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Interview – Cytokinetics muscles up in Lou Gehrig's disease

Date August 23, 2016

It is perhaps a sign of how difficult drug development has been for amyotrophic lateral sclerosis that a project agent that missed its phase II goal could yet become the first new drug in decades for the degenerative disease. This is the case for Cytokinetics’ tirasemtiv, which last month completed enrolment in a phase III trial that aims to slow the decline in patients’ respiratory capabilities.

The California-based group believes that its approach of preserving muscle function will succeed where others have failed. “ALS drug development has been unfortunately an area of nothing but failures historically, because every approach previously has been directed toward a [flawed] hypothesis for what may cause this disease: slowing the loss of neurons,” the company's chief executive, Robert Blum, tells EP Vantage.

Comeback kid

Few might have predicted tirasemtiv to reach phase III based on the disappointing phase II Benefit-ALS trial. That study missed significance on a composite measure called the ALS functional rating scale, and Cytokinetics' share price took a battering as a result (Cytokinetics sees its second miss in a year as ALS drug fails, April 28, 2014).

In the days that followed, a finding of benefit on a spirometry measure, slow vital capacity, gave glimmers of a path forward for tirasemtiv, which as an activator of skeletal muscle troponin aims to improve muscle contractility. The hypothesis is that tirasemtiv slows the decline in diaphragm strength and therefore delays respiratory disability in ALS.

While ALS causes disability in many different ways, patients' loss of breathing function is the most significant, Mr Blum says: “Most of them succumb to respiratory failure. Patients and clinicians alike ultimately measure disease progression by monitoring the rate of change in slow vital capacity.”

It was on this basis that regulators in the US and Europe allowed the design of a pivotal programme around slow vital capacity. “They are comfortable with approving a drug based on a change in respiratory function,” Mr Blum says. “But it needs to be demonstrated across quantitative measures like slow vital capacity, but also clinical interventions that track with change in slow vital capacity.”

Thus the 743-patient Vitality-ALS trial will measure the change in slow vital capacity at 24 weeks, and in addition some 48-week measurements that include progress to respiratory failure, mechanical breathing assistance or death. The respiratory components of the ALS functional rating scale will be used, but other parts such as handwriting, dressing and feeding will not be considered.

Since the 2014 collapse Cytokinetics shares have come back, more than doubling to $12.17 yesterday, on the continued progress of tirasemtiv and a heart failure candidate, omecamtiv mecarbil. Indeed, while the rest of the biotech sector imploded last autumn, Cytokinetics surged; it fell in tandem with the Nasdaq biotechnology index in January 2016, but on the year has outperformed the index with 16% growth.

Strategic plan

Investor confidence has perhaps been encouraged by the decision of the company's collaborator, Astellas, to sign an option to license tirasemtiv and the next-generation troponin activator CK-2127107 outside North America and Europe. The deal carried with it $65m in financial commitments, including up-front fees, as well as $30m in R&D funding.

Thanks to an existing collaboration with Astellas on CK-2127107, as well as a deal with Amgen on omecamtiv mecarbil, Cytokinetics has not had a secondary share offering since before the tirasemtiv phase II results in early 2014 – missing the hottest period of the biotech bubble. The company had $96m in cash at June 30, and says it will achieve $25-50m in milestones over the next year.

And with another $65m due from Astellas it should have cash for at least two years, Mr Blum says – long enough to finance it through the readout of the tirasemtiv trial in the second half of 2017.

Mr Blum believes that Cytokinetics would be able to launch tirasemtiv solo in the US. A market of about 75 ALS centres of excellence and another 75 centres able to diagnose patients would make for a small market that can be served by a commercial organisation that could be built by a smaller company like Cytokinetics.

Building towards this goal could stretch the group beyond its existing finances, he admits. “As we may still build out our commercial planning activities there may ultimately the need to do other financings down the road.”

Study  Trial ID 
Vitality-ALS  NCT02496767 

To contact the writer of this story email Jonathan Gardner in London at jonathang@epvantage.com or follow @ByJonGardner on Twitter

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