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Experimental ALS Drug Triggers Social Media Hype, But Doctors Say Facts about GM604 Are Slim

Fitzgerald, Susan

doi: 10.1097/
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ALS researchers and clinicians are skeptical about a push to expedite access and approval of an experimental drug, GM604, which has not been published in the scientific literature.

Company-generated reports that an investigational drug for amyotrophic lateral sclerosis (ALS) called GM604 could be a much-needed treatment breakthrough have caused a lot of excitement among patients and families, and even prompted an online petition to urge the Food and Drug Administration (FDA) to accelerate approval of the drug.

But many ALS researchers and clinicians are skeptical of the drug developer's claims, which are based on findings from a 12-person phase 2 trial that have not been published in the scientific literature. What little is known about GM604 comes from the website of the drug's developer, California-based Genervon Biopharmaceuticals (, which has been repeated and discussed on social media.

“The company has not presented any data in a peer-reviewed fashion that would warrant my endorsing their product for our ALS patients,” said Stanley H. Appel, MD, FAAN, director of Houston Methodist Neurological Institute, echoing the sentiments of several other ALS experts who spoke with Neurology Today about GM604.

Jeremy M. Shefner, MD, PhD, FAAN, a professor and chair of neurology and associate director of the Barrow Neurological Institute at the University of Arizona in Phoenix, said that when his patients eagerly inquire about GM604, he explains, “We don't have any data to suggest this is a useful drug.”

Experts say it is unclear what the drug's mechanism of action is, though Genervon describes its drug development process as focusing on “master regulators.” There's also a lack of clarity surrounding where GM604 stands in the regulatory process. In the spring, Genervon indicated that it had formally asked the FDA to put GM604 on the fast track to approval, noting that ALS patients alive today had no time to wait for lengthy, large-scale phase 3 testing to be done.

The FDA normally does not comment on the status of drugs going through the testing and approval process, but the agency took the unusual step of issuing a statement in April in an attempt to clarify confusion around GM604.

“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 said. “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.”

The agency said it “will continue to provide detailed advice and support to Genervon as they pursue further study of GM604 to determine if it is safe and effective to treat ALS.”

Genervon did not grant an interview to Neurology Today but did respond to some questions emailed to Dorothy Ko, its chief operating officer. The company said that contrary to some media reports, “Genervon never said it has submitted a NDA [new drug application]. We cannot because we need FDA to agree to our formal request for FDA to consider an accelerated approval pathway.”

When asked if Genervon had submitted phase 2 data to the FDA, Ko replied, “Yes, before the end of phase 2 meeting in February.”

The two principal investigators for the trial also declined to speak with Neurology Today. “I have a DCA [data confidentiality agreement], thus I cannot talk,” said Hiroshi Mitsumoto, MD, FAAN, the Wesley J. Howe professor of neurology and director of the Eleanor and Lou Gehrig MDA/ALS Research Center at Columbia University Medical Center, in an email.

Merit Cudkowiz, MD, chief of neurology at Massachusetts General Hospital and the Julieanne Dorn professor of neurology at Harvard Medical School, said she would be available to discuss the agent once results are published in a peer-reviewed paper.

Genervon, which describes GM604 as “one master regulator peptide drug that functions through multiple pathways,” says on its website that the drug was tested in 12 patients, who were given a six-dose treatment over two weeks. “The drug effects are measured by clinical outcome and biological effects as evidenced by biomarker changes,” the website states. “Both biomarker and clinical trial data in this 12 patient small trial showed dramatic effect in disease modification.”

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Dr. Shefner said the approach Genervon has taken — to release summaries of their research through web-based press releases and other statements — is unusual.

“As far as I can understand, this has never been presented in a public forum,” he said. “Every company I work with presents their results in scientific meetings as soon as it is possible to do so and they subject their data to public review.”

Dr. Shefner, who is the principal investigator for three multicenter ALS trials, said he can fully understand why ALS patients grab onto seemingly positive news. “ALS is a disease without an adequate treatment where the prognosis is dismal, and patients and their families and caregivers are desperate. As a community, we are all vulnerable to being overly hopeful and taking preliminary data that is expressed positively on face value.”

