Safety and Efficacy of Clenbuterol in Individuals With Late-onset Pompe Disease and Receiving Enzyme Replacement Therapy

This is a 52 week Phase I/II double-blind, randomized, placebo-controlled study of adjunctive
clenbuterol in LOPD (Table 2, Section 6). All subjects will be evaluated at Week 0 and Week 6
to establish a baseline for motor function testing. At Week 6, subjects will be randomized
3:2 to clenbuterol or placebo, and evaluated for safety and efficacy during the Week 12 and
18 visits. The Investigational Drug Service will maintain double-blinding by providing either
the study drug or placebo (over-encapsulated tablets) directly to subjects. The drug (or
placebo) will be initiated at the Week 6 visit in a staged manner (first once daily and later
BID), and the dose will be increased at the Week 12 visit in a similarly staged manner to
minimize AEs and related attrition. All subjects will return for a final visit after a total
of 52 weeks in the study.

In terms of standard of care, the subject will have two clinical visits (charged to the
subject and/or the subject's insurance company), one at the initiation of the study drug
(baseline) and one at the study completion (52 weeks). Study drug will be attempted to be
initiated during the "off week", approximately one week following a dose of ERT, and ERT will
continue throughout the duration of the study. Thereafter, study visits will be during the
"off week". The 6, 12, and 18 week visits will be research visits (not charged to the subject
and/or the subject's insurance company) in order to determine subject's overall health status
and measure early signs of motor improvement. The initial dose of clenbuterol will be 40 mcg
per oral each morning for one week, followed by 40 mcg BID for the next 5 weeks until the
week 12 visit. If the 40 mcg BID per oral is well tolerated, the dose will be increased to 80
mcg each morning/40 mcg each evening for one week, followed by 80 mcg BID for the next 5
weeks until the Week 18 visit. If 80 mcg BID is tolerated at Week 18, the subject will
continue on that dose until Week 52.

Compliance will be discussed at the Week 6, Week 12, and Week 18 visits. The subject will
have phone visits during Week 1, 7, 13, 36, and 52, and compliance will be discussed then. We
will call subjects daily during the first week following initiation of study drug (Week 7)
and dosage escalation (Week 13) to support subjects through the early adverse effects of
tachyphylaxis that may lead to premature termination. An interim call will occur during Week
36 to monitor compliance. Subjects who admit non-compliance, missing >6 doses of the study
drug, will be considered non-compliant and withdrawn from the study. Subjects will be called
during Week 1 and Week 52, 3 days following the muscle biopsy. All phone calls will review
AEs (Table).

The efficacy of clenbuterol treatment during ERT in patients with LOPD will be evaluated with
muscle and pulmonary function testing as the primary endpoints. A secondary endpoint, the
urinary Glc4 biomarker, will be monitored when the subjects are evaluated at baseline, week
18 and week 52. The impact of enhanced CI-MPR-mediated uptake of GAA will be analyzed by
comparing the muscle function, pulmonary function, and biochemical correction of muscle in
subjects with LOPD treated with ERT, both prior to and during simultaneous β2 agonist
therapy.

Inclusion Criteria:

1. Diagnosis of Pompe disease by blood acid alpha-glucosidase assay and acid
alpha-glucosidase gene sequencing,

2. Age: 18+ years at enrollment,

3. Receiving ERT at standard dose (20 mg/kg every 2 weeks) for at least 52 weeks,

4. Subjects are capable of giving written consent.

Exclusion Criteria:

1. Continuous invasive ventilation (via tracheostomy or endotracheal tube)

2. Clinically relevant illness within two weeks of enrollment including fever > 38.2 C,
vomiting more than once in 24 hours, seizure, or other symptom deemed contraindicative
to new therapy.

3. Chronic heart disease (Myocardial infarction, arrythmia, cardiomyopathy)

4. Tachycardia

5. History of seizure disorder

6. Hyperthyroidism

7. Pheochromocytoma

8. Pregnancy

9. History of diabetes

10. History of hypersensitivity to beta 2-agonist drugs such as albuterol, levalbuterol
(Xopenex), bitolterol (Tornalate), pirbuterol (Maxair), terbutaline, salmeterol
(Serevent),

11. Patients on a non-standard schedule for ERT; for example, weekly infusions as opposed
to infusions every two weeks.

12. Treatment for asthma in the previous 12 months.

13. The use of the following concommitant meds is prohibited during the study:

- diuretics (water pill);

- digoxin (digitalis, Lanoxin);

- beta-blockers such as atenolol (Tenormin), metoprolol (Lopressor), and
propranolol (Inderal);

- tricyclic antidepressants such as amitriptyline (Elavil, Etrafon), doxepin
(Sinequan), imipramine (Janimine, Tofranil), and nortriptyline (Pamelor);

- Monoamine oxidase inhibitors such as isocarboxazid (Marplan), phenelzine
(Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine
(Parnate); or

- other bronchodilators such as albuterol, levalbuterol (Xopenex), bitolterol
(Tornalate), pirbuterol (Maxair), terbutaline (Brethine, Bricanyl), salmeterol
(Serevent), isoetherine (Bronkometer), metaproterenol (Alupent, Metaprel), or
isoproterenol (Isuprel Mistometer).