Clenbuterol as an add-on therapy appears to be safe and significantly improves the effectiveness of enzyme replacement therapy (ERT) in patients with late-onset Pompe disease, according to the results from a Phase 1/2 trial.
The study, “Correction of Biochemical Abnormalities and Improved Muscle Function in a Phase I/II Clinical Trial of Clenbuterol in Pompe Disease,” was published in the journal Molecular Therapy.
Pompe disease is caused by a mutation in the GAA gene that leads to a deficiency in an enzyme called acid alpha-glucosidase. This leads to an accumulation of glycogen in a cellular compartment called the lysosome, causing damage to muscles and nerve cells throughout the body.
Patients with Pompe disease are generally treated with ERT. However, effective doses for ERT in Pompe disease are up to 100 times higher than those in similar disorders.
This is because there is a low abundance of cation-independent mannose-6-phosphate receptor (CI-MPR) on skeletal muscles. CI-MPR are proteins located on the surface of cells that help target enzymes, such as those administered through ERT, to lysosomes.
Animal studies have shown that a compound called clenbuterol increases the amount of CI-MPR, thereby increasing the efficacy of ERT.
Researchers from Duke University School of Medicine in Durham, North Carolina, hypothesized that administering clenbuterol as an add-on therapy to standard ERT may help improve the treatment of Pompe disease patients.
Duke researchers conducted a 52-week, Phase 1/2 randomized study (NCT01942590) to assess the safety and efficacy of clenbuterol in patients with late-onset Pompe disease (LOPD) who were stably treated with ERT.
Researchers recruited 13 participants, 11 of whom completed the study.
Use of clenbuterol was found to be safe with no incidence of serious therapy-related adverse events. The minor adverse events included slightly high levels of creatine kinase (a marker of muscle damage), muscle spasms, and tremors.
Researchers used the six-minute walk test to determine the effectiveness of treatment. At week 52, patients in the clenbuterol group increased the six-minute walk test distance by an average of 16 meters.
The participants’ maximum inspiratory pressure, a measure of inspiratory muscle strength, increased by an average of 8% for patients in the clenbuterol group.
Researchers also conducted muscle function assessments, which included the gait, stairs, gower, and chair (GSGC) test as well as the quick motor function test. Results showed that the GSGC test improved by an average of two points while the quick motor function test score improved by an average of seven points in the clenbuterol group.
At the molecular level, use of clenbuterol was associated with a decrease in glycogen levels in the vastus lateralis (a muscle in the thigh) by 50% at week 52.
Also, an analysis of gene activity following clenbuterol add-on treatment revealed more normal muscle gene activity for 38 of the 44 genes related to Pompe disease.
The placebo group demonstrated no significant changes over the course of the study compared to baseline (start of the study). Researchers said the difference in the length of time that the control group and the clenbuterol group spent on ERT did not allow for the comparison of results between the groups.
“This study provides important preliminary data regarding the safety and efficacy of clenbuterol in participants with LOPD on ERT,” the investigators wrote.
“The benefits demonstrated following oral clenbuterol in patients with LOPD support the further development of this adjunctive therapy for the treatment of Pompe disease.”