Despite sometimes emotional testimonials from boys with Duchenne muscular dystrophy (DMD) and their families, the Food and Drug Administration's (FDA's) Peripheral and Central Nervous System Drugs advisory committee has determined that studies of the investigational drug eteplirsen don't provide persuasive evidence that the drug is effective in DMD.
But the vote was close, illustrating how some panel members were torn between two different interpretations of the presented data. In the end, 3 members felt that substantial evidence was provided to support eteplirsen as effective for treating DMD, compared to 7 who didn't and 3 who abstained.
Some panel members acknowledged that the public speakers — there were 52 of them during the day-long proceedings — were compelling and that there is a profound unmet need for boys with DMD.
But while many agreed that the drug does produce dystrophin — the protein that's lacking in DMD — most said it's unclear what effect this actually has clinically.
In the end, for most members there were too many issues surrounding an important study of the drug that was small, had ambiguous results, and used a questionable external control.
DMD is a progressive, debilitating, and ultimately fatal inherited X-linked neuromuscular disease. It's caused by mutations of the dystrophin gene that disrupts the mRNA reading frame, resulting in a lack of dystrophin.
Eteplirsen was developed to cause "skipping" of exon 51 in mRNA, which could increase production of a truncated but partially functional dystrophin protein. About 13% of the approximately 9000 to 12,000 people with DMD in the United States have mutations of the dystrophin gene that are amenable to therapies that skip exon 51.
Other drugs that act through a similar mechanism have so far met with mixed success. In January, the FDA declined approval of drisapersen (Kyndrisa, Biomarin Pharmaceutical Inc) for the treatment of DMD, after the FDA advisory committee recommended against it.
Another drug, ataluren (Translarna, PTC Therapeutics), has a "conditional" approval in the European Union, a mechanism that allows patients with serious or life-threatening disorders to receive a drug before it has gone through the full approval process. Conditional approval must be renewed yearly and can be revoked if confirmatory studies don't show a drug is safe and effective. It is not yet approved in the United States.
For eteplirsen, the company, Sarepta Therapeutics, is seeking accelerated approval (AA) for the treatment administered as weekly 30 mg/kg intravenous infusions for these patients. The AA pathway allows for an acceptable degree of uncertainty about whether the therapy will actually result in the anticipated clinical benefit.
In some circumstances, the FDA is amenable to trials using external controls, or historical controls, if these are adequate and well controlled.
For review by the FDA, the company submitted studies of eteplirsen, including Study 201, a randomized, double-blind, placebo-controlled trial in 12 boys with DMD who were in the ambulatory decline phase of the disease. The primary endpoint was percentage dystrophin-positive fibers.
In this study, significant dystrophin production was observed at 24 weeks for the 30 mg/kg dose group but not at the earlier 12-week time point for the 50 mg/kg group. This, said the company, suggests that duration for eteplirsen therapy is more important than dose.
After 24 weeks, the 4 placebo recipients rolled over to an open-label phase along with the 8 patients randomly assigned to eteplirsen for a pooled group of 12 patients (Study 202). The primary endpoint of Study 202 was change in the 6-meter walking test (6MWT) at 48 weeks.
A difference between groups was not observed, mainly because of 2 boys receiving eteplirsen who lost ambulation. According to the company, these boys may have received the treatment too late in the course of their disease.
An analysis excluding these patients found that the 10 treated boys performed better on the 6MWT than those receiving placebo.
On the basis of these results, Study 202 was extended. The primary endpoint of percentage dystrophin-positive fibers at week 48 was achieved, said the company.
The 12 boys from Study 201/202 were compared to an external control group of 13 boys with DMD mutations amenable to exon 51 skipping who were of similar age and had similar steroid use. The company reported that the eteplirsen-treated patients had a 148-meter (P = .005) advantage at year 3 on the 6MWT compared with the external control group.
An updated year 4 analysis of 6MWT showed a sustained benefit for eteplirsen vs the external control patients, with a 162-meter (P = .0005) advantage.
According to the company, "these results are both clinically relevant and statistically persuasive."
Sensitivity analyses — including baseline covariates of age and steroid use — also demonstrated a greater than 100-meter treatment benefit for the eteplirsen-treated group compared with the external control group. The findings were also supported by comparisons to a larger, more conservative external control group of 50 boys amenable to any exon skipping.
The supportive endpoint of the 17-item North Star Ambulatory Assessment (NSAA), which assesses activities such as standing, walking, hopping, and climbing, showed that after the first year, decline in function for the eteplirsen group slowed and by the end of year 3, there was a 2.4-point greater decline for the untreated boys. This difference may represent loss or impairment of up to 2 activities of daily living.
