The flimsy case for a miracle ALS drug collapses under expert scrutiny


Pioneer Founding member
Fierce Biotech
April 15, 2015 | By John Carroll

By his own account, Steve Perrin didn't spend much time considering the potential of a drug like GM604 after a low-profile biotech named Genervon--which has claimed biblical prophecy as an inspiration--announced the "data" it had collected in a study that recruited 12 patients with amyotrophic lateral sclerosis. After all, nothing's been published in any scientific journal since the top-line results were posted last fall. And the study was so tiny that Perrin, president and chief scientific officer of the ALS Therapy Development Institute, considered it nothing much more than a simple safety trial to prove the drug held no hidden dangers.

Given the varying ways that individual ALS patients progress, gradually growing paralyzed and dying in 3 to 5 years, he reasoned, the results from 8 patients after only 12 weeks of treatment, with four patients reserved for the placebo arm, couldn't provide a reliable look at efficacy.

But the biotech also touted the amazing story of one compassionate use patient who had made a remarkable personal improvement in swallowing capacity after he was given the drug and after the disease had made him a quadriplegic. And there was an equally amazing set of data provided to suggest a radical improvement in the decline of forced vital capacity, or FVC, among the patients in the drug arm.

According to Genervon, the FVC rate declined 5.6% among patients taking the drug, compared to a dramatic 22% decline for placebo.

The single case study, otherwise known as an anecdote, along with the "positive" FVC data, created the patient population's hallelujah moment.

Petitions followed, gathering more than 100,000 signatures, demanding that the FDA approve the drug now based on the results Genervon had promoted. Protests were mounted, with Genervon issuing releases in which it beat the drum for accelerated approval.

A few weeks ago, in a statement to "ALS patients and caregivers," the company ruled out a compassionate use program, adding that most of today's patients will be dead before Genervon can complete any late-stage study required by regulators.

"Even though the FDA has promised to help Genervon expedite the approval process for a Phase III trial, it would still take at least 3 years for GM604 to reach NDA," stated the company, which is run by Winston Ko. "This means the majority of this generation of ALS patients would not survive to try GM604."

The message came through loud and clear: If patients and their families want access to this drug, the FDA has to approve it immediately.

Driven by the massive popular outpouring of support for dying, desperate patients, a string of prestigious media outlets like the Washington Post and The Guardian published accounts that included both sides of the argument, without any examination of the data. The din grew louder after one ALS patient included a heartfelt plea in a column in the New York Times. Better to try something, anything, patients reasoned, than wait to die. And the dogs of war over access to experimental drugs were unleashed.

A skeptical Perrin, who has designed studies for ALS drugs and partnered with biotechs in the field, decided to take some time to scrutinize the results that are available, modeling the data to see how well it stands up against historical data for a much larger group. And there's even less than meets the eye after you consider some of the efficacy results being advertised as a basis for an accelerated approval.

In a blog post, Perrin notes that he turned to the public PRO-ACT database--which gathered 45,000 FVC measurements from 7,854 ALS subjects--to find a relevant group of patients that could be used to compare the efficacy of GM604. He ended up with data from 777 ALS patients covering a period of 70 to 120 days.

During that time there was a mean change from baseline of -4.33% in the rate of FVC--nothing even close to the figure that Genervon provided, and slightly better than the result the biotech provided for its drug.

"Based on the modeling demonstrated here from a very large patient cohort it does not appear plausible that the cohort of patients enrolled in the Genervon trial would represent a "normal" cohort of ALS patients," writes Perrin. "Therefore based on the model I continue to be very skeptical that there is any way that GM604 could have provided any therapeutic benefit in this small of a trial with this short of an exposure."

There are ways to explain the data, he adds. The results could have been collected improperly, though he doubts that. (The two investigators for this study, Hiroshi Mitsumoto and Merit Cudkowicz, work at at Columbia Medical Center and Mass General.) Fast-progressing patients could have been enrolled in the study, which would skew the results. Or maybe there was a problem with the way the patients were screened to make sure their FVC capacity was 65% or greater.

The FDA will only confirm that it provided orphan drug status for GM604, which is public record, declining to make any comment about Genervon's case, which is SOP at the agency.

