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

Background

1. In the early 1990s Genervon hypothesized that Central Nervous System / Peripheral Nervous systme (CNS/PNS) and rare motoneuron diseases and disorders involve the interplay of a highly complex, multifactorial process of many non-dominant effectors in an interactive dynamic network. Therefore Genervon decided for its drug development strategy the classic single target drug development paradigm is not likely leading to a cure.
2. Genervon also hypothesized that aging is likely the initial multifactorial triggers that lead to multiple defective or degraded gene products accumulating with advancing years. However the key to a cure for many human neurological disorders is in the subsequent common terminal cascade coinciding with the onset of neurological deficits. The terminal cascade involves the shared pathways of interactive multifactorial pathogenic mechanisms that lead to the ultimate demise of neurons. Therefore Genervon's strategy is not to find the triggers or the residue debris of neuron death in discrete areas of the central nervous system.
3. Genervon recognized the limited human capacity to design a drug that can dynamically and interactively modulate multiple pathways and genes. Therefore one possible drug development strategy is to find the endogenous early stage regulatory molecule(s) that controls the development, monitoring and correction of the human nervous system.
4. Genervon developed a novel proprietary technology platform named Protein Bands Selection by Function to find the fetal signal regulators. One of the discoveries is a 33 amino acid peptide we named human Motoneuronotrophic Factor (MNTF), its gene sequence and its chromosome location.
5. Genervon developed another novel platform named In Silico Analysis to find active sites within bigger proteins. Within the MNTF peptide, Genervon identified a family of nine embryonic stage human multifactorial master regulators which govern nervous system development, protection and correction. These master regulators are highly expressed in week 9 of embryonic/fetal development, a time of incredible intricacies, but truly remarkable consistency as well.
6. Genervon has developed one of the nine master regulators named GM6 for disease modification of CNS/PNS and neurodegenerative diseases and disorders with shared or common pathways of interactive multifactorial pathogenic mechanisms. GM6 binds to Insulin Receptor beta sub-unit and Insulin Growth Factor Receptor 1 and Receptor 2 (IGF1R/IGF2R) which also have the identical sub-unit. GM6 penetrates the Blood Brain Barrier (BBB) and activates many appropriate genes through multiple pathways to induce anti-inflammatory, anti-apoptotic, anti-oxidative and regenerative effects in response to the dynamic distress signals from the nervous system.
7. GM6 is also known as GM604, GM602 and GM608. Drug name GM604 is assigned to ALS indication. GM602 is assigned to stroke indication. GM608 is assigned to Parkinson Disease indication.
8. The investigational drug GM604 is a regulatory/signaling peptide with a sequence identical to one of the nine active sites of human Motoneuronotrophic factor (MNTF), also referred to as GM6 in studies. MNTF is a novel human endogenous developmental stage neurotrophin for the nervous system with a specific human chromosome location.
9. Pre-clinical efficacy studies: The investigators' preclinical animal study has shown that intravenously injected GM604 is able to penetrate the blood-brain barrier and enter the brain. GM604 has shown neuroprotection in a variety of in vitro and animal models of numerous CNS diseases including ALS, ischemic stroke, spinal cord injuries, Parkinson's disease (PD), multiple sclerosis (MS), Alzheimer Disease (AD) and Huntington Disease (HD).
10. GM6 provided neuroprotection for neurons in vitro against soluble inflammatory factors in human CSF from patients with various CNS diseases. It increased neurons survival by 175% after exposure to ALS patients' CSF, by 191% in AD patients' CSF, by 198% in PD patients' CSF, by 205% in Stroke patients' CSF, by 246% in MS patients' CSF and by 273% in HD patients' CSF.
11. Preclinical research in animal models indicates GM604 to be a neuroprotective agent in animal models of ALS, motoneuron disease, Parkinson's disease and stroke. In ALS model, SOD1 mice from Jackson Lab stock #G93A were treated with GM604 at 0, 1 and 5 mg/kg. SOD1 mice were examined for age of disease onset, age of death, and behavioral expression of the disease (CS=Clinical score). GM604 prolonged life span in ALS mice SOD1 by 30% [(163.5-126)/126 = 30%], delayed median clinical score by 53%, delayed symptoms onset by 27% [(145.5-114.5)/114.5 = 27%] at 5 mg/kg dose. The conclusion is that GM6 significantly showed a dose dependent effect in delaying age of onset of the disease, age of death, increasing grip strength and rota-rod performance, and improving clinical score of the treated animals.
12. The investigators found out later in the study of Wobbler Mouse model that the optimal dose for SOD1 mice model should probably be 20 mg/kg and will probably see even more significant effects if 20 mg/kg were used in the SOD1 mice study.
13. GM604 20mg/kg dramatically increased the survival life span by 500% (6 fold from 7-14 weeks to 55-65 weeks) and the control animals and animals treated with low doses of GM6 showed a continual decrease in grip strength. Wobbler mice treated with GM6 at 10-20 mg/kg showed an improvement in grip strength out to 4 weeks (3 fold). GM604 10 and 20 mg/kg treatment showed a significant increase in body weight out to 8 weeks following treatment.GM604 10 and 20 mg/kg treatment increased of preservation of motor neurons by 160% (2.6 fold).

The conclusion is that GM604 was found to be efficacious in an in vivo mouse model of neurological disease. The effectiveness of GM604 was dose-dependent and indicates that GM604 may be beneficial in treating various neurological disorders.

Rationales

1. This pilot trial is designed to test proof of principle, i.e. determine if a 2-week IV bolus treatment with this agent can (1) change ALS protein expression (target biomarkers and efficacy biomarkers) after treatment (2) have preliminary effects measures of ALS disease clinical progression.
2. Previous human experience: A Phase 1 Clinical Trial Study has been completed. The Phase 1 Trial primary objective is to determine the safety and tolerability and to establish the pharmacokinetic and pharmacodynamic properties of GM602 at 0.5, 1.5, and 5.0 mg/kg administered as a single bolus intravenous dose in human subjects and after 3 consecutive daily doses of GM602 at the highest safe and tolerated dose of 5.0 mg/kg. The Phase 1 study established that 3 consecutive daily doses of 5.0 mg/kg of GM602 are safe and tolerated.
3. Concurrently, other Investigational New Drug (IND) and on-going clinical trials with GM6 are: