Summary of GM604

French neurologist Jean-Martin Charcot discovered the ALS disease in 1869. Since the discovery of ALS 147 years ago, little progress has been made in developing effective treatments. It isn't for lack of effort. During the last twenty years, more than 170 ALS drug candidates have been developed only to fail in clinical trials. This record of failure could be attributed to the fact that the classic drug development model - which aims to design single-target drugs - is simply inadequate for complex, multi-factorial diseases like ALS. In contrast, Genervon's approach has been to trying to positively impact the disease by focusing on the discovery of the endogenous regulator(s) that is responsible for differentiation of those very complexities of the central nervous system in the human embryo, which, Genervon believes, can be activated in the adult to monitor, protect, and repair the biological systems damaged by ALS. 

Genervon's innovative hypothesis, drug discovery, drug development and clinical trials results for the last 20 years are summarized here below.

New Multi-Target Development Paradigm: 
In the 1990s, Genervon realized that the many failures of clinical trials for the treatments of central nervous system ("CNS") diseases can be attributed to the fact that the classic drug development paradigm of designing single target drugs is inappropriate for these highly complex, multifactorial diseases. 

Genervon's drug development strategy was to search for endogenous regulator(s) that control the development and function of the nervous system by monitoring distress signals and modulating the expression of multiple genes, thus restoring homeostasis and health. Through this approach, Genervon discovered nine active analogs that are the embryonic/fetal stage motor neuron trophic factor that are the master regulators of the human nervous system. Genervon selected GM6 to be the first drug candidate to be developed. GM6 binds specifically and only to the beta subunit of the tyrosine kinases of the Insulin Receptor. IGF1R and IGF2R have the identical beta subunit.

ALS is universally fatal. It is heterogeneous in its expression and potentially in its pathophysiology. Genervon's novel approach is to treat with a drug which is an endogenous master regulator Genervon believes can address the condition no matter the source. While most drugs are uni-directional, either decreasing or increasing a physiological effect, GM604, as a master regulator, can restore health by regulating multiple genes and their protein expressions in the either direction back to normal range, the hallmark of homeostatic processes in healthy living organisms, as illustrated in some of the patient histories below. The drug, referred to as GM604, is the endogenous embryonic stage growth factor regulator signaling multi-target peptide drug that can modulate hundreds of ALS related genes. Genervon believes that initial loading dose treatments of the investigational drug can modulate or slow down ALS disease progression and improve quality of life for patients.

Discovery of a Multi-Target Regulatory Peptide: 

During early in-vitro studies, GM6 was shown to protect neurons against soluble inflammatory factors in the human cerebrospinal fluid of patients with various CNS diseases. GM6 also modulated the expression of a large number of ALS-related genes in both DNA microarrays and PCR arrays. The potential benefits of GM6 include reduced inflammation and apoptosis, increased expression of kinesins and dynactins leading to improved axonal transport efficiency, modulation of undesirable gene expressions, and reduction of toxic protein aggregates. These beneficial impacts lead ultimately to attenuation of ALS disease progression, improvement in clinical outcomes, and reduction in disability caused by neurological deficit.

Genervon has produced data, which has been reviewed and confirmed by an external and independent bioinformatics CRO, demonstrating that its clinical stage signal peptide GM6 being developed for Amyotrophic Lateral Sclerosis (ALS) as well as other neurodegenerative disorders, modulates many genes associated with the nervous system, many of which are known to have significant impact on defense against stress and maintenance of cellular homeostasis. The independent CRO has analyzed the complete expression profile of cells treated with GM6 versus controls (7 folders and 83 files, figures and tables) which can be organized into 24 known pathways for neurological development, maintenance, and repair. The number of specific genes modulated by GM6 in one cell line (SH-SY5Y neuroblastoma cells) was as follows: 
15597 genes measured on array
13452 expressed genes

