Investors didn't wait for the outcome of a potential FDA advisory committee showdown with its class competitor to flee Sarepta Therapeutics Inc., acting instead on 144-week phase IIb results – data that the company characterized as favorable – with exon-skipping eteplirsen for Duchenne muscular dystrophy (DMD).

The Cambridge, Mass.-based company reported that the extension trial known as Study 202 showed a decline in walking ability at a rate slower than would be expected based on available DMD findings, with respiratory muscle function staying stable as well.

But such apparently wasn't good enough for investors in the closely watched DMD space. Sarepta's shares (NASDAQ:SRPT) closed Thursday at $22.54, down $3.35, or 13 percent, after trading as low as $18.59. "This is one of those stories where people look through the lens of their position going into it," said CEO Chris Garabedian.

Study 202 already met its primary endpoint of increased novel dystrophin as assessed by muscle biopsy at week 48. At week 144, patients in the 30 mg/kg and 50 mg/kg eteplirsen cohorts who were able to perform the six-minute walk test, or 6MWT, (modified intent-to-treat or mITT population; n = 6) showed a decline of 33.2 meters, or about 8.5 percent, from baseline in walking ability. Data turned up a statistically significant treatment benefit of 75.1 meters (p </= 0.004) for the mITT population compared with the placebo/delayed-treatment cohort (n = 4), which began treatment at week 25 after 24 weeks of placebo.

Showing a decline of 68.4 meters from baseline to week 36, the placebo/delayed-treatment cohort had a drop of 39 meters in walking ability from week 36 through week 144. This is the period from which meaningful levels of dystrophin were likely produced, Sarepta said, and researchers based the analyses on the maximum 6MWT score when the test was done two days in a row.

"We now have nearly three years of follow-up data in a disease that is highly progressive and irreversible," Garabedian said. "In any natural history study or clinical trial that's been done to date – and most of them don't even go out to three years – we see this progressive decline in walking ability over the course of a year. After two years, all of the natural history studies suggest that they should be losing well over 100 meters per year in this age population."

Eteplirsen is "not producing a full-length dystrophin," he pointed out. "At best, we're producing a Becker muscular dystrophy phenotype, a milder muscular dystrophy. That all said, we have one data point where it ticked down, [and it's] erroneous to draw conclusions that this is somehow a signal that the drug has reached its maximum effect."

Caused by abnormalities in the dystrophin gene, DMD strikes one in 3,500 newborn males and puts them in wheelchairs by their early teens, when the disease moves from the limbs to the heart and respiratory system. Patients typically die between 25 and 30 years of age.

Deutsche Bank analyst Robyn Karnauskas, in an email alert to investors, sounded cautious about the latest from Sarepta while maintaining her "hold" rating with a price target of $35.

"While the data vs. placebo patients continue to remain statistically significant, we highlight that a decline of 23-32 meters was observed (using various measures) among the treated patients from the baseline," Karnauskas wrote. "At 120 weeks this change was -17.5 meters to +4.7 meters vs. baseline. We do not know if this decline is driven by just one patient or this was seen with all patients. If this decline is across the board, there may be questions around the long-term efficacy of the drug. We expect to get more color at a future medical meeting."

Garabedian told BioWorld Today that the boys in the study average 12 years of age, and all are still ambulatory. "A few patients contributed to the overall decline," he said. "I'm not going to say one or two contributed to the entire analysis. That would be inappropriate. In the treatment arm there was one that was probably contributing more than the others on the average decline. On placebo, we had two boys who were below 300" on the 6MWT, one of whom had broken his foot.

MORE TRIALS TO ENROLL

The compound uses Sarepta's phosphorodiamidate morpholino oligomer-based chemistry and exon-skipping approach to hop over exon 51 of the dystrophin gene, thus enabling the repair of genetic mutations that affect about 13 percent of the total DMD population.

