Cytokinetics to Release Phase 3 Tirasemtiv Data Next Month in Support of Likely FDA Filing, EVP Says in Interview

Findings from a Phase 3 study of tirasemtiv to improve muscle strength — particularly of respiratory muscles — in amyotrophic lateral sclerosis (ALS) patients will likely be announced for a first time on Dec. 8 at the 28th ALS/MND meeting in Boston, a vice president of Cytokinetics, its developer, said in an interview.

And if those VITALITY-ALS trial results are strong and positive, Cytokinetics will certainly use them to request that the oral therapy be approved, both in the U.S. and Europe, to treat ALS — possibly making it the second treatment to advance in the U.S., following Radicava (edaravone) in May, after a more than 20-year drought.

“Hopefully the results of VITALITY, as they bear out, will be sufficient to support regulatory approval,” Dr. Fady Malik, executive vice president of research and development for Cytokinetics, said in a recent interview with ALS News Today.

“We certainly intend, if the trial is positive, to take those results to the FDA and EMA and discuss with them the potential approval paths,” he added, referring to the U.S. Food and Drug Administration and the European Medicines Agency. If analyses finish early, some results might even be released in advance of the meeting.

Tirasemtiv is a fast activator of the skeletal muscle protein troponin, which forms a complex with another protein called tropomyosin. The binding of the two proteins underlies skeletal muscle contraction and depends on the intracellular levels of calcium.

By increasing the sensitivity of fast skeletal muscle to calcium, tirasemtiv improves the force of muscle contraction and, consequently, the physical abilities of people with diseases where neuromuscular function is compromised. In ALS patients, declines in muscular strength extend to respiratory muscles ­— those of the diaphragm and between the ribs — ultimately leading to respiratory failure.

A Phase 2 learning process

Tirasemtiv’s benefits in ALS have been extensively studied in four randomized, placebo-controlled Phase 2 trials (NCT01089010, NCT01378676, NCT01486849, and NCT01709149).

The first three trials confirmed its safety profile and showed significant improvements in patients’ muscle strength and rate of muscle fatigue. But these studies were too short in duration (two to 21 days following therapy initiation) to draw conclusions regarding tirasemtiv’s efficacy.

That was especially true of a measure called the ALS Functional Rating Scale (ALSFRS), whose revised version — ALSFRS-R — is designed to incorporate assessments of respiratory function, in addition to standard measures of disability progression in ALS. It now evaluates parameters of dyspnea (shortness of breath), orthopnea (shortness of breath when lying), and the need for ventilatory support.

The FDA, to date, favors ALSFRS-R as a measure of a treatment’s effectiveness in ALS studies.

Patients in those trials did show positive changes in measures of ALSFRS-R and in maximal voluntary ventilation, or the amount of air a person can inhale and exhale in one minute. But data collected were far from conclusive.

“From those early studies, what emerged was a picture of improving muscle function and patients identifying that they felt better having taken the drug in a way that was dose-related and statistically significant,” Malik said.

So, in the fourth and final Phase 2 trial, called BENEFIT-ALS, patients were treated for 12 weeks — with a primary goal of determining if tirasemtiv, taken with or without Rilutek (riluzole), was better than placebo at improving ALSFRS-R total scores from initial, or baseline, measures.

It did not. The study “failed to meet the primary endpoint — it didn’t have a positive effect on ALSFRS-R,” Malik said simply.

“The story could have ended there,” he continued. “But in looking at one of the secondary endpoints, which was an endpoint called slow vital capacity [SVC] — which is related to the breathing function of ALS patients — we saw a slowing in the decline of their breathing function.”

Indeed, BENEFIT  showed “that the rate of [respiratory] decline was substantially slowed in patients taking tirasemtiv.”

ALS patients lose an average of 3 percentage points per month in their breathing function, where 100 percent is the normal range for someone of their height, age, and sex. At the end of BENEFIT-ALS, patients treated with tirasemtiv showed a 6 percentage point difference relative to those in the placebo group.

“In 12 weeks, it seemed quite a substantial difference developed, and that result was highly statistically significant,” Malik said of the potentially clinically meaningful improvements seen in SVC. “It was not likely just random chance.”

SVC and a possibly decisive Phase 3 study

After evaluating these results with experts, Cytokinetics “decided to move on and conduct VITALITY-ALS, and try to confirm and extend the finding of benefit in ALS,” Malik said.

The Phase 3 trial (NCT02496767) was designed to assess tirasemtiv’s effectiveness in improving respiratory function and muscle strength over 48 weeks.

This time, SVC was set as its primary outcome; specifically, the change seen from baseline in slow vital capacity at week 24. Because slow vital capacity measures the strength of skeletal muscles responsible for breathing, it’s “an important aspect of patient function in ALS,” Malik said. “No one would argue that breathing function is vital to patient survival.”

ALSFRS-R scores on its three respiratory measures, change in ALSFRS-R total scores, and time to assisted ventilation or respiratory insufficiency — all at 48 weeks — were set as secondary trial goals. Positive data here will support potential findings of benefits in SVC, especially in an FDA review.

VITALITY enrolled 744 ALS patients, who received 125 mg of the treatment twice a day for two weeks. They were then randomized to one of three tirasemtiv doses — 125 mg, 375 mg, or 500 mg — twice a day, or placebo.

Malik is cautiously optimistic that SVC results, if positive, will be accepted by the FDA as proof of tirasemtiv’s efficacy in treating ALS.

“I think they have demonstrated flexibility in considering other endpoints,” he said. “And we’ve had specific feedback that they would consider vital capacity as a primary endpoint if it’s supported by trends or movement in secondary endpoints.”

So, while “SVC by itself may not be enough to give approval to the drug, I think the FDA wants to leave itself some room for flexibility,” he added.

With the VITALITY-ALS trial now complete, and researchers examining data to present at the upcoming ALS/MND meeting, many of its patients are moving to an extension study, called VIGOR-ALS (NCT02936635), evaluating tirasemtiv’s safety and efficacy over the long term — up to three years.

This trial enrolled its first patients in 2016 but results likely won’t be available until late 2018, Malik said. “Our attention’s been focused on getting VITALITY to the point of readout,” he said, although he saw a “positive finding” in that some 90 percent of VITALITY patients “elected to go on into VIGOR … wanting to continue therapy when they had the option to quit it.”

Cytokinetics has no plans to test tirasemtiv as a combination treatment this point. Instead, its focus is on running those basic, short studies in healthy volunteers that would support tirasemtiv’s approval application to the FDA by evaluating “things that go into a drug label,” Malik said.

But the future of ALS treatment, he added, is likely in a combination treatment. “Given that we don’t really know what the root cause is of ALS, and there may not be a single root cause — there probably isn’t — I do believe that combination treatments are going to become the standard.”

“There’s no reason to think that tirasemtiv wouldn’t work together” with other ALS therapies, whether riluzole or Radicava, he said. “What we hope is that tirasemtiv will become part of the standard of care in ALS.”