A Phase 2 Study to Evaluate the Dose and Pharmacodynamic Efficacy of Sialic Acid-Extended Release (SA-ER) Tablets in Patients With GNE Myopathy or Hereditary Inclusion Body Myopathy

GNE myopathy or hereditary inclusion body myopathy (HIBM) is a severe progressive metabolic
myopathy caused by a defect in the biosynthetic pathway for sialic acid (SA). Substrate
replacement therapy is a potential therapeutic strategy based on the success of replacing
missing SA and reducing muscle disease in a relevant mouse model of the human disease
(Malicdan et al., 2009). Successful use of SA replacement therapy in humans is believed to
depend upon providing steady long-term exposure to the compound in an extended release form
(such as Sialic Acid-Extended Release [SA-ER]), given SA's short half-life. Following a
Phase 1 study to establish the pharmacokinetics (PK) for SA-ER, Ultragenyx is conducting
this study to assess the dose and potential pharmacodynamic effect of restoring sialylation
of muscle by treatment with SA-ER at two dose levels as compared to placebo when
administered over two 24 week periods of time. The study will also evaluate safety, as well
as the effect of SA-ER on clinical measures of muscle strength, mobility, function and
self-reported disability and quality of life. Effects on muscle volume/mass and function
and on serum biomarkers will be evaluated as exploratory measures. These data should allow
the selection of a dose and the appropriate design for a Phase 3 clinical study.

Inclusion Criteria:

1. Must be between 18 and 65 years of age, inclusive.

2. Must be willing and able to provide written, signed informed consent after the nature
of the study has been explained, and prior to any research-related procedures.

3. Must have a documented diagnosis of GNE myopathy, HIBM, distal myopathy with rimmed
vacuoles (DMRV), or Nonaka disease due to previously demonstrated mutations in the
gene encoding the GNE/MNK enzyme. Genotyping will not be conducted in this protocol.

4. Must be able to walk 20 meters independently (may use orthotics and assistive
devices).

5. Must be able to provide reproducible force in bilateral elbow flexors and knee
extensors during hand-held dynamometry testing (unilateral between test variability
of < 15% for both muscle groups).

6. Must be willing and able to comply with all study procedures including fine needle
muscle biopsies of the upper (e.g., triceps brachii or posterior deltoid) and lower
(e.g., biceps femoris or vastus lateralis) extremities at Baseline and 24 and 48
weeks.

7. Sexually active subjects must be willing to use an acceptable method of contraception
while participating in the study.

8. Females of childbearing potential must have a negative pregnancy test at Screening
and be willing to have additional pregnancy tests during the study. Females
considered not of childbearing potential include those who have been in menopause for
at least two years, or have had tubal ligation at least one year prior to Screening,
or who have had total hysterectomy.

Exclusion Criteria:

1. Pregnant or breastfeeding at Screening or planning to become pregnant (self or
partner) at any time during the study.

2. Use of any investigational product or investigational medical device within 30 days
prior to Screening, or requirement for any investigational agent prior to completion
of all scheduled study assessments.

3. Ingestion of N-acetyl-D-mannosamine (ManNAc), SA, or related metabolites; intravenous
immune globulin (IVIG); or anything that can be metabolized to produce SA in the body
for the prior 60 days.

4. Has a condition of such severity and acuity, in the opinion of the investigator, that
it warrants immediate surgical intervention or other treatment or may not allow safe
participation in the study.

5. Has had any hypersensitivity to SA or its excipients that, in the judgment of the
investigator, places the subject at increased risk for adverse effects.

6. Has a concurrent disease or condition that, in the view of the principal
investigator, places the subject at high risk of poor treatment compliance or of not
completing the study, or would interfere with study participation or would affect
safety.

7. Has serum transaminase (i.e., alanine aminotransferase [ALT], aspartate
aminotransferase [AST], or gamma-glutamyl transpeptidase [GGT]) levels greater than
three times the upper limit of normal or serum creatinine of greater than 2.0 mg/dL.