Nitisinone for Type 1B Oculocutaneous Albinism

Objective: The primary objective of this study is to evaluate oral nitisinone as a treatment
that improves ocular pigmentation in adult participants with oculocutaneous albinism, type 1B
(OCA1B). Secondary objectives of this study are to determine whether the selected outcome
measures are robust enough to use in a larger trial and to assess whether oral nitisinone
improves visual function, skin pigmentation, and hair pigmentation in participants with
OCA1B.

Study Population: Five participants with OCA1B will be enrolled initially. However, up to an
additional three participants may be enrolled to account for participants who withdraw from
the study for any reason before the Month 12 visit.

Design: In this pilot, phase 1/2, single-site, prospective, open label trial, participants
will receive 2 mg of oral nitisinone daily for at least one year, and they will be followed
for at least 18 months. Ocular and non-ocular data will be collected at least every three
months, with the first follow-up visit occurring three months after the final baseline visit.
Participants will be required to have at least 8 outpatient visits at the NEI clinic over a
period of 18 months. This study has a common termination date and therefore may continue for
up to four years.

Outcome Measures: The primary outcome for the study is the absolute mean change in iris
pigmentation on an 8-point scale at 12 months as compared to baseline. Participants left and
right eyes will be analyzed. The absolute mean change in iris pigmentation for each eye on an
8-point scale at 3, 6 and 9 months compared to baseline will be assessed as secondary
outcomes. Other secondary outcomes include the absolute and percent change in
semi-quantitative iris pigmentation on image analysis; the absolute change in electronic
visual acuity (EVA) for each eye and binocular vision; the absolute change in contrast
sensitivity without glare, with medium glare, and with high glare for binocular vision; the
absolute change in full-field ERG measures for each eye; and the absolute and percent change
in melanin content in skin using skin reflectometry at 3, 6, 9 and 12 months as compared to
baseline; Qualitative changes in hair, skin, and fundus pigmentation at 3, 6, 9 and 12 months
as compared to previous visit will be assessed. The absolute and percent change in hair
melanin will also be assessed at 12 months as compared to baseline. The number and severity
of adverse events and the number of withdrawals will be assessed as safety outcomes.

- INCLUSION CRITERIA:

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

1. Participant must be 18 years of age or older.

2. Participant must understand and sign the protocol s informed consent document.

3. Participant must have normal renal function, liver function, and platelet counts or
have mild abnormalities no greater than grade 1 as defined by the Common Terminology
Criteria for Adverse Events v4.0 (CTCAE).

4. Any female participant of childbearing potential must have a negative pregnancy test
at screening and must be willing to undergo pregnancy testing immediately prior to the
start of the investigational product and while on the investigational product.

5. Any female participant of childbearing potential and any male participant able to
father children must have (or have a partner who has) had a hysterectomy or vasectomy,
be completely abstinent from intercourse, or must agree to practice two effective
methods of contraception while taking the investigational product and for at least two
months following the last dose of investigational product. Acceptable methods of
contraception include:

- Hormonal contraception (i.e., birth control pills, injected hormones, dermal
patch, or vaginal ring),

- Intrauterine device,

- Barrier methods (diaphragm, condom) with spermicide, or

- Surgical sterilization (tubal ligation).

6. Participant must have OCA1B, as defined by ALL (a-d) of the following criteria:

1. Participant has ophthalmic signs or symptoms of albinism, including:

- Bilateral visual acuity E-ETDRS EVA letter score of less than or equal to 83
(i.e., Snellen equivalent of 20/25 or worse) that is not attributable to any
other pathology.

- Bilateral iris transillumination that can be seen in clinical photographs.

2. Predominant contralateral decussation of ganglion cell axons, as determined by
pattern visual evoked potential (VEP).

3. Participant has at least one definitive mutation in the OCA1 gene (tyrosinase).

4. Participant has no definitive mutations in the OCA2 gene.

EXCLUSION CRITERIA:

- Participant is pregnant or breast-feeding.

- Participant is a male AND has a definitive mutation in the OA1 gene.

- Participant has any of the following abnormal laboratory test results:

1. Serum potassium < 3.0 mEq/L,

2. Serum CK > 500 U/L,

3. Hemoglobin < 10.0 g/dL,

4. White blood cell (WBC) count < 3.0 k/microL,

5. Plasma tyrosine > 150 microM,

6. ESR > 100 mm/h, and/or

7. Serum T4 > 15 microg/dL OR Serum T4 < 4 microg/dL.

- Participant has keratopathy.

- Participant has a current malignancy.

- Participant has open skin lesions.

- Participant is on a diet that deliberately increases protein intake to
disproportionate levels (e.g., Atkins diet). The diet must be reasonably balanced, as
determined by a dietician.

- Participant has uncontrolled hypertension, defined as systolic blood pressure above
180 mmHg or diastolic blood pressure above 95 mmHg.

- Participant has another chronic ocular disease that may confound the results of visual
tests, such as age-related macular degeneration, cataract of possible visual
significance, or uncontrolled glaucoma.

- Participant drinks more than the equivalent of two glasses of wine per day on average,
has a history of alcohol abuse, or has a severe liver illness.

- Participant s liver is > 3 cm below the right costal margin.

- Participant has a muscle disease.

- Participant is currently taking a medication known to cause elevated liver function
tests including statins/HMG-Co-A reductase inhibitors (e.g., lovastatin, simvastatin);
anti-epileptic medications (e.g., carbamazepine, phenytoin, phenobarbital);
tetracycline or its derivatives, if used chronically; acetaminophen, if used
daily/chronically; amiodarone; and any other medications with known significant liver
toxicity.