The ALS Association

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Carrie Munk
The ALS Association
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Drug Company Working Group: New Tools for Speeding Clinical Trials and a Tirasemtiv Update

Washington, D.C. (May 3, 2016)— Two important new trials were discussed by Jinsy Andrews, M.D., of Cytokinetics and by R. Elizabeth McNeil, M.D., from Biogen; a “machine learning” approach to understanding ALS was presented by David Ennist, Ph.D., M.B.A., of Origent Data Sciences Inc.; and finally Ammar Al-Chalabi, Ph.D., FRCP, DipStat of King’s College London gave insights into the complex genetics of ALS at the annual Drug Company Working Group meeting, held at the American Academy of Neurology meeting in Vancouver, B.C., in April. The goals of the meeting are to provide a forum for discussion of ALS research and therapy development and to establish academic-industry collaboration to advance the ALS field. This meeting takes place annually through a partnership with The Association’s Research, Public Policy and Care Services departments.

ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Eventually, people with ALS lose the ability to initiate and control muscle movement, which often leads to total paralysis and death within two to five years of diagnosis. For unknown reasons, veterans are twice as likely to develop ALS as the general population. There is no cure, and only one drug approved by the U.S. Food and Drug Administration (FDA) modestly extends survival.

Dr. Ammar Al-Chalabi, recipient of this year’s Sheila Essey Award for his contributions to ALS research, began by discussing what is known and not known about the genetic contribution to ALS. “Much of what we thought we knew about ALS twenty years ago, we now realize is wrong,” he said, including the idea that it is one disease. Discovery of several critically important genes, which cause the disease through different mechanisms, has shown that to be incorrect. And there are likely many more genes yet to be found. ALS genetics is advancing rapidly, and understanding more about the genes involved will allow us to develop new therapies,” he said. More details of his talk can be found here.

Tirasemtiv to be Tested in Large Phase III Trial

Jinsy Andrews, M.D., Senior Director of Clinical Research and Development and Head of Neuromuscular Therapeutics at Cytokinetics, provided an update on tirasemtiv, the calcium activator for muscle that appears promising for symptomatic treatment of ALS. A new trial, called VITALITY-ALS (Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year-ALS) began in July 2015, in order to test the drug’s ability to aid muscle strength, especially of breathing muscles. The trial, which is expected to complete enrollment in 2016, is taking place at ALS centers across the United States and Canada, as well as several European countries.

The trial follows the BENEFIT-ALS trial, in which 12 weeks of treatment led to better performance on “slow vital capacity” (SVC) versus placebo in a large group of patients. SVC is a measure of respiratory function. Evidence from the BENEFIT-ALS trial suggested that slowing the decline of SVC predicted a reduction in risk of other clinically meaningful outcomes as well, but a longer and larger trial would be needed to confirm that, which is the intent of the new trial.

VITALITY-ALS is a 48-week, placebo-controlled trial with a two-week, open-label “run-in” period at the beginning. Previous experience has shown that common early adverse events (principally dizziness, fatigue, and nausea) limited tolerability, but these effects lessen over time. The run-in period is meant to reduce the number of patients who have to withdraw from the trial due to these events, while allowing investigators to be sure that those going ahead with the blinded portion of the trial are able to tolerate increasing doses of the drug. Dose increases will be slower and more flexible than in previous trials, which should also increase tolerability of the drug. At the end, there will be an off-drug observation period, in order to rule out any rebound worsening. Overall, an enrolled patient will be involved for 14 months. As in the BENEFIT-ALS trial, those taking riluzole will have their dose reduced, because tirasemtiv increases the potency of a given dose of riluzole by slowing its metabolism. Further details on the trial can be found here:

