During the Drug Company Working Group session at the recent American Academy of Neurology annual meeting in Vancouver, Canada, a top researcher from Cytokinetics gave an update on a new Phase 3 study of tirasemtiv as a potential treatment for amyotrophic lateral sclerosis (ALS), and another from Biogen talked about a new trial to assess outcome measures in ALS patients.
Origent Data Sciences’ chief scientific officer also presented a “machine learning” method of predicting ALS progression, which may one day replace placebo control groups in these trials, according to an ALS Association release on the session.
Tirasemtiv, a skeletal muscle troponin activator, is being investigated by Cytokinetics as a potential treatment for people with ALS and other debilitating conditions associated with muscle weakness and fatigue, or neuromuscular dysfunction. VITALITY-ALS (Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year-ALS), which began in July 2015, is a 48-week Phase 3 double-blind, randomized, placebo-controlled, and parallel group study to evaluate the safety, tolerability, and efficacy of tirasemtiv in ALS patients. Its primary outcome is change from baseline to week 24 in percent predicted slow vital capacity (SVC), a measure of respiratory function.
According to Jinsy Andrews, MD, senior director of Clinical Research and Development and head of Neuromuscular Therapeutics at Cytokinetics, tirasemtiv appears promising for symptomatic treatment of ALS. The trial expects to complete enrollment this year, and is taking place at ALS centers across the United States and Canada, and at sites in France, Spain, the U.K., Ireland and the Netherlands. It includes a two-week initial “run-in” period, because evidence has shown that early adverse events (fatigue, dizziness, and nausea) reduce drug tolerability, although these effects diminish over time.
VITALITY-ALS follows the BENEFIT-ALS trial, a 12-week study in which, compared to a placebo, tirasemtiv treatment led to improved SVC scores.
The trial is currently recruiting participants, and more information is available through it clinical trials.gov website (NCT02496767).
Dr. D. Elizabeth McNeil, with Biogen, summarized a new trial that company is beginning to assess outcome measures of ALS progression. The trial, “Methodology Study of Novel Outcome Measures to Assess Progression of ALS,” will compare outcome measures head-to-head and against the “gold standard,” the ALS Functional Rating Scale (ALSFRS), to find reliable but easier-to-administer measures that quickly show evidence of change. “The ALSFRS wasn’t developed for use in phase II trials,” Dr. McNeil said. Phase 2 trials are smaller and shorter than the Phase 3 trials required for drug approval, and ALSFRS lacks precision in a shorter time frame, she said.
Outcome measures to be assessed include muscle electrophysiology tests as well as respiratory function, muscle strength, and imaging of spinal cord assessments. “Our goal is to find which of these will change significantly over a short time frame, and to find those with the greatest predictive value,” Dr. McNeil said.
The Biogen trial (NCT02611674), which is also now recruiting, intends to enroll 200 ALS patients across the United States, Canada, and Europe. Eligible patients must be within two years of their ALS diagnosis, and have a forced vital capacity (FVC) of at least 50 percent of predicted.
“Our hope is to then use the most responsive measure or measures in upcoming phase II trials,” Dr. McNeil said, including the Biogen-funded study of antisense against the SOD1 gene, which is currently underway.
Accurate predictors of survival and function are critical for trials, as well as for ALS patients. For the person, they play an important role in knowing what lies ahead. For trials, accurate predictors allow the stratification of patient groups by rate of disease progression, so that a treatment can be tested separately in groups with fast or slow progression to diminish the “noise” of clinical measurements and to help a treatment benefit “signal” to clearly appear.
Origent Data Sciences is a recent spinoff of the marketing analysis firm Sentrana, which in 2012 won the Prize4Life ALS Prediction Challenge. Among the 1,073 teams in the competition, Sentrana took first place for its disease progression model and was singled-out for its success at predicting individual patients.
In addition to modeling two common endpoints in ALS trials, ALSFRS and ALSFRS-R scores, Origent also developed progression models that focus on targeted symptoms of the disease, such as bulbar, respiratory, and limb functions.
Algorithms are created with “machine learning tools,” Dr. David Ennist, chief scientific officer of Origent Data Sciences, said at the session. “The tools don’t’ really try to understand nature. Instead, we let our algorithms find the eventual path to the outcome measure” through trial, error, refinement and repetition. By assessing different possibilities, the algorithms ultimately come up with one that predicts the actual outcome from initial clinical variables, like respiratory function and ALSFRS score.
The algorithms can be used in trials to create a set of “virtual controls,” which might replace the need for a placebo group. In this approach, clinical information from patients receiving treatment would be used to develop predictions about how each would progress without treatment, and actual outcomes would then be compared to predicted outcomes to determine the benefit of treatment.
Origent is currently in discussions with the U.S. Food and Drug Administration regarding the use of the algorithms in clinical trials for this purpose. The company is also planning to assess their predictive power in the VITALITY-ALS trial.
“We are in a time of great hope in ALS therapy development,” said Barbara Newhouse, ALS Association president, speaking to the Drug Company Working Group. “The efforts highlighted here are poised to accelerate progress in clinical trials and to bring new treatments to people living with ALS.”