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Hopes -- And Questions -- Are Raised By Study Of French Biotech's ALS Drug

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ALS, Lou Gehrig's Disease


A new drug developed by a small French biotechnology company appears to slow amyotrophic lateral sclerosis, or ALS, by 27%, providing another new weapon against the deadly neurodegenerative disease, two weeks after the U.S. Food and Drug Administration approved the first new medicine for the disease in 22 years.

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A new drug developed by a small French biotechnology company appears to slow amyotrophic lateral sclerosis, or ALS, by 27%, providing another new weapon against the deadly neurodegenerative disease, two weeks after the U.S. Food and Drug Administration approved the first new medicine for the disease in 22 years. “This looks like another positive result for the ALS community,” says Nathan Staff, an ALS expert at the Mayo Clinic.

If only the story could stay that simple. The company, AB Science, has a spotty track record and recently announced that French regulators are auditing its past studies to see if they conformed with “good clinical practice.” And many researchers shown the new data by Forbes or AB Science say that while they are encouraged by the result, they believe another study will be needed to be certain the new medicine, masitinib, is really slowing the disease. (AB Science shared the data with me; it will presented at the ENCALS meeting in Slovenia today.)

Jeremy Shefner, chair of the department of neurology at the Barrow Institute in Phoenix, was more skeptical. “I think any study of this size that shows an effect between treatment and placebo is hopeful,” says Jeremy Shefner, the chair of neurology at the Barrow Institute and Phoenix and the biggest skeptic I talked to. He expressed concern about “internal inconsistencies” in the data. “I do have serious reservations about several parts of the study,” he said.

AB Science is already in the process of starting another clinical trial to try prove masitinib’s benefit in ALS. The big question is whether regulators in Europe, where AB Science has already filed for conditional approval, or the U.S. will allow the drug to be sold even before those data are in. The issues neurologists raised about the study are could be a particular problem at the U.S. Food and Drug Administration, which re-analyzes clinical trial data with a fine-toothed comb.

Here’s what the data show: patients who received masitinib at a dose of 4.5 milligrams per kilogram per day scored 3.4 points higher on the ALSFRS, the 48-point scale used to measure the severity of the disease, at the end of 48 weeks. Results for a 3.0 milligram per kilogram per day dose were numerically higher, but not statistically significant.

Those results, however, only applied to a subset of the 420 patients in the study. At the beginning of the study, researchers separated out the 64 patients who were losing 1.1 ALSFRS point per month. The study’s main analysis doesn’t include those patients. When the fast progressors are included, the benefit is no longer statistically significant.

ALS experts unanimously said making such a division was the right thing to do. But they worried about the details.

“The illness is so widely different between people,” says Merit Cudkowicz, director of the ALS Clinic at Massachusetts General Hospital, who also said she wanted to see additional clinical data. “You have people like Stephen Hawking who have 50 years [to live] and you have people who have six months. I think it’s okay to try to get a more homogenous group to make your primary assessment on.”

But AB Science will not present an analysis of the fast progressors on their own. Shefner worries that the placebo group may have ended up with sicker patients than it was supposed to. “I am concerned that the progression rate of the placebo group is higher than one would expect, and higher than would be predicted based on either way of predicting the pre-study rate of progression,” he says. That could make the drug look better, by comparison.

Erik Pioro of the Cleveland Clinic and Cudkowicz both say they would have also expected to see a bigger benefit in the faster-progressing patients, not to see the benefit disappear. AB Science speculates that the faster-progressing patients may have disease that is biologically different, and that masitinib may not work as well on. “Fast progressors are almost their own entity,” argues Angela Genge, director of the ALS clinic at Montreal Neurological Institute, and one of the researchers who will conduct AB Science’s next study of masitinib. “No matter what you throw at them you can’t get ahead of the disease.” Genge thinks the result is “a very strong result for an ALS study” but also says that “it requires a confirmatory study.”

Alain Moussy, the chief executive of AB Science, argues that the company’s data was actually made worse because it didn’t exclude another group: the slow-progressing patients (again, think of physicist Stephen Hawking) were still included in the study, and if they are excluded, he says the effect would have been bigger.

Another concern: Only 66% of the normal progressor patients in the placebo group, and 65% of those in the 4.5 mg group, stayed on drug for the entire 48 weeks of the study.

But Moussy has a single, strong argument for masitinib's chances of FDA approval: the approval two weeks ago of Radicava, the new ALS drug from Mitsubishi Tanabe Pharma, a Japanese firm. That drug failed in a broad population of patients, but seemed to have a benefit in those who were newly diagnosed. Moussy argues that the situations are similar. For Radicava, the FDA even took the unusual step of waiving that any studies be done in the U.S.

There is an important difference: a hypothesis was generated about Radicava in one study, and then confirmed by a second. AB Science only has a single study. “I think those studies were thoughtfully designed and the confirmatory study built on a hypothesis generated by the prior study,” Shefner says. “I think there is a significant difference in the level of evidence between the two drugs at this point.”

Still, European and U.S. regulators have both shown more willingness to approve drugs for deadly diseases like ALS on less thorough studies, with follow-up to be done later. But, particularly in the U.S., an approval will probably involve analyzing and re-analyzing the data to see if it remains convincing. Nathan Staff at the Mayo Clinic points out another advantage Radacava had: the drug had been used in Japan for more than a decade for stroke, and was very safe, whereas masitinib is still new but has had safety issues in other studies.

To ALS doctors, the big story remains that, after years where nothing worked, real progress is happening. What, they wonder, if they can combine Radacava and masitinib? Would that slow decline even more?

“I’m really anxious to do the confirmatory study,” says Montreal’s Genge. “There is a real reason for our enthusiasm because of what we see in our preclinical models. The science behind this is actually very strong. The mice and rats and all these guys, their results are quite strong and what they’re seeing really makes sense.”

“I’m excited,” says Mass. General’s Cudkowicz. “I think it’s potentially another drug with positive results for people in ALS. And it works by a completely new mechanism of action. And if it’s real, it opens up all these other drugs that are out there.”

She added: “The worst thing we can do in ALS is throw out a drug that might be positive.”


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