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Eteplirsen Wows in DMD, Sarepta Shares Double

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By Marie Powers
Staff Writer

Sarepta Therapeutics Inc. (formerly AVI BioPharma Inc.) wowed clinicians and investors Tuesday with Phase IIb findings for its exon-skipping compound, eteplirsen, in Duchenne's muscular dystrophy (DMD).

Administered once weekly at 50 mg/kg over 36 weeks, eteplirsen resulted in a 69.4 meter benefit on the primary clinical outcome, the six-minute walk test (6MWT), compared to placebo for 24 weeks followed by 12 weeks of eteplirsen in an open-label extension.

In the predefined prospective analysis of the study's intent-to-treat population on the primary clinical outcome measure – change in 6MWT distance from baseline – patients who received 50 mg/kg of eteplirsen weekly (n = 4) demonstrated a decline of 8.7 meters in distance walked from baseline (mean = 396 meters), while patients who received the placebo/delayed-eteplirsen combination for 36 weeks (n = 4) showed a decline of 78 meters from baseline (mean = 394.5 meters) – a statistically significant treatment benefit of 69.4 meters over 36 weeks (p is less than or equal to 0.019).

The average benefit in the 6MWT for approved drugs in other diseases is 30 to 40 meters, according to the company.

No treatment-related adverse events, serious adverse events or discontinuations were associated with use of eteplirsen, and no treatment-related changes were detected on any safety laboratory parameters, including several biomarkers for renal function.

The results generated instant buzz on the Street, rocketing shares of Bothell, Wash.-based Sarepta (NASDAQ:SRPT) to more than double at Tuesday's opening bell. The stock reached $9.10, advancing 163 percent, before closing at $8.52 for a gain of $5.06 on the day. Nearly 16 million shares changed hands.

The stock movement represented a welcome about-face from investor response in April, when the company reported eteplirsen resulted in the production of significant levels of novel dystrophin after 24 weeks of treatment – specifically, an average of 22.5 percent of dystrophin-positive fibers as a percentage of normal.

Surprisingly, that disclosure prompted investors to abandon the stock, which dropped 27.9 percent to close at $1.11. (See BioWorld Today, April 3, 2012.)

The 36-week data suggested that "previously reported levels of dystrophin we observed in muscle biopsies after 24 weeks of treatment are translating to a clinical benefit," said Chris Garabedian, Sarepta's president and CEO, noting the data suggested that "meaningful levels of dystrophin are not present in muscle biopsies until beyond 12 weeks of treatment."

In October, the company expects to report 48-week data from the ongoing study, including safety and clinical outcomes as well as biopsy results from all 12 study participants. The data will be used to prepare a briefing document for the FDA to discuss the design of a pivotal study, according to Garabedian, who expects the meeting to occur around year-end.

A 'Perfect' Application for PDUFA V

"This is a perfect application for PDUFA V, basically encouraging the FDA to consider accelerated approval for rare diseases where we have markers that would reasonably predict a clinical benefit," Garabedian told BioWorld Today. "Here we have a marker, dystrophin, that hits statistical significance that would reasonably predict a clinical outcome. More importantly, we have clinical outcomes, with a "p" value, despite the small sample size.

"We have to talk to the FDA about this package," he added, "but it could be that we are on a parallel track of preparing for accelerated approval while we prepare for a confirmatory study for traditional approval."

Under PDUFA V, the FDA has 60 days to validate a new drug application or biologics license application before starting the PDUFA clock for a 10-month standard review or six-month priority review. (See BioWorld Today, June 20, 2012.)

The enabling legislation, the Food and Drug Administration Safety and Innovation Act, also gives the FDA the provision to work on speeding up the development of "breakthrough therapies" that demonstrate early promise and faster patient access to new medical treatments. (See BioWorld Today, July 19, 2012.)

The company expects the Phase III design largely to mirror the Phase IIb, using the 6MWT as a clinical endpoint.

"It's really a question of what type of safety database is needed for traditional approval," Garabedian said. "We're confident we can show a similar treatment effect."

Sarepta is optimizing sequences for two preclinical exon-skipping compounds, Exon 45 and Exon 50, and expects to file an investigational new drug application by the end of 2013.

Although the DMD advocacy and clinical community support accelerated development of the additional exons, "we need to have a discussion with the FDA about how much incremental data they need to see for every follow-on exon-skipping drug," Garabedian said.

The next-generation exons are essentially built from the same toolbox, but use a different assembly to sequence the genetic subunits, he explained. The FDA already has indicated some flexibility in reviewing new iterations of such drugs, and "this clinical outcome is encouraging for us to pursue those other exons more aggressively," Garabedian said.

Although Sarepta could commercialize eteplirsen on its own, the DMD program has attracted interest from a number of potential partners who were waiting to see if the technology would translate to a clinical benefit.

"They have their answer now, but the price has gone up," Garabedian said.

Sarepta's lead candidate for the Marburg virus, AVI-7288, also recently demonstrated up to 100 percent survival in a non-human primate (NHP) study exploring the drug's effect when treatment is delayed. The study demonstrated a significantly higher rate of survival among NHPs treated with AVI-7288 compared to the placebo-treated group when treatment was administered up to 96-hours post-infection.

The DMD findings may help turn the corner for Sarepta, which was renamed earlier this month in conjunction with a reverse stock split, evoking the ancient Phoenician city where the prophet Elijah was said to have multiplied the meal of a widow and raised her son from the dead. The new moniker is designed, in part, to distance the company from "the 32-year-old history of a platform research company that had not produced this level of success in the clinic," Garabedian admitted.

However, "I've always been intrigued by the near-death experiences of biotech companies that suddenly become one of the more successful companies in the industry," he added, hoping eteplirsen will help Sarepta blaze a similar path to success.