FDA Controversy Over ALS Drug Trial Highlights Urgent Need For Further Research

In a highly unusual move, last Friday the U.S. Food and Drug Administration (FDA) issued a statement calling on pharmaceutical firm Genervon to release all data pertaining to a recent small study involving the company’s ALS drug candidate GM604.

In its statement, the FDA affirms that it recognizes the critical unmet medical need for new, effective treatments for amyotrophic lateral sclerosis (ALS), and its commitment to working with drug companies and the ALS community to facilitate development and approval of drugs designed to treat this devastating disease. The FDA says it is prepared to utilize all expedited development and approval pathways available to the agency toward furthering this mutual goal.

The FDA also acknowledges that ALS patients, their families, and others in the ALS community are concerned about the status of Genervon’s experimental drug GM604 for the treatment of ALS, and that it is prohibited by law, under usual circumstances, from releasing confidential information about experimental drugs, including GM604.

Consequently, the federal regulator says it is calling upon Genervon to release “all” data from the company’s recently completed trial in order to permit and facilitate better-informed discussion of the trial findings among ALS stakeholders. The FDA says such a release should include the pre-specified clinical outcome measures as assessed by observed changes from baseline observations taken immediately prior to random assignment of drug or placebo to trial participants, noting that such data provide the strongest basis to assess for drug-related changes in efficacy and safety parameters.

The FDA says 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.

In a TranslateALS blog, ALS Therapy Development Institute president and chief scientific officer Steve Perrin delivered a scathingly skeptical critique of a recent Genervon press release, noting that their trial was only of 12 patients and 12 weeks of exposure to GM604, which in his estimation would make such a study just the first check box in the long and arduous process of testing to determine if a drug is safe and provides any measurable benefit to ALS patients, and that in Genervon’s trial, too few people were enrolled for scientific evaluation of whether the drug is helpful or harmful.

Nevertheless, Perrin notes that the ALS patient community latched on to the Genervon trial announcement, focusing on the seemingly amazing results of the Phase IIA safety trial as well as a subsequent single patient compassionate use trial conducted by Genervon, with many becoming convinced that GM604 should receive fast track approval by the FDA for all ALS patients. He reports that hundreds of thousands of people have signed a petition launched by ALS patient Nicholas Grillo appealing to the FDA for accelerated approval of GM604 for all ALS patients based on the data from the 12 patients in the phase II safety study. He goes on to cite criticisms of the methodology applied in the trial.

On April 20, Genervon’s Chief Operating Officer Dorothy Ko issued a sharply-worded riposte to Steve Perrin’s blog post, pointing out what she alleges to be shortcomings in the blog critique, and suggesting that Perrin had “made deliberate effort to use wrong assumptions to perform his confusing analysis” that she finds “misleading and puzzling.” The release goes on to expand on the results of Genervon’s Phase 2A trial data analysis.

As for the FDA statement requesting public release of additional data from Genervon’s clinical investigations of GM604, Ms. Ko says Genervon is reviewing that request, that Genervon has submitted all raw data, analysis and reports to FDA, and that the FDA has already approved Biomarker as the primary end point of the Phase 2A trial.

She says Genervon is trying to understand what the FDA is getting at in its unique request, and affirming the importance for all ALS patients, ALS researchers, competitors and stakeholders (all of whom except patients have the duty to provide full disclosure in order to avoid any possible conflict of interest) to learn about what she describes as “the innovative and advanced science of GM604.”

She notes that in an April 13,2015 press release entitled “GM604 in a Nutshell,” Genervon linked to a layman’s version of the science behind GM604, and suggests that interested parties carefully read that document before making any comments, and at least get the basic facts right. The full text of that release can be found in the Appendix at the end of this report, but Ms. Ko emphasizes three summary points in particular:

1. To date, this innovative paradigm has resulted in the ownership of 66 patents by Genervon. Genervon would rather have their data subject to the detailed and repeated reviews from the scientific examiners from all the patent offices around the world and from FDA. The US scientific community has not been receptive to our 20 years old innovative hypothesis. Genervon has received both Fast Track and Orphan Drug designations from FDA for GM604 in the treatment of ALS.

