There has been a lot of recent controversy surrounding the experimental treatment in clinical trials known as GM604. A lot of misinformation has been tossed around on both sides of the issue. I want to beg your attention for a little while to explain what’s really going on.
First, as many of you know, I was the single late-stage PALS who received GM6 in compassionate use. The intent behind this was to get a look at differences in biomarker candidate levels between earlier-stage and late-stage PALS. Any outward physical manifestation of improved condition noticed would be a bonus and, due to my advanced condition, no improvement in condition was expected. Nevertheless, Genervon and I came up with the idea to try to chart improvements in the tongue. The rationale is that since my tongue is only moderately affected, and because the hypoglossal nerve contains one of the shortest motor neurons in the body, any possible improvement would be noticed there first.
Because of my growing cooperative relationship with Genervon dating back to my first blog post on GM6, I was granted the only Expanded Access outside of trial. They were interested in getting a look at GM6 behavior in late-stage PALS and I had proven to them my organizational skills in preparing my own medical surveillance team and in communications by preparing the mechanism for data capture. Even a single Expanded Access Program can be a burden on such a small company not optimized for such work. My knowledge and experience gained over the past few years was of considerable help in filling out and transmitting (and following up on) my own paperwork.
Thousands of single Expanded Access requests would be overly burdensome and even if Genervon enlisted the help of the ALS Emergency Treatment Fund, the maximum number of patients who would be able to participate would be measured in the few hundreds. Not only would patients have to pay for drug but would also have to pay for their own medical surveillance team and at least one hospital visit for the first infusion (this alone represents several thousand dollars). If you are required to give biological samples, the cost tops $10,000.
Genervon shared with me much of the top-level data from the Phase 2 to compare against my own data. Even though the trial population was small, the data were stronger in separation between treatment/placebo cohorts than in any legitimate trial results I had seen before. And GM6 was demonstrated safe over a much larger group spread over three different neurological diseases (including ALS) plus a healthy safety group. For these reasons I suggested to and worked with Genervon on applying for the FDA Accelerated Approval Program in order to get GM6 to all PALS paid for by insurance and Medicare.
And thus began the shitstorm…
Researchers, neurologists, and leaders of certain advocacy organizations who believe in the FDA’s 60 year old regulatory formula – comprised of designing, completing, and analyzing Phase 1, 2, 3 trials over a period of 5-15 years – are failing in their proclaimed mission. They simply have to stop regarding patients as helpless victims willing to eat rat poison if someone said it cured ALS, Genervon as somehow the 19th Century snake oil salesman, and themselves as the White Knight riding to our rescue. The very process of obtaining an experimental drug requires a lot of medical oversight, which we appreciate and rely on. However, patients are intelligent adults whose only desire is to change the status quo of scientific research for the benefit of both the current and future generations of PALS.
The 1992 FDA Accelerated Approval Program (AAP) was designed to meet the needs of patient populations where there is an urgent and unmet need. In 2012, Congress passed and the President signed into law the Food and Drug Administration Safety and Innovation Act (FDASIA), strengthening the agency’s ability to advance public health by equipping the FDA with tools intended to expedite the development and review of innovative new medicines that address certain unmet medical needs. Among the objectives, Title IX expanded the scope of products that qualify for accelerated approval. Specific language in this law states that the FDA is to incorporate novel approaches to the review of surrogate endpoints based on pathophysiologic and pharmacologic evidence in such guidance, especially in instances where the low prevalence of a disease renders the existence or collection of other types of data unlikely or impractical. It is obvious that Congress and the President had in mind diseases just like ALS when passing and signing FDASIA into law, yet the FDA has done very little to incorporate these guidelines.
With Congress now discussing the 21st Century Cures Act, we at Hope Now for ALS believe that we are on the right side of history by insisting that PALS are given opportunities to access new investigational treatments through the FDA’s Accelerated Approval Program which, with its requirement for post-marketing Phase 4 data surveillance to confirm efficacy and safety, will continue to provide invaluable data on new treatments for ALS. As most patients are ineligible for standard clinical trials, this is our only option to contribute to research that will provide the same data at a faster rate among a larger population of patients – providing much needed data on subsets of the patient population. The Phase 4 requirements of Accelerated Approval also have the ability to save billions of dollars in research that is better spent developing more new and better investigational treatments for a myriad of neurological conditions.
