Methods of using GM604 in modulating ALS disease biomarkers leading to prognosis and therapeutic treatment for ALS disease
Inventors
Ko, Pui-Yuk Dorothy • SWINDELL, William R.
Assignees
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Publication Number
US-10632169-B2
Publication Date
2020-04-28
Expiration Date
Abstract
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 expression of ALS disease related genes, through pathways that bring about homeostasis of pertinent ALS biomarkers. The statistical significance in biomarker changes also correlate with treatment effects in clinical observations. 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.
Core Innovation
The invention relates to a method of treatment for amyotrophic lateral sclerosis (ALS) in which a subject is selected, an ALS biomarker is quantified, and the subject is classified as in need of treatment when the quantity of the biomarker is above normal for a healthy subject. The biomarker is selected from the group consisting of TDP-43, SOD1, and Tau. The method then treats the subject for ALS by administering a MNTF peptide consisting of the amino acid sequence FSRYAR [SEQ ID NO:2] (GM604).
The described approach uses biomarker quantification and classification to guide administration of GM604, and clinical evidence is described as showing biomarker changes in ALS biomarkers including TDP-43, SOD1, and Tau, plus Cystatin-C, correlated with clinical outcomes and progression measures. A Phase 2A randomized double-blind placebo-controlled trial is described as supporting modulation of disease biomarkers toward homeostasis, with follow-up biomarker effects assessed after dosing.
The document also provides mechanistic and supportive evidence that GM604 regulates ALS-related genes and is associated with pathways including insulin receptor/IGF-1 and PI3K. In addition, the document includes narrative examples of compassionate-use in an end-stage patient in which CSF biomarkers including SOD1, Tau, Cystatin-C, and TDP-43 show bidirectional normalization, up or down toward normal, supporting the described homeostasis concept for biomarker monitoring, prognosis, and therapeutic efficacy.
Claims Coverage
The independent claim is clm-00001. It is directed to an ALS treatment method that combines subject selection, biomarker quantification and threshold-based classification, and treatment with a specific MNTF peptide (GM604; FSRYAR [SEQ ID NO:2]).
Biomarker-guided classification for ALS treatment
selecting a subject, quantifying a biomarker for ALS selected from TDP-43, SOD1, and Tau, classifying the subject as in need of treatment for ALS when the quantity of the biomarker is above normal for a healthy subject
Administration of MNTF peptide GM604 for ALS
treating the subject for ALS by administering a MNTF peptide consisting of the amino acid sequence FSRYAR [SEQ ID NO:2] (GM604) to the subject
Across the independent claim, treatment is specified as biomarker-quantification and above-normal classification for TDP-43, SOD1, or Tau, followed by administering the MNTF peptide GM604 (FSRYAR [SEQ ID NO:2]).
Stated Advantages
Modulates disease biomarkers toward homeostasis.
Shows biomarker changes correlated with clinical outcomes and progression measures.
Provides bidirectional normalization (up or down toward normal) of CSF biomarkers in a compassionate-use end-stage patient.
Supports monitoring, prognosis, and therapeutic efficacy using biomarker effects.
Documented Applications
Use in a Phase 2A randomized double-blind placebo-controlled trial (GALS-001; GALS-001/GM604) to assess modulation of ALS biomarkers and correlation with clinical outcomes/progression measures.
Compassionate use in an end-stage patient (GALS-C) with described CSF biomarker normalization (SOD1, Tau, Cystatin-C, TDP-43) for monitoring/prognosis/therapeutic efficacy.
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