Combination Therapies Emerge as a Path to Disease Modification in Parkinson's Disease
核心洞察
No disease-modifying therapies currently exist for Parkinson's disease (搜索), with only three of 84 Phase 2 and 3 DMT studies registered over the last decade testing combination approaches.
A Cure Parkinson's (搜索) workshop in June 2025 explored how combination therapies, proven in oncology and infectious disease, could address the molecular complexity and patient heterogeneity of PD.
Case studies including Auvelity (dextromethorphan-bupropion) and AMX0035 (sodium phenylbutyrate-TUDCA) illustrate the mechanistic, regulatory, and patenting considerations for developing combination treatments.
While a broad range of treatments are available for symptomatic management of Parkinson's disease (搜索) (PD), there are currently no disease-modifying therapies (DMTs) — agents that slow, stop or reverse disease progression. The lack of success in clinical trials exploring potential DMTs is likely attributable to the complexity of PD, gaps in understanding causal biology, variability between patients, limitations in biomarkers for stratification, advanced stage of pathology at diagnosis, and the appropriateness and sensitivity of clinical endpoints.
The majority of potential DMTs tested to date in PD trials have been individual molecules directed towards specific molecular targets or biological pathways, which may not address enough of the complex mechanisms to impact disease progression. Combinations of treatments are increasingly being employed in other multifaceted diseases to address molecular complexity. Since combining chemotherapies for the treatment of acute leukaemia in 1965, combination therapies have become a "cornerstone of cancer therapy." Between January 2011 and December 2023, Chen et al. (2024) reported that of the 292 US Food and Drug Administration (FDA) approval entries (encompassing 110 drugs for oncological indications), one third were combinations.
The Case for Combination Approaches in PD
Over the last decade, 84 Phase 2 and 3 DMT studies were registered on ClinicalTrials.gov; however, only three of these trials were assessing combinations of agents as potential DMTs for PD (not including herbal formulations). These comprised two Phase 2 studies — assessing the combination of insulin and glutathione (NCT05266417, registered February 2023) and metabolic cofactor supplementation (L-serine, N-acetyl-L-cysteine, nicotinamide riboside, and L-carnitine tartrate; NCT04044131, registered July 2019) — and one Phase 3 study (NCT05576818, registered October 2022) investigating a synbiotic mixture of a probiotic with prebiotic fibres.
Trial evidence to date suggests it may be overly optimistic to expect a single molecule targeting a specific biological pathway to result in a clinically meaningful response across a PD patient cohort. An alternative strategy could involve combining therapies that have evidence-based support for more than a single target or pathway, which in combination may help expedite the development of treatments that slow this complex and heterogeneous condition.
To address these matters, Cure Parkinson's (搜索) held a workshop in June 2025, attended by individuals from the community. The goal was to use the information gained as guidance for applicants and evaluators in future research funding calls, and to stimulate discussion and inspire researchers to consider new strategies for experimental combination DMTs for PD.
Defining Combination Drugs Versus Combination Therapies
Workshop attendees distinguished between combination drugs and combination therapies. Combination drugs are defined as fixed-dose treatments containing two or more active pharmaceutical ingredients, an example being carbidopa/levodopa. This "gold standard" symptomatic treatment for PD combines two active agents necessary for the treatment to have the desired effect. Oral administration of the amino acid precursor levodopa alone results in the majority of the agent being converted to dopamine in the gut, leading to nausea and vomiting; only in combination with carbidopa (a peripheral DOPA decarboxylase inhibitor) are these side effects reduced and brain-specific dopamine produced at the required levels. While combination drugs are often easier to administer, they lack a personalised approach due to fixed dosages.
In contrast, combination therapies involve multiple interventions administered separately — either in parallel or sequentially. Since the first joint use of streptomycin and para-aminosalicylic acid for the treatment of tuberculosis in the 1950s, combination therapies have been widely applied in oncology and antibiotic fields, where enhanced synergistic effectiveness can broaden the therapeutic spectrum and reduce the chance of resistance developing.
Pharmacologically, combination therapies can be divided into different basic subtypes — congruous, syncretic, and coalistically additive. Congruous combinations involve agents targeting distinct but complementary, essential biological pathways or targets. Syncretic combinations lead to a synergistic effect by simultaneously impacting essential and non-essential targets (carbidopa/levodopa is an example). Coalistically additive combinations involve agents that act on synthetically functional, non-essential targets, where therapeutic effects are observed only by acting on both targets.
Combination therapies do not have to solely rely on drug-drug paradigms; drug and device or drug with lifestyle interventions may also be considered. A recent example was a pilot study investigating the combinatorial impact of D-beta-hydroxybutyrate and nicotinamide riboside with or without exercise on brain energy metabolism (NCT04322461, registered March 2020).
