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Antisense Therapy for ALS Found Safe in Small Trial, but More Safety Data Are Sought

Robinson, Richard

doi: 10.1097/01.NT.0000415803.26705.54
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An antisense oligonucleotide tailored to target part of the messenger RNA of superoxide dismutase 1 (SOD1) was found safe in a small trial involving 21 patients with amyotrophic lateral sclerosis (ALS), but the investigators contend they need to do more long-term experiments in animal models of ALS before moving forward.

NEW ORLEANS—Antisense oligonucleotide therapy for ALS took a big first step forward with the release of safety results from a single-dose trial in a small group of patients. But the road ahead is longer still, with no new trial expected for at least 18 months, as the manufacturer and research team conduct more safety testing and contemplate redesigning the therapeutic molecule.

The antisense oligonucleotide was tailored to target part of the messenger RNA of superoxide dismutase 1 (SOD1), the mutation responsible for about 13 percent of familial ALS, or about 1 percent of all ALS cases. Binding of the antisense molecule to the SOD1 mRNA causes cellular defense machinery to destroy the mRNA, preventing production of the SOD1 protein. Testing in animal models of ALS has shown the strategy to improve survival even after onset of symptoms.

The trial, which was led by Timothy Miller, MD, PhD, assistant professor of neurology at Washington University in Saint Louis, and Merit Cudkowicz, MD, professor of neurology at Harvard Medical School in Boston, was supported by Isis Pharmaceuticals of Carlsbad, CA.

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The trial enrolled 21 patients, with a wide range of ages, time since diagnosis, and SOD1 mutations. Enrollment was difficult, Dr. Miller reported in a platform presentation here at the AAN annual meeting, since there are so few SOD1-positive ALS patients in the United States — perhaps no more than 150, he said. Patients were randomized into one of three ascending-dose cohorts and received either active treatment or placebo (3:1); some patients elected to enroll in a second cohort as well. The treatment was infused into the intrathecal space over 11.5 hours, with patients remaining in the hospital for up to 48 hours.

This was a safety trial, and in that respect, it was a “huge success,” Dr. Miller said. Adverse events were mild and not related to the dose. The most common and significant events were nausea, vomiting, and back pain, typical of lumbar puncture. Scores on the ALS Functional Rating Scale changed “only in those patients who were progressing rapidly. In other words, if it was changing when you came into the trial, it also changed during the trial.” In the few patients who received a second dose, no new safety issues emerged.

The other important and heartening result was an alignment between the pharmacokinetics (PK) observed in animal models and that seen in the patients, Dr. Miller reported. “The PK was a major concern in our discussions with the FDA, since this kind of drug has never before been delivered to the CSF,” he said. There was a dose-dependent increase in the molecule in plasma, at levels very close to what the team had predicted. “In the pharmacokinetics world, this is considered spot on.”

There was no expectation that the single treatment would have an effect on the progression of the disease, and the trial was not designed to test the efficacy of the drug to lower SOD protein. CSF samples were collected before administering the second dose in those patients who received it, and these will be analyzed, “but based on the small amount of drug given, we would not anticipate a change in SOD levels,” Dr. Miller said. Autopsy tissue is available from one patient, and this too will be analyzed.

But long-term treatment will be needed if antisense therapy is to provide any benefit, and that means more toxicology testing in animals, probably stretching out for another year. “We want to move as quickly as possible, but also as safely as possible,” he said. At the same time, the research team has begun to re-evaluate whether the current oligonucleotide can be redesigned to better target SOD1 and reduce the risk of inflammation, an effect not seen in this trial but observed in long-term, high-dose treatment in animals. “Taking all that into consideration, I think it will be 18 to 24 months before we are ready for the next SOD1 clinical trial,” Dr. Miller said.

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“I think these results are very helpful in determining how to go forward,” commented Benjamin Brooks, MD, director of the Carolinas Neuromuscular ALS/MDA Center in Charlotte, NC. The researchers accomplished their goal, he said, but now need to show the drug is safe over the longer term.

The same view was shared by Jeremy Shefner, MD, PhD, chair of Neurology at State University of New York Upstate Medical University in Syracuse. “The trial achieved its goal, and the treatment showed itself to be safe with a single administration. Based on the presentation, whether it is going to go forward, depends on the long-term toxicology, and whether they can find a compound that has a greater knockdown potential for SOD protein. It gets you to the next stage, if you choose to go there. But it doesn't mean a lot right now, because I think they are years away from the next study.”

Furthermore, he said, “At the moment, it is a potential therapy for a small number of patients. It isn't going to be a blockbuster for most patients, no matter how it comes out,” since it is meant for those patients with SOD1 mutations only.

Some limited research suggests that normal SOD protein may play a role in sporadic ALS; if that turns out to be the case, and if antisense treatment can reduce the protein, and if that reduction is therapeutic, there would be a rationale for treating a much larger number of ALS patients. “That's worth taking a look at,” but the evidence is not there yet, Dr. Shefner said. The antisense molecule in the current trial targets part of the gene that is not mutated, and so, in that scenario, it may be useful in patients with non-SOD1 ALS.

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In an interview with Neurology Today, Dr. Miller stressed that the entire research team, including those at Isis, the pharmaceutical company who manufactures the drug, remain highly committed to moving this treatment ahead. “We've learned a great deal about how to make antisense oligonucleotides against particular targets in the last several years, and there is an opportunity to capitalize on all of that increase in knowledge, and so to do that we will also take a little more time in jumping back in. But the results from this trial will greatly enable the next trial.” That trial is not likely to be a repeat of the current one, he said, even if the molecule is changed, but instead will likely use higher doses over longer times.

In addition, he noted, the safety demonstration in this trial is likely to speed development of the same strategy in other inherited neurodegenerative diseases in which reduction of mRNA may be therapeutic, such as Huntington's disease.

“We are already moving forward on screening thousands of oligos already,” to determine if there is a sequence that may better target SOD1 mRNA, Dr. Miller said. “We understand this a long time to wait, and we appreciate the tremendous commitment already from the SOD1 ALS community.”

Watch here as Neurology Today Editor-in-chief Steven Ringel, MD, and Associate Editor Robert Holloway, MD, discuss the promise and challenges ahead for antisense oligonucleotide therapy for ALS:

©2012 American Academy of Neurology