Ambroxol May Hold Promise in Parkinson Disease With and Without GBA1 Mutations


Findings from the small-scale study showed that the drug had target engagement with β-glucocerebrosidase as well as cerebrospinal fluid penetration.

Results from the phase 2 AiM-PD study of ambroxol demonstrated a safe and tolerable profile, with the drug meeting cerebrospinal fluid (CSF) penetration and target engagement endpoints with β-glucocerebrosidase (GCase) in patients with Parkinson disease (PD).

The single-center, open-label, phase 2 trial (NCT02941822) included 24 participants and evaluated the safety, tolerability, and pharmacodynamics of ambroxol in patients with PD. Of the 24 patients with moderate PD, 18 ultimately completed the study.

Seventeen of the 18 patients were included in the primary analyses, including 8 patients with glucocerebrosidase gene (GBA1) mutations and 9 without. Over the course of 6 months, patients self-administered ambroxol 3 times daily at 5 intra-dose escalations: days 1 to 7, 60 mg; ; days 8 to 14, 120 mg; days 15 to 21, 180 mg; days 22-28, 300 mg; and days 29 to 186, 420 mg.

Investigators assessed the detection of ambroxol in CSF and change in CSF GCase activity at 186 days. In addition, the investigators recorded CSF and serum α-synuclein levels, as well as changed in PD symptoms measured via the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS).

At day 186, investigators recorded a 156-ng/mL increase in the level of ambroxol in CSF (95% lower confidence limit, 129 ng/mL; P <.001). Additionally, investigators recorded a 19% decrease from baseline CSF GCase activity (0.059 nmol/mL per hour; 95% CI, -0.115 to -0.002; P = .04) and a mean increase of 88 pmol/L (35%) in CSF GCase protein levels (95% CI, 40-137; P = .002). They also observed a mean increase of 50 pg/mL (13%) in total CSF α-synuclein concentration (95% CI,14-87; P = .01). Notably, investigators reported an improvement of 8.7 points on the MDS-UPDRS (95% CI, —15.3 to –2.2; P&thinsp;=&thinsp;.01). This change was primarily associated with the part 3 motor score, which showed an improvement of 6.8 points from baseline to day 186 (95% CI, -10.4 to -3.1; P = .001).

No serious adverse events were recorded, and patients found the drug to be well tolerated. The total amount of AEs were 176, 121 of which were unrelated to treatment and 32 unlikely to be related. Some of the AEs that were perceived to be related to the treatment were nausea, vomiting, burning sensation after swallowing the product, and loose stool.

Ambroxol appeared to have no adverse effects on motor features of the patients’ PD. A future placebo-controlled trial in needed to better understand the association between ambroxol and changes in the natural progression of PD.


Mullin S, Smith L, Lee K, et al. Ambroxol for the treatment of patients with Parkinson disease with and without glucocerebrosidase gene mutations. JAMA Neurol. Published online January 13, 2020. doi:10.1001/jamaneurol.2019.4611.

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