Assessment of Clemastine Fumarate as a Remyelinating Agent in Acute Optic Neuritis (ReCOVER)

Optic neuritis is an inflammatory, demyelinating disease of the optic nerve. It is most often
characterized by visual loss or blurred vision along with dyschromatopsiaaccompanied by pain
(especially with eye movement) and no demonstrable evidence of an alternate diagnosis such as
ischemia or retinal disease. It can also be associated with a swollen optic disc (Optic
Neuritis Study Group 1991, Hutchinson, W.M. 1976) and optic nerve enhancement on MRI
(Kupersmith 2002).

Functional high-throughput screening for compounds that promote remyelination presents a
major unmet need in the therapeutic arsenal for multiple sclerosis and other demyelinating
conditions such as optic neuritis. Screening for myelin repair is problematic, as functional
remyelination requires the presence of intact neuronal axons. Standard methods are not suited
for high-throughput formats. We performed a detailed screen of over 1500 FDA approved small
molecule drugs to identify agents that could be promising for remyelination. Engineered with
conical dimensions, our micropillar technology permitted resolution of the extent and length
of membrane wrapping from a single 2-dimensional image. Confocal imaging acquired from the
base to the tip of the pillars allows for the fluorescence detection of concentric wrapping
observed as "rings" of myelin membrane. The platform was formatted in 96-well plates,
amenable to semi-automated random acquisition and automated detection and quantification.
Upon initiating a screen of 1500 bioactive molecules, we identified Clemastine as a compound
that potentially enhances oligodendrocyte differentiation and remyelination. We then
validated this and other drugs in preclinical assays as well as in animal models of primary
myelination and remyelination after inflammatory and chemical demyelination. Together, our
findings illustrate the proof of concept for a novel high-throughput screening platform for
potential regenerative therapeutics in MS (Chan JR et al. 2014).

This study is intended to assess for clinical evidence of remyelination using Clemastine
Fumarate in patients with acute inflammatory injury causing demyelination of the anterior
visual pathway as a consequence of acute demyelinating optic neuritis. The study is designed
to assess tolerability and clinical efficacy of Clemastine using outcomes intended to assess
for (a) adverse events and (b) recovery of myelin. This study is complementary to an earlier
study evaluating clemastine in chronic demyelinated optic neuropathy and serves as part of a
proof of concept program intended to evaluate methods for conducting remyelination trials in
MS.

Inclusion Criteria:

- Patients diagnosed or suspected to have an acute demyelinating optic neuritis in at
least one eye within 2 weeks from the onset of any visual symptom other than pain

- Use of disease modifying therapies is not a contraindication

- Use of appropriate contraception during period of trial (women)

- Understand and signed informed consent

Exclusion Criteria:

- Other major ophthalmologic disease / concomitant ophthalmologic disorders (e.g.
diabetes, macular degeneration, glaucoma, severe myopia, etc)

- Disc hemorrhages in qualifying eye

- No light perception in qualifying eye

- Simultaneous bilateral optic neuritis

- Cotton wool spots in qualifying eye

- Macular star in qualifying eye

- History of significant cardiac conduction block

- History of cancer

- Suicidal ideation or behavior in 6 months prior to baseline

- Pregnancy, breastfeeding, or planning to become pregnant

- Involved with other study protocol simultaneously without prior approval

- Concomitant use of any other putative remyelinating therapy as determined by
investigator

- Serum creatinine > 1.5 mg/dL; aspartate transaminase (AST), alanine transaminase
(ALT), or alkaline phosphatase > 2 times the upper limit of normal

- History of drug or alcohol abuse within the past year

- Untreated B12 deficiency (as determined by B12 serological assessments and metabolites
including methylmalonic acid (MMA) and homocysteine) or untreated hypothyroidism

- Clinically significant cardiac, metabolic, hematologic, hepatic, immunologic,
urologic, endocrinologic, neurologic, pulmonary, psychiatric, dermatologic, allergic,
renal, or other major diseases that, in the PI's judgment, may affect interpretation
of study results or patient safety

- History or presence of clinically significant medical illness or laboratory
abnormality that, in the opinion of the investigator would preclude participation in
the study.