Sarepta's Exondys 51 is not cost-effective, nor particularly beneficial for DMD patients — ICER
Parents with children suffering from Duchenne muscular dystrophy (DMD) — a rare, progressive muscle wasting disease that disproportionately affects young boys — cheered in 2016 when Sarepta Therapeutics’ Exondys 51 (eteplirsen) was controversially approved by the FDA, under pressure from patient advocates and despite stiff opposition from within and outside the agency. Critics lambasted the agency’s decision, citing insufficient data — and now, an increasingly influential ICER has concurred: The underlying evidence supporting the drug is sparse, and given its current pricing, it is certainly not cost-effective.
There are roughly 6,000 young boys suffering from DMD — caused by the absence of dystrophin, a protein that helps keep muscle cells intact — in the United States. Symptoms tend to kick in and progressively worsen between the ages of 3 to 5, leading the patient to be typically wheelchair-bound by their early teens. Eventually, patients succumb to the disease by their 30s. Corticosteroids, which work by diminishing inflammation and limiting the immune system’s activity, are commonly used to treat DMD.
The generic steroid prednisone is also frequently used to treat DMD. In 2017, the corticosteroid deflazacort, branded Emflaza, was also sanctioned FDA approval, with an eye-popping $89,000-per-patient annual price tag by Marathon Pharmaceuticals. Marathon did not invent the drug, and previously US patients had been able to import it for as little as $1,000. Under fire for its pricing, Marathon agreed to be acquired by PTC Therapeutics $PTCT, which pledged to reduce the price.
ICER evaluated the efficacy, safety and cost-effectiveness of four treatments, in its draft report on Wednesday. It looked at the steroids deflazacort and prednisone — as well as the exon-skipping drugs: the approved eteplirsen and the experimental golodirsen (both come from Sarepta $SRPT, and each treatment is designed to treat a different subset of DMD patients).
Overall, the evidence supporting each of the four treatments is lacking, and their impact on patients unclear, ICER found.
Despite evidence that corticosteroid treatment benefits all DMD patients, the “optimal dosing…and duration of therapy remain unclear. Relatively small clinical trials have provided only short-term efficacy data, even though long-term use…is the norm,” ICER reviewers said. “Although observational studies have provided longer-term data, uncertainty about the natural history of the disease, lack of consistent dosing and outcome measures, and a paucity of comparison data between corticosteroids leave a substantial gap in understanding the efficacy and adverse effects of long term steroid therapy, particularly with respect to differences between deflazacort and prednisone.”
Observational — but inconsistent — data suggests there may be some greater benefit on motor function with deflazacort, and the magnitude of the benefits may be small, reviewers said, adding that deflazacort has not been shown to improve pulmonary function outcomes compared with prednisone. Given the side-effects of corticosteroids, deflazacort has been in the spotlight for its potential of smaller adverse-events: Undesired weight gain appears to be greater with prednisone than deflazacort, while cataract formation and reduction in growth appear to be greater with deflazacort, the non-profit found.
For exon-skipping therapies — which are designed to work by skipping the deleted exon, allowing the remainder to join and form a complete gene to boost dystrophin production — data are “limited to surrogate outcomes from very small trials, and the threshold for dystrophin expression sufficient for meaningful clinical improvement has yet to be defined,” reviewers said, noting that overall, eteplirsen and golodirsen treatment results “in very small increases in dystrophin.”
Extremely limited randomized data for eteplirsen did not show improvements in the six-minute walk test, versus placebo — although no functional outcome results have been reported for golodirsen. The safety profile of eteplirsen appears to be benign, and no safety data are yet available golodirsen, they added.
ICER conducted its cost-effectiveness analysis using quality-adjusted-life-years (QALYs), a measure of the state of health of a person or group in which the benefits — in terms of length of life — are adjusted to reflect the quality of life.
DMD drug dosing is weight-based, and ICER used to calculate cost-effectiveness using annual cost estimates for a 30 kg patient.
Based on the available evidence, when compared to prednisone, deflazacort is projected to have very high costs relative to its benefits, ICER said.
The ICER report does not accurately represent Emflaza’s real value, a PTC spokesperson told Endpoints News in an emailed statement. “ICER’s reliance on the QALY standard is not particularly useful for evaluating the actual needs of individual patients with rare disorders and the impact Emflaza has on the lives of patients and families…”.
In addition, “(P)reservation of ambulation and upper extremity function were not reflected in the cost analysis given the data demonstrated that patients taking deflazacort were able to have nearly an additional 3 years of ambulation over patients taking prednisone,” the spokesperson added.
For eteplirsen, at its current price, no plausible treatment effects were found to make this treatment reach cost-effectiveness thresholds below the $150,000 benchmark, per QALY gained. Similar results are expected of golodirsen if it is priced similar to eteplirsen, ICER concluded.
Sarepta, unsurprisingly, was not happy with ICER’s findings. In a statement, the company called the institute’s approach “fatally flawed” as it relates to rare and genetic disease and ill-equipped to “accommodate the FDA accelerated approval process”.
“If the goal is to support a cost effectiveness approach that promotes true innovation while acting as a watchdog for waste in the system, ICER is failing,” Sarepta said on Thursday.
ICER’s DMD draft report is now open to public comment until June 18. Akin to NICE in the UK, ICER is an independent body that analyzes the cost-effectiveness of drugs and other medical services in the United States. Unlike NICE, though, ICER is not government-affiliated, but its determinations are becoming increasingly pivotal with respect to payers and lawmakers.
Image: Kristoffer Tripplaar for Sipa USA. AP Images