  1. Strong increase (FDR < 0.10, FC > 2.00) → 581 genes
  2. Mild increase (FDR < 0.10, FC > 1.50) → 1418 genes
  3. Weak increase (FDR < 0.10, FC > 1.00) → 1600 genes
  4. Strong decrease (FDR < 0.10, FC < 0.50) → 678 genes
  5. Mild decrease (FDR < 0.10, FC < 0.67) → 789 genes
  6. Weak decrease (FDR < 0.10, FC < 1.00) → 998 genes
  7. No change (FDR > 0.10) → 7388 genes

As shown above, > 1,200 genes showed strong expression shifts in response to GM6 treatment, based upon the most stringent statistical thresholds. However, given less conservative statistical criteria, > 3,000 genes showed altered expression. This affirms that GM6 has major regulatory effects in human neuronal cells.

Safety, Tolerability and Efficacy: 
GM6 is a small, endogenous regulatory signaling peptide that has been shown to be safe and tolerable in intravenous injections of six to twelve doses of 320 mg each given over a two-week period. The Phase 1 and Phase 2A trials showed no clinically significant shift in ECG readings, neurological indicators, hematology, or clinical chemistry. There were no reported deaths or withdrawals due to Adverse Events (AE) or any reported clinically Serious Adverse Events (SAE).

With respect to efficacy, usually no one expects statistically significant results from Phase 2A trials. In fact, most trials have a hard time even finding a positive trend. However, Genervon's randomized placebo controlled Phase 2A trials in ALS disease showed improvements in the treated group in both clinical measurements and multiple biomarker measurements. The differences between the treated groups and the placebo groups were statistically significant despite the fact that the trials were small and thus not designed to produce such dramatic effects. 

ALS Biomarkers Data and Results: 
In addition to statistically significant clinical measurements (ALSFRS-R and FVC) of disease progression, biomarkers are an objective way to measure the biological underpinnings of disease progression. There are no validated ALS biomarkers in CSF or Plasma, but FDA encouraged and approved Genervon to set up the exploratory endpoints, not for the purpose of a priory but exploring as many ALS biomarkers as possible in the CSF and plasma of each subject. The FDA has encouraged Genervon to use biomarkers as endpoints in our Phase 2A proof of concept and exploratory clinical trials and approved biomarkers as primary endpoints of our protocol. For more information, please see the following letter from Dr. Robert Bowser, a leading ALS researcher and the foremost U.S. expert in ALS biomarkers, who examined biofluid samples and identified changes in specific biomarkers in patients enrolled in Genervon's Phase 2A trial: View Details

Paul J. Lupinacci, (PhD Director of Biostatistics WCCT Global our data management and analysis CRO) addressed the question whether our 12 patients double blinded randomized placebo controlled Ph2A is too small to get good results. "This result should not be mitigated because of the small sample sizes. In fact, this result should be considered quite strong given the lack of power to detect that difference. If there was only one significant result, one could argue that it was spurious and even what you would expect with a Type I error rate of 0.05, regardless of the size of the clinical trial. However, when several endpoints show statistical significance and others are trending that way and have p-values near the 0.05 threshold in the presence of small sample sizes, there is an obvious signal that the active treatment is working. The active treatment is demonstrating an efficacious response that should be heralded, not as a random result found due to the small sample sizes, but as a powerful result found in spite of the small sample sizes." View Details

The spinal fluid and plasma samples collected in both the ALS Phase 2A trial (GALS001 trial) and the compassionate trial (GASL-C) were examined by Dr. Bowser. Changes were identified in specific biomarkers for target and efficacy. Among these biomarkers were superoxide dismutase 1 (SOD1), Cystatin C, Tau, TDP43 and pNFH.

SOD1 Biomarker: 
SOD1 was the first gene mutation linked to ALS. This genetic mutation, of which multiple types have been identified, comprises only about 20% of genetic cases of ALS and about 2% of all cases. However, there is growing evidence that the wild-type misfolded SOD1 protein is capable of assuming a form toxic to motor neurons. Moreover, misfolded wtSOD1 is capable of inducing extracellular spread of the misfolded form allowing SOD1 to appear in increased quantities in the plasma of patients with ALS. A single misfolded copy of this protein is sufficient to cause the spread of the misfolded form in sporadic ALS patients.

