A medicine approved in the late 1970s to clear the respiratory tract and thin mucus can also cross the blood-brain barrier and possibly protect cells there from the damage seen in Parkinson’s disease, a small Phase 2 clinical trial has found.
The study detailing these results, “Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations – A Nonrandomized, Noncontrolled Trial,” was published in JAMA Neurology.
Mutations in the GBA gene are one of the most common genetic risk factors for Parkinson’s. The GBA gene contains instructions to produce an enzyme, called beta-glucocerebrosidase (GCase), that is active in lysosomes — special compartments within cells that break down and recycle different types of molecules.
When the GCase enzyme fails to work as it is supposed to, toxic substances like abnormal alpha-synuclein accumulate inside dopamine-producing neurons, leading to the inflammatory and neurodegenerative processes that are observed in Parkinson’s.
In theory, boosting GCase activity through the “repurposing” of this medicine could slow disease progression.
Repurposed medicines are those approved to treat diseases other than that now under study (in this case, Parkinson’s). Because their mechanisms of action and safety are known to differing degrees, the expensive and lengthy process of discovering and testing a new compound is typically not necessary.
Ambroxol (brand names are Mucosolvan, Mucobrox, and Mucol, among others) has been used worldwide for decades to treat respiratory diseases associated with sticky or excessive mucus, and is known to boost beta-glucocerebrosidase activity.
But for it to work in the context of Parkinson’s, it needs to reach the brain and central nervous system. This means it needs to cross the blood-brain barrier, the semi-permeable membrane that protects the brain from the external environment. This barrier often blocks medicines from being carried into the brain.
Researchers at the University College London Institute of Neurology designed an open label, Phase 2 trial (NCT02941822) to test ambroxol in Parkinson’s patients at a single center, evaluating its safety, tolerability and pharmacodynamics (how the body affects a medicine) in people with and without GBA mutations.
Twenty-four patients, all with moderate, idiopathic Parkinson’s and on “dopaminergic therapy” were enrolled in the study; 17 completed the six months of treatment and required tests. Most withdrew due to discomfort or complications with the lumbar puncture used to collect cerebral spinal fluid (CSF).
These 17 people — eight with GBA mutations and nine without GBA mutations; average age of 60 — were given a daily dose of oral ambroxol that gradually escalated from 120 mg (60 mg three times a day) to 1.26 grams (420 mg three times a day).
Clinical examination and blood testing were performed on day 11, and at three months, six months and nine months after starting the treatment. Cerebrospinal fluid samples were collected via lumbar puncture at the study’s beginning and end. Five patients also underwent a third puncture for spinal fluid collection nine months after treatment initiation.
The study’s primary goal, in addition to safety, was to assess ambroxol’s ability to cross the blood-brain barrier and to change beta-glucocerebrosidase’s activity in the brain. This was determined by measuring beta-glucocerebrosidase and ambroxol levels in patients’ blood and CSF after six months of treatment.
A significant increase of 156-ng/mL in ambroxol levels in the cerebral spinal fluid was seen at this point, indicating the therapy could cross the brain-blood barrier to reach the central nervous system. Its use was also found to be well-tolerated, without any serious side effects reported.
“This finding is important, as the administered dose was approximately 10 times higher and was administered for a longer duration than specified in its license,” the researchers wrote.
People with Parkinson’s are known to have lower levels of alpha-synuclein in their CSF than others. This may be the result of compensatory mechanisms that cells use to sequester toxic soluble alpha-synuclein, studies suggest.
After six months of ambroxol’s use, the concentration of alpha-synuclein in patients’ cerebral spinal fluid rose by 13% (an increase of 50 pg/mL) and beta-glucocerebrosidase protein levels in the CSF by 35% (an increase of 88 ng/mol). These changes underscored the therapy’s neuroprotective effect, the researchers wrote.
“The increase in total CSF [alpha]-synuclein concentration implies, based on previous in vitro and in vivo data, that ambroxol has also had an association with [alpha]-synuclein metabolism,” they said.
Compared to the beginning of the study and in line with previous research, the increase in alpha-synuclein was accompanied by a 19% decrease in beta-glucocerebrosidase’s enzymatic activity.
Ambroxol’s use also did not “aggravate motor symptoms,” the study reported, and may have helped to ease them in all treated patients (those with and without GBA mutations).
These results suggest that ambroxol can cross the blood-brain barrier and increase beta-glucocerebrosidase levels in tissues, meaning the enzyme may be able to counter the abnormal build-up of alpha-synuclein in the brain of people with Parkinson’s, stopping or slowing it from becoming toxic to brain cells.
“Placebo-controlled clinical trials are needed to examine whether ambroxol therapy is associated with changes in the natural progression of PD [Parkinson’s disease],” the team concluded.
The Cure Parkinson’s Trust also reported on this study and its findings on its website.
“By using a drug which has shown to reduce the build-up of alpha-synuclein, and which also has a long and well-understood safety record, it is hoped that we might have a candidate for long term use that will reduce or even halt the progression of the disease,” the Trust wrote.
Larger trials are necessary, the U.K. group wrote.
“As Ambroxol is already approved as a drug … if a larger trial is successful, this drug would be readily accessible and could be seen as a treatment to slow down Parkinson’s within a short time-frame. This would have a huge impact on the lives of many people living with Parkinson’s today.”