Cytokinetics remains positive on negative Phase II reldesemtiv study in ALS

Despite the trial not showing statistical significance on the primary or secondary efficacy endpoints, the company views the data as supportive of reldesemtiv’s Phase III development

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A drugmaker developing a treatment for amyotrophic lateral sclerosis hopes to move it into Phase III development despite presenting data from a Phase II study showing it failed to meet its primary or secondary efficacy endpoint.

South San Francisco, California-based Cytokinetics on Sunday presented data from the Phase II FORTITUDE-ALS study of reldesemtiv in ALS at the American Academy of Neurology’s annual meeting in Philadelphia. The trial did not show statistical significance for a dose-response relationship on the primary endpoint of change in slow vital capacity (SVC) after 12 weeks of dosing, with a p value of 0.11. A p value of 0.05 or lower is the usual bar for statistical significance. It also did not show statistical significance on the analysis of change in revised ALS Functional Rating Scale (ALSFRS-R) score, a secondary endpoint.

Shares of Cytokinetics opened down 7.3 percent Monday morning, but had risen nearly 9 percent by the early afternoon. The drug is being developed in partnership with Japan-based Astellas.

The company nevertheless said a post-hoc analysis pooling together the three dose levels – 150mg, 300mg and 450mg – indicated that patients on reldesemtiv declined less than those on placebo, with clinically meaningful magnitudes of effect on the primary and secondary endpoints observed at 12 weeks. That included a 27 percent reduction in SVC decline, albeit with a 0.1 p value.

“Admittedly there’s already being demonstrated some skepticism around these results in communications that have been put forward regarding this trial,” CEO Robert Blum said in a conference with investors at AAN. The efficacy analysis, he said, was not achieved but was “borderline achieved” with the 0.11 p value. “I hope you will appreciate these are impressive data in the context of new medicines for ALS.”

ALS remains a devastating disease with few treatment options. In 2017, Mitsubishi Tanabe Pharma’s Radicava (edaravone) became the first new drug to treat the disease in decades, and the field was so sparse that the Food and Drug Administration encouraged the company to file for approval based on clinical experience in Japan.

Blum said the Phase II data support moving the drug into a Phase III study, where it would be necessary to demonstrate a 0.05 or lower p value. Moreover, investigator Dr. Angela Genge, director of the ALS program at McGill University’s Montreal Neurological Institute and Hospital, noted that the study enrolled a broad group of patients and did not control for slow-progressing patients in the placebo arm. Consequently, Fady Malik, Cytokinetics’ executive vice president for research and development, said it would be important in Phase III to be more careful and ensure the patients selected were less likely to be slow progressors.

Blum said the company would probably begin the Phase III study next year.

Dr. Elijah Stommel, a neurologist at Dartmouth College’s Hitchcock Medical Center in Lebanon, New Hampshire, who did not participate in FORTITUDE-ALS, wrote in an email that the drug shows some promise, but is pharmacologically making muscles stronger rather than targeting the underlying pathophysiology of ALS. “Of course, the company is interested in making money,” he wrote when asked if he agreed with the idea that the drug should be moved into Phase III development. “Remember when a large Phase III trial is done, it prevents those ALS patients from participating in another trial that might have more efficacy.”

In a phone interview, Blum acknowledged that the drug’s mechanism of action does not address ALS’s underlying pathogenesis or etiology, but added that investigators in FORTITUDE-ALS had commented that the data were the most impressive they had seen in decades. He also disputed the notion that the company’s motives are only financial, pointing to the fact that it has continued providing an earlier drug, tirasemtiv, to patients free of charge despite having no plans to commercialize it.

Although FORTITUDE-ALS, with 458 patients, had sufficient statistical power to show a significant improvement on the primary and secondary endpoints, Blum said in the interview that one reason it didn’t was because the event rate in the placebo arm was lower than expected. Moreover, he said the company was willing to accept a p value of 0.1 in the Phase II study given that it was designed to provide information for a Phase III trial. “So we don’t look to that p value as be all,” he said. “Rather we look at totality of evidence and consistency of effects across doses and time points so we don’t look to that p value as be all, rather we look at totality of evidence and consistency of effects across doses and time points.”

Photo: FotografiaBasica, Getty Images