Cytokinetics needs an SPA for ALS drug

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease caused by progressive degeneration of motor neurons. When the motor neurons die, the ability of the brain to control muscle movement is lost. Patients in later stages of ALS may become completely paralyzed, which includes losing the ability to control their breathing.

ALS became well known worldwide since the Ice Bucket Challenge became popular in 2014. More than 12,000 people in the U.S. have ALS, for a prevalence of 3.9/100,000. Riluzole (rilutek) is the only treatment shown to improve survival, but only for 2-3 months. Sales of Riluzole peaked at around $50 million per year.

BrainStorm Cell Therapeutics (NASDAQ: BCLI) and Neuralstem (NASDAQ: CUR) are developing stem cell therapies for the treatment of ALS. Cytokinetics (NASDAQ: CYTK) and MediciNova (NASDAQ: MNOV) are testing orally bioavailable, small molecules (tirasemtiv and ibudilast) in clinical trials.

Cytokinetics’ tirasemtiv (CK-2017357) is a fast skeletal troponin activator[1] which sensitizes muscle to calcium, enabling more powerful contractions. The drug does not affect the degeneration of motor neurons. It is treating symptoms and not the cause of the disease.

On April 25, 2014, Cytokinetics announced top-line results from the Phase IIb BENEFIT-ALS trial. Tirasemtiv failed to reach the primary endpoint of ALSFRS-R. The company’s stock plummeted 65% to $4.5 on news of the failure. Recently, the stock price has rebounded to $7.5.

While the trial did not meet its primary efficacy endpoint, treatment with tirasemtiv resulted in a statistically significant improvement in Slow Vital Capacity (SVC). The rate of decline in SVC for tirasemtiv was only one-third that of control patients.

SVC Placebo (n=210) Tirasemtiv (n=178) All (n=388)
Baseline 89.7 85.7 87.8
Changes from Baseline p-value
Week 4 -3.89 -0.99 0.001
Week 8 -5.81 -2.85 0.004
Week 12 -8.66 -3.12 <0.0001

SVC is the maximum volume of air that can be exhaled slowly after slow maximum inhalation. It is an indicator of the strength of the skeletal muscles that are responsible for breathing.

However, the drug didn’t show statistically significant improvement in any secondary endpoints other than SVC. It showed no effect on sniff nasal inspiratory pressure (SNIP) and maximum voluntary ventilation (MVV), another two measures of pulmonary function.

Tirasemtiv appears to be really effective for certain patients. Here is a feedback from a patient called Susan Speranza.

As a patient suffering from ALS & a P2 participant I pray for approval. I was able to get up from a chair and roll over in bed unassisted, a HUGH improvement in my quality of life! True, not a cure but to the hundreds of thousands worldwide suffering every day, moving a little easier prolongs independence. The improvement in respiratory function alone justifies approval of Tirasemtiv since all of us die from respiratory failure. Millions of dollars and a decade of research have gone into this drug and PALS have nothing else (Rilutek extends life 2-3 months). As part of P3 trial, provide an open label arm for prior participants that benefited. It’s cruel & inhumane not to offer this drug.

Will the FDA accept SVC as the primary efficacy endpoint for regulatory approval? For most diseases, the FDA would not accept a surrogate measure like SVC as a primary endpoint. Investors expect an SPA agreement with the FDA before Phase III trial.

PS: Special Protocol Assessment (SPA) is a declaration from the FDA that an uncompleted Phase III trial’s design, clinical endpoints, and statistical analyses are acceptable for FDA approval.

Cytokinetics have communicated with the FDA regarding results from Phase IIb, however, no SPA agreement has been announced so far. Here is Cytokinetics’ statement in Form 10-Q filed on November 11, 2014.

We have begun regulatory interactions with the FDA regarding results from BENEFIT-ALS and have received initial feedback from the FDA. We believe that effects on SVC could be a Phase III clinical trial endpoint and could support registration of tirasemtiv as a potential treatment for patients with ALS. As a result, we have initiated planning for a potential Phase III clinical trial of tirasemtiv that could begin in 2015.

I don’t know whether Cytokinetics will run a Phase III trial without an SPA. Considering the urgently medical need, many key opinion leaders may advise the FDA to accept SVC as the primary endpoint. All the same, it is a huge risk must be considered.

[1] Nat Med. 2012, 18(3), 452-455.

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