Just how clinically effective are three newer therapies for Duchenne muscular dystrophy (DMD) and are they cost-effective? The answers to those questions vary, interviews with neuromuscular experts and patient advocates, and a report from a drug pricing watchdog reveal.
What most will agree on, however, is that advances in DMD therapies have been fast and furious in recent years and that access to these therapies, due to their high cost and other restrictions, will continue to be a challenge.
In the last three years alone, the US Food and Drug Administration (FDA) has approved two of three marketing applications for DMD treatments: Eteplirsen (Exondys 51), the first disease-modifying drug for DMD, was approved in September 2016, for DMD patients who have mutations amenable to exon 51 skipping. Deflazacort (Emflaza), the first corticosteroid option other than prednisone, was approved in February 2017; previously, it was available in the US only by importing it from other countries.
And on August 19, the FDA reviewed but rejected an application for golodirsen (Vyondys 53), developed for patients with a confirmed mutation amenable to exon 53 skipping. The FDA in its response letter cited concerns about the drug's risk of infections related to intravenous infusion ports and renal toxicity,
The decision caught its drug manufacturer Sarepta by surprise. “Renal toxicity with golodirsen was observed in pre-clinical models at doses that were ten-fold higher than the dose used in clinical studies,” Sarepta said in a statement following the FDA decision. Renal toxicity was not observed in the study on which the golodirsen application was based, it said, adding that the drug maker would “address the issues raised in the [FDA] letter and, to the fullest extent possible, find an expeditious pathway forward for the approval of golodirsen.”
The ICER Report
The setback for the third therapy came days after an August 15 report by the Institute for Clinical and Economic Review (ICER), which concluded that golodirsen and the two other DMD therapies did not live up to their billing.
ICER found deflazacort may be superior to prednisone, but needs a price cut of at least 73 percent to be deemed cost-effective. And it said the exon-skipping therapies—eteplirsen and golodirsen—cannot be assessed for cost-effectiveness because “no persuasive evidence yet exists to demonstrate the clinical effectiveness of either drug.”
ICER did not express concerns about golodirsen's toxicity; the FDA, in its letter rejecting Sarepta's marketing application, did not express concerns about its effectiveness.
ICER had published its views in preliminary form in July. In response, PTC Therapeutics, which makes deflazacort, and Sarepta, the manufacturer of the two exon-skipping therapies, opted not to attend the July 25 meeting at which ICER's New England Comparative Effectiveness Public Advisory Council discussed the assessment.
Instead, Sarepta issued a press release calling ICER's approach to assessing treatments for rare diseases “fatally flawed”: “As a result, we have chosen not to participate in reviews by ICER until it adapts its model to address the inherent limitations and biases that compromise its evaluations of therapies intended to treat patients with serious, rare diseases.”
At its meeting in July, ICER used two empty chairs at the table to make the drug makers' absence clear.
Steven Pearson, MD, ICER's founder and chairman, lamented that, three years after winning controversial approval from the FDA for eteplirsen, Sarepta had not published evidence showing clinical effectiveness, even though its list price for the therapy exceeds $1 million.
“...this is the weakest effort I've ever seen for a company to try to do good research and bring it to the FDA,” he said.
Patient advocate Mindy Leffler disagreed, adding that ICER's assessment, which might spur insurers to deny coverage of FDA-approved DMD treatments, should have been postponed until more evidence is assembled...
The ICER report agreed that published evidence for the three therapies was lacking. In its review, ICER found that deflazacort was no more effective on three attributes—improved muscle strength, improved motor function, and pulmonary function—than prednisone, although deflazacort may be more effective in delaying loss of ambulation. Deflazacort has a different side-effect profile than prednisone, ICER said, including lower rates of undesired weight gain.
Before its FDA approval, deflazacort was available to be imported from other countries for about $1,000 a year. Since its approval in the US, many insurers cover the treatment, but they often either require prior authorization or that patients try less-costly prednisone first.
In ICER's view, its benefits do not justify its US list price—$117,400 per year—or even its net price (what it actually costs, on average, after discounts and rebates) of $81,400 per year. Rather, based on the benefits it offers to patients, ICER said a fair price would be $19,900 to $31,700 annually, according to its cost-effectiveness methodology.
ICER said both eteplirsen and golodirsen have been shown to increase production of dystrophin, which is deficient in DMD, although dystrophin levels remained very low. The best results were for golodirsen, according to the report; at 48 weeks, the mean level of dystrophin had increased to 1.019 percent of normal. There is no validated threshold in dystrophin levels associated with meaningful clinical improvement, ICER said. Further, it found no evidence demonstrating improvements in muscle strength, motor function, ambulation, or pulmonary function.
Advocates Push Against ICER
But some advocates question the outcome measures used in clinical trials, such as time from supine to standing, time to climb four stairs, or the 6-minute walk test. Brian Denger, whose two sons were diagnosed with DMD, said: “A significant proportion of the (DMD) community are off their feet, but are they any less valuable to their family members and the community? I would say no.”
Leffler said patients with DMD want to be able to move their bodies so they can preserve a degree of independence. Outcome measures based on timed performance are off point, she said.
“As my son will say, ‘Nobody cares about speed walking. I never wanted to speed walk and don't have any desire to do so. And it has nothing to do with my quality of life,’” she said...
Leffler showed videos, taken over seven months, that showed her son regain the ability to get into a car independently after receiving eteplirsen. That is not an outcome measure that a clinical trial would use—or that ICER considered in its assessment—but it is an outcome that is meaningful to a patient, she said.
Robert C. Griggs, MD, FAAN, a University of Rochester neurology professor who has directed a National Institutes of Health-funded training program in the Experimental Therapeutics of Neurological Disease for three decades, is convinced that eteplirsen and golodirsen are clinically effective.
“The evidence was less good for eteplirsen at the time of the (FDA) approval, but there's been subsequent evidence that is more impressive,” he said. “For (golodirsen), the evidence is very impressive.”
Peter Karachunski, MD, clinical director of the Paul and Sheila Wellstone Muscular Dystrophy Center at the University of Minnesota Medical School, said the high cost of eteplirsen has not been a barrier for most of his patients who are eligible because their insurers have approved coverage.
“My problem with the drug is not necessarily its cost; it's that it is really hard to see any perceptible benefit,” he said. “You just have to believe that it's working for any given person. So that's the challenge.”