Oral Guanabenz for Multiple Sclerosis

OBJECTIVE:

This Phase 1 clinical study will aim to determine whether therapeutically adequate dosages of
guanabenz are safe and well tolerated in patients with multiple sclerosis (MS). It will
further provide pharmacokinetic data important for determination of optimal dosing schedule
for possible future Phase 2 study.

STUDY POPULATION:

Six patients, ages between 18-55 inclusive, and diagnosis of definite multiple sclerosis by
2010 Revised McDonald Diagnostic Criteria (Polman et al, 2010) will be enrolled. All patients
will have been on treatment with glatiramer acetate, a Food and Drug Administration (FDA)
approved disease-modifying therapy, for a minimum of year. Four of the patients will be
clinically stable with no clinical relapse in the preceding year and no evidence of active
inflammation by MRI during the 2-month screening period; 2 patients will be selected based on
evidence of on-going, active inflammation seen by MRI during the screening period.

DESIGN:

In this open-label, single site, dose escalation study, the maximum tolerated dose (MTD) of
guanabenz in MS patients will be determined. Patients will be screened for participation
under the existing MS natural history study 89-N-0045. Sequential patient enrollment will be
spaced at least 6 weeks apart. Five study drug doses will be explored: 4mg, 8mg, 16mg, 32mg
and 64mg. Dose escalation will ensue if the preceding dose is tolerated, defined both by
patient-reported outcomes and objective clinical and imaging assessments. Patients will be
maintained on lower doses (4mg-16mg) for 14 days and on higher doses (32 and 64mg) for 28
days.

OUTCOMES:

The primary outcome is MTD, defined as the maximum dose that produces dose-limiting toxicity
(DLT) in at most 2 out of the 6 participants. Secondary outcomes include patient-reported
outcomes, objective clinical and imaging assessments at 32mg and 64mg, and pharmacokinetics.

- INCLUSION CRITERIA:

- MS as defined by the 2010 Revised McDonald MS Diagnostic Criteria (19)

- Age 18-55, inclusive, at the time of the first screening baseline visit

- EDSS 1.0 to 6, inclusive, at the time of the first screening baseline visit

- Able to provide informed consent

- Willing and able to participate in all aspects of trial design and follow-up

- Undergoing treatment with glatiramer acetate for a period of at least 1 year prior to
enrollment in the study

- For female patients, agreeing to commit to the use of a reliable/accepted method of
birth control (i.e. hormonal contraception, including

birth control pills, injected hormones, and vaginal ring; intrauterine device; barrier
methods with spermicide, including diaphragm and condom; or surgical sterilization,
including hysterectomy, tubal ligation, and vasectomy) for the duration of the study

ADDITIONAL INCLUSION CRITERION FOR ACTIVE MS COHORT

-Development of new T2 hyperintense or contrast enhancing lesions by MRI during the
screening phase, but 3 such lesions on any single scan

EXCLUSION CRITERIA:

- Alternative diagnoses that better explain neurological disability and MRI findings

- Clinically significant medical condition that, in the best judgment of the
investigators, may expose the patient to undue risk of harm or prevent the patient
from completing the study (examples include, but are not limited to, cerebrovascular
disease, substance abuse, ischemic cardiomyopathy, clotting disorder, brittle
diabetes, neurodegenerative disorder)

- Undergoing treatment with medications that may interact with guanabenz, including
anti-hypertensive agents and/or agents leading to increase in catecholamines (such as
tricyclic antidepressants and monoamine oxidase inhibitors)

- Medical contraindication to MRI

- Determination, in the best judgment of the investigators, of the need to treat a
prospective participant with steroids for management of MS during the screening period

- Pregnant or breastfeeding woman

- Abnormal screening/baseline blood tests exceeding any of the limits defined below:

A) Serum alanine transaminase or aspartate transaminase levels greater than 3 times the
upper limit of normal values

B) Total white blood cell count < 3000/mm3

C) Platelet count < 85000/mm3

D) Serum creatinine level > 2.0 mg/dl and eGFR (estimated glomerular filtration rate) < 60

ADDITIONAL EXCLUSION CRITERIA FOR STABLE MS COHORT

- Evidence of 1 or more clearly documented MS relapses within the last 1 year

- Development of more than 2 lesions per year relative to an MRI performed at least one
year before the first screening MRI (the prior MRI can be an outside MRI)

- Development of new T2 hyperintense or contrast-enhancing lesions by MRI during the
screening phase