With Phase III Failure, Cytokinetics Shelves Tirasemtiv, Pivots To ALS Backup

Partnered with Astellas, the San Francisco-area biotech hopes next-generation CK-107 will succeed in a measure of slow vital capacity due to stronger potency and better tolerability compared to tirasemtiv.

Cytokinetics Inc. thought it had the answer in mid-2016 when it decided to design a Phase III in amyotrophic lateral sclerosis (ALS) around a secondary endpoint it hit in Phase II with tirasemtiv, but it didn't. The company reported Phase III results showing the novel skeletal muscle activator did not hit the primary or any secondary endpoints in the VITALITY-ALS study and now it is shelving the compound.

The San Francisco-area biotech revealed the Phase III failure Nov. 21, but added that it is not giving up on its mechanism of action in ALS. It has CK-107 (also known as CK2127107), a next-generation skeletal muscle fast troponin activator, in Phase II in four indications, including ALS, and thinks the drug’s better tolerability profile and potency compared to tirasemtiv may enable it to show a clinically significant benefit in slow vital capacity, the primary endpoint used in VITALITY-ALS.

On a same-day investor call, Cytokinetics CEO Ronald Blum said the company is “profoundly disappointed that we cannot share positive results” from the Phase III study. He added that the results only increase the biotech’s resolve to continue working toward a drug therapy for ALS.

“We have been executing on a business plan that enables us to push forward with operational, financial and programmatic persistence, resolve and strength, much like the patients with ALS,” Blum said, adding that thanks to strategic planning with its board of directors, Cytokinetics finds itself in a situation it had planned for while hoping to avoid. It had more than $300m in cash at the end of the third quarter to finance other efforts, including development of CK-107, he said.

Cytokinetics is partnered with Astellas Pharma Inc. on CK-107 under an R&D partnership that has been revised twice since initial signing in 2013, most recently in 2016 when ALS was added as a specific indication. [See Deal] Structured initially as a research collaboration of skeletal muscle activation in muscle diseases, the Japanese pharma paid Cytokinetics $30m up front, $35m in R&D funding and a $15m milestone pegged to initiation of a Phase II trial to obtain ALS rights for CK-107. The revised deal also gave Astellas rights to opt in on tirasemtiv outside North America and the EU.

Cytokinetics revealed that tirasemtiv failed to show statistical significance on an endpoint of change from baseline in SVC compared to placebo at 24 weeks or in any of the secondary endpoints that were measured at 48 weeks. VITALITY-ALS tested three daily doses of the oral drug (250 mg, 375 mg and 500 mg) against placebo in a 3/2/2/2 randomization structure and showed that the two highest doses showed a positive trend on the primary endpoint, but not statistical significance.

Attempt To Replicate Phase II Results

The biotech made change in SVC the primary endpoint for the 700-patient Phase III study after the CK-107 showed statistical significance for that measure (at 12 weeks) in the Phase II BENEFIT-ALS study, while failing to hit a broader endpoint based on the ALS-Functional Rating Scale (ALS-FRS). (Also see "Cytokinetics Seeks ALS Success By Focusing On Lung Function" - Scrip, 19 Aug, 2016.) Cytokinetics hoped demonstrating an ability to slow reduction in lung function would prove adequate for approval in an indication that at the time had no approved drug therapies.

In May, however, Japan’s Mitsubishi Tanabe Pharma Corp. obtained US approval of Radicava (edaravone) following an unusual process in which US FDA worked with the drug sponsor to okay the drug for ALS following an initial approval in Japan. (Also see "Keeping Track: Neurology And Breakthroughs Stay In Spotlight As US FDA Approves Radicava, Imfinzi; TaiMed Submits Ibalizumab" - Pink Sheet, 5 May, 2017.) FDA granted the approval based entirely on studies conducted outside the US, as well as a dataset that showed evidence of slowing of disease progression, but no clear signal of a mortality benefit.

Cytokinetics noted that a number of patients randomized to the 375 mg or 500 mg dose of tirasemtiv who could tolerate the dose and continue treatment showed a smaller decrease in SVC from baseline compared to placebo. But it is not continuing with development of tirasemtiv because Phase I data for CK-107 suggest the follow-on will be better tolerated and more efficacious in ALS. While instances of dizziness have been seen with tirasemtiv, Cytokinetics thinks CK-107 might avoid that issue because it was specifically designed not to cross the blood-brain barrier.

CK-107 is in clinical development for four neuromuscular and non-neuromuscular indications – Phase II for ALS, spinal muscular atrophy (SMA) and chronic obstructive pulmonary disease; and Phase Ib for limited mobility in elderly subjects (frailty). SMA data are expected in the first quarter of 2018 and data in ALS later in the year. Cytokinetics noted that in vitro testing indicated that CK-107 offers 50%-100% greater potency than tirasemtiv and said a peer-reviewed article outlining Phase I safety/tolerability, pharmacokinetics and pharmacodynamics of CK-107 will be published soon.

In a Nov. 21 note, JMP Securities analyst Jason Butler voiced agreement with Cytokinetics’ strategy in ALS and maintained a “market outperform” rating for the firm’s stock, based on the potential of CK-107, as well lead candidate omecamtiv mecarbil in chronic heart failure. Under a collaboration with Amgen Inc., that drug candidate is in Phase III. (Also see "Amgen, Cytokinetics Checked With Payers Before Taking Omecamtiv Into Phase III" - Scrip, 2 Sep, 2016.)

Investors took a dimmer view of Cytokinetics prospects, as the company’s stock price tumbled 26% on the day’s trading, closing at $8.25.

Butler likes CK-107’s chances to perform better than its predecessor because it “was generated from a distinct family of molecules to tirasemtiv and was specifically designed not to cross the blood-brain barrier.” The drug theoretically works by slowing the troponin complex’s release of calcium, which in turn can increase muscle fibril contractility. This effect “has been found in preclinical and clinical trials to enhance muscle endurance and strength at sub-maximal effort,” the analyst wrote.

Being funded by Astellas, Cytokinetics now is conducting the Phase II FORTITUDE-ALS study of CK-107 in ALS, designed as a dose-ranging study of roughly 450 US and Canadian patients. They will be randomized to daily doses of 150 mg, 300 mg or 450 mg or placebo, with a primary endpoint of change in SVC from baseline at 12 weeks.