2. Phase 2A trials are not powered to find statistical significance between the treated and placebo groups, unless the effect size of the drug candidate is very large and powerful. When comparing ALS patient receiving GM604 and placebo in our Phase 2A trial, the GM604 treated group achieved statistical significance not only in FVC clinical data but also in three well known ALS biomarkers. Such extraordinary efficacy across two data systems and four matrices with the same patients in the same trial gave Genervon the human evidence it has seen in the pre-clinical data over the last 15 years. That is why Genervon is confident to ask FDA for Accelerated Approval pathway (AAP). See Genervon 12 Scientific Reports: https://www.genervon.com/genervon/medicines_trialdata.php

3. Through AAP, the FDA can get the large population data they could never get from Phase 3 trials while at the same time today’s 30,000 ALS patients in the US will have access to treatment options. It takes a lot more courage for Genervon to allow GM604 to be exposed to a full spectrum of heterogeneous ALS patients through AAP with Phase 4 surveillance requirements than pursuing the much safer route of a very narrowly defined, controllable, small number of ALS patients in a Phase 3 trial. “It is a more secure and conservative approach to go through the traditional phase 3 trial and then apply for a New Drug Application. We do not think that people really understand the sacrifice Genervon is making to try and save the lives of 30,000 US ALS patients alone.”

It’s to early to determine how the dust will settle in this extraordinary controversy, and it would be prudent to withhold judgment until more is known through additional research. An ALS News Today report in February cited Muscular Dystrophy Association (MDA) scientific program director Grace Pavlath commenting on the Genervon studies that “Although both trials were short and had few patients, demanding further studies by researchers, the ALS community is waiting for the FDAs approval of GM604, any hint of efficacy in ALS is worth pursuing, and we hope that Genervon will continue to test this drug in larger and longer clinical studies.”

In the meantime, and acknowledging the urgency that obtains with regard to ALS, which the FDA acknowledges in its statement, in evaluating treatments and medicines for ALS, science demands that scientific process be followed to establish the effectiveness and safety of new drugs like GM604. However, it would be reasonable to suggest that the FDA’s compassionate use protocols in this instance be interpreted as broadly as possible, and that avenue opened to whatever extent is possible for any ALS patients making informed decisions regarding the drug’s experimental and unproven status.

Sources:
U.S. Food and Drug Administration
TranslateALS
Genervon Biopharmaceuticals LLC

Appendix:

Below is the full text of Genervon’s April 13, 2015 “GM604 in a Nutshell” press release: “The layman version of the advance and innovative science summary of GM604.”

While many ALS patients wrote to Genervon apologizing for not having the energy to read or the ability to understand the science of GM604, Genervon should be the one who apologizes for not expressing the innovative science in layman terms. We would like to do so now so everyone can more easily separate fact from fiction.

It is important for all to know the science of GM604 because recently some individuals in the general and trade press including researchers, with impunity to their conflict of interest, commented on Genervon and GM604 in a couple news articles that have worried some ALS patients. Quoting one microbiologist patient: “I have great hope for your neurotrophine drug but I am deeply concerned about the recent article in the XXX. If their intent was to discredit you, they did an excellent job. I know you are fighting the established ALS research community.”

History: ALS is a rare and the most debilitating neurological disease. The average life expectancy of an ALS patient is 2-5 years. There is no curative drug for ALS in its 160 years of recorded history. Over the last 50 years, more than 160 ALS clinical trials by over 60 companies have failed except riluzole which is not curative with modest effect of increase survival by a few months but no effect of quality of life.

Genervon: In the 1990s, Genervon realized that the 100% failures of all curative ALS clinical trials can be attributed to the fact that the traditional drug development model — designing single-target drugs — simply cannot target the multiple factors of complex diseases like ALS. We were quite sure that no one had the knowledge to design a multi-target neural drug. We decided to look for the regulators the Creator has put into every human embryo. Thus Genervon’s innovative drug development strategy was to find the substances that naturally occur(endogenous) within each human embryo that control the development and function of the nervous system and ultimately restore the natural internal stability and health(homeostasis) to the human body. Genervon did not use or destroy any human embryo during its discovery, research and manufacturing of GM604.

