The US Food and Drug Administration recently approved two drugs that target the genetic error underlying spinal muscular atrophy (SMA), a muscle-wasting disorder, often fatal before the age of two, that was previously untreatable. The treatments—Zolgensma from Novartis Gene Therapies and Spinraza from Biogen—come with hefty price tags, yet a report in Science Translational Medicine today (November 11) argues that they offer only modest benefits with possible health risks, leaving patients with unmet medical needs and possibly with substantial healthcare bills.

“This paper highlights the complexity of developing treatments for rare diseases and paying for those treatments,” health policy researcher Stacie Dusetzina of Vanderbilt University who was not involved in the research writes in an email to The Scientist. “The review of outcomes for SMA treatments are particularly sobering, with small but meaningful gains in motor response outcomes for some infants with SMA . ....

Spinal muscular atrophy, in which mutation of a protein called SMN causes loss of motor neurons and consequent muscle wasting, affects approximately 500 newborns in the US each year. The condition is often fatal before the age of two and, until recently, there were no drug treatments.

In 2017, the FDA approved the drug Spinraza, an antisense oligonucleotide that promotes correct splicing of an SMN-encoding RNA to increase production of the protein. The drug, which is injected into the spinal canal, costs $125,000 dollars per treatment. With the injection being repeated every four months for life, and assuming the child’s survival is prolonged as trial results indicate, the cost can quickly run into millions.

See “FDA Approves First Treatment for Spinal Muscular Atrophy

In 2019, the FDA approved Zolgensma, a gene therapy that provides a functional copy via viral vector of the gene encoding SMN. The one-time treatment, an intravenous infusion, costs $2,125,000—the most expensive single treatment ever.

See “FDA Approves Gene Therapy for Spinal Muscular Atrophy

These high prices prompted Jonathan Darrow, a bioethicist at Harvard Medical School, and colleagues to thoroughly investigate the treatments’ benefits and risks. (The team did not assess the new oral SMA drug risplidam, approved by the FDA this August.)

The authors’ analysis of trial data and FDA reports show that the administration’s approval of Spinraza was granted on the basis of a Phase 3, placebo-controlled trial involving 78 infants with SMA. In that trial, 41 percent of the 51 Spinraza-treated infants showed marginal improvements in motor function, compared with no improvements in the placebo group. This means 59 percent of treated patients showed no improvement, the authors point out. Additional trials completed after the FDA’s approval have showed similarly marginal improvements in some treated patients, the authors say.

Darrow and his coauthors also question Zolgensma’s efficacy, largely because the FDA’s approval of this treatment was based on just 15 patients in an open-label Phase 1 trial. While treated patients showed improvements, most did not reach the motor milestones of healthy infants.

The authors additionally point to potential safety concerns with the two treatments, including toxicity and infection risk (because of repeated injections) in the case of Spinraza, and elevated liver enzymes, which may indicate inflammation or damage, in the case of Zolgensma.

“The paper nicely summarizes. . . the inadequacies of the studies” that supported the drugs’ approval, says health policy researcher James Chambers of Tufts University who was not involved in the study. “It emphasizes that the FDA, not inappropriately, approved these products based upon evidence that healthcare payers would argue maybe is insufficient to really prove that the product works.” But, he adds, performing the large-scale clinical trials for any rare disease is tricky because there are so few patients.

See “Gene Therapy Finds a Fertile Home in Ohio

Chambers also points out that these “are very important therapies” and that while the clinical improvements might seem small, “[they] can be huge for a patient who can still maintain some sort of quality of life. . . . Those marginal health benefits can be life-changing.”

For a disease where previously a parent could only watch as their child got sicker and died, “[Zolgensma] is a breakthrough,” writes Jerry Mendell of Nationwide Children’s Hospital in an email to The Scientist. Mendell studies neuromuscular disorders and was part of the team running the original Zolgensma trial. He also rebukes Darrow and colleagues’ safety concerns, saying Zolgensma “is very safe. . . .  Risk-benefit is not even close to being an issue.” Regarding Zolgensma’s price tag, he writes, “the cost is not a factor when it comes to saving lives.”

In justification of Zolgensma’s cost, a spokesperson from Novartis Gene Therapies writes in an email to The Scientist, “All available data demonstrate Zolgensma delivers transformative benefit without the need for add-on therapy. Gene therapies such as Zolgensma have the potential to reduce the long-term financial burden on patients, families, and the overall healthcare systems by replacing repeat, lifelong therapies with a single treatment.”

And, in justification of Spinraza’s price, a Biogen representative writes that “the prices of our medicines reflect the unique advancements that they bring to patient treatment. . . . SPINRAZA is a major therapeutic advance that can change the course of SMA and offer meaningful improvements to the lives of those affected by the disease, as well as reducing the burden on healthcare systems.”

But, the promise of reduced burdens on healthcare systems and reduced need for further treatment “isn’t guaranteed,” Dusetzina says. “In many cases, we also have these drugs available without understanding the long-term effects. How long will they work? Will the patient need to be treated again in the future?”

Indeed, some patients that received Zolgensma treatment were later started on Spinraza, according to a report by the Institute for Clinical and Economic Review (ICER), possibly “because their health state started to deteriorate or because they did not improve as much as desired.”

Because “we allow manufactures to set a price [for a drug] unrelated to cost effectiveness. . . our current system of paying for drugs is broken,” says Marc Rodwin of Suffolk University in Boston who studies health law and politics and was not involved in the report.

The problem is largely a US-specific one, he explains. In other countries, regulatory bodies such as National Institute for Health and Care Excellence (NICE) in the UK and the Transparency Committee in France assess a treatment’s cost-effectiveness and negotiate more reasonable prices with drug companies. But in the US, while ICER informs insurance companies on cost-effectiveness of drugs, it has no regulatory power, explains Darrow. To establish an administrative body with such power would require significant legislative reform, he says.

Treatments for rare disease, so-called orphan drugs, are always likely to be expensive, because with limited numbers of patients low prices would be unprofitable. But the “premiums for health insurance cannot just continue to climb to cover these costs,” Dusetzina says. “At some point we have to acknowledge that we are making tradeoffs and decide if we could make better decisions about how much we pay so that we can make sure that we balance innovation and affordability.”

J.J. Darrow et al., “Efficacy and costs of spinal muscular atrophy drugs,” Sci Transl Med, 12:eaay9648, 2020.

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