An Open Label Phase 2 Study of ManNAc in Subjects With GNE Myopathy

GNE myopathy, previously known as hereditary inclusion body myopathy (HIBM), is a rare,
autosomal recessive myopathy with onset in early adulthood that is characterized by
progressive muscle weakness and atrophy, which leads to wheelchair use and dependent care.
The causative gene, GNE, encodes the rate-limiting enzyme in the biosynthesis of sialic acid.
While the exact pathophysiology of GNE myopathy remains unknown, decreased sialic acid
production and subsequent hyposialylation of muscle glycoproteins are thought to be key
factors leading to muscle deterioration in GNE myopathy. This hypothesis is supported by
prevention of disease after administration of N-acetyl-D-mannosamine (ManNAc) in mouse models
of GNE myopathy. A recent first-in-human, Phase 1 single ascending dose study evaluated the
safety, pharmacokinetics, and pharmacodynamics of a single dose of 3,000, 6,000, or 10,000 mg
drug product-grade ManNAc in subjects with GNE myopathy (ClinicalTrials.gov NCT01634750; IND
No.78,091). ManNAc was safe and well-tolerated in all subjects who participated in this
study. In this Phase 2, open-label, single-center study we propose to administer ManNAc
orally to 12 subjects for 912 days (30 months). The objectives of the study are to assess the
safety, tolerability, pharmacokinetics, pharmacodynamics and biochemical efficacy of orally
administered ManNAc in GNE myopathy subjects and to evaluate disease-related biomarkers and
relevant clinical endpoints. In the first phase of pharmacokinetic assessment, two cohorts of
6 subjects will receive ManNAc at doses of 3,000 mg twice a day (6,000 mg per day) or 6,000
mg twice a day (12,000 mg per day) for 7 days while admitted to the NIH Clinical Center to
assess PK and safety. Safety and tolerability will be assessed on an individual basis. In the
second phase of the study, all subjects will receive treatment with ManNAc at a dose of 6,000
mg twice daily for the remainder of the study. Follow-up safety and efficacy evaluations will
occur at 42 days, and at 91 (3 months), 182 (6 months), 365 (12 months), 548 (18 months), 730
(24 months) and 912 (30 months) days. Safety lab evaluation will be performed also at 456 (15
months), 638 (21 months) and 820 (27 months) days either at the NIH clinical center or
subjects home laboratory or physician s office. Final dosing will occur at the 30-month
visit. After the final dose, all Grade (Bullet)2 AEs at least possibly related to study drug
will be followed to resolution. Safety will be evaluated by adverse events (AEs), clinical
laboratory tests, vital signs, and physical examinations. PK will be assessed for plasma
ManNAc and Neu5Ac. Biochemical efficacy will be measured by change in the sialylation of
proteins and clinical efficacy will be assessed using a battery of clinical assessments
deemed to be relevant based on disease natural history.

- INCLUSION CRITERIA:

- Subject is age 18-60 years, inclusive, and of either gender.

- Subject has a diagnosis of GNE myopathy based upon a consistent clinical course and
identification of two GNE gene mutations.

- Subject must be willing to stop any treatment with ManNAc, sialic acid, intravenous
immunoglobulin (IVIG), and/or other supplements containing sialic acid (e.g. St. John
s wort, sialyllactose) 90 days prior to dosing and remain off such treatment for the
duration of the trial.

- Subjects must have a body mass index (BMI) between 18 and 30 kg/m2, with a bodyweight
of >50 kg

- Subjects must have 20-75% of predicted strength measured by QMA at baseline on at
least one of the following: 1) ankle dorsiflexion, 2) knee flexion, 3) hip extension,
4) grip, 5) elbow flexion, shoulder abduction

- 20-75% of predicted strength measures by OMA at baseline, or

- If predicted muscle strength above 75%, a documented change of at least 10% per
year.

- Subject has the ability to travel to the NIH Clinical Center for admissions.

- Subject has an INR less than or equal to 1.5 and must have stopped warfarin and other
anticoagulants 2 weeks prior and after muscle biopsy procedures. Aspirin and
clopidogrel should be stopped 3 days and 5 days before the procedure, respectively.

- Subject must be able to comply with requirements of the protocol, including blood
collection, drug administration, muscle MRI/MRS, muscle biopsy and muscle strength
assessments.

- If a woman of reproductive age, subject must be willing to use an effective method of
contraception for the duration of the trial.

- Subject must be able to provide informed consent.

EXCLUSION CRITERIA:

- Subject had a clinical significant infection or medical illness 30 days prior to the
first protocol visit.

- Subject has a psychiatric illness or neurological disease that would interfere with
the ability to comply with the requirements of this protocol. This includes, but is
not limited to, uncontrolled/untreated psychotic depression, bipolar disorder,
schizophrenia, substance abuse or dependence, antisocial personality disorder, panic
disorder, or behavioral problems, which interfere with effective communication.

- Subject has hepatic laboratory parameters (AST, ALT, GGTP) or renal laboratory
parameters (creatinine, BUN) greater than 3 times the upper limit of normal.

- Subject has known adverse reactions to anesthetic or sedatives utilized for muscle
biopsy.

- Subject is anemic (defined as Hematocrit <30%) or has platelets <100,000 or white
blood cell count less than 3,000.

- Subject shows evidence of clinically significant cardiovascular, pulmonary, hepatic,
renal, hematological, metabolic, or gastrointestinal disease, or has a condition that
requires immediate surgical intervention.

- Subject is pregnant or breastfeeding at any time during the study.

- Subject has received treatment with another investigational drug, investigational
device, or approved therapy for investigational use less than 90 days prior to the
first protocol visit.

- Subject has hypersensitivity to DEX-M74/ManNAc or in the judgment of the investigator,
has a condition that places the subject at increased risk for adverse effects.

- Subject has received ManNAc, sialic acid, intravenous immunoglobulin (IVIG), and/or
other supplements containing sialic acid (e.g. St. John s wort, sialyllactose) less
than 90 days prior to the first protocol visit.

- The presence of persistent diarrhea or malabsorption that could interfere with the
subject s ability to absorb drugs or to tolerate ManNAc therapy.