 states have passed laws or approved regulations adding SMA to their newborn screening panels. Five states have implemented universal screening and others are working towards it.

That presents several challenges, including the ability to treat newly diagnosed patients very quickly. The therapy is most effective if it is delivered to a patient before symptoms present, said Emma Ciafaloni, MD, FAAN, director of pediatric neuromuscular medicine at the University of Rochester Medical Center.

Each state is, or will be, developing protocols so that newborns who screen positive for SMA are immediately referred to a specialist for treatment. With a few exceptions, nusinersen is administered only in academic medical centers or children's hospitals. The dosing protocol requires four lumbar punctures during the first two months of treatment and frequent treatments and monitoring thereafter.

“With the newborn screening becoming universally available in an awfully short time, this requires an evolution of the (care-delivery) infrastructure,” Dr. Ciafaloni said at a March 7 meeting of the New England Comparative Effective Public Advisory Council, an ICER board that voted on the clinical effectiveness and value of the two therapies.

More than 2,600 infants, children, and adults in the United States—and more than 6,600 worldwide—have been treated with nusinersen, according to a March 5 letter from Biogen, its manufacturer, posted on the Cure SMA website.

Within the US, 95 percent of patients who started nusinersen remained on treatment as of December 2018, the manufacturer said. Patients ranging from 3 days old to 79 years of age have been treated with the drug.

More than 35 percent of patients receiving nusinersen are 18 years old or older. The AAN Evidence in Focus document said those older patients with type 3 and type 4 SMA “may prove responsive to nusinersen as they carry more SMN2 copies but the cost–benefit ratio is different in these populations.” (SMN2 copies mitigate the damage caused by the mutated SMN1.)

Although recent trials demonstrate the safety and feasibility of nusinersen administration in adult patients, efficacy data are needed before its cost-effectiveness can be determined, said Gregory J. Esper, MD, MBA, FAAN, chair of the AAN Health Services Research Subcommittee.

The costs of administration need to include the use of a multidisciplinary team of clinicians because of the complexities of administering nusinersen in adult patients who have structural and physiological problems stemming from longstanding SMA, he said.

“Ultimately, while these drugs represent new hope for SMA patients, the realities of limited resources for global medical spending must be addressed in order to ensure unintended consequences, such as limited access to care and treatment for other patients with other diseases,” said Dr. Esper, professor and vice chairman of clinical affairs for the department of neurology at Emory University School of Medicine, said in an email interview. “My desire is that we can somehow make it all work.”

Link Up for More Information


•. Institute for Clinical and Economic Review. Spinraza® and Zolgensma® for spinal muscular atrophy-Effectiveness and Value: Evidence report. Feb. 22, 2019. http://bit.ly/NT-ICER-SMA
    •. Lally C, Jones C, Farwell W, et al. Indirect estimation of the prevalence of spinal muscular atrophy Type I, II, and III in the United States https://ojrd.biomedcentral.com/articles/10.1186/s13023-017-0724-z. Orphanet J Rare Dis 2017;12(1):175.
      •. Michelson D, Ciafaloni E, Ashwal S, et al Evidence in focus: Nusinersen use in spinal muscular atrophy. Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology https://n.neurology.org/content/91/20/923.long. Neurology 2018;91(20):923–933.
        •. Wurster CD, Winter B, Wollinsky K, et al. Intrathecal administration of nusinersen in adolescent and adult SMA type 2 and 3 patients https://link.springer.com/article/10.1007%2Fs00415-018-9124-0. J Neurol 2019; 266(1):183–194.
          •. Stolte B, Totzeck A, Kizina K, et al. Feasibility and safety of intrathecal treatment with nusinersen in adult patients with spinal muscular atrophy https://journals.sagepub.com/doi/10.1177/1756286418803246. Ther Adv Neurol Disord 2018; 11:1756286418803246.