The Current State of Clinical Trials in ALS

Even though the cause of ALS is still unknown, “We are in a revolution of ALS therapy trials,” said Merit Cudkowicz, M.D. Dr. Cudkowicz summarized the state of clinical trial research in ALS for The ALS Association’s Drug Discovery Workshop, held in Washington, D.C., in March 2012. That revolution is manifested both by the number of completed and ongoing trials and the increasing quality of those trials. Current trials include drugs, stem cells, and gene therapy and include treatments that aim to alter the course of the disease as well as one that targets symptomatic muscle weakness.

There are multiple reasons for the increase in trial number and quality. The Association’s support for drug development, and for young researchers to develop their skills in ALS, has been crucial. In addition, the Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS) trial network—a national and now international consortium of ALS clinical researchers—has grown significantly in the past decade, allowing the group to conduct larger and more sophisticated trials. Similar consortia are in place and expanding throughout Europe. “We are all working together and sharing resources,” Dr. Cudkowicz said.

A key question in the decision to take a new drug to trial is how much weight to give results from animal models. All models are imperfect, and the effects of a drug in an animal model can only tell scientists so much. Improvements in mice have not yet translated to improvements in people with ALS. “We need to not be too rigid about mouse success,” she said. An alternative approach to insisting on success in animals before taking a drug to humans is to be sure that the proposed beneficial mechanism of the drug in ALS makes sense, that the drug can hit the target in humans, and that it is safe. In some cases, that may be good justification to proceed with a clinical trial.

Two drugs—dexpramipexole and ceftriaxone—are currently in so-called “Phase III” clinical trials with large numbers of patients receiving drug or placebo over the course of six months or more. Such trials are the final step before a drug can be approved by the United States Food and Drug Administration.

“Placebo acceptance is a challenge for both patients and physicians,” Dr. Cudkowicz said. However, the use of a placebo increases the rate of discovery of effective treatments because without a placebo, both patients and physicians may incorrectly perceive a benefit from a treatment that is not helping. Worse, some drugs may harm patients, an effect which can rarely be seen clearly without a control group for comparison.

Dexpramipexole

Douglas Kerr, M.D., Ph.D., of Biogen Idec in Massachusetts, gave an overview and update of the ongoing development program of dexpramipexole. “The high metabolic activity in the brain is an Achilles’ heel” for the central nervous system, he said, because that activity increases the likelihood of damage to the neuron’s mitochondria, which are the power plants of the cell. Dexpramipexole is thought to work by increasing the efficiency of mitochondria in motor neurons, which are placed under significant stress in ALS patients. The drug is the three-dimensional mirror image of a symptomatic treatment for Parkinson’s disease, but that difference prevents it from having the same (and unwanted) side effects in ALS.

A Phase II study of the drug in 102 early ALS patients showed trends on functional outcomes and survival. A Phase III trial has enrolled almost 1,000 patients for treatment of up to 18 months and is scheduled to be completed in the second half of 2012.

CK2017357

Jesse Cedarbaum, M.D., formerly of Cytokinetics in California, gave the group an update on CK2017357. This drug works at the muscle level, to increase the muscle’s strength when it contracts, without requiring more energy expenditure. The drug has its greatest effect at mid-levels of exertion, not at the top, he said. “The middle is where we do most of our function,” including walking, reaching, and speaking. The drug reduces fatigue and improves function in ALS patients when given as a single dose. New results examining the effect of prolonged dosing were presented at The American Academy of Neurology in New Orleans on April 25, 2012.

Antisense Against SOD1

Frank Bennett, M.D., of Isis Pharmaceuticals in California, reported that results from the initial blinded Phase I clinical trial of an SOD1 “antisense” therapy, and the results were presented at the American Academy of Neurology Meeting on April 25, 2012. The antisense molecule is a short string of nucleotides (nucleotides are the building blocks of both DNA and RNA) whose sequence is complementary to that of the SOD1 messenger RNA. This allows the antisense molecule to bind to the SOD1 messenger, triggering the cell machinery to destroy it before it can be used to make SOD1 protein. The goal is to reduce the amount of mutant SOD1 protein, which researchers believe will be therapeutic.

The anti-SOD1 antisense molecule has been well-tolerated during the trial with no safety concerns emerging. According to Dr. Bennett, antisense molecules have been tested in more than two thousand subjects in more than 60 clinical studies in a variety of diseases, an indication of their safety. Antisense molecules will not cross the blood-brain barrier when injected in the periphery, which means they must be delivered into the central nervous system directly.

Dr. Bennett noted that the same strategy, using an antisense molecule of a different sequence, might be considered against ALS caused by mutations in the newly discovered C9ORF72 gene. The utility of this strategy will depend on how the mutation causes disease. If the mutation creates a new, toxic function, rather than a loss of function, then shutting it down with antisense may be therapeutic.

“We would never have been able to do all this work without support from The ALS Association,” Dr. Bennett said. “This has been probably one of the best examples of collaboration between academia, industry, and foundations that I know of.”