An FDA advisory committee said the evidence supporting BioMarin's application for drisapersen is weak and that the drug doesn't appear to be effective in Duchenne muscular dystrophy (DMD).
The Peripheral and Central Nervous System Drugs Advisory Committee meeting was unusual in that participants weren't asked to vote directly on whether or not to recommend approval of the drug. Instead, they voted on the strength or weakness of evidence from the three separate trials BioMarin presented in its application.
The key discussion centered around whether a phase III trial, which was not statistically significant for its primary endpoint, strengthened or weakened the totality of the evidence -- and the majority of panelists (15) said it weakened the overall package, while only two said it had no effect.
"The study diminished my conviction about the findings in studies 1 and 2, and of the post-hoc analyses or [the drug company's] potential explanations such as including patients with more advanced disease, inadequate treatment duration, expertise of various centers, or lack of a loading dose," said FDA advisory committee chair , of Johns Hopkins Bloomberg School of Public Health in Baltimore.
"I wasn't convinced ... and [study 3] decreased my belief in the persuasiveness of the first two studies," he added.
In the first study, there were positive effects for those who took the drug for 24 weeks compared with placebo, but none of the secondary endpoints were significant. Nine of the panelists voted that the caveats weakened evidence of the drug's efficacy, while seven said it had no effect and one said it strengthened the evidence.
The second study yielded ambiguous results, with a large impact on the significance of the primary outcome with the removal of only one patient, as well as numerically worse results for patients on the higher dose of the drug compared with placebo. Most panelists (12) said there was no effect on the persuasiveness of the efficacy results, while five said the findings weakened the evidence.
The third study was the larger phase III pivotal trial, which was not significant for its primary endpoint at 48 weeks. The study was powered to detect a 30-meter difference in walk test scores, but there was only a 10-meter difference at the end of that time period.
BioMarin noted, however, that the results were significant at 96 weeks, adding several other explanations for the lack of difference at 48 weeks, including that the study was open to a wider range of patients with more advanced disease and that there was no loading dose.
FDA reviewers noted all of these caveats, and highlighted adverse events including thrombocytopenia, which occurred in 10% of those on the drug compared with 3% on placebo, and renal toxicity as measured by abnormal 24-hour urines in 30% of patients compared with 4% of placebo patients. Two patients also had nephritic-range proteinuria, the reviewers said.
Reviewers also noted a high rate of injection-site reactions, which occurred in 79% of patients and were associated with significant redness and swelling.
The question of whether the results suggest clinical relevance, despite not achieving statistical significance, came up several times throughout the trial. One of the two panelists who voted that the phase III results had no impact on overall efficacy said she based her response on how parents might answer the question.
"If a parent looked at this, they would take the possible 10-meter advantage," said , the patient representative on the panel. "In the face of a lethal diagnosis, it's better than what we've got."
Several parents testified during an unusually long 2-hour public comment period. Most of the parents who spoke also brought their children and testified about significant clinical improvement while being on the drug. Many noted that the side effects of the drug -- including the red, swollen injection site reactions -- were minimal and tolerable, especially given the fact that their children have few other therapeutic options besides steroids that seem to do little to stop disease progression.
, a family practitioner who is also the mother of a DMD patient, said during the public comment period that there are "moments when statistical analysis has not captured the benefits of a new drug."
Panelists were also asked whether there's evidence that the drug does indeed work by its proposed mechanism of action: boosting dystrophin levels. Most said that the evidence was spare, and they had significant concerns that many biopsies were taken but could not be used in the final analysis.
"If the drugs act via increasing dystrophin levels ... I would have expected a more discernible increase following exposure to the study drug," Alexander said.
Panelist , of Harvard ľֱ School in Boston, said studies of dystrophin levels "were not able to show increased dystrophin in those biopsies, and these negative and unimpressive results weakened my impression of the phase III trial results."
During a final discussion of the totality of the evidence, some panelists noted that DMD involves significant heterogeneity, and that the drug may have benefits for some individuals -- getting a better understanding of which patients may stand to benefit more could be helpful.
Drisapersen is the first of two novel drugs for DMD that are before the FDA. Many had expected eteplirsen, developed by Sarepta Therapeutics, to be evaluated in conjunction with drisapersen, but that drug will be evaluated separately in January.