Ambroxol as a Treatment for Parkinson's Disease Dementia

The increasing prevalence of dementia is a serious threat to the medical system and society. About 500,000 Canadians are affected with dementia, and this number will rise to more than 1 million in the next 20 years. Dementia already costs the Canadian economy 15 billion dollars per year. While much of the focus of dementia is on Alzheimer's disease, autopsy studies suggest that up to 30% of dementia is due to diseases caused by abnormal alpha-synuclein accumulation (Synucleinopathies) such as Parkinson's Disease Dementia (PDD). People with Parkinson's disease (PD) typically present with motor symptoms, but the disease is also characterized by insidious cognitive decline, increasing in relation to disease duration. Glucocerebrosidase (GCase) is a degradative enzyme that resides in a subcellular compartment called the lysosome, and cleaves a neutral glycolipid, glucocerebroside, present in the plasma membrane of most cells. GCase is intimately linked with PD. Being an "asymptomatic carrier" of a GCase mutation is currently the highest genetic risk factor for PD, with some studies suggesting up to 1/3 of patients carry mutations.

Reductions in GCase activity most likely also plays a role in sporadic PD, as these patients have lower levels of GCase in their brain and cerebrospinal fluid, even when they do not carry a mutant GCase allele. Reducing GCase genetically or pharmacologically in animal studies results in cognitive impairment. The aggregates causing the impairment can be cleared by re-introduction of normal GCase back into the brain. In addition, overexpressing GCase in the brain of a PD mouse model improves cognition. GCase therefore appears to be an excellent target for a therapy that addresses the underlying pathophysiology of PDD to improve or stop disease progression.

Ambroxol is an expectorant that has been available over the counter in more than 50 countries for over 30 years. Recently, the Mahuran Lab identified Ambroxol by screening a library of compounds as an agent that stabilizes wild-type (normal) GCase. By stabilizing GCase, Ambroxol is able to markedly increase GCase protein and activity in normal and Gaucher disease fibroblasts at doses of 10 micromolar. Ambroxol can also increase GCase in normal mouse neuronal cultures to more than 150% of normal at a dose of 30 micromolar. Ambroxol has good lipophilicity (cLogP = 2.8) and low polar surface area (PSA 58 Å2), predicting good CNS penetration. Unpublished studies performed by ExSAR corporation demonstrate that in single and multiple dose experiments in rats, Ambroxol crossed rapidly into the brain and exhibited brain to plasma concentration ratios of greater than 10 indicating outstanding CNS penetration. Ambroxol has an excellent safety record, and has been studied in >15,000 patients in more than 100 trials. Ambroxol is sold over the counter in much of the world as an expectorant at doses of 75-120 mg/day. Furthermore, Ambroxol is considered so safe that it is approved for intravenous use in pregnant women at a dose of 1000 mg/day IV (15 mg/kg) to improve fetal lung maturation before preterm delivery. Clinical trials in more than 390 pregnant women have been performed using doses up to 3000 mg in one day and 1300 mg/day for up to 33 days. Critically ill neonates have also been given doses as high as 30 mg/kg for respiratory distress. The fact that Ambroxol has been used at very high doses in pregnant women and neonates suggests that these doses are safe. In pilot studies, Ambroxol was effective at improving GCase function in humans. In a trial aimed at non-neurological Gaucher disease, 12 patients received 150 mg/day for 6 months, and all but one had some measureable improvement. The best response was in the lightest patient (who received 3 mg/kg/day), suggesting that Ambroxol was under dosed. Ambroxol has also been administered to three Japanese Gaucher disease patients with severe neurological disease, at 1000-3000 mg/day for 12-31 months. These patients had improvements in seizure frequency and neurological symptoms; one patient regained the ability to sit unsupported and to walk.

Ambroxol has never been examined in PD or Lewy Body Dementia patients; however, trials of pharmacological chaperone therapy have been suggested in a recent review in the journal "The Proceedings of the National Academy of Sciences." A successful outcome of this trial will greatly accelerate the development of therapeutics for neurodegenerative disease. This proposal outlines a completely novel pharmacological target for PDD, namely the enzyme GCase. It also proposes a completely novel therapy using the drug Ambroxol, an agent considered safe enough to give to pregnant women, which has improved GCase function in pilot studies in humans. This strategy could stop or reverse the underlying pathology of PD; it might allow patients to get better. Furthermore, re-purposing an existing medication with excellent safety record will greatly shorten the time to bring this therapy to general use, allowing us to leapfrog the normally decades-long drug development process.

