The phase IIb failure of tirasemtiv in amyotrophic lateral sclerosis (ALS) jolted Wall Street, though some analysts had been wary from the start about the chances for the fast skeletal muscle troponin activator.

Is the drug dead in ALS? “It’s not our view that that’s the case,” Cytokinetics CEO Robert Blum told BioWorld Today. “We don’t know yet. There’s a great deal more that we have to learn by delving into these data, and understanding them from the standpoint of a potential regulatory path forward. “

Shares of the South San Francisco-based company (NASDAQ:CYTK) plunged 64.7 percent Friday to close at $4.59, down $8.40.

Tirasemtiv’s main endpoint in the 680-patient trial known as BENEFIT-ALS (Blinded Evaluation of Neuromuscular Effects and Functional Improvement with Tirasemtiv in ALS) was the mean change from baseline in the ALS Functional Rating Scale (FRS) in its revised form. The outcome was -2.98 points in the tirasemtiv group vs. -2.40 points in the placebo group (p = 0.11).

Secondary measures of tirasemtiv’s effects on respiratory function and other gauges of skeletal muscle function turned up results that the company described as mixed.

Cytokinetics’ candidate “joins a very long list of clinical trials, where the FRS failed to demonstrate a treatment effect,” Blum said. “That’s why we do phase II studies, and that’s why we assign secondary endpoints in these trials, and there’s much more in those secondary endpoints that we look forward to sharing.”

Detailed results from BENEFIT-ALS will be offered tomorrow during the 66th Annual Meeting of the American Academy of Neurology in Philadelphia. Meanwhile, remarks made by the company have been “purposely very succinct,” Blum said.

Earlier this month, Roth Capital Partners analyst Joseph Pantginis called the phase IIb data’s release “a potential transformational event for the company, especially with prior data suggesting clinical benefit and improvement to ALS patients.” He had changed his tune Friday. “This is a very disappointing outcome for tirasemtiv and our call was wrong,” Pantginis wrote. “We now need to assess where the drug and the company stand today.”

Last June, when Cytokinetics signed a potential $490 million deal with Tokyo-based Astellas Pharma Inc., Piper Jaffray analyst Charles Duncan wrote in a research report that the decision – probably made by Cytokinetics – to retain ownership of tirasemtiv was “a savvy strategy that preserves upside,” if the drug works. Duncan wrote Friday that the findings mean “near-zero chance that the candidate moves forward.” (See BioWorld Today, June 26, 2013.)

Joseph Schwartz of Leerink Swann noted that he’d “had cautiously optimistic expectations (50 percent probability of success) based primarily on a different mechanism that focuses on augmenting muscle responsiveness rather than neuroprotection.”

Cowen and Co.’s Simos Simeonidis had expected even less, pegging the trial’s probability of success at 35 percent and likelihood that tirasemtiv would reach the market at 23 percent. Simeonidis predicted that the failure “is not going to be a major surprise” for many Cytokinetics supporters. “We don’t expect investors to assign any value to tirasemtiv or its follow-on compound CK-107, which is partnered with Astellas,” he added.

For drug developers, ALS – also known as Lou Gehrig’s disease – is turning out to be a challenge as formidable as Alzheimer’s disease. Cortellis Clinical Trials Intelligence database lists 30 phase I, II and III trials recruiting in ALS, a disease that Blum called “ruthless. And while in Alzheimer’s disease we have reasonably good hypotheses for what underlies the pathophysiology, in ALS, that is elusive. We don’t know what causes this disease. We have only one drug that’s been approved in the care of ALS patients [specifically], and that’s a drug where the mechanism is unclear and the treatment effect is modest at best.” He was referring to Paris-based Sanofi SA’s Rilutek (riluzole), approved in December 1995, which extends survival only about two to three months. “There has never been a study in ALS patients that demonstrated a statistical benefit that can be confirmed,” he added.


Recently discovered genetic markers seem to herald progress. Late last year, the New York-based nonprofit organization Project A.L.S. disclosed its plan to examine molecules developed and studied preclinically by Indianapolis-based Eli Lilly and Co. scientists for the treatment of cancer to assess their potential in the treatment of ALS. The effort will explore possible inflammatory targets for drug development. (See BioWorld Insight, Nov. 25, 2013.)

Varied approaches have drawn the energies of researchers in ALS. In February of this year, gene therapy player Voyager Therapeutics Inc. pulled down $45 million in series A cash for its adeno-associated virus approach in central nervous system disorders. Formed by Third Rock Ventures LLC, the Cambridge, Mass.-based firm has preclinical programs investigating a monogenic (mutation in the SOD1 gene) form of ALS and Friedreich’s ataxia. (See BioWorld Today, Feb. 12, 2014.)

With Cytokinetics, all eyes now are on oral omecamtiv mecarbil, in a phase II trial called COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure) with collaborator Amgen Inc., of Thousand Oaks, Calif. The double-blind, randomized, placebo-controlled, multicenter experiment is designed to assess the pharmacokinetics and tolerability in patients with heart failure and left ventricular systolic dysfunction. The expansion phase is expected to enroll about 450 patients randomized 1:1:1 to placebo, 25 mg or 50 mg twice daily of the drug. COSMIC-HF is expected to finish next year, and the companies will decide whether to proceed into phase III. (See BioWorld Today, Jan. 4, 2007, and May 27, 2009.)

The tirasemtiv fizzle cast more doubt on Cytokinetics’ other candidate, in Duncan’s view. “Our probability of success for omecamtiv goes from 70 percent to 40 percent as we view the tirasemtiv result as increasing the level of risk for Cytokinetics’ platform (i.e., enhancing muscle function with small molecules),” he wrote.

No Comments