Reducing elevated SOD1 levels can control this mechanism and also indicates reduced levels of oxidative stress in the spinal fluid. SOD1 levels in ALS patients were tested as a biomarker to monitor the efficacy of the treatment to lower SOD1 levels in animal models of ALS and human patients in early clinical trials. The normal range of SOD1 in healthy individuals is 50-200 ng/ml. During the ALS Phase 2A, the slope change in SOD1 in the treated patients was -1.975 through week 5, in the placebo group it was 15.523. In the advanced stage ALS patient, his CSF SOD1 level at baseline was 27.22 ng/mL, below the normal range. After two weeks of treatments, his CSF SOD1 level was 30.996 ng/mL, an increase of 13.84%, and closer to the normal range. Please note that GM604 can modulate the SOD1 levels in both directions. In the ALS Phase 2A trial, plasma SOD1 percentage changes were lower than placebo at week two, p=0.0550. GM604 modulated SOD1 in both directions: down-regulation (when SOD1 were high in the Phase 2A trial patients) and up-regulation (when SOD1 were low in the advanced-stage ALS patient).

Cystatin C: 
Cystatin C is a cysteine protease inhibitor widely expressed in the body that has neuroprotection properties. The normal range of Cystatin C in the spinal fluid of healthy subjects is 3.0-8.0 ug/mL. Cystatin C levels in the advanced-stage ALS patient at baseline were 1.97 ug/mL, well below the normal range. After 2 weeks of treatments, the level was 2.35 ug/mL, an increase of 19% towards the normal range. In the Phase 2A trial we found the Cystatin C levels in both the treated and placebo groups to be at the low end of the normal range. GM604 raised Cystatin C levels in the treatment group, but the levels in placebo group dropped.

Tau has been used as a biomarker of neurodegeneration for many years and is extensively used for Alzheimer's disease. Tau is a protein that stabilizes microtubules. Microtubules make up the cytoskeleton necessary for axon extension and provide "roadways" for intracellular transport. Tau is mainly expressed in neurons of the central nervous system and is crucial in axonal maintenance and transport. It is a major component of abnormal neuronal aggregates in many central nervous system disorders, including Alzheimer's disease. High concentrations of Tau may be the result of broken microtubules and are evidence of active neuronal degeneration during the early stages of neurodegenerative diseases such as ALS. In an advanced-stage ALS patient, there are much fewer intact Microtubules to be broken to release Tau, and as a result, the Tau concentration may be low. Reducing the overall levels of this protein in patients during the active stage of neural degeneration may slow disease progression. The fact that Tau accumulation can only be reversed in the early stages of disease highlights the need for therapeutic strategies to slow or even stop that accumulation. Researchers have previously used Tau as a biomarker to monitor the effects of treatment in ALS patients in phase 2 clinical trials. It has been shown that reduction of Tau levels in ALS patients correlated to reductions in the clinical parameters of ALS disease progression.

The normal range of plasma Tau in healthy subjects is 0-20 pg/mL. In the Phase 2A trial patients, plasma Tau levels at baseline were all higher than normal. After treatment, the plasma Tau levels of the treated group at week 6 were reduced significantly (by 28%) from baseline. GM604 reduced plasma Tau in a statistical significant fashion between the treated and placebo groups. The normal range of Tau in the spinal fluid of healthy subjects is 100-350 pg/mL. In the Phase 2A trial, the Tau levels in the spinal fluid of the patients at baseline were at high end of normal or higher than normal. After treatment, the treated group had spinal fluid tau levels lowered while the placebo group's levels had increased, showing continued disease progression. In the compassionate use case, the patient was already in the very advanced stages of the disease, and his Tau level at baseline was 60.55 pg/mL, well below the normal range. After treatment, the level was 63.33 pg/mL, an increase of 4.59 %, closer to the normal range. GM604 modulated spinal fluid Tau in both directions: down-regulation (when Tau was high as in the Phase 2A trial patients) and up-regulation (when Tau was low as in the advanced-stage patient). 

TDP-43 Biomarker: 
TDP-43 is a pathologic hallmark of ALS and prior studies have shown increased levels of TDP-43 in ALS biofluid samples (Kasai et al., 2009; Noto et al., 2011). An in vitro study by Egawa et al (2012) using patient-derived motor neurons generated from iPS cells to screen for drugs that reduce expression levels of TDP-43 showed that higher levels of TDP-43 can be neurotoxic and generate cytoplasmic aggregates that impede cellular functions. Compounds that reduce TDP-43 level improve neurite health (Egawa et al., 2012).

In an estimated 97 percent of people with ALS/motor neuron disease (MND) and 45 percent of those with one form of dementia such as Alzheimer's disease (AD), the protein TDP-43 clumps inside brain or nerve cells. Cells with TDP-43 aggregates typically have concomitant loss of nuclear TDP-43, indicating loss of nuclear TDP-43 function, while the presence of cytoplasmic protein inclusions (clumps) suggests gain of one or more toxic properties. Thus the pathogenic mechanisms for TDP-43 are likely to be a combination of both loss-of function and gain-of-toxic properties (Ling et al., 2013).

In an article published in the journal Science by Ling and co-workers, Dr. Philip Wong at Johns Hopkins University reported a study on TDP-43 proteinopathy (Ling et al., 2015). TDP-43 is a ribonucleic acid (RNA)-binding protein (RBP) that represses the splicing of non-conserved crytic exons (unwanted stretches of the genetic material RNA), maintaining intron integrity.

TDP43 is normally responsible for keeping unwanted stretches of the genetic material RNA from being used by nerve cells to make proteins. When TDP43 bunches up inside those cells, it malfunctions, lifting the brakes on cryptic exons, random segments of RNA usually blocked by cells from becoming part of the final RNA are used to make random defective proteins and causing a cascade of events that kills brain or spinal cord cells (Ling et al., 2015). Many genetic mutations associated with familial ALS-frontotemporal dysfunction (ALS-FTD) - valosin-containing protein (VCP), progranulin (GRN), optineurin (OPTN), ataxin 2 (ATXN2), sequestosome-1 (SQSTM1), ubiquilin-2 (UBQLN2), profilin-1 (PFN1), TANK binding kinase-1 (TBK1), and especially C9orf72 - result in TDP-43 proteinopathy, suggesting a convergent mechanism of neurodegeneration with multiple genes.

Studies conducted by many different scientific research centers have shown that reducing the expression of TDP-43 will help to increase the health of motor neurons and positively modulate ALS disease. In Genervon's Phase 2A ALS trials, GM604 lowered the levels of TDP-43 in treated patients by a statistically significant amount relative to placebo patients. The normal range of TDP 43 in plasma is 0-50 pg/ml. In the ALS Phase 2A trial, slope in plasma TDP-43 through week 12 in the treated group (-3.513 pg/mL/wk) was lower than the placebo group (0.493 pg/mL/wk) with statistical significance, p=0.0078. In this trial, TDP-43 plasma was reduced significantly by 30% below baseline at week 12. The mean percentage change in TDP43 at 12 weeks in the treated patient group was -34% and the mean of percentage change in the placebo patient group was +6%.

The plasma TDP43 biomarker data analysis for our single patient compassionate trial showed a plasma TDP43 baseline level of 144.54 pg/ml. This value is as high as those of all the definite ALS patients in the phase 2A trial whose mean was 138.88 pg/ml at baseline (all patients were within 2 years of ALS onset). At the end of two weeks the plasma TDP43 value of the compassionate patient was 92.59 pg/ml and at the end of 12 weeks it was 52.53 pg/ml. The percentage change in plasma TDP43 from baseline in the compassionate patient was -63% in 12 weeks.