Perrin, though, concludes emphatically that there's a lot more long-term safety and efficacy data that must be gathered before a drug like this can be considered for an approval. And in the meantime, he notes, patients and families should consider that anyone taking this drug would be excluded from a study of a potentially much more promising therapy (and there are several in the pipeline).

"A potential treatment," he concludes, "that might actually slow down disease in ALS."

-- John Carroll


New member
This story to me, indicates the current situation is quite insane...I myself haven't the slightest idea, how this crap can be really fixed....

Trying to imagine the plight of countless thousands of of terrified people, and then trying to really understand that I may very well be among them in one way or the other, in the near/far future, are actually rather terrifying to ME....



Pioneer Founding member
The FDA calls on Genervon to release data from controversial ALS study

Hopefully, anyone with ALS or anyone with a loved one that suffers from it, is keeping informed. Personally, with this disease that takes its toll so rapidly, I support any and all avenues that ALS patients want to explore, but the FDA is right in asking for this data.

Fierce Biotech
By John Carroll

Steve Perrin
Yesterday, FierceBiotech reported how an expert review of a tiny study for Genervon's ALS drug GM604 raised serious questions about the data that were provided by the company, which has aroused a furious campaign by ALS patients to gain an accelerated FDA approval. Today, in a rare break from the agency's standard "no comment" approach to experimental drugs, the agency called on the biotech to come clean and publicly release the actual results.

"We call upon Genervon to release all the data from their recently completed trial in order to allow a more informed discussion of the trial findings among ALS stakeholders," the FDA, noting the ALS community's interest, says in its statement. "Such a release should include the pre-specified clinical outcome measures as assessed by change from baseline observations that were taken just prior to randomization to drug or placebo. Such data provide the strongest basis to assess for drug-related changes in efficacy and safety parameters."

That's a remarkable position for an agency that abides by strict rules when it comes to the way it handles data, leaving it to biotechs to handle the talking points. A spokesperson for the agency noted that they had seen the Perrin piece, but said that today's statement had been in the works "to address the ongoing questions we've received about that drug from many people, including patients, families, media, etc."

FierceBiotech has followed up by asking Genervon CEO Winston Ko a simple question: Has the company actually filed a new drug application--which would be necessary for any kind of approval, accelerated or otherwise, that it's been demanding--and how has the FDA responded? If an NDA was filed, then the agency would have had a chance to see if the application was acceptable for review, or not.

There was no immediate response from the company, which is based in Pasadena, CA, and has cited biblical prophecy as an inspiration for its work.

FierceBiotech also contacted the two investigators for this study, Hiroshi Mitsumoto at Columbia University Medical Center and Merit Cudkowicz at Mass General, but has not yet received a response. Mitsumoto has not returned numerous messages in recent days.

Genervon's tiny 12-person study, with four people assigned to a placebo arm, assessed the drug's performance on several biomarkers for the disease, which would not be sufficient to gain an accelerated approval. But it also assessed an impact on ALSFRS-R rates and forced vital capacity, or FVC, among the patients. Genervon has not publicly revealed the ALSFRS-R data, which should reflect a specific change from baseline in patient performance. It did discuss, with considerable fanfare, what the biotech claimed was a major improvement in the rate of decline for FVC compared to placebo as well as one remarkable case in which a compassionate use patient experienced a rebound from the disease.

Reviewing the FVC data, Steve Perrin, president and chief scientific officer of the ALS Therapy Development Institute and an early skeptic of this drug, says the data didn't hold up on a review of a public database including hundreds of ALS patient experiences that could be used as a comparison measure. In that comparison, Genervon's drug arm actually performed slightly worse than the database average. There was no big improvement for patients taking GM604, says Perrin, raising questions about the way in which the data were collected, the patients were screened and selected for this study, and its importance to the ALS community.

"Based on the modeling demonstrated here from a very large patient cohort it does not appear plausible that the cohort of patients enrolled in the Genervon trial would represent a 'normal' cohort of ALS patients," Perrin noted. "Therefore based on the model I continue to be very skeptical that there is any way that GM604 could have provided any therapeutic benefit in this small of a trial with this short of an exposure."

While patients often say that this drug represents their only hope, Perrin has been quick to point out that there are a number of ALS drugs in the clinic. And if the patient campaign were to succeed, patients taking the drug would be excluded from trials for a drug that might actually work.

Here's the FDA's statement: