Biogen Trial Aims to Improve Identification of Most Promising ALS Drug Candidates

Objective measures of disease progression have emerged in recent years as perhaps the most important unmet need in the field of ALS clinical trial design. A new study just getting underway aims to propel the field forward, by comparing more than a dozen ALS outcome measures to identify the most useful ones for assessing disease progression in Phase II trials. The ultimate goal of the trial is to improve the design of Phase II drug trials to be more predictive of success in Phase III and in patients. The study is sponsored by Biogen and has already opened for enrollment to people with ALS (PALS).

With an over-reliance on the ALS Functional Rating Scale-Revised (ALSFRS-R) as an outcome measure, Phase II trials have either been underpowered, or have necessarily been larger and longer than investigators would otherwise choose, “simply to achieve enough power to see a small signal in a big sea of noise,” says Steve Han, Associate Medical Director at Biogen and Medical Director of the trial. Unfortunately, many candidate ALS drugs, including dexpramipexole, have failed to achieve the anticipated positive effect in Phase III after a positive signal in Phase II (see Nov 2011 newsJan 2013 news). There were many lessons learned from the dexpramipexole trial, and this experience motivated Biogen to develop the new study to help the field better “make the leap from Phase II to Phase III trials.”

One of the primary objectives of the study is to assess the longitudinal changes over six and twelve months of promising novel outcomes measures, to identify the most sensitive ones for assessing disease progression in the time frame appropriate for Phase II trials. Ultimately, the goal is to identify and advance the most promising drugs into Phase III trials, and focus the most time and resources on the drugs that are most likely to succeed. Studies have shown that the utility of the ALSFRS-R for these shorter trials is limited, since individual patient scores are variable over time, and the scale evaluates function globally, rather than selectively in the most affected regions of the body. This is appropriate for adequately-powered Phase III trials, Han said, to assess a promising drug’s overall benefit to the patient. But it is less so in Phase II, as investigators try to determine whether, and how, a drug is changing the course of the disease.

The trial will encompass a broad range of different outcome measures that were selected as particularly promising for assessing disease progression. These include electrophysiological measures, such as electrical impedance myography (see Feb 2011 news), muscle strength measures, such as hand-held dynamometry, and respiratory measures such as slow vital capacity (the full list of included measures can be found here). To leverage the most recent advances in spinal cord imaging in ALS, the study will also include spinal cord neuroimaging in a subset of the patients. In addition to the clinical outcomes, researchers will be examining DNA, RNA and biofluids to tease out molecular predictors of progression. The question in the study, Han said, is which of these measures perform the best over the short run (i.e., six months) to predict ALSFRS-R scores and survival over the long run (i.e., 12, 18, and 24 months).

“The best result would be that a few of these measures emerge as clear top candidates that could be used in a Phase II trial,” Han said. The optimal measures would exhibit a large change without significant variability over a short time, which would facilitate identification of promising drug candidates more rapidly, and would also need to be feasible to administer in a large number of patients across multiple sites.

David Ennist Origent

David Ennist of Origent Data Sciences.  Image used with permission.

Enrolled patients will be tested at baseline, seven days later for test-retest reliability, and then approximately every three months for the first year, with ALSFRS-R and survival assessed out to two years. The primary outcome measures are longitudinal standardized mean changes on each ALS outcome measure from baseline to six and twelve months.

Nazem Atassi of Massachusetts General Hospital in Boston and Leonard van den Berg at UMC Utrecht in The Netherlands are the primary investigators for the study, which will engage a total of 25 sites from the United States, Canada, and Europe. As of this writing, the first site is active and the first patient has been enrolled.

David Ennist, of Origent Data Sciences, a company launched based on one of the winning solutions of the Prize4Life ALS Prediction Prize (see Nov 2012 news), who is not involved in the study, commented that  “This data, together with an understanding of the proposed mechanism of action for a therapeutic under development, will make it possible for drug developers to choose the outcome measure or measures most relevant and most likely to register an improvement for a given drug.” Origent’s focus on ALS disease progression models gives them a strong interest in the results, Ennist said. “Incorporation of more sensitive predictors into our algorithms will lead to better ALS models,” which can, in turn, accelerate trials further.

This is an important effort, and should have benefits that extend beyond whatever trials that Biogen is planning, to the entire ALS community,” commented Jeremy Shefner of Barrow Neurologic Institute in Phoenix, Arizona, who is helping to train investigators to perform Motor Unit Number Estimation (MUNE), an electrophysiological measure being used in this study, “Although ALS clinical trials have been ongoing for decades, we are still searching for outcome measures that are robust and clearly disease related, and which predict clinically important outcomes.”

Jeremy Shefner

Jeremy Shefner. Image used with permission.

The biggest challenge in the study is likely to be recruitment, Shefner said. “While ALS patients are usually happy to participate in biomarker studies, this project involves multiple visits which may last a number of hours.  For mobility-challenged patients, the study is asking for a large commitment in time and effort. However, the study is important, and I expect that patients will be eager to participate.”

Terry Heiman-Patterson of Drexel University in Philadelphia and co-chair of the Northeast ALS Consortium (NEALS) Executive Committee, agreed. “The biggest challenge for recruitment will be to impress people with ALS of the importance of this study and to maintain subject participation over the entire course of the study”, she said.

Terry Heiman-Patterson

Terry Heiman-Patterson. Image used with permission.

“We are cognizant we may have significant recruitment challenges with this study,” said Han, who also is an ALS clinician at Massachusetts General Hospital. “Although many want to participate in trials with a [therapeutic] intervention,there are a significant number of PALS who get very enthusiastic and can see that, while this study may not help them, it may have profound implications for how we develop therapeutics for the next generation of patients. I’ve found ALS patients to be quite altruistic and savvy with science, and many will understand the merits of a study like this”. The study has incorporated a travel assistance program to help participants and caregivers get to and from the study visits.

The study, which aims to enroll 250 PALS, is entitled “Methodology Study of Novel Electrophysiological, Physical, and Imaging Outcome Measures to Assess the Progression of Amyotrophic Lateral Sclerosis” and can be found on at:

Further Reading:

Benatar M, Boylan K, Jeromin A, Rutkove SB, Berry J, Atassi N, Bruijn L. ALS biomarkers for therapy development: State of the field and future directions. Muscle Nerve. 2016 Feb;53(2):169-82. Pubmed.

Blood Marker May Predict ALS Progression. 4 Jun 2015.

NEALS: Desperately Seeking ALS Biomarkers. 28 Oct 2011.

disease-als topic-clinical topic-newmethods
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