Summary: GM6 MoA in ALS

Genervon Biopharmaceuticals has developed a peptide drug (GM6) based upon a novel concept and approach to ALS treatment. In contrast to existing ALS drug candidates, GM6 does not selectively interact with a single receptor target, but rather interacts with multiple receptors linked to diverse pathways.

1.    Receptors include insulin receptor, Notch receptors 1 – 4, patched 1, and smoothened frizzled class receptor. Stimulation of these and other receptors by GM6 leads to activation of the insulin signaling cascade, Notch Intracellular domain and mitogen-activated protein kinase signaling.

2.    Signal transduction pathways converge upon a core network of transcription factors such as hes family bHLH transcription factor 7 (HES7), GLI family zinc finger 1 (GLI1), homeobox D11 (HOXD11), and signal transducer and activator of transcription 3 (STAT3).

3.    Signal Transduction is the process by which extracellular signals are propagated intracellularly to activate signaling pathways that are in turn linked to downstream transcriptional responses. We identified a complex set of signaling pathways activated by GM6, which converge downstream to activate or inhibit core transcription factors. Consistent with data demonstrating positive regulation of insulin receptor (IR), GM6-stimulated cells have increased phosphorylation of IR at tyrosine 972 in HBMVECs, modulating downstream proteins, such as Shc, PTB domain, IRS-1, PI3 kinase and SOCS.

4.    Transcription factors together modulate expression of thousands of genes (2867 protein coding genes in SH-SY5Y with 77 ALS specific genes). In neurons, GM6-regulated genes are associated with axon guidance, intrinsic apoptosis, microtubule stability, synaptic transmission and glutamate clearance.

5.    Transcriptional Response We have identified 2867 protein-coding genes with expression significantly altered by GM6 (FDR < 0.10) in SH-SY5Y cells. We have further identified a subset of 77 GM6-regulated genes associated with ALS and linked to axon guidance and the intrinsic apoptosis pathway. GM6 appears to blunt expression of genes associated with acute phase and immune responses, lymphocyte proliferation, leukocyte migration, and production of pro-inflammatory cytokines such as TNF and IL-1. Gene expression responses to GM6 are thus linked to both neurogenesis and anti-inflammatory effects in distinct cell types.

6.    Pharmacology we have demonstrated that GM6 has good drug-like properties and is able to cross the blood-brain barrier, with an estimated volume of distribution of 7.8 L/kg and good penetration into neuronal tissues.

7.    SOD1-G93A transgenic mice to demonstrate in vivo efficacy of GM6 as an ALS treatment, we evaluated effects in a well-validated mouse model. (GM6 increases survival in this model and confers dose-dependent improvements in physical performance measures of disease progression and biomarkers in CSF and spinal cord sections.

8. Phase 2A clinical trial to translate these findings we performed a double-blind, randomized, placebo-controlled to evaluate effects of GM6 in ALS patients (NCT01854294). The phase 2A study confirmed safety of GM6 in humans, with no serious drug-related treatment-emergent adverse effects. We additionally observed favorable trends in GM6-treated patients, including slowed decline in forced vital capacity and ALS Functional Rating Scale, along with decreased plasma abundance of ALS biomarkers (e.g., TDP-43, Tau and SOD1). These findings have supported the hypothesis that GM6 favors neuron survival in ALS patients, slowing symptom progression and promoting a biomarker profile consistent with less severe disease.