A Pilot Study of Inosine 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. As a first step towards development of
inosine as a potential treatment for ALS, in this study we will test whether inosine
administration in ALS is safe and correlates with changes in the levels of biomarkers of
oxidative stress and damage (as biomarkers of the intended biological effect).

The primary outcome measures will be safety, as measured by adverse events and clinically
meaningful changes in vital signs, physical examination, and standard clinical laboratory
tests, and tolerability, defined as the ability of subjects to complete the entire 12-week
study.

The secondary objective of the study is to quantify the effect of the treatment on biomarkers
of oxidative damage and stress.

An exploratory objective of the study is to measure whether changes in these biomarkers are
different in people with bulbar-onset ALS compared to people with limb-onset ALS.

This study will be conducted in people who meet the El Escorial criteria of possible,
laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS. At
screening, eligible individuals must be at least 18 years old and must provide written
informed consent prior to screening. Subjects on a stable dose of riluzole and those not
taking riluzole, and women of child-bearing age at screening are eligible for inclusion as
long as they meet specific protocol requirements.

Study participants will be administered oral inosine daily. The dose of inosine will be
titrated to obtain serum urate levels of 7 - 8 mg/dL.

Study participants will remain on treatment until the Week 12 visit. Each participant will
also have a Week 16 Follow-up Telephone Interview to assess for adverse events (AEs), changes
in concomitant medications and to administer the ALSFRS-R.

Inclusion Criteria:

1. Age 18 years or older.

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

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

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

5. Willingness to undergo magnetic resonance spectroscopy (MRS) at Baseline and at Week
12 of the study.

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.

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. Urate crystalluria at Screening.

4. History of gout.

5. History of stroke or myocardial infarction.

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

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

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

9. Contraindications to undergo magnetic resonance spectroscopy (MRS) at Baseline and at
Week 12 of the study such as history of claustrophobia, inability to lie flat for
approximately one hour, or metal implants (metal pins or plates, extensive
non-removable dental work, cerebral aneurysm clips, pacemaker).

10. Women who are pregnant or lactating.

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

12. Anything 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.

13. 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.

14. Known hypersensitivity or intolerability to inosine.