To date, this approach has resulted in the ownership of 66 patents by Genervon. Genervon would rather have their data subject to the detailed and repeated reviews from the scientific examiners from all the patent offices around the world. The US scientific community has not been receptive to our 20 years old innovative hypothesis. Genervon has received both Fast Track and Orphan Drug designations from FDA for GM604 in the treatment of ALS.

Pre-clinical and Phase 1 trials: In 2013 we started the Phase 2 trials of GM6 for Ischemic Stroke, ALS and Parkinson’s disease. This was after almost 20 years of research, discoveries, drug development, in vitro and in vivo experiments of validation and confirmation, and a Phase 1 trial for safety in human subjects.

Phase 2a trials: The randomized and placebo controlled trial was designed to determine whether a six-dose treatment of the curative ALS drug candidate GM604 in two weeks will start the ALS disease modification process. The results are measured from screening/baseline to multiple time points within 12 weeks or after cessation of dosing for 10 weeks. The drug effects are measured by clinical outcome and biological effects as evidenced by biomarker changes. Both biomarker and clinical data in this 12 patients small trials showed dramatic effect in disease modification.

The positive results of clinical trials are determined by achieving what researchers call “statistical significance” between the treated and placebo groups. This means we proved there was a very strong relationship between GM604 and the improvements seen in the traditional “clinical data” and the advanced “biomarker data” of the trial patients. Results of ALS Phase 2a clinical trial with detailed data were posted on October 19, 2014 on Genervon’s website:
https://www.genervon.com/genervon/about_pressreleases.php

Clinical data #1: GM604 reduced the decline in ALL patients forced vital capacity (FVC) at both sites from screening to week 12 with statistical significance favoring GM604 treated group.FVC change from screening, p=0.0476. FVC % change from screening, p=0.0359. Any P value smaller that 0.05 is very or extremely significant. See detail data in March 21, 2015 posting:
https://www.genervon.com/genervon/about_pressreleases.php

Clinical data #2: In a comparison between the treated and placebo groups of definite ALS patients in the trial with regards to disease progression before and after the start of treatment, the GM604 treated group progressed slower when compared to before treatment administration. GM604 in Phase 2a ALS trial achieved a positive trend of slowing down disease progression as measured by ALSFRS-R slope. GM604 in Phase 2a ALS trial achieved a positive trend of slowing down disease progression. A further analysis as specified in the FDA approved protocol by using historical data (placebo control in the Ceftriaxone trial) in ALSFRS-R for definite ALS patients as the placebo data to compare with GM604 treated patient was performed and such comparison showed statistical significance, p=0.0047.

Biomarker data #1-3: A biological marker or “biomarker” is a natural substance found in the body whose presence indicates a phenomenon such as disease, infection, or environmental exposure. GM604 also achieved in the same trial statistical significance and strong trend in decreasing the expressions between the treated and placebo groups of ALS patients across 3 matrices of the same patients: TDP43 (p=0.0078), Tau (p=0.0369) and SOD1 (p=0.055). The Parkinson’s disease (PD) trial biomarker BDNF achieved statistical significant increase by GM608, p=0.035.

Excessive TDP43 and Tau are very harmful proteins found in the brains of ALS and Alzheimer patients. The private video link of a GM604 treated patient and the high science of TDP43 will be available upon request by emailing to [email protected]

Phase 2a with 12 patients: Phase 2 trials are held for safety and efficacy seeking some signs of positive trend. Phase 2 trials are not powered to find statistical significance between the treated and placebo groups, unless the effect size of the drug candidate is very powerful. When comparing ALS patient receiving GM604 and placebo in our Phase 2a trial, the GM604 treated group achieved statistical significance not only in FVC clinical data but also in not one but three well known ALS biomarkers. Such extraordinary efficacy across two data systems and four matrices with the same patients in the same trial gave Genervon the human evidence it has seen in the pre-clinical data over the last 15 years. That is why Genervon is confident to ask FDA for AA marketing approval. See Genervon 12 Scientific Report:
https://www.genervon.com/genervon/medicines_trialdata.php

Very advanced ALS patient: As we predicted, the single, very advanced ALS patient who was treated with GM604, with the approval of the FDA through compassionate use had biomarker values below the normal range before treatment. GM604 increased the expression of SOD1, Tau and Cystatin C from the baseline data. The importance of this data is that it showed that GM604 can modify the same biomarkers in both directions. Within 2-years of disease onset ALS patients in phase 2A trial have those biomarkers above the normal range and they were lowered by GM604. This is the hallmark of health for a living organism to seek the tendency of the correct balance.