According to the company, eteplirsen "unequivocally" demonstrated production of de novo dystrophin. It reported an 11.6-fold increase from baseline on the Western blot test at week 180 in treated patients, representing a mean percentage of normal dystrophin protein of 0.93%.
This 0.93% became a point of discussion during the day-long meeting. For some boys with DMD, this amount is meaningful and not to be dismissed. As one public speaker said, very low levels of dystrophin can have significant effects on muscle function.
Along with Western blot, other common methods of showing production of "skipped" mRNA and restored dystrophin protein are reverse-transcriptase polymerase chain reaction (used to provide evidence that the desired mRNA is produced) and immunofluorescence (used to localize protein and is semi-quantitative for total immune-reactive signal). But according to some speakers, there are issues with these measurements.
The company reported no significant safety risks, with most adverse events being mild and consistent with the population. There was a low rate of discontinuations and serious adverse events.
This was echoed consistently by patients and families — some of whom had come from as far away as the United Kingdom — during the public hearing portion of the meeting. Many were from groups called Make Duchenne History and Duchenne Connect.
These passionate speakers repeatedly relayed how the drug has improved their — or their son's — quality of life with absolutely no adverse effects. "This drug is not a false promise," said one mother. "My son is not an outlier," said another.
It was such testimonials that clearly touched the panel. "I have been extraordinarily influenced and impressed by the people who spoke about this drug and their observations," said Mark W. Green, MD, professor, neurology, anesthesia and rehabilitative medicine, and director, headache and pain medicine, Icahn School of Medicine, New York, New York.
But Ronald Farkas, MD, PhD, clinical team leader, Division of Neurology Products, Center for Drug Evaluation and Research, FDA, raised many issues regarding the analyses presented by the company.
Although the FDA felt the Western blot was the most accurate method to determine relative levels of total dystrophin protein, it raised some technical issues with some of the biopsies. For example, control samples were from different muscle groups, healthy controls weren't sex matched (a female and two healthy males were combined for a mean value), and dystrophin varied from 51% to 95% in healthy controls.
Dr Farkas also pointed out that instead of the expected dystrophin levels of 25% to 50%, which were indicated by the company early in the clinical development program, a "very low level" of 0.93% was reported from the fourth biopsy.
By the most reliable Western blot methods, dystrophin less than about 3% of normal muscle appears to be associated with the typical DMD phenotype, he said.
The FDA also raised questions about the appropriateness of the external control group. Dr Farkas pointed out that 2 of the 13 external controls were able to perform the 10-meter walk/run test reasonably well (10 and 12 seconds) yet were deemed unable to attempt the 6MWT, that eteplirsen recipients had two opportunities to perform the 6MWT, and that 2 external control patients with missing data were analyzed as "0" for the NSAA.
Glen Nuckolls, PhD, program director and executive secretary, Interagency Muscular Dystrophy Coordinating Committee, National Institutes of Health, was among the panel members swayed by this information. "It caused me to question the objectivity and comparability of the 6MWT."
Further, Dr Farkas noted, eteplirsen recipients were treated with steroids for about a year longer than the controls. Such seemingly small differences may have large effects in age of loss of ambulation, he said.
There is some suggestion that physical function may be affected simply by being enrolled in an efficacy study. Also, motivation may have been different in the two groups, as perhaps were the judgments and attitudes of caregivers, investigators, and patients themselves.
There was also some question about why the study outcomes assessed only lower-limb function. Several panel members noted that the litany of benefits the public speakers referred to were not captured by the 6MWT or the secondary endpoint of NSAA.
As for the outcome of percentage positive fibers, "because of poorly matched controls, the proportion of the dystrophin that was produced by eteplirsen, as opposed to the dystrophin that can be present at baseline, appears to be uncertain," said Dr Farkas.
"Ratios of treated to control values presented by the applicant appear to be 'apples to oranges' comparisons because of poorly matched controls and lack reliability because of small and questionably calculated denominators."
Another issue for the FDA, and some panel members, was the lack of a traditionally controlled trial. The FDA had consistently strongly encouraged the company, beginning back in 2011, to perform an adequately powered randomized, double-blind, controlled trial and expressed strong doubts along the way about the interpretability of comparison to external controls.
The sponsor indicated that there initially was not enough study drug available to carry out this type of trial.
Yet another concern for the FDA was lack of apparent correlation between dystrophin levels and change in 6MWT. Dr Farkas noted that for the 4 patients with the most preserved 6MWT, 2 had among the lowest and 2 had among the highest levels.
