Ambroxol hydrochloride is a commercially available cough and cold medicine that has shown promise as a pharmacological chaperone for Gaucher disease. Chaperone therapy uses small molecule compounds that can specifically bind to faulty enzymes and help them fold properly.

If clinical trials are successful, ambroxol hydrochloride could provide a new therapeutic avenue to treat both non-neuropathic (type 1) and neuropathic Gaucher disease (types 2 and 3). Neuropathic Gaucher disease patients do not respond well to enzyme replacement therapy (ERT), a common treatment for Gaucher disease, because the infused enzyme cannot cross the blood-brain barrier. Because ambroxol hydrochloride can cross the blood-brain barrier, it has the potential to treat neuropathic symptoms of the disease.

How ambroxol hydrochloride works

Gaucher disease is caused by mutations in the GBA gene encoding the glucocerebrosidase enzyme. This enzyme normally breaks down a complex lipid molecule called glucocerebroside in a specialized compartment in the cell called the lysosome.

The mutation causes the newly synthesized enzyme to fold incorrectly. Therefore, the enzyme is targeted for degradation by the quality control system of the cells, which prevents it from reaching its destination, the lysosomes. Hence, glucocerebroside, the substrate of glucocerebrosidase, accumulates in the lysosomes and causes symptoms such as enlarged liver and spleen, bone pain and fragility, low counts of red blood cells (anemia) and platelets (thrombocytopenia), and neuropathy.

Ambroxol hydrochloride is a small molecule that binds to the glucocerebrosidase enzyme and facilitates its proper folding. It is hoped that this will facilitate the translocation of glucocerebrosidase to the lysosomes, where it can metabolize glucocerebroside and alleviate the symptoms of the disease.

Ambroxol hydrochloride in clinical trials

Preliminary investigations showed that ambroxol hydrochloride can bind to the glucocerebrosidase enzyme and increase its concentration and activity in the lysosome of primary cells derived from Gaucher disease patients as well as in experimental animals.

For example, in skin fibroblasts isolated from Gaucher disease patients with various mutations in the gene encoding for the glucocerebrosidase enzyme (namely the N370S, F213I, N188S/G193W, and R120W mutations), ambroxol hydrochloride significantly increased enzyme activity.

Similarly, when normal mice were treated with ambroxol hydrochloride for a week, the activity of glucocerebrosidase enzyme was significantly increased in the brains, spleens, and hearts of the animals. Ambroxol hydrochloride treatment of healthy adult male cynomolgus monkeys for 28 days also increased glucocerebrosidase activity by 20 percent in different parts of the animals’ brains,  such as the midbrain, cortex, and striatum.

An open-label pilot study was conducted in five neuropathic Gaucher disease patients to assess the safety, neurological efficacy, and tolerability of high-dose oral ambroxol hydrochloride in combination with ERT. The study showed that high-dose oral ambroxol hydrochloride had good safety and tolerability. It permeated the blood-brain barrier and significantly increased glucocerebrosidase activity in white blood cells. It also markedly improved myoclonus (quick, involuntary muscle jerks), seizures, and pupillary light reflex dysfunction in all patients. In two patients, ambroxol hydrochloride treatment led to relief from myoclonus, resulting in the recovery of gross motor function, allowing the patients to walk again.

A single-arm, Phase 2 clinical trial (NCT03950050) is investigating the safety and efficacy of ambroxol hydrochloride in patients with type 1 Gaucher disease who showed a suboptimal response to ERT. The study is recruiting up to 60 participants at the Shaare Zedek Medical Center in Israel and is expected to be completed in March 2021.

During the 12-month study, patients will receive a total dose of 600 mg per day of ambroxol hydrochloride. The primary outcome measures that will be evaluated include platelet counts, bone mineral density, and Lyso-GB1 biomarker. Secondary outcomes, such as adverse events and fatigue severity, will also be monitored.


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