Biomarkers are not as commonly used in ALS drug development as in the drug development process for oncology. Biomarkers are important component of the ALS drug development pathway to demonstrate drug effect and target engagement, in a recent Phase 2A double-blind, randomized, placebo controlled clinical trial with GM604 (AKA MNTF, GM6), where ALS patients were treated with six doses of GM604 for two weeks and then continued to be evaluated for disease progression until 10 weeks after cessation of GM604 treatment, it was demonstrated that GM604 can modulate protein expression of ALS disease related genes, through pathways that bring about homeostasis of pertinent ALS biomarkers, in most ALS patients with symptom onsets within two years, many of the ALS pathology biomarkers such as TOP 43, SOD1 and Tau were over expressed (Higher than normal range) at baseline. The patients treated with GM604 had these over-expressed biomarkers lowered to approach normal range, a sign of homeostasis. On the other hand, in an end stage ALS patient, the CSF SOD1 and CSF Tau were below normal range at baseline, treatment of GM604 up regulated them to approach normal range. This phenomenon that GM604 can modulate the same biomarker in both up and down direction is the hallmark of bringing homeostasis. The statistical significance in biomarker changes also correlate with treatment effects in clinical observations. Comparing blood-based biomarkers between treatment and placebo groups, plasma Tau levels decreased 28% in the treated group at week 6 (p=0.04), plasma TDP-43 levels decreased 30% in the treated group at week 12. The slope in plasma TDP-43 through week 12 in GM604 treated patients (-3.513 pg/ml/wk) is lower than that in placebo treated patients (0,493 pg/ml/wk), with statistical significance, (p=0.008). SOD1 levels were also lowered in the treated group at week 2 while all three biomarker levels were increased in the placebo group (p=0.055>. The patients treated with GM604 also had more favorable clinical observation in Forced Vital Capacity (FVC) from screening to week 12 than the placebo group (p=0.0476), the decline in FVC was significantly reduced in the treated group. This correlation of disease progression with the modulation of the biomarkers suggest that GM604 can be used effectively in modulating ALS disease biomarkers, and consequently can be used for prognosis of ALS disease progression and therapeutic treatment to slow down ALS disease progression. The biomarker modulation can be a measure of drug efficacy.
METHODS OF USING GM604 IN MODULATING ALS DISEASE BIOMARKERS LEADING TO PROGNOSIS AND THERAPEUTIC TREATMENT FOR ALS DISEASE