Phase 2A Study of GM 608 in Mild to Moderate Parkinson Disease

Background The investigational drug GM6028 is a synthetic oligopeptide containing 6 amino
acids with a sequence identical to one of the 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.

The investigators' preclinical animal study has shown that intravenously injected GM608 is
able to penetrate the blood-brain barrier and enter the brain. GM608 has shown
neuroprotection in a variety of in vitro and animal models of numerous CNS diseases
including ischemic stroke, spinal cord injury, Parkinsons Disease (PD), ALS, MS, Alzheimer
and Huntington Disease. In particular, the MPTP and 6-OHDA mouse model for PD all showed
GM608 has neuroprotective effect. GM608 also enhanced neuron cell survival very
significantly in the CSF of patients with Huntington disease, MS, Stroke, Parkinson,
Alzheimer and ALS.

This pilot trial is designed to test proof of principle, i.e. determine if a 2-week
treatment with this agent can restore the nonfunctioning nigral dopaminergic neurons in PD
over a 3month period, during which the placebo-treated arm is expected to have little or no
worsening of the total UPDRS score compared to baseline. 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 GM608 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 GM608 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.

Mechanism of Action Motoneuronotrophic factor (MNTF) is highly specific to the human nervous
system. It is expressed rapidly during the first trimester of human fetal development,
peaking at week nine. MNTF is a developmental stage regulatory (antisense) neuro-signaling
molecule that binds perfectly on very specific receptors. Using In Silico Analysis, Genervon
identified and developed as a drug candidate one of the active sites of MNTF, an analog of
six amino acids named GM608.

In the investigators' testing for efficacy in Parkinson disease MPTP and 6-OHDA animal
models, GM608 demonstrated a dose dependent attenuation of PD in the mice with 20 mg/kg
showing the most efficacious. Behavioral, biochemical and histological analysis demonstrated
the attenuation illustrating a unique effect for GM608 in PD. These data suggest that GM608
is effective in the mouse model of PD following IV injection and may be a potential
treatment for PD patients.

In the investigators' in vitro study in Parkinson disease, treatment with wortmannin (PI3K
inhibitor) abrogated the protective effects of GM608 on SH-SY5Y cells which were subjected
to salsolinol exposure for 24 hours. The results suggested that GM608 may function through
the phosphatidylinositol 3-kinase (PI3K) pathway which is an important pathway in neuronal
diseases.

Although the neuroprotective mechanism in each of the animal studies is not well understood,
the investigators hypothesize that GM608 respond to specific distress signal anywhere from
the human nervous system through a common underlying mechanism by triggering specific
pathway(s), possibly through the PI3 pathway and other pathways that protect neural tissues
by increasing or decreasing specific gene(s) expressions.

This is a single-center, prospective, randomized, double-blind, and placebo-controlled pilot
study, involving 6 subjects not on any dopaminergic medication (i.e. levodopa or dopamine
agonist). Subjects will be randomized 2:1 into one of two treatment arms: (1) 4 subjects
will receive i.v. injections of GM608 and (2) 2 subjects will receive a matching placebo.
Progression of clinical PD will be assessed using the UPDRS over 12 weeks. Safety and
tolerability will also be compared between treated and placebo group.

There will be 2 weeks of active treatment, followed by 10 weeks of assessment without active
treatment. During the 2-week active treatment phase, each subject will receive one IV bolus
injection once a day for three times a week during these 2 weeks for a total of six
injections. Subjects will be evaluated by UPDRS at screening, at baseline, and the ends of
weeks 2 (at visit 6 after dosing), 6, and 12. The study duration for each subject is 12
weeks.

Inclusion Criteria:

- with mild-moderate idiopathic PD diagnosed based on UK PD Brain Bank criteria.

- Age > 30

- Motor UPDRS Score ≥ 15

- Hoehn & Yahr stage <3

- Diagnosis of PD <10 years

- Have fully completed informed consent form

- May be on antiparkinsonian medications of an MAO-B inhibitor, an anticholinergic, or
amantadine, but not levodopa or dopamine agonist

Exclusion Criteria:

- Patients with atypical parkinsonism (such as suspected PSP, MSA or CBD) and secondary
parkinsonism (such as NPH, drug-induced, or vascular parkinsonism).

- Patients with uncertainty as to having classical Parkinson disease, such as those who
might have scans without evidence of dopaminergic deficit (SWEDDs)

- Patients not willing to give an informed consent

- Patients who are on a dopaminergic medication (levodopa or dopamine agonist)

- Presence of a medical or psychiatric comorbidity that can compromise participation in
the study