Updated Summary on Genervon Science & GM604

Genervon has received many inquiries from ALS patients, caregivers and doctors requesting the access of GM604. The following updated summary is an attempt to answer some of their questions.

Science, safety and efficacy of GM604 
Genervon has summarized below our 20 years of research and development for your understanding of the science, discovery, development, safety and efficacy of GM604.

No curative drug has been discovered in the ~150 year history of ALS 
ALS is very heterogeneous and fatal, and the disease progression is usually very fast. It is important to Genervon that the neurologists working with the patients know, understand, and believe that the endogenous embryonic stage signaling master regulator of the human nervous system, GM604, is novel and may be curative for ALS

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. Instead, 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 GM6, a form of the embryonic/fetal stage motor neuron trophic factor that is the master regulator of the human nervous system. 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.

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 potential beneficial impacts may lead ultimately to attenuation of ALS disease progression, improvement in clinical outcomes, and reduction in disability caused by neurological deficit.

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 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 drug-related 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. See Genervon's Safety and Efficacy Summary of GM6.

ALS Biomarkers Data and Results
In addition to clinical measurements (ALSFRS-R and FVC) of disease progression, biomarkers are an objective way to measure the biological underpinnings of disease progression. The FDA has encouraged their use as endpoints in clinical trials and approved biomarkers as primary endpoints of our protocol. Dr. Robert Bowser, a leading ALS researcher and the foremost U.S. expert in ALS biomarkers, examined biofluid samples and identified changes in specific biomarkers in patients enrolled in Genervon's Phase 2A trial.

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 nonconserved 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. See Video

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 additional information.

Phase 3 or Phase 4? 
GM604 randomized placebo controlled Phase 2A clinical trial patients' data were collected by doctors at Columbia and Massachusetts General Hospital. The data were studied, analyzed, and reported by scientists from independent CROs. After FDA reviewed all the confidential data, analysis, and reports, an "End of Phase 2 Meeting" was set up by FDA in February 2015. FDA encouraged Genervon to conduct a Phase 3 SPA (special protocol assessment) clinical trial, but that will take at least 3-5 years to receive a final approval. This generation of 450,000 ALS patients from around the world will not survive that wait. While Genervon is planning for a Phase 3 clinical trial, Genervon suggested conditional or Accelerated Approval Program with Phase 4 surveillance requirements for GM604 in order to provide a possible life saving option to the ALS patients who may not survive the wait for the final approval of GM604. See Facebook.

U.S. vs. International Individual named-patient treatment 
FDA granted GM604 orphan drug designation in 2014 and fast track status in 2013.

FDA is well known for its high standard and stringent rules. While FDA has not yet granted approval for GM604, it has already approved and granted Individual Patient Expanded Access use of GM604 for a U.S. ALS patient, Patient #202 in our Case Report Summaries.

Due to cost and liability, Genervon cannot offer expanded access (compassionate) or Right to Try use to the many deserving patients in the United States requesting treatment. Some international patients have received GM604 by requesting that Genervon export the investigational drug GM604 to their treating physicians under their countries' individual named-patient special access programs.