Eteplirsen's regulatory road has been anything but easy. Sarepta said about a year ago that its meeting with the FDA provided enough information about what the agency wanted and the company felt confident about filing a new drug application (NDA) in the first half of this year. In September 2013, though, Leiden, the Netherlands-based Prosensa Holding NV's exon 51 skipper drisapersen, partnered with Glaxosmithkline plc, of London, blew up in phase III trials. The primary endpoint in the study was a statistically significant improvement on the 6MWT after 48 weeks. Although those in the drug treatment group (n = 125) attained a mean improvement of 10.33 meters over those in the placebo group (n = 61), the result was not statistically significant (p = 0.415). The 95 percent confidence interval spanned -15 m to +35 m. Drisapersen's fizzle seemed to affect the agency's outlook on eteplirsen. (See BioWorld Today, Oct. 14, 2009, April 17, 2013, July 25, 2013, and Sept. 23, 2014.)

Sarepta took pains to convince the agency about the differences between the two drug candidates, arguing for eteplirsen's better skipping activity and pointing to a dose that ranged five to eight times higher than drisapersen. The company submitted more documents and NDA modules.

It worked, apparently. After four meetings that spanned from November of last year to March of this year, Sarepta in April disclosed plans to submit an NDA by the end of 2014, based on a guidance letter from U.S. regulators that suggested a potential accelerated approval pathway. The FDA said that "with additional data to support the efficacy and safety of eteplirsen for the treatment of DMD, an NDA should be fileable" and provided examples of what's necessary.

Piper Jaffray's Edward Tenthoff was skeptical, opining in a research report that "the benefit seems to be waning" from eteplirsen over time." The view of his firm that "phase III data will be required before any approval is granted has only been reinforced following today's readout." Tenthoff maintained his "neutral" rating on Sarepta shares with a $37 price target.

Another clinical-stage player in DMD is PTC Therapeutics Inc., of South Plainfield, N.J., which in January said the European Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion on the marketing authorization application for conditional approval of Translarna (ataluren), a protein restoration therapy designed to enable the formation of a functioning protein in patients with genetic disorders caused by a nonsense mutation. PTC has a 48-week, 220-patient confirmatory phase III trial under way, likely to complete enrollment in the middle of this year, with top-line data expected in mid-2015. By last month, though, the CHMP, responding to PTC's request for a re-examination, adopted a positive opinion regarding the company's application for a conditional marketing authorization of Translarna for nonsense mutation DMD in patients 5 years and older.

There's also recent phase III winner idebenone, an oral drug that does not depend on patients' mutational status, from Liestal, Switzerland-based Santhera Pharmaceuticals AG, which in May reported favorable data and had the company talking with the FDA about the path forward. Rather than use the 6MWT as an endpoint, which requires younger, more mildly afflicted patients, Santhera in its DELOS (DuchEnne Muscular Dystrophy Long-term IdebenOne Study) trial enrolled mostly wheelchair-bound subjects and measured the contrast between idebenone and placebo in the change from baseline to week 52 in peak expiratory flow (p = 0.04), when idebenone was given at 900 mg per day. (See BioWorld Today, May 14, 2014.)

For now, eyes are on eteplirsen and Prosensa's drisapersen. Because Prosensa, like Sarepta, made public in early June its aim to file for an NDA later this year, Sarepta watchers have been expecting an FDA advisory panel meeting at which both drugs would be evaluated.

"We don't know how long [eteplirsen] can keep an ambulant population on their feet," Garabedian said. "If we see these boys continuing to walk for another year or another two years, [then] that would be a huge finding in and of itself."

Sarepta is expanding the push into new trials. One that will enroll this quarter is testing the drug in as many as 80 ambulatory patients. Another later this year will focus on a younger population, signing up about 20 boys. A third will examine eteplirsen's effects in a more advanced, non-ambulatory group of another 20 patients. In order to grant accelerated approval, Garabedian said, the FDA wants an ambulatory confirmatory study enrolling at the time the agency gives its marketing go-ahead. The agency has provided guidance on how the study should be designed.