This study will test the hypothesis that Ambroxol can improve the course of cognitive impairment or motor function in PDD by raising GCase levels in blood and CSF. The study specific aims will be 1) to demonstrate the efficacy of Ambroxol in improving, or slowing the progression of cognitive deficits, motor symptoms, or CSF/neuroimaging biomarkers, 2) to acquire additional pharmacokinetic and pharmacodynamic data for use in future trials and 3) to demonstrate the safety and tolerability of Ambroxol in patients with PDD.

This study is a randomized, placebo-controlled, double-blind trial of Ambroxol 1050 mg/day in individuals with mild to moderate PDD. Participants will be allowed but not required to be receiving concomitant treatment in a stable regimen for Parkinson's disease and dementia. Eligibility for enrollment will be assessed initially at one or more Screening visits, which are to occur within 28 days of Baseline. Eligible subjects will be randomly assigned (1:1) at the Baseline visit to one of the following two groups: Ambroxol 1050 mg/day or placebo.

Patients will be randomized to receive placebo or Ambroxol (1050mg). Participants randomized to Ambroxol group will begin with a dose of 225mg (3 mg/kg/day), increasing bi-weekly by ~3mg/kg to a dose of 1050 mg/day (~l5 mg/kg/day).

After 52 weeks, all patients will be offered a 6-month open label extension of Ambroxol 1050 mg/day.

For minor AE's (e.g. GI upset), patients will be allowed to spread the medication dose over a longer interval, or to reduce the dose to the highest dose tolerated. The dose can be advanced again after 2 weeks. For significant but non-threatening laboratory abnormalities, doses can be reduced to the highest dose tolerated. Patients will be allowed to stop taking medication if there is concern about a drug reaction of a clinically significant alteration in laboratory values. They can be re-challenged 2-4 weeks after these abnormalities have resolved.

If one experiences a severe allergic reaction that is possibly related to the study medication, the participant will be discontinued from the trial.

The dose-plasma level and plasma concentration-response relationships will be assessed by measuring plasma Ambroxol levels and lymphocyte GCase at baseline and 2 weeks after each dose escalation. At 12 weeks, blood and CSF Ambroxol and GCase activity will be quantitated. Patients will be followed at weeks screening, baseline, week 2, 4, 6, 8, 12, 18, 26, 34, 42 and 52 for blood work, ECG,and interview. Physical exam occurs at all visits except week 2 and 8. Neurological examinations occur at baseline, and weeks 6, 12, 18, 34, 42 and 52. Neuropsychological exam and movement testing will take place at baseline, week 26 and week 52. An MRI will be performed at screening and week 52. CSF will be collected at baseline, week 12 and week 52.

Patients will undergo clinical neuropsychological assessment at baseline, week 26, and week 52. At each assessment they will be administered standard tests of cognition such as the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog), ADCS-Clinician's Global Impression of Change (CGIC), Parkinson Disease-Cognitive Rating Scale (PD-CRS), Clinical Dementia Rating Scale (CDR), Montreal Cognitive Assessment (MoCA), Trail Making Test (TRAILS), Stroop, Geriatric Depression Scale (GDS), Neuropsychological Inventory (NPI); and tests of motor function/Parkinsonism such as the motor subscale of UPDRS and Quantitative Movement Testing, including Purdue Pegboard, Timed up and Go, and gait kinematics. MRI will be performed during screening and week 52. Mini-Mental Status Exam (MMSE) will be performed at all visits except weeks 2 and 8. A lumbar puncture will be performed at Baseline, week 12 and week 52.

The Primary Outcome measures will be the: ADAS-cog and the CGIC. These are standard cognitive and clinical measures used in almost all cognitive clinical trials. Secondary/ Exploratory outcome measures will include

1. Standard tests of cognition such as the MMSE, MoCA, CDR, , TRAILS, NPI, PD-CRS

2. Tests of motor function/Parkinsonism: UPDRS, Purdue Pegboard, Timed Up and Go, and Quantitative Movement Testing

3. CSF and Neuroimaging biomarkers