Safety of Urate Elevation in Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease for which there is
no cure. Multiple lines of evidence have implicated oxidative stress in the pathophysiology
of ALS. Urate (uric acid) is an endogenous antioxidant system, and urate may serve as a major
defense against oxidative stress. Urate has emerged as a promising neuro-protectant and
therapeutic target based on convergent epidemiological, laboratory, and clinical data in
multiple neurodegenerative diseases, most notably Parkinson's disease (PD). In PD, urate
elevation has been pursued as a potential therapy by administration of inosine, a urate
precursor that is available as an over-the-counter supplement. Administration of inosine
results in a predictable elevation of urate levels and has been shown to be safe and well
tolerated in PD.

Analysis of ALS databases revealed that higher urate levels are an independent predictor of
slower progression and prolonged survival in ALS. However, whether elevating urate in people
with ALS would result in better outcomes is unknown.

The Principal Investigator has recently concluded a Pilot Study of Inosine in ALS, which was
a short, open label, single center study involving 25 subjects [NCT02288091]. The study
showed safety and feasibility of urate elevation in patients with ALS. The Principal
Investigator is now pursuing a multi-center Phase II trial to confirm these findings with
longer exposure time.

Inclusion Criteria:

1. Age 18-85.

2. Sporadic or familial ALS diagnosed as possible, laboratory-supported probable,
probable, or definite as defined by revised El Escorial criteria (Appendix 1).

3. Slow vital capacity (SVC) ≥ 60% of predicted for age, height, and gender at the
Screening Visit.

4. Capable of providing informed consent and following trial procedures.

5. Serum urate < 5.5 mg/dL at screening (i.e. below the population median serum urate
levels).

6. Women must not be able to become pregnant (e.g. post menopausal, surgically sterile,
or using adequate birth control methods) for the duration of the study and 3 months
after study completion. Adequate contraception includes: abstinence, hormonal
contraception (oral contraception, implanted contraception, injected contraception or
other hormonal (patch or contraceptive ring, for example) contraception), intrauterine
device (IUD) in place for ≥ 3 months, barrier method in conjunction with spermicide,
or another adequate method.

7. Is able and willing to participate in the Mobile app study procedures.

Exclusion Criteria:

1. History of urolithiasis.

2. Urine pH < 5.5 at screening (as acidic urine is a major determinant of uric acid
urolithiasis).

3. History of gout.

4. History of stroke or myocardial infarction.

5. History of symptomatic coronary artery disease (e.g. angina pectoris) or symptomatic
peripheral arterial disease within 1 year prior to Screening.

6. Symptomatic congestive heart failure with a documented ejection fraction below 45%.

7. Poorly controlled arterial hypertension (SBP>160mmHg or DBP>100mmHg at Screening).

8. Women who are pregnant or lactating.

9. The presence of unstable psychiatric disease, cognitive impairment, or dementia that
would impair ability of the subject to provide informed consent, according to Site
Investigator judgment, or a history of active substance abuse within the prior year.

10. Anything that, in the opinion of the Site Investigator, would place the subject at
increased risk or preclude the subject's full compliance with or completion of the
study.

11. Use of the following within 30 days prior to Screening: inosine, allopurinol,
probenecid, more than 300mg vitamin C daily (note that a subject may take a standard
multivitamin up to one tablet or capsule daily). Use of thiazides is permissible as
long as the subject is on a stable dose from 1 week prior to Screening.

12. Known hypersensitivity or intolerability to inosine.

13. Renal insufficiency as defined by eGFR < 60 mL/min/1.73m2 at the time of screening.