For patients, it must be “a terrible feeling to think there is something out there they can't have access to,” he said, adding, “I have also talked to patients who feel terribly manipulated” by what has unfolded with GM604.

Dr. Shefner noted that there have been previous instances of patients and advocates getting excited about early results for a potential treatment for ALS that didn't hold up in later testing. Lithium is a case in point, he said. Another example is pioglitazone, which looked promising in animal studies but not in human testing.

It's also important to have thorough vetting of drugs in clinical trials because deleterious effects may surface, Dr. Shefner added. When the anticonvulsant topiramate was tested for ALS in clinical trials, for instance, those who took the drug lost much more weight than those in the placebo group, he said.

“If we ever want to improve treatment for ALS, you have to do evaluations in a systematic way.”

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Jeffrey Rothstein, MD, PhD, a professor of neurology and neuroscience at Johns Hopkins University School of Medicine, said Genervon officials approached him about three years ago at a research conference to ask if he would be interested in conducting a phase 2 trial of GM604. He said he turned down the offer because the information they showed him was very thin and lacking a solid scientific rationale.

Dr. Rothstein said the Genervon officials characterized GM604 in a way that suggested there were “40 different pathways that the drug works on.” He said he was highly skeptical of this because most drugs being developed today target a specific pathway. Genervon has suggested that GM604 has a positive effect on a number of biomarkers, or one clearly relevant to ALS or neurodegeneration, but Dr. Rothstein, who is the director of the Robert Packard Center for ALS Research at Johns Hopkins, said that even if that were the case, proving a clinical response is a whole other level.

“Having a drug response marker — a pharmacodynamic marker — would be useful in the early drug discovery process, but would likely not have meaning for actual clinical efficacy,” he said.

The fact that the company has not done larger-scale testing of the drug or reported the findings at medical conferences or in peer-reviewed journals raises “red flags right and left,” he said.

It's understandable that ALS patients and their families would jump at any potentially good news, Dr. Rothstein said, because it has been more than 20 years since riluzole, the only FDA-approved drug for ALS, became available. Because “we live in this age of social media and communication,” he said, patients and their families can go online and quickly find websites, blogs, and patient forums with all kinds of information — some reliable, some not.

Dr. Rothstein said that while he tries to sort out fact from speculation for his patients, giving such advice could “sound like you're trying to slow progress down.”

To help provide some perspective to the debate over GM604, a group of ALS researchers, including Drs. Shefner and Rothstein and Terry Heiman-Patterson, MD, a professor of neurology at Drexel University College of Medicine, issued a public letter to the ALS community. They wrote: “We hear the rally to hasten GM604's approval; however, the clinical study is very small and short in duration, and like other studies of this size it is difficult to determine whether there would be any benefit to people with ALS if we were to repeat this in a larger study.”

Dr. Heiman-Patterson told Neurology Today that absent the release of the phase 2 data in a formal way, there is no way for scientists to evaluate the trial's methodology to determine if the findings were sound and further testing is warranted. She, too, has gleaned almost everything she knows about GM604 from the company's website. While she sees some scientific rationale for the drug, she is concerned that the heterogeneity of ALS mandates a large phase 3 trial to be certain of the drug effects. Small trials can be skewed depending on patient selection due to this variability in disease, she said.

“It's important to be certain that you do no harm and that you have a good drug that works,” said Dr. Heiman-Patterson, who is medical director for Drexel's MDA/ALS Center of Hope. “That's why we have the FDA. They are not the bad guys, and the scientific community is not the bad guys.”

A spokesperson for the FDA told Neurology Today: “While the FDA is supportive of patient access to experimental new treatments through expanded access (compassionate use) when appropriate, we believe that the drug approval process represents the best way to assure the development of and access to safe and effective new medicines for all patients.”

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•. GM604 Phase 2A Randomized Double-blind Placebo Controlled Pilot Trial in Amyotrophic Lateral Disease (ALS) (GALS):
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