Phase I Clinical Trial of ManNAc in Patients With GNE Myopathy or Hereditary Inclusion Body Myopathy (HIBM)

Hereditary inclusion body myopathy (HIBM) is an autosomal recessive, neuromuscular disorder
characterized by progressive muscle weakness with onset in early adulthood. The causative
gene, GNE, codes for the bifunctional enzyme uridine diphospho-N-acetylglucosamine
(UDP-GlcNAc)-2-epimerase/N-acetylmannosamine (ManNAc) kinase (GNE/MNK), which catalyzes the
first 2 steps in the biosynthesis of sialic acid. The subsequent paucity of sialic acid
production is presumed to cause decreased sialylation of HIBM muscle glycoproteins, resulting
in muscle deterioration. In this Phase 1, randomized, placebo-controlled, double-blind,
escalating single-dose study, we propose to provide ManNAc (N-acetyl-D-mannosamine
monohydrate) orally as a liquid solution to 3 cohorts of 6 subjects (Cohorts A, B, C) at
doses of 3,000 mg, 6,000 mg, and 10,000 mg ManNAc, respectively, or up to the maximum
tolerated dose (MTD). The objectives of this study are to evaluate the safety, tolerability,
and pharmacokinetics (PK) of a single dose of orally administered ManNAc to HIBM subjects, to
identify the MTD of a single dose of orally administered ManNAc to HIBM subjects, and to
explore the effect of a single dose of ManNAc on potential pharmacodynamic (PD) markers of
HIBM. All subjects will be randomly assigned in a 2:1 ratio to receive ManNAc (n equals 4) or
placebo (n equals 2) and the decision to dose-escalate will be the responsibility of the
Safety Review Committee (SRC). Safety will be assessed by adverse events (AEs), clinical
laboratory tests, vital signs, physical examinations, and electrocardiograms (ECGs). PK will
be assessed for both ManNAc and sialic acid.

- INCLUSIONI CRITERIA:

- Subject is 18-70 years, either gender, inclusive.

- Subject has a diagnosis of HIBM (or IBM2, GNE myopathy, DMRV or Nonaka myopathy) based
upon a consistent clinical course and identification of 2 GNE mutations. Molecular
confirmation of the diagnosis will be obtained for all subjects in the study.

- Subject must be willing to stop any treatment with ManNAc, sialic acid, IVIG, and/or
other supplements containing sialic acid (eg, St John s wort, sialyllactose) 30 days
prior to randomization and remain off such treatment for the duration of the trial.

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

- Subject (if a woman of reproductive age) must be willing to use an effective method of
contraception for the duration of the trial.

- Subject provides written informed consent.

EXCLUSION CRITERIA:

- Subject has a severe disease manifestation that would interfere with the ability to
comply with the requirements of this protocol.

- 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, or
panic disorder.

- 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 a QTcB >450 msec (males) or QTcB >470 msec (females).

- Subject is anemic (defined as two standard deviations below normal for age and
gender).

- 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 within 4 weeks of initial
screening.

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