Ambroxol Hydrochloride

Pictured: Conceptual illustration of a person standing on a stairwell within a series of head-shaped doorways. April is Parkinson’s Awareness Month, and with new approaches to treating Parkinson’s disease in the pipeline, 2023 is poised to be a pivotal year for this space. First, a handful of new formulations of the traditional levodopa/carbidopa drugs are nearing the market. The new formulations are designed to improve treatment outcomes, in particular by reducing the severity of symptoms associated with “off” periods with periodic dosing. And hot on their heels are several new therapeutic entities, mostly in Phase II trials, that build upon existing mechanisms of action or hit entirely novel targets. Old Drugs, New Formulations The Levodopa/carbidopa combination has long been considered the gold standard for treating Parkinson’s disease. Approved by the FDA in 1975, the drug duo is administered together because carbidopa reduces the amount of levodopa needed to achieve the desired therapeutic effect within the brain. When initially marketed as an immediate-release combination tablet, the first formulation, known as Sinemet, had to be administered multiple times a day, with precise timing needed to optimize effects. This led to adherence issues and complications such as potential motor fluctuations. Companies then developed longer-lasting oral formulations such as Rytary capsules, but even these led to cycles of “on” and “off” periods, where patients only intermittently experienced well-controlled symptoms. The move to other routes of administration has been driven by several factors. The gastrointestinal system can break down levodopa before the it can reach the brain for therapeutic activity, and previous oral formulations sought to fight this effect by administering higher doses. While bypassing the gastrointestinal system leads to better safety and efficacy outcomes, the FDA is treading cautiously because subcutaneous formulations of levodopa/carbidopa have not yet been approved. In March 2023, the FDA declined to approve AbbVie’s subcutaneously administered formulation, ABBV-951, to treat motor fluctuations in Parkinson’s disease. AbbVie’s formulation contains foscarbidopa and foslevodopa, prodrugs designed to activate after administration to the body. In Phase III trials, foslevodopa/foscarbidopa led to increases in “on” time without dyskinesia and significantly reduced “off” time compared to standard-of-care treatment. Although AbbVie’s data contained no safety or efficacy issues, the FDA said it needed more data on the subcutaneous pump device to proceed. Meanwhile, Mitsubishi Tanabe Pharma Corporation reported positive Phase III trial results in January 2023 for its subcutaneous liquid formulation, ND0612. Although slightly behind AbbVie, Mitsubishi’s collaboration with NeuroDerm uses a continuous subcutaneous infusion of levodopa/carbidopa, which showed improved control over Parkinson’s disease symptoms when combined with supplemental oral levodopa/carbidopa, compared to traditional oral levodopa/carbidopa alone. Refining the Capsule In terms of extended-release oral formulations, Amneal Pharmaceuticals submitted its levodopa/carbidopa capsule formulation to the FDA in November 2022. Known as IPX203, Amneal’s product has a unique mixture of immediate-release granules and extended-release beads to extend “on” periods of symptom control and decrease “off” periods. While the immediate-release granules contain carbidopa and levodopa, the extended-release beads only contain levodopa and are enterically coated to prevent stomach acid from affecting the beads. Amneal is scheduled to hear back from the FDA on June 30, 2023. Multiple Paths to Treatment While new formulations of levodopa/carbidopa are further along in the development process, companies continue to look at other pharmacologic targets to treat Parkinson’s disease. While some investigators such as Denali Therapeutics and Biogen are focused on LRRK2 inhibitors, others are trying to repurpose existing agents such as ambroxol, a mucolytic approved in the EU to fight respiratory disease by clearing mucus secretions. In December 2022, Denali and Biogen launched a Phase III trial called LIGHTHOUSE to investigate the use of its LRRK2 inhibitor, BIIB122, also known as DNL151. The Phase IIb LUMA trial was still at the dosing phase as of February 2023. As a first-in-class small molecule, BIIB122 is hypothesized to function by decreasing LRRK2 kinase activity to reduce lysosomal impairment in Parkinson’s patients. As for ambroxol, a Phase III trial will be launched in early 2023 by the University College of London to assess the drug’s use in Parkinson’s disease. Data from the Phase II AiM-PD study, reported in January 2020, showed ambroxol was able to cross the blood-brain barrier, increase GCase activity and reduce alpha-synuclein levels. Because GCase activity is lower in patients with GBA1 mutations and Parkinson’s disease, scientists hope Phase III trials of ambroxol will demonstrate clinical efficacy. Because ambroxol's Phase III data may not arrive until 2027, and Denali and Biogen's Phase III data not expected to be finalized until 2031, it is likely that newer formulations of levodopa/carbidopa will be marketed first. But as more compelling treatments make their way toward the market, the coming years could be pivotal for Parkinson’s disease research. Jia Jie Chen writes analyses focusing on drug development in the biotech and pharma industries for BioSpace. He has a doctorate degree in pharmacy and experiences ranging from biotech equity research to business intelligence analysis. Follow him on LinkedIn.