GM604 down-regulated plasma TDP43 in both the Phase 2A trial patients and the advanced stage patient as ALS patients in both studies had plasma TDP43 levels at baseline that were higher than normal. According to Kyoto University research results, as TDP43 leaks out of the nucleus it becomes toxic, causing the death of other motor neurons. In ALS patients, high concentrations of TDP43 result in shorter axons in motor neurons than in healthy subjects. As TDP43 decreases, the death of neurons is prevented and the previously shortened projection of nerves becomes longer. Therefore, a slowing of ALS disease progression is expected. TDP43 and TAU are the major disease proteins found in the brains of ALS and Alzheimer patients

C9orf72 Biomarker: 
Mutations in, or over-expression of, the C9orf72 gene have been found to cause ALS, perhaps because the protein that is produced by the gene may be altered and thus may interfere with cell function. Although there is no good robust assay to test for C9orf72, in in-vitro studies, GM604 reduced the expression of C9orf72 by 47% within 2 hours of application to the affected cells. See the following link for additional information: View Details

Orphan Drug Designation 
FDA granted GM604 orphan drug and fast track status in part because it is a very safe peptide signaling drug that can pass through the BBB at a very high bolus IV and SC doses of 320mg. Genervon conducts clinical trials and lab analysis in the U.S. only.

GM604 has also received orphan drug designation from the European Medicines Agency after it was thoroughly studied and evaluated by leading scientists in the field who conclude that the drug is scientifically sound, safe, and a promising treatment. This designation demonstrates that the scientists representing every EU country also conclude that GM604 is a good and promising drug for the rare disease ALS. 

Phase 3 or Phase 4? 
GM604 randomized placebo controlled Phase 2A clinical trial patients' data were collected by doctors at Columbia and MGH. The data were compiled, studied, analyzed, and reported by scientists from WCCT Global, an independent CRO. After FDA reviewed all the confidential data, analysis, and reports, an "End of Phase 2 Meeting" was set up by FDA February 2015. FDA wanted Genervon to begin a Phase 3 SPA (special protocol assessment) clinical trial which would take at least 3-5 years until completion. This generation of 450,000 ALS patients from around the world will not survive that wait. Genervon suggested conditional or AAP approval with Phase 4 surveillance requirement. FDA did not agree. But FDA may have a change of heart for the terminal ALS patients. But the process may take time. Genervon decided to collect more data by treating more diverse ALS patients internationally and improve treatment protocol at the same time.

Phase 2A Clinical Trial Patient 
Under normal circumstances, Genervon would not know the identities of our trial patients. However, Columbia University Medical Center and our PI, Dr. Hiroshi Mitsumoto, chose to be interviewed with one of the patients from Genervon’s ALS trial by Asahi TV in Japan for a television special on ALS. As a result, we could see the video of a GM6-treated patient one year after the clinical trial. View video:

Compassionate treatment of international ALS patients 
Clinical trial enrollment is very restrictive (definite ALS patients with onset in less than 2 years). No one can access GM604 in the U.S. until FDA (conditional or final) approval is received. 

Genervon can legally export the investigational drug GM604 to physicians treating ALS patients in 35 countries under various special access programs, treating named patients or under compassionate use in those countries for patients suffering fatal diseases such as ALS. A broad range of ALS patients from around the world have been treated with GM604.

While it may take some time until the multiple pathophysiological causes of ALS are understood, and the mechanism of GM604 as a master regulator is definitely proven, the ultimate measure of the strength of Genervon's hypothesis is in the response of patients to GM604. US laws permit the export of investigational drug to 35 countries for local doctors to treat terminal disease named patients who has no other treatment options. Therefore, provided below are four patient histories which verify the promise of the Company's treatment:

Patient #202 is a journalist introduced in the link below: View Details. She produced and hosted the videos below. She was diagnosed with ALS in May 2013, receiving 18 doses of GM604 in late 2015. Filming of the videos below was started right before GM604 treatment.