All treated patients have declined substantially on NSAA, including the several older patients (age about 14) and those with more preserved 6MWT, he said. "There appears to be little reason to believe a loss of ambulation for these patients will exceed the typical range in untreated patients with DMD."
It doesn't seem possible to conclude that differences in physical performance between eteplirsen-treated patients and external controls resulted from an effect of the drug "instead of from other differences and influences, both known and unknown, between the groups, both at baseline and during conduct of the study," Dr Farkas concluded.
Following discussions, the committee voted 5 to 8 that the applicant provided substantial evidence from adequate and well-controlled studies that eteplirsen induces production of dystrophin to a level that is reasonably likely to have a clinical benefit.
"We don't have a clue about how much dystrophin is clinically significant, and it's also hard to know if what is produced is as clinically active as natively produced normal dystrophin," commented committee chair, G. Caleb Alexander, MD, associate professor, epidemiology and medicine, Johns Hopkins School of Public Health, Baltimore, Maryland.
Dr Alexander said he was "surprised" that experts are not further along "in figuring out what amount of dystrophin would constitute a clinically meaningful response."
Although he said he was "willing to accept" that eteplirsen did lead to some dystrophin production, Chiadi Onyike, MD, associate professor, psychiatry and behavioral sciences, Division of Geriatric Psychiatry and Neuropsychiatry, The Johns Hopkins University School of Medicine, Baltimore, said it's still "very small and within the range of what people with the disease have."
'In my mind it's very important to have some sort of coupling between the dystrophin production and a clinical effect; we don't have that," he said.
However, Dr Onyike pointed out that it is possible for a medication to have an effect without knowing why. He used acetaminophen (Tylenol) as an example. "I'm not entirely sure you should lock the clinical effect to the dystrophin production."
On the other hand, many committee members strongly agreed that there's plenty of evidence to the support mechanism of action of the drug.
The committee voted 5 to 7 (1 abstention) that decisions to administer the 6MWT were sufficiently objective and free of bias and subjective decision making by patients, caregivers, and/or health care professionals to allow for a valid comparison between patients and an external control group.
Dr Onyike noted the discrepancy between the outcomes as depicted by the FDA analysis, which "don't line up as a positive effect," and the testimony of patients and family members, who, one after the other, talked about how the drug allows them to do things like open cans and grip bottles.
"None of that is captured by the NSAA or the 6MWT or the 10-meter walk test, so you have an unfortunate discrepancy between what the families are describing as tangible benefits and what is actually measured."
Dr Onyike, who works in the field of dementia, also pointed out that caregiver outcomes are routinely included in clinical trials of dementia.
Richard Kryscio, PhD, professor, statistics and chair, biostatistics, University of Kentucky, Lexington, noted that for some diseases — for example, amyotrophic lateral sclerosis, which has similar loss of ambulation — there are well-designed trials that use functional rating scales.
In a vote on the impact of the NSAA on the persuasiveness of the study findings, 2 members thought it strengthened the impact while 5 thought it weakened it and 6 felt it had no effect.
Most (10) members felt that the other tests of physical performance, such as the rise time, had no effect on the persuasiveness of the studies presented. As Richard Hoffman, PharmD, a drug information consultant and medical writer in Hernando, Florida, commented, "there is a difference of opinion between the FDA and the sponsor and neither proved the case one way or the other."
Another panel member said that in the absence of a concurrent control group, it's difficult to interpret any of these secondary outcome measures.
In the final vote, 3 members felt that substantial evidence was provided to support eteplirsen as effective for treating DMD compared with 7 who didn't and 3 who abstained.
On this vote, Dr Hoffman abstained, noting, "I was torn between my mind and my heart and I don't want to make a type 1 error and I don't want to make type 2 error."
Paul Romitti, PhD, professor, Department of Epidemiology and Interdisciplinary Program in Toxicology, University of Iowa, Iowa City, also abstained, saying he was "conflicted" because while he "can't say" that the study was adequate and well controlled, he "was moved by the public testimony."
Many of the others raised various concerns regarding the ability to draw valid conclusions from a small study with an externally controlled comparison.
"The ways that the controls were selected and analyzed didn't meet the threshold that I would consider to be adequate and well controlled," said Dr Alexander.
On the other side, though, were panelists such as Reghan Foley, MD, a pediatric neuromuscular specialist, at the National Institute of Neurological Disorders and Stroke at the National Institutes of Health.
"For me, there is substantial evidence that there is clearly amelioration of the clinical phenotype of DMD. But I believe more data is needed and I also believe that looking at other biomarkers would be very helpful as well."
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Cite this: FDA Panel Finds Evidence Inadequate for Eteplirsen in DMD - Medscape - Apr 27, 2016.