Word hardly shook the world in early April when Cambridge, Mass.-based Acceleron Pharma Inc. dropped ACE-2494, a systemic muscle agent in phase I tests in healthy volunteers, because anti-drug antibodies (ADAs) developed. Although the compound had shown signs of early target engagement and ADAs had not been associated with any adverse event, Acceleron said the candidate wasn't worth going ahead with.

There's more (and possibly better) in the muscle pipeline anyway. And, a day later, the company with partner Celgene Corp., of Summit, N.J., said Celgene submitted the BLA for luspatercept, an erythroid maturation agent for adults with very low- to intermediate-risk myelodysplastic syndromes (MDS)-associated anemia who have ring sideroblasts and require red blood cell (RBC) transfusions. The compound also is intended for adults with beta-thalassemia-associated anemia who require RBCs.

Luspatercept has been the show-stealer for Acceleron. The BLA, based on safety and efficacy findings from pivotal phase III studies called Medalist and Believe, came as no surprise after last summer's unveiling of Medalist results. Top-line numbers emerged from the 299-subject study that signed up participants with MDS with chronic anemia and refractory to, intolerant of or ineligible to receive an erythropoietin-stimulating agent, the usual treatment. To be eligible, each patient's case had to be ranked by a commonly used prognostic scoring system as either very low risk, low risk or intermediate risk, and test positive for sideroblastic anemia. Luspatercept helped patients achieve "a highly statistically significant improvement" in the primary endpoint of RBC transfusion independence of at least eight consecutive weeks out of the first 24 weeks of treatment. (See BioWorld, July 2, 2018.)

So the stoppage of ACE-2494 was regarded as small potatoes, although some may have fretted that problems with the compound might extend to another in the Acceleron hopper, ACE-083, the lead neuromuscular candidate. It's considered potentially useful in diseases of focal muscle loss such as muscular dystrophies, including facioscapulohumeral muscular dystrophy (FSHD) and Charcot Marie Tooth (CMT) disease. ACE-083 binds to and inhibits select proteins in the TGF-beta protein superfamily that reduce muscle growth, such as activins and myostatin (GDF8). The so-called "myostatin-plus" strategy should increase muscle mass and strength in the muscle where the drug is administered – and local administration is a key to ACE-083's likelihood of not turning up ADAs, as in the case of ACE-2494. Based on encouraging part one results from the company's two-part phase II trials in FSHD and CMT, the company has kicked off part two. During Acceleron's earnings call in February, well before ACE-2494 fell by the wayside, the company's investor relations chief, Todd James, said it would be "fairly difficult" to read anything from data with one candidate to the other because of the contrasts in the molecule. Locally acting ACE-803 "we can take [into] very high therapeutic dose levels, inject it right into the target muscle, and there we've seen in part one increases of 14-plus percent at the high doses, whereas a systemic agent like ACE-2494 you most likely to see mid to high single-digit increases," he added.

Eylea in (more) peril?

At the Muscular Dystrophy Association meeting in Orlando, Fla., Acceleron updated data with ACE-803 in FSHD. Cowen analyst Yaron Werber sounded cautious in his April 16 report. "The data showed some correlation between fat fraction and outcomes, but it is still unclear whether increased muscle volume will directly lead to clinical benefits," he said. "Also, new data shows lower contractile muscle volume than previously. We remain on [the] sidelines on ACE-083, given uncertainty about outcomes."

In any case, the nixing of ACE-2494 might be seen to favor another neuromuscular player: Regeneron Pharmaceuticals Inc., of Tarrytown, N.Y. That firm is moving ahead with a pair of systemic muscle disease anabolics: garetosmab, an activin A antibody in a phase II experiment for fibrodysplasia ossificans progressiva (FOP); and trevogrumab, a GDF8 antibody in phase I combination studies with garetosmab against undisclosed muscle-wasting diseases. The compounds are specific for their respective ligands, thus allow for a "mix-and-match" approach, while Acceleron's use of engineered ligand traps provides an "all-or-nothing" bid, as SVB Leerink analyst Geoffrey Porges pointed out in an April 5 report. "Furthermore, Regeneron's antibodies seem unlikely to elicit significant ADA responses, at least based on the profile of the company's many other successful antibody development programs," he said. ACE-2494's removal "gives Regeneron an opportunity to build a leadership position in the treatment of neuromuscular disease where systemic treatment is required," including the likes of amyotrophic lateral sclerosis and Duchenne muscular dystrophy, as well as more common disorders such as sarcopenia.

Regeneron needs the break. Basel, Switzerland-based Novartis AG's tissue factor inhibitor, brolucizumab, is coming down the pike in age-related macular degeneration (AMD) to compete against already beleaguered, VEGF-targeted Eylea (aflibercept). The BLA filing for brolucizumab was accepted by the FDA on April 15, with Novartis using a priority review voucher to expedite approval, which could mean a launch by about the end of this year. Jefferies analyst Biren Amin said his firm polled ophthalmologists and the news for Regeneron sounded less than good. "Our proprietary survey indicates brolucizumab is likely to see a robust launch, shifting share from existing anti-VEGF particularly among treatment-experienced patients," he wrote in an April 17 report. "Conservatively, incorporating doctor estimates for brolucizumab uptake cuts Eylea revenues in wet AMD by 13% over the next 2 years, and our revised Eylea estimates fall below consensus by 4-7% from fiscal year 2020-2023." Wall Street "underestimates the impact of brolucizumab's entry," in his view, and Amin predicted that the debut could replicate events seen when Eylea launched and stole market share owned at the time by VEGF inhibitor Lucentis (ranibizumab, Roche Holding AG).