Methodology Study Will Compare Outcome Measures to Speed Trials

Dr. D. Elizabeth McNeil from Biogen, outlined an ambitious new trial testing outcome measures in ALS, called the Methodology Study of Novel Outcome Measures to Assess Progression of ALS. The goal of the study is to compare outcome measures head to head, and against the “gold standard” ALS Functional Rating Scale (ALSFRS), in order to find measures that are reliable, easy to administer and show evidence of change in a shorter time than the ALSFRS. “The ALSFRS wasn’t developed for use in phase II trials,” Dr. McNeil said, which are smaller and ideally shorter than the phase III trials needed for final drug approval. A phase II trial is designed to test a drug’s safety, find a potentially useful dose and determine if the drug is “hitting its target,” (i.e. reaching the intended cells and affecting the molecules there in the expected way). While the ALSFRS is an important measure of overall function, it doesn’t have the precision over the short term that is needed for short phase II trials.

The measures to be tested in the upcoming study include various tests of muscle electrophysiology, muscle strength, respiratory function and imaging of the spinal cord. “Our goal is to find which of these will change significantly over a short time frame,” she said, “and to find those with the greatest predictive value.”

The study will enroll 200 patients at centers throughout the United States, Canada and Europe. Patients are eligible if they are within two years of diagnosis and have a forced vital capacity (FVC) of at least 50% of predicted (a standard respiratory measure).

“Our hope is to then use the most responsive measure or measures in upcoming phase II trials,” Dr. McNeil said, including the Biogen-sponsored trial of antisense against the SOD1 gene, which is underway. More details about the methodology study can be found here:

Prediction Algorithms Aim to Speed Trials

Having accurate predictors of function and survival is important both for clinical trials and the individual person with ALS. For the individual, it may mean knowing better what lies ahead, often the most challenging part of early planning in ALS. For clinical trials, it would allow groups of patients to be stratified by rate of progression, so that a new treatment could be tested separately in groups with fast or slow progression, reducing the “noise” of clinical measurements and allowing a treatment benefit “signal” to emerge more clearly.

Origent Data Sciences, Inc. has developed computational tools to make those predictions. The company was the winner of the Prize4Life disease progression algorithm challenge, in which groups competed to develop a tool that could predict progression based on baseline clinical data. The data for the challenge was drawn from the ProAct database, a combination of patient data from multiple large clinical trials in ALS.

Origent Data Sciences, Inc. was an outgrowth of Sentrana, a marketing analysis firm, which uses detailed information about customer behavior to make predictions about future purchases. That same idea—that by accumulating the right information, you can make an accurate prediction about the future—is the basis of Origent’s prediction algorithms.

The prediction algorithms are developed using “machine learning tools” explained Dr. David Ennist, Chief Scientific Officer of Origent Data Sciences, Inc. “The tools don’t' really try to understand nature,” he said, and make no assumptions about the disease. “Instead, we let our algorithms find the eventual path to the outcome measure” through trial, error, refinement and repetition. By testing many different possibilities, the algorithms eventually come up with one that tightly predicts actual outcome from initial clinical variables, such as respiratory function or ALSFRS score.

The algorithms can then be used in trials to develop a set of “virtual controls,” which might take the place of a placebo group. In this scenario, data from individual patients receiving treatment would be used to develop predictions about how each patient was likely to progress without treatment. Actual progression could be compared to this prediction to determine treatment benefit.

Origent Data Sciences, Inc. is currently in discussion with the Food and Drug Administration about using their algorithms in clinical trials for this purpose. Meanwhile, they plan to test the predictive power of the algorithms in the VITALITY-ALS trial.

“We are in a time of great hope in ALS therapy development,” said ALS Association President Barbara Newhouse, 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.”

About The ALS Association
The ALS Association is the only national non-profit organization fighting Lou Gehrig’s Disease on every front.  By leading the way in global research, providing assistance for people with ALS through a nationwide network of chapters, coordinating multidisciplinary care through certified clinical care centers, and fostering government partnerships, The Association builds hope and enhances quality of life while aggressively searching for new treatments and a cure.  For more information about The ALS Association, visit our website at

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