The enobosarm saga
Enobosarm is a drug that, by all accounts, builds muscle mass and strength with acceptable side effects. Yet it failed because of regulatory constraints that all companies in the atrophy space must confront.
Discovered and developed by the Memphis, Tennessee–based biotech company GTx, enobosarm, as a SARM, binds the androgen receptor like testosterone but with tissue selectivity. Enobosarm lacks testosterone's steroid rings and thus cannot convert to dihydrotestosterone, which promotes prostate growth (and cancer). Another advantage is it doesn't have testosterone's masculinizing side effects in women, nor can it be converted by aromatases to estrogen. Its effects are largely confined to muscle, and it works; SARMs “will at relatively high doses increase muscle strength,” says St. Louis University geriatrician John Morley. “I don't think there's any real question.”
In a phase 2 trial of testing individuals with sarcopenia, GTx reported a 3% increase in lean body mass and a 15% boost in muscle stair-climbing power11. Enobosarm was well-tolerated, although it lowered serum high-density lipoprotein. So to advance the drug further in sarcopenia, the FDA required a cardiovascular safety study, which GTx estimated would cost $500 million, well beyond its means. “You have to do some really big cardiovascular safety studies if you're going into an otherwise healthy population like frail men and women,” says James Dalton, GTx's former CSO. The company scrapped plans for phase 3 in sarcopenia and chose to test enobosarm in cancer cachexia instead, where the FDA was less concerned about long-term heart effects.
In phase 3 testing, enobosarm boosted lean muscle mass in two separate trials, but stair-climbing power only in one, and only relative to placebo (i.e., no absolute increase was demonstrated). That could have been enough for approval in Europe, but not in the US, where the FDA wanted to see strength grow. That's something very hard to show in declining cancer patients undergoing aggressive therapy, says Dalton, now dean of pharmaceutical sciences at the University of Michigan. GTx decided not to file, giving up on enobosarm for treating muscle disorders. “A business and regulatory decision, more than anything else,” says Dalton, who is convinced that enobosarm is safe and effective at building and strengthening muscle. “I would take the drug today,” he says. Many people do. Illegal sales of enobosarm, also known as ostarine, are rampant on the internet.
Cancer cachexia was a problematic indication, in Morley's view, because the severity of the background illness muddied enobosarm's positive effects on muscle. Enobosarm “did wonderfully well when it was tested in old people,” he says. “Really as good as anybody's seen, both for building muscle and strength in a short period of time.” Dalton's one regret is that GTx didn't test a higher dose that would have overcome the negative effects of cancer and proven to the FDA's satisfaction that enobosarm works.
http://www.nature.com/nbt/journal/v34/n5/box/nbt.3557_BX2.html?foxtrotcallback=true