The 23rd International Symposium on ALS/MND (motor neuron disease), held in Chicago Dec. 5-7, 2012, brought together more than 900 researchers, clinicians and other health care professionals from 30 countries to hear presentations on the latest in ALS care and research.
Among the presentations were updates on a number of important clinical trials in amyotrophic lateral sclerosis (ALS).
Update (March 29, 2013): This news item was updated to reflect the publication of a paper and commentary on the ISIS-SOD1-Rx trial.
Timothy Miller, assistant professor of neurology at Washington University School of Medicine, reported results on an MDA-supported phase 1 trial for ISIS-SOD1-Rx (ISIS 333611) in ALS.
ISIS-SOD1-Rx is an experimental "antisense" drug under development by Isis Pharmaceuticals that interferes with the production of toxic SOD1 protein. (Abnormal, toxic SOD1 protein, produced from mutated SOD1 genes, is the root cause of ALS in approximately 1 to 3 percent of people with the disease.)
The trial of ISIS-SOD1-Rx was designed to evaluate the safety, tolerability and pharmacokinetics of ISIS-SOD1-Rx. ("Pharmacokinetics" is the science of how the body absorbs, distributes, metabolizes and excretes a substance.)
The experimental drug was administered into the spinal fluid as a single, 12-hour infusion. There were eight trial participants for each of four dosage levels. At each level, six participants were randomly assigned to receive ISIS-SOD1-Rx, and two received a placebo.
Adverse events were mild to moderate and were related to the drug delivery procedure, not the drug itself.
Overall, ISIS-SOD1-Rx was well-tolerated at doses up to 3 milligrams. In addition, Miller noted that seven trial participants enrolled twice and two participants enrolled three times; re-exposure to the drug in these participants was well-tolerated.
Concentrations of the drug in both blood and spinal fluid were dose-dependent.
Miller noted that the ISIS-SOD1-Rx molecule currently is being redesigned.
For more information, please see:
Robert Miller of California Pacific Medical Center in San Francisco confirmed results from a phase 2 study of NP001 in ALS, that were first reported by Neuraltus Pharmaceuticals on Oct. 29, 2012, in a press release.
In the multicenter, double-blind, placebo-controlled phase 2 trial of NP001, 136 people with ALS were randomly selected to receive the drug at either 1 milligram per kilogram of body weight (low dose) or 2 milligrams per kilogram of body weight (high dose), or a placebo (inactive substance).
Treatment was administered via intravenous infusion over a period of six months, after which participants went through a six-month follow-up period.
The trial was designed to:
As previously reported by MDA, NP001, which works by modifying the immune system, was found to be safe and well-tolerated, with some clinical benefit seen in the high-dose group.
Analysis that included data from a historical controlgroup (people with ALS who participated in other studies) showed that participants who received NP001 had a slowing in the rate of symptom progression. Data showed a 19-percent decrease in the slope of decline in ALSFRS-R scores.
In addition, the high dose halted progression in a subset (27 percent) of trial participants.
The data, Miller said, support the proposed anti-inflammatory mechanism of action of NP001, and encourage the continued development and testing of the drug.
Jonathan Glass, director of the MDA/ALS Center at Emory University School of Medicine in Atlanta, reported on a completed phase 1 trial of NSI-566 neural stem cells in ALS.
As previously reported, the stem cells and the surgical method used to transplant them were found to be safe and well-tolerated in all trial participants, with evidence of a treatment effect — an interruption of the progression of the disease — in some. (See Neural Stem Cell Trial in ALS 'Very Successful' So Far.)
Biotherapeutics company Neuralstem, developer of the neural stem cells, is studying whether the cells can improve respiratory function and prolong life span in ALS. Neural stem cells generate muscle-controlling motor neurons and glia (a type of motor neuron support cell) in the brain.
This first U.S.-based trial of spinal cord stem cells in ALS opened at the MDA/ALS Center at Emory University in January 2010 and followed a "risk-escalation" format.
Fifteen trial participants received a total of 18 neural stem cell treatments. (Three participants who were treated in an earlier phase were allowed by the U.S. Food and Drug Administration to return later in the trial.)
The first 12 participants each received neural stem cell injections to the lumbar (lower back) region of the spine, with treatment being administered first to those who had lost the ability to walk and then to those who still were ambulatory. The trial then advanced to transplantation in the cervical (upper back) region of the spine. Three participants received injections in the cervical region only. The last three participants received injections in the cervical region in addition to the lumbar injections they had received earlier in the trial.
Glass noted that trial investigators were able to detect transplanted stem cells in the autopsies of six trial participants who had died (five of ALS progression and one of unrelated heart failure).
Results from the first six trial participants were published online May 15, 2012, in Stem Cells. (Readers can access the abstract at no charge; the full paper is available to those with a subscription.)
The next phase of the study has received funding from the National Institutes of Health and is awaiting FDA approval. In the phase 2 study, investigators will administer injections into the cervical spinal cord at increasing doses.
Timothy Lenglet from the Pitié-Salpêtrière Hospital in Paris, France, announced results from a phase 3 study of olesoxime in ALS, in which it was found that the drug was well-tolerated but did not increase survival.
Olesoxime, developed by Trophos, is a mitochondrial pore modulator, designed to promote the function and survival of the muscle-controlling nerve cells called motor neurons.
The double-blind, placebo-controlled trial evaluated the efficacy and safety of olesoxime against a placebo. In 512 people with ALS who were taking riluzole, a 330-milligram dose of olesoxime was taken one time per day.
After 18 months of treatment, olesoxime did not demonstrate significant benefit over riluzole on the primary goal of extending survival.
The study was conducted at 15 trial sites in Belgium, France, Germany, Spain and the United Kingdom, as part of a three-year collaborative project named Mito Target.
For more information, read Trophos announces results of phase 3 study of olesoxime in Amyotrophic Lateral Sclerosis.
Analysis that included data from three completed phase 2 clinical trials showed that the pharmacokinetic properties of tirasemtiv were not affected by the presence of riluzole (the only drug approved for the treatment of ALS by the FDA).
In addition, investigators found that riluzole levels are approximately doubled when taken with tirasemtiv. For example, one daily 50-milligram dose of riluzole taken with tirasemtiv resulted in about the same blood concentration level as two daily 50-milligram doses of riluzole taken alone.
Tirasemtiv (formerly CK-2017357) is being developed by biotech Cytokinetics for the treatment of ALS.
Across all three clinical trials, tirasemtiv appeared to produce positive effects on multiple functional measures, including maximum grip strength, handgrip fatigability, breathing function and ALSFRS-R scores. (The ALSFRS-R is a validated scale used to measure the functional capabilities of people with ALS.)
Jeremy Shefner from Upstate Medical University, State University of New York, who reported the results, said the data are "encouraging." (Shefner directs the MDA/ALS center at that institution, but MDA is not involved with this study.)