Safety and Therapeutic Potential of the FDA-approved Drug Metformin for C9orf72 ALS/FTD

The C9orf72 repeat expansion is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Metformin, a well-tolerated diabetes drug, blocks a key pathway for expression of toxic proteins produced from the C9orf72 repeat expansion via repeat associated non-canonical start codon - in RNA (non-AUG) (RAN) translation. In mouse model of C9-ALS/FTD, metformin treatment decreases RAN protein levels and improves disease features. This current study is a small-scale clinical trial to assess the safety and potential efficacy of metformin for the treatment of C9-ALS/FTD.

Inclusion criteria

• Subjects have a diagnosis of probable or definite ALS in accordance with the Revisited El-Escorial Criteria.
• Subjects have a likely diagnosis of chromosome 9 open reading frame 72 (C9orf72) positive ALS/FTD.
• Subjects must be currently on an oral diet and able to take foods, pills and liquids by mouth equivalent to a score of 4 or above on the Functional Oral Intake Scale
• Subjects must have no known allergy to barium sulfate or Metformin.
• Subjects or subject's legally authorized representative must be willing and able to complete informed consent/assent and HIPAA authorization.
• Ability to comprehend and be informed of the nature of the study, as assessed by the PI or Co-Investigators.
• Subjects prescribed to take Metformin at or before the time of first dosing. (The study is open to subjects currently taking Metformin or subjects who have taken Metformin in the past).
• Availability to participate for the entire study duration.
• Female subjects of childbearing potential must have a negative urine pregnancy test prior to Videofluoroscopic Swallow Study (VFSS) exam during Visit 1, 3, and 4.

Exclusion criteria

• Subjects who score 3 or below on the Functional Oral Intake Scale
• Subjects who do not carry the C9ORF72 hexanucleotide repeat expansion as determined by laboratory analysis.
• Subjects with a history of clinically significant liver disease, renal disease, or any other medical condition judged to be exclusionary by the investigator.
• Subjects who are unwilling to sign informed consent or subjects who for any other reason in the judgment of investigator are unable to complete the study.
• Female subjects who have a positive urine pregnancy test (βhCG) at screening or visit 1, are trying to become pregnant or are breastfeeding.
• Subjects with active cancer within the previous 2 years, except treated basal cell carcinoma of the skin.
• Subjects who have taken any experimental drug within 30 days prior to enrollment or within 5 half-lives of the investigational drug -whichever is the longer period.
• Subjects with known history or presence of moderate or severe renal impairment as defined by an estimated glomerular filtration rate (eGFR) value below 30 mL/min/1.73 m2.
• Subjects with hepatic impairment as defined by baseline elevations of serum aminotransferases greater than 5 times upper limit of normal or evidence of liver dysfunction (e.g., elevated bilirubin).
• Use of potentially hepatotoxic drugs: (e.g., allopurinol, methyldopa, sulfasalazine).
• Subjects with clinically significant abnormal laboratory values in the judgment of the investigator.
• Subject with implanted electrical device (i.e. cardiac pacemaker or a neurostimulator), metal or metallic clip(s) in their body (i.e. an aneurysm clip in the brain) that will be damaged by participation in the MRI portion of the study.
• Anything else that, in the opinion of the investigator, would place the subject at increased risk or preclude the subject's full compliance with or completion of the study.