As illustrated in the videos, while waiting for FDA Expanded Access approval to treat with GM604, Patient 202's ALS disease progression accelerated, with demonstrated muscle wasting and tongue fasciculations, with repeated falls requiring emergency room visits, After receiving 12 doses with the first treatment started on September 8, 2015, her limb deterioration plateaued and her tongue fasciculations stopped as can be observed in the documentary and her debriefing recorded in the treating physician's report.

She joined the observational clinical trial of Cedars-Sinai Medical Center using the ATLIS device to measure muscle strength ( After the first 2 data points (6/24/15 and 8/19/15) were collected showing clear losing of muscle strength, on 11/18/15 after GM604 treatment, all 12 of muscle groups demonstrated reversal of documented prior deterioration except 2 out of 12 muscle groups were not tested. Without any further treatment 7 muscle groups continued to strengthen, while the other 5 of 12 muscles showed a minimal decrease in strength, averaging a decrease of 0.0116 from last treatment, but muscles strength are still higher than the projected loss of muscles strength if not treated by GM604.

Patient #111 
Hospitalized for respiratory problems in May 2015. Diagnosis of ALS at the Second University of Naples later in the year. Her disease progression as measured by ALSFRS-R stopped for 2 weeks after initial 6 doses of GM604. Her ALSFRS-R score indicated ALS disease reversal with an increase from 30 to 33 points after 6 more doses of GM604. ALS disease progression was reversed by 3 points from baseline to 4 weeks after GM604 treatment. If she has not received GM604 treatment her projected ALSFRS-R would have dropped to 24 by that time. Patient #111 with a long history of respiratory problem has her FVC reversed after GM604 treatment. Case Reports are available upon request subject to signing of a confidential disclosure agreement (CDA).


Patient #112's disease progression as measured by ALSFRS-R stopped for four weeks after initial treatments. Four weeks after the completion of her treatments, her ALSFRS-R score indicated ALS disease reversal with an increase from 19 to 21 points. Without treatment, her score would have been projected to have dropped to 9.5 by that time. Case Reports are available upon request subject to signing of a confidential disclosure agreement (CDA). Patient #112's FVC has remained at baseline, while her dyspnea improved from 3 to 4 points. 

Report from the treating neurologist: 
"With science and conscience I can say that the patient in question (Patient #112), during and after therapy had not said no slightest side effect and psychologically and more serene. 
As can be observed clinically and improved muscle tone as well as swallowing. Subjectively and objectively and improved oxygenation is always remained stable. In conclusion you have noticed even if slight improvements in general. XXX (treating doctor of Patient #112, Google translate) 27/06/2016"


Patient #113 
In April 2014 he was admitted to the NEMO, clinical centre for neuromuscular diseases in Milan where he was discharged with a diagnosis of motor neuron disease. There is no ALSFRS-R or FVC record. Patient managed to obtain the ALSFRS-R score 21 on 6/6/16 before the first dose of GM604. After 12 doses treatment ending on 7/1/16 and follow up visit on 7/13/16 his ALSFRS-R score was 26, a 5 points reversal of ALS disease from the first dose.

CERTIFICATE from treating neurologist: 
"It is certifying that Patient #113 suffering from amyotrophic lateral sclerosis (ALS), made a first cycle of treatment with the experimental drug GM604 product from Genevan from which drew particular benefit. In particular after several days of the treatment has started to present an improvement as regards the fasciculations and muscle strength. To the above I think it is useful for the patient to do another course of therapy with twenty-four vials of drug GM604.Therefore, I ask that my client is granted the aforementioned drug for another treatment cycle (24 vials), with dosing as recommended last Genervon protocol. Roma, 06/09/2016 (September 9, 2016)"