I will grant that the biomarker candidates are new and not yet “proven”, but FDA did allow them as endpoints in the Phase 2. They are not brand-new fabrications by Genervon and are backed by a lot of recent research by respected researchers. And they were all quite uniform in response to GM6 while the placebo group all continued in the abnormal direction. In my n=1 case report the biomarker candidates sometimes went in the reverse direction, but ALWAYS TOWARD NORMAL LEVELS. This is a great indication that GM6 promotes neuronal homeostasis – the holy grail for ALS research.
The Phase 2 was indeed also only a very small population, and in previous ALS trials of similar size it was impossible to collect reliable efficacy data in such a small cohort. However, this trial was very different from previous trials. The effect registered was much larger than in previous such trials (especially dexpramipexole) and was backed up by multiple secondary measurements not subject to any placebo effect. The combination of surprisingly-large effect size and objective biological markers sets this aside from previous trials (which also used the ALSFRS almost exclusively). There was an erroneous though well-intentioned attempt to use the released FVC information as evidence of poor trial design. However, the comparison used a very inappropriate analogy population and was built on an assumption based on incorrect data.
I do have serious issues with a point used in arguments against GM6: The lithium debacle. The media reports which came out obviously created a lot of excitement within the patient community. Our first reaction was asking and pleading the research community to quickly follow up with more trials to confirm that study and the response from the research committee was absolute disinterest. Therefore the patient community took it upon themselves to create a verification study, which we did. We did *NOT* merely go out and start using lithium off-label. In fact, it was only after our trial data was being released that the research community decided to do a confirmation study. By then we had already demonstrated that lithium had no effect in ALS and begged the research community to not waste time and millions of dollars.
But again, the research community ignored the patient community.
The Hope Now for ALS movement isn’t for GM6 to skip the regulatory process. It’s to get FDA to use its existing programs and Congressional mandate to provide potentially life-saving treatment to PALS. This is especially important now that truly-effective treatments are very near (including NP001, Neurown, etc.). Caution is obviously warranted but ALS is a race against a clock that doesn’t care. More aggressive strategy is thus required which necessitates a little less caution and a lot more courage.
In summary, the facts are:
- Genervon asked FDA for Accelerated Approval at the post-Phase 2 meeting where they presented the complete trial data plus the case report for my Compassionate Use project. I know this to be true because I co-wrote the cover letter to the data package and it specifically asked for Accelerated Approval (and it was me who urged Genervon to pursue AAP).
- The FDA should have responded with specific instructions on how to file. They did not and thus we were all left in a state of confusion. Then FDA took the unusual step of calling on Genervon to publicly release proprietary data. Genervon has no duty to do so and FDA has no authority to make such a request.
- Genervon has perfectly complied with law and regulation. All they want is to help and they believe GM6 can do that. The data so far looks good (and I can say that, having actually seen it where all others commenting otherwise have not). It’s not a slam-dunk, but it’s positive and safe enough that I think all PALS should have access to it – not just those eligible for clinical trial.
- The FDA Accelerated Approval Program, in place since 1992 to deal with fatal diseases for which no other treatments exist, is the best way to save lives. It opens access WHILE CLINICAL TRIALS STILL CONTINUE. It’s used for cancer and other diseases with less-severe prognosis. Why not ALS?
- GM6 has a perfect safety record in over 50 patients across 3 separate neurological conditions plus a healthy initial safety cohort.
- This is about patients deciding for themselves what risk to take in treatment. This is NOT about a company trying to avoid the clinical trial process or enrich itself on patients desperation. The AAP is an existing program which gives patients access to potentially life-saving treatment while collecting the valuable efficacy data.
- Contrast Genervon’s completely legal and transparent actions to other companies marketing unproven products such as lunasin and aimspro directly to patients using email. Those companies use slick pitches with “proof” based purely on non-accepted metrics and anecdotes.
- The movement behind GM6 is entirely grassroots.
The above are facts. All of the “expert opinion” going around is just biased speculation.