Neither the smallish trial size nor two extra-sick patients in the lower-dose arm could dampen Wall Street's enthusiasm for eye-opening Phase IIb results disclosed by Sarepta Therapeutics Inc. in Duchenne muscular dystrophy.

Bad news from the Department of Defense – a contract to develop Ebola drugs canceled due to "funding constraints" – did little to quell investors' cheers, either, as the Cambridge, Mass.-based company's stock (NASDAQ:SRPT) closed Wednesday up 199.7 percent, or $29.94, reaching $44.93.

Sarepta said its exon-skipper eteplirsen hit the primary endpoint, an increase in novel dystrophin (DMD, a neuromuscular disorder that strikes young boys, is often caused by mutations in the dystrophin gene).

Eteplirsen also gained significant clinical benefit on the primary outcome, the six-minute walk test, over the placebo/delayed treatment cohort in a Phase IIb extension trial.

The results put Sarepta in a workable position against competitor Prosensa Therapeutics BV, of Leiden, the Netherlands, for exon-skipping approaches to DMD, which ultimately could benefit as much as 85 percent of the disease population, said Chris Garabedian, president and CEO of Sarepta.

"There's a lot of activity in DMD, but it's supportive care, nondisease modifying," he added.

Eteplirsen, given intravenously once weekly at either 30 mg/kg or 50 mg/kg for 48 weeks (n = 8), resulted in a statistically significant increase (p = 0.001) in dystrophin-positive fibers to 47 percent of normal.

The placebo/delayed treatment cohort, given 24 weeks of eteplirsen at either 30 mg/kg or 50 mg/kg after 24 weeks of placebo (n = 4), also showed a statistically significant increase in dystrophin-positive fibers to 38.3% of normal (p = 0.009).

In the walk test, eteplirsen once weekly at 50 mg/kg over 48 weeks resulted in an 89.4 meter benefit compared to patients who received placebo for 24 weeks followed by 24 weeks of treatment with eteplirsen.

The predefined prospective analysis of the study's intent-to-treat population showed that eteplirsen-treated patients who received 50 mg/kg of the drug weekly (n = 4) demonstrated an increase of 21.0 meters in distance walked from baseline (mean = 396.0 meters).

Patients who got placebo/delayed-eteplirsen treatment (n = 4) showed a decline of 68.4 meters from baseline (mean = 394.5 meters), for a statistically significant treatment benefit of 89.4 meters over 48 weeks (p = 0.016, using analysis of co-variance for ranked data).

Investigators turned up no statistically significant difference between the cohort of patients who received 30 mg/kg weekly of eteplirsen and the placebo/delayed treatment cohort.

Garabedian acknowledged the trial was small, but said it need not be large in rare disease to win approval – only prove efficacy on a relevant endpoint, and generate convincing safety data. "If you have a high treatment effect, then the numbers can be small," he said.

Cambridge, Mass.-based Genzyme Corp.'s Cerezyme (imiglucerase) was approved on data from 12 patients, and the same company's Myozyme (alglucosidase alfa) – the latter for which Sarepta's chief medical officer was the chief architect – gained full approval on results in 18 patients, Garabedian pointed out.

In non-oncology, rare-disease orphan drug approvals, "the large majority of trials are less than 100 [subjects], many far less than 100," he said.

For second-indication approvals, the trials can be especially small, Garabedian noted, citing Cheshire, Conn.-based Alexion Pharmaceuticals Inc.'s Soliris (eculizumab), cleared by the FDA last month for all pediatric and adult patients with atypical hemolytic uremic syndrome. Soliris, a first-in-class terminal complement inhibitor, had previously been given the nod for paroxysmal nocturnal hemoglobinuria.

Another example, Garabedian said: The FDA in late August cleared Basel, Switzerland-based Novartis AG's mTOR inhibitor Afinitor (everolimus) for childhood brain tumors caused by tuberous sclerosis, based on brain scans of nine patients. In April, the agency had approved the drug for noncancerous kidney tumors.

In Sarepta's DMD trial with eteplirsen, two patients randomized to the 30 mg/kg weekly drug cohort showed signs of rapidly worse disease within weeks after enrollment and were unable to "perform measures of ambulation" beyond 24 weeks, the company said.

"We're not saying the drug is not having an effect on these boys; it was just too late to have an effect on the ambulatory measures," Garabedian told BioWorld Today.

The deck was stacked against the boys, since they started with the lowest baseline walk-test scores, were taller than other boys (a risk factor for worsening) and were in the older segment of the cohort (another risk factor).

"They were already too far gone" by the time eteplirsen might have started helping them, Garabedian said.

Aiming for a Quick Review

In July, Sarepta (formerly AVI Biopharma) said the 48-week data disclosed Wednesday would be used to put together a briefing document for the FDA to discuss the design of a pivotal study, with an eye to preparing for accelerated approval while getting ready to do a confirmatory study for traditional marketing clearance.

"That was the plan back then," Garabedian told BioWorld Today. "But, with this data set [in hand], I think we want to talk with them very simply about the fastest path to approval." It could come in the form of full approval, given the clinical outcomes in the latest results, or accelerated approval, given the effects shown on dystrophin.

Sarepta is crafting questions for the FDA and likely will submit the request for a meeting "sometime in the next month," with an agency sit-down probable around the first part of 2013, Garabedian said.

South Plainfield, N.J.-based PTC Therapeutics Inc. also tried targeting a genetic mutation for DMD with its ataluren, but the drug missed its primary endpoint in a Phase II trial of 174 patients. The mixed results ended up costing PTC its partnership with Genzyme Corp., of Cambridge, Mass., after the latter was acquired by Paris-based Sanofi SA. (See BioWorld Today, Sept. 6, 2011, and March 4, 2010.)

Garabedian said the PTC approach would only improve the condition in about 15 percent of DMD patients, unlike the exon-skipping technology of Sarepta, and competitor Prosensa, partnered with London-based GlaxoSmithKline.

Prosensa's lead candidate PRO051 (GSK2402968) is undergoing a Phase III trial that began early last year, as part of its DMD alliance with GSK in 2009. Several Phase II trials are under way, too. (See BioWorld Today, Oct. 14, 2009, and Jan. 27, 2011.)

Sarepta also disclosed that the DoD has dropped the Ebola portion of the company's contract for developing hemorrhagic fever virus therapeutics, but the Marburg-virus portion of the deal remains in effect. The DoD had two programs pursuing Ebola, and elected to keep the one in progress with RNAi-focused Tekmira Pharmaceuticals Corp., of Vancouver, British Columbia.

"It was a hedge for them, and gave them an opportunity to bet on chemistry, another mechanism," Garabedian said. "We think they lost a little bit, in terms of the power of platform."