Safety: GM604 is a 6-amino acid endogenous peptide (a natural small molecule found in the human body that consists of two or more amino acids). It is very safe and tolerable in the human body as shown in Phase 1 (32 subjects), ALS Phase 2A (12 subjects), Parkinson’s disease Phase 2A (6 subjects), and Ischemic Stroke (28 of 36 subjects, not yet un-blinded). That is a total of 78 patients that have tried GM604 for different illnesses. Those who claim GM604 was only given to 12 patients are misleading others. Any adverse events and serious adverse events were comparable to the placebo group, with no reported drug related clinically serious adverse event.

A safety fact that is seldom mentioned is the peptide biology, a high science specialty and well known to those at the FDA. Most other neural drugs are being used in very small doses (the Nano to micro gram level) to reduce toxicity. We suggested optimal dose at 320 mg for our GM604 peptide drug. Demonstrating confidence of safety, the FDA wanted Genervon to push to 480 mg in our stroke trial and we did.

GM604 is a peptide that passes through the blood brain barrier requiring special manufacturing process to ensure safety and security, Genervon is the only manufacturer and supplier of GM604 in the world. More importantly, it is a small peptide drug. Peptide drugs are often very potent, lower accumulation in tissues and have lower toxicity than small molecule drugs. The only risk is immunogenic effects (the possibility of a response by the immune system) because it is bigger in size than small molecule drugs. Still, GM604 has very low risk of immunogenic effects because (1) it is very small in size, smaller than the threshold size that is known to induce an immunogenic response and (2) it is an endogenous peptide, which the body will not reject. Link:
https://pubs.acs.org/cen/business/83/i11/8311bus1.html

Clinical sites: For the Phase 2a ALS trial of GM604 two clinical trial sites, Site #1 in New York and Site #2 in Boston,were chosen and contracted by Genervon to recruit and collect data from ALS patients per our FDA approved protocol. The Principle Investigators (PIs) were not contracted to perform data and statistical analysis. To insure the integrity of data management and analysis per FDA requirements, Genervon contracted a specialized research organization (CRO).

Genervon has submitted the confidential Clinical Study Report including statistical reports, raw data and supporting documents to FDA. The top line data released at genervon.com has also been submitted to FDA. The Federal Health Insurance Portability and Accountability Act of 1996 ensures that Individual patient data is always confidential information.

Genervon did not select, meet or know the identity of the enrolled trial patients (even now) except for one of the treated patients from Site 1 who volunteered to go on Asahi TV, and one of the treated patients from the Site 2 who wrote and thanked Genervon. There are well established regulations and procedures in place for the protection of patient privacy.

Phase 3: Genervon has no hesitation in proceeding with Phase 3 other than the following reasons:
1. Due to the aggressive nature of ALS, most of the current generation of ALS patients will die because their life expectancy is shorter than the time it will take to complete the Phase 3 trial and achieve standard FDA approval.

2. Comparing to the need of 30,000 and 100,000 patients in the US and worldwide respectively, there are only a hundred patients lucky enough to be enrolled. Patient recruitment conditions are very restrictive.

3. One-third of those enrolled patients are randomized to placebo and therefore, they will not get the benefit of GM604 therapy.

4. Through AAP, the FDA can get the large population data they could never get from Phase 3 trials while at the same time today’s 100,000 patients will have access to treatment options.

5. It takes a lot more courage for Genervon to allow GM604 to be exposed to a full spectrum of heterogeneous ALS patients through AAP with Phase 4 marketing requirements than pursuing the much safer route of a very narrowly defined, controllable, small number of ALS patients in a Phase 3 trial. It is a more secure and conservative approach to go through the traditional phase 3 trial and then apply for a New Drug Application. We do not think that people really understand the risk Genervon is taking to try and save the lives of ALS patients.

6. The commercial sale of GM604 after Accelerated Approval will pay for some of Genervon’s expenses in the development of our new treatment. It may not be enough to pay for our 20-year investment in the discovery and development of GM604.