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Expensive Drugs for Rare Muscle Disease Bring Only Minor Benefits

pill bottle spilled over money
Some costly drugs for rare conditions yield only small clinical benefits. | Michael Quirk/ iStock

Two expensive and recently approved drugs for the rare condition spinal muscular atrophy (SMA) offer only modest benefits for patients despite their high costs, argue scientists after revisiting data and FDA documents from clinical trials.

The discussion, published in the November 11 issue of Science Translational Medicine, raises questions about how to allocate the enormous resources that are being dedicated to certain drugs for rare diseases, even though these therapies may lead to only mild clinical improvements for some patients.

The piece also highlights persistent issues with prohibitive drug pricing that have characterized many of these compounds. The researchers point out that these high costs force employers and government payors to shift resources away from education, housing, and other goals that are relevant to health.

"Expanded insurance coverage has allowed prices to rise to unprecedented levels, yet many of today's drugs continue to leave patients with substantial unmet need," said Jonathan Darrow, an assistant professor at Harvard Medical School in Boston, Massachusetts and lead author of the new article. "SMA drugs are simply a recent example of this larger phenomenon."

Zolgensma and Spinraza are gene therapies that were approved by the FDA in 2019 and 2016, respectively, to treat SMA, a rare muscle-wasting disease that is often fatal by the age of two. Their approval was widely met with praise, and these drugs have been described as "dramatically effective" and "lifesaving," according to the authors.

However, both drugs are also extremely pricey. Spinraza costs $125,000 per injection, which must be administered every four months for the rest of a patient's lifetime. Zolgensma is even more expensive: it costs a staggering $2,125,000 per infusion, the highest price tag for a one-time drug treatment ever marketed.

Clinical Benefits v. Lofty Costs

These costs reflect a larger pattern in drugs for rare diseases, which represent an ever-growing proportion of recently approved drugs. In 2018, drugs for rare diseases accounted for 58% of new drug approvals in the U.S, according to the authors. Many of these compounds, such as the gene therapy Luxturna for inherited blindness, cost hundreds of thousands of dollars per patient.

Drug manufacturers have explored offering various payment and access programs to help defray the price of these innovative therapies. But some researchers still question the efficacy of these drugs and whether they can meet lofty expectations in the clinic.

Darrow and colleagues decided to more closely examine the clinical benefits of Zolgensma and Spinraza. They started by parsing FDA documents from late-stage trials that served as the basis for the approval of these drugs.

Spinraza was approved largely based on a trial involving 78 infants with a subtype of SMA, which judged the drug's performance according to the HINE scoring criteria. This scoring system gauges an infant's motor abilities, movements, and behavior; an average baby without SMA would be expected to score at least 22 points.

Darrow's team noted that although 21 of the 51 treated infants (41%) showed an objective response, the benefits from the drug were quite modest. The infants improved from a median HINE score of 1 point before treatment to just 3.6 points after six months. Furthermore, the remaining 30 infants showed no responses, and some of the treated patients still required permanent ventilation.

Other open-label studies of Spinraza showed similar marginal improvements in children with the two other main types of SMA. Adult patients seemed to have mixed views about the treatment and were concerned about high costs. In one interview study, some participants said they would prefer to forgo treatment and instead direct funds to resources such as wheelchairs and transportation.

The researchers reported modest benefits in documents from two clinical trials of Zolgensma, which judged the drug according to the CHOP-INTEND scoring system of motor skills. In one phase 1 trial, infants who received Zolgensma seemed to show some improvements (going from a mean score of 28.2 points to 49.7 points after six months), but most still failed to reach the "healthy" maximum score of 64 points.

Darrow's team also catalogued the various safety concerns that come with both treatments. Spinraza needs to be given through repeated injections, which can raise the risk of infections. The drug can also accumulate in the liver, and some of the infants in the phase 3 trial showed signs of toxicity to the kidneys and slower growth rates.

Zolgensma avoids some of the injection-associated risks of Spinraza, but concerns remain about a potential link between liver cancer and the viral carriers that are used to deliver the therapy, according to the team.

Setting Financial Priorities

Importantly, the conclusions don't mean that Spinraza and Zolgensma are completely ineffective. The scientists say that the drugs represent "marked advances" in how scientists understand disease genetics, and both compounds seem to be more beneficial than most new drugs.

Nevertheless, there are serious problems about the costs involved with the drugs. Spinraza and Zolgensma were funded with taxpayer money at every stage of the development process, according to the authors. The burden of financing these and other expensive therapeutics can have far-reaching impacts for governments and companies.

For example, government payors are left with the choice of raising taxes or redirecting funding from other priorities such as infrastructure, housing, and education. On the other hand, employers who cover rising health premiums are faced with allocating fewer resources to increasing wages, the team said.

Darrow argued that these issues are affecting other drugs outside of the SMA space. He believes that there has been a large disconnect between the perceived value of many new drugs and their actual performance in clinical trials and ability to meet the needs of patients.

Anita Wagner, an associate professor at Harvard Medical School and an author of the piece, has a similar message. She noted that less stringent benefit requirements for approval, powerful lobby industries, insurance coverage, and a lack of price regulation have all combined to spread high drug costs across society in both therapeutics for SMA and drugs more broadly.

"When rising healthcare costs divert resources from other essential programs, there is a need to engage in critical cost-benefit analysis," Darrow concluded.

The authors believe the expected spread of similar high-cost drugs in the future demands immediate attention from legislators, as well as a stronger focus on providing honest information about drugs to patients and clinicians.

"The most important change needed to address the high cost of drugs is to more clearly communicate the benefits and risks of new drugs to patients and physicians," Darrow said. "High drug prices are possible, in part, because the market mistakenly believes that drugs are worth more than the data support."

A "drug facts box" similar to nutrition labeling might help address this information gap, Darrow said. He also suggested that legislators should think outside of the box for future rare disease treatments, as medicines may not always serve as the best or most cost-effective solutions for incurable conditions.