Oral Metformin for Treatment of ABCA4 Retinopathy

To be eligible, the following inclusion criteria must be met, where applicable.

1. Participant must be at least 12 years of age.
2. Participant (or legal guardian) must understand and sign the protocol s informed consent document.
3. Participant must have at least one definite pathogenic or likely pathogenic mutation in ABCA4 and a typical clinical presentation of Stargardt disease and phenotypic presentation of ABCA4 retinopathy in both eyes.

4. Participant must have at least two years of natural history data from at least four data points (a) The separation between any two consecutive data points must be at least six months (b) The most recent data point must be at least 4.5 months and no more than 16 months prior to the baseline visit (c)

   1. Potential participants with three natural history data points may be enrolled to obtain their fourth natural history data point on protocol.
   2. The separation between any two consecutive data points may fall short of 6 months by no more than 45 days; however, the total separation among the data points must allow for at least two years of natural history data.
   3. Potential participants with four or more natural history data points completed off protocol, all of which having occurred more than 16 months prior to the baseline visit, may be enrolled to complete an additional natural history data point on protocol within the required timeframe from the baseline visit.
5. Participant must agree to adhere to Lifestyle Considerations throughout study duration.
6. Any female participant of childbearing potential must have a negative urine pregnancy test at screening and be willing to undergo urine pregnancy tests throughout the study.

7. Any female participant of childbearing potential must:

   • Have had a surgical sterilization OR
   • Completely abstain from intercourse OR
   • Practice at least one form of contraception while actively taking IP on the study and at least one week after IP discontinuation OR
   • Have a partner who had a surgical sterilization OR
   • Have a partner who practices one form of contraception while the female participant is actively taking IP and at least one week after the female participant discontinues IP.

Any male participants must:

• Have had a surgical sterilization OR
• Completely abstain from intercourse OR
• Practice at least one form of contraception while actively taking IP on the study and at least for 3 months after IP discontinuation OR
• Have a partner who had a surgical sterilization OR

• Have a partner who practices one form of contraception while the male participant actively takes IP and at least 3 months after the male participant discontinues IP.

  1. Acceptable forms of surgical sterilization include: vasectomy, hysterectomy, or tubal ligation.
  2. Acceptable methods of contraception include: hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring), intrauterine device, or barrier methods (diaphragm, condom) with spermicide.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Participant is actively receiving study IP in another investigational study.
2. Participant has a condition that would preclude participation in the study (e.g., unstable medical status including blood pressure and glycemic control) by interfering with the participant s ability to engage in the required protocol evaluation and testing and/or comply with study visits.
3. Any female participant of childbearing potential that is pregnant or breast-feeding at the time of enrollment or planning to become pregnant during the study.
4. Participant has definitive pathogenic or likely pathogenic mutations in RDS/peripherin (PRPH2), PROM1, and/or ELOVL4.
5. Participant has a history of chronic renal impairment as measured in the acute care panel estimated glomerular filtration rate (eGFR)\<45 ml/min/1.73 m2) or severe hepatic, pulmonary, or cardiovascular disease (hypoxic state).
6. Participant is taking any medication that could adversely interact with metformin (e.g., cimetidine, furosemide, nifedipine) and cannot switch to an alternative medication.
7. Participant is currently taking metformin or participant has taken metformin during the period of natural history data collection that will be used for this study for a cumulative total of more than one month (> 31 days).
8. Participant has a known hypersensitivity to metformin.
9. Participant has not stopped taking a glucagon-like peptide 1 (GLP-1) agonist at least two weeks prior to enrollment or is currently taking a GLP-1 agonist.
10. Participant has a history of chronic lactic acidosis, including diabetic ketoacidosis, with or without coma.
11. Participant has type 1 diabetes mellitus.
12. Scarring due to choroidal neovascularization (CNV) is present in either eye.

QUALIFYING EYE ELIGIBILITY CRITERIA:

In order to participate in the study, the participant must have at least one qualifying eye that meets all of the inclusion and none of the exclusion criteria listed below.

Qualifying Eye Inclusion Criteria:

1. A growth rate of square root AreaEZloss > 0.025 mm/year based on calculation from natural history data.

Qualifying Eye Exclusion Criteria:

1. Retinal degeneration has advanced beyond a point where reliable measurement of the integrity of the IS-OS on OCT is possible.