Background

Ambroxol is a mucolytic compound and the main ingredient of over-the-counter cough medicines sold in many countries. Syrup, tablet, and other forms are used at doses of 30 to 120 mg per day to reduce or thin mucous secretions and ease sore throat pain. The most common side effects are gastrointestinal. Ambroxol is unavailable in North America.

Interest in repurposing ambroxol to treat Parkinson’s disease stems from its activity as a molecular chaperone for the lysosomal enzyme glucocerebrosidase (GCase) (Maegawa et al., 2009). Loss-of-function mutations in the GCase gene, GBA1, are the leading genetic risk factor for the synucleinopathies Parkinson’s disease and dementia with Lewy bodies (DLB).

GCase activity and α-synuclein are linked: GCase deficiency causes pathologic accumulation of α-synuclein (Cullen et al., 2011), while GCase overexpression in brain reduces pathology and memory deficits in a synucleinopathy mouse model (Sardi et al., 2011). GCase activity is also diminished in cases of idiopathic PD and DLB without GBA1 mutations, and lower GCase correlates with earlier disease onset and worse cognitive and non-motor symptoms (Gegg et al., 2012; Chiasserini et al., 2015). GBA1 mutations were originally identified as the cause of parkinsonism in Gaucher’s disease, a lysosomal storage disorder characterized by the buildup of sphingolipids, and, in some cases, α-synuclein pathology (Lwin et al, 2004; Mazzulli et al., 2011).

In cells derived from patients with Gaucher’s or PD, ambroxol stabilized mutant GCase and facilitated its movement from the endoplasmic reticulum to lysosomes, increasing protein levels, enzyme activity, and lysosome function (Bendikov-Bar et al., 2013; McNeill et al., 2014). In flies with GCH1 mutations, ambroxol increased GCase activity, decreased ER stress, and protected motor function (Sanchez-Martinez et al., 2016).

In wild-type and GCH1-mutation-bearing mice, ambroxol induced brain GCase activity, and in mice overexpressing human α-synuclein, it decreased total and phosphorylated α-synuclein (Migdalska-Richards et al., 2016). In a mouse model of amyotrophic lateral sclerosis, ambroxol improved motor function and extended survival (Bouscary et al., 2019).

In healthy, non-human primates, daily ambroxol increased brain GCase activity (Migdalska-Richards et al., 2017).

Findings

In December 2016, an open-label pilot study in Parkinson’s disease, called AIM-PD, began at University College London. It enrolled 23 patients, half with a GBA1 mutation and half without, to assess safety, tolerability, CNS penetration and target engagement of ambroxol. After a one-month dose escalation, participants received 1,260 mg per day for five months—a dose 10 times higher than used to treat cough. Primary endpoints were ambroxol levels and GCase activity in CSF. Secondary outcomes included safety, GCase protein and activity, α-synuclein and tau in CSF and blood, and measures of cognitive and motor function.

Results were presented at a 2018 AD/PD conference and later formally published (Apr 2018 conference news; Mullin et al., 2020). Eighteen patients completed the study, five withdrew due to problems related to lumbar-puncture, but no serious adverse events were reported. The study met its primary endpoints: Ambroxol crossed the blood-brain barrier and in the CSF achieved a concentration of 11 percent of blood levels. CSF GCase activity decreased by 19 percent, consistent with ambroxol’s ability to inhibit the enzyme at neutral pH. Other findings included a 35 percent increase in CSF GCase protein levels, and a significant increase in CSF α-synuclein, with no change in tau or glucosyl ceramide. Participants improved on the Unified Parkinson’s Disease Rating Scale, mainly due to gains in motor function. Drug effects were detected in patients with or without GBA mutations.

In November 2015, a Phase 2 trial at the Parkwood Institute, Ontario, Canada, began recruiting 75 people with Parkinson’s and mild to moderate dementia (Silveira et al., 2019). Participants were to receive 525 or 1,050 mg daily ambroxol or placebo for one year. Primary outcomes are changes on ADAS-Cog and ADCS-CGIC; secondary outcomes include additional cognitive measures, movement testing, CSF biomarkers of α-synuclein, tau, phospho-tau, and Aβ, MRI measures of ventricular volume and hippocampal atrophy. The trial also assesses GCase activity in lymphocytes and plasma ambroxol levels. As of July 2018, the trial had enrolled 25 patients, with 10 completing one year of treatment (see AAIC abstract). Blood levels of ambroxol were sufficient to increase GCase activity in peripheral lymphocytes. The drug was well tolerated. The trial is slated to end in December 2021. Sometime after this report, the lower-dose group was discontinued and the enrollment target reduced to 58. Enrollment is expected to be complete in the summer of 2021.

In May 2020, the same investigators registered an additional Phase 2 trial to test a higher dose of 1,350 mg/day. The study will treat 15 people with PDD for one year, with primary outcomes of MMSE, safety, pharmacokinetics, and GCase activity in blood and CSF.

In March 2019, an open-label Phase 2 began in Israel for 60 participants with Gaucher’s disease who responded poorly to enzyme replacement therapy.

Japanese researchers published a pilot study on five people with neurological symptoms due to Gaucher’s, in whom open-label ambroxol ameliorated muscle spasms (Narita et al., 2016). In September 2019, this group registered a larger, open-label trial in 25 patients in Japan.

In spring 2021, a Phase 2 trial will begin testing ambroxol in people with dementia or mild cognitive impairment with Lewy Bodies. The study, at seven centers in Norway, will enroll 172 participants for 18 months treatment with 1,320 mg daily or placebo. Treatment groups will be stratified based on ApoE4 and CSF Aβ42 concentrations. Primary outcomes are adverse events, treatment discontinuations, and other safety signs, plus measures of cognition, functional decline, and neuropsychiatric symptoms. Secondary outcomes will assess sleep, cognitive fluctuations, motor symptoms, and falls. The trial offers a one-year, open label extension.

In May 2020, an investigator-initiated global registry of ambroxol use in 300 patients with Gaucher's or GBA-Parkinson's disease was listed as an observational study of real-world evidence on clinicaltrials.gov. In March 2021, it published data from the first 41 participants, reporting no severe adverse effects related to ambroxol, and clinical benefit in 25 of them (Istaiti et al., 2021). 

For details on ambroxol trials, see clinicaltrials.gov.