Learning From Approved Combination Products
Since 2020, approximately 250 new medications have been approved by the US FDA. Of these, two were combination therapies developed by the same company, Axsome Therapeutics. One of these approved treatments, "Auvelity" (dextromethorphan-bupropion), was presented and reviewed at the workshop to better understand the requirements of developing a combination drug.
Dextromethorphan, first described in 1946 and approved in 1958, is an over-the-counter antitussive with multiple mechanisms of action, including NMDA receptor antagonism, σ1 receptor agonism, and serotonin–norepinephrine reuptake inhibition. However, its therapeutic benefits as an antidepressant have been limited due to rapid metabolism by CYP2D6 (搜索), resulting in a half-life of 4 hours. Auvelity's second active component is bupropion, an atypical antidepressant that acts via norepinephrine and dopamine reuptake inhibition and is also a potent CYP2D6 inhibitor. Clinical testing demonstrated that, by blocking CYP2D6, bupropion increases concentrations of dextromethorphan in the blood, providing a more rapid and sustained antidepressant effect than each agent alone.
A large number of Phase 1 clinical trials were undertaken to develop this combination. Of the 14 studies registered on ClinicalTrials.gov for the testing of Auvelity, 11 were Phase 1 trials. Despite being well-characterised generic agents, the safety, tolerability, dose optimisation, drug-food interactions, and pharmacokinetics of combining dextromethorphan and bupropion all needed to be thoroughly addressed. Following successful Phase 3 testing, Auvelity was approved by the US FDA for the treatment of major depressive disorder (搜索) in August 2022.
A second case study, AMX0035 (also known as Relyvrio) developed by Amylyx, represents a congruous combination of sodium phenylbutyrate and tauroursodeoxycholic acid (TUDCA) that simultaneously targets two major pathways of neurodegeneration. Sodium phenylbutyrate acts as a chemical chaperone, inhibiting endoplasmic reticulum stress responses and neurodegeneration induced by accumulation of misfolded or mutant proteins, while TUDCA inhibits mitochondrial-mediated apoptosis and formation of reactive oxygen species. Despite encouraging results in a Phase 2 trial for ALS (搜索), subsequent Phase 3 testing could not replicate the findings. While not as successful as Auvelity, AMX0035 represents a useful case study of a unique combination therapy that others can learn from.
Regulatory and Intellectual Property Considerations
Repurposing of generic agents for PD is often viewed as a means of accelerating the development of novel therapies. While in theory this is correct, achieving regulatory approval and a marketed product remains extremely challenging, and repurposing of individual agents should be viewed as "proof-of-concept." To strengthen chances of regulatory approval, a robust case of support from the commercial world must be made in addition to clinical success. In the case of Auvelity, extended-release tablets of 45 mg dextromethorphan and 105 mg bupropion were impossible to obtain generically, making the formulation unique and difficult to replicate.
At the workshop, it was emphasised that, in order to be patented, a combination therapy must be both new and inventive. Different options are available when thinking about patenting combinatorial therapies: a new combination of active ingredients leads to a new composition of matter; new formulations can provide the basis of a patentable claim; and new medical use claims may be possible even if a combination is already known. Importantly, information in the public domain can affect patentability, ultimately restricting the ability to get potential treatments to patients.
Given the additional complexity of combination therapies, researchers should engage with relevant regulators as early as possible. The FDA considers a "combination product" as being composed of any combination of a drug and a device that are physically, chemically, or otherwise combined or mixed and produced as a single entity. Importantly, the FDA does not consider a therapy consisting solely of two or more drugs to be a "combination product." For drug+drug combinations, the Center for Drug Evaluation and Research is assigned to handle inquiries and reviews. For drugs already approved for other disease indications but being combined for a new indication, the primary regulatory framework is the 505(b)(2) pathway, which requires "bridging" studies providing pharmacokinetic data demonstrating that the new combination does not negatively alter the safety or efficacy profiles of the original drugs. For fixed-combinations, the 21 CFR 300.50 rule requires sponsors to demonstrate the meaningful contribution of each component to the claimed therapeutic effect.
Designing Future Combination DMT Trials in PD
Successful disease-modifying combination therapies in other disease indications have typically begun from the foundations of an identified DMT, an advantage that the PD field is currently lacking. In terms of preclinical studies, attendees determined that multifaceted approaches are likely to be required, utilising both in vitro assays of human iPSC-derived cultures as well as in vivo models (preferably alpha-synuclein (搜索) over-expression/preformed fibril models). Greater consideration will also need to be given to pharmacokinetic investigations and dose-finding studies, in parallel to determining efficacy.
Clinical trials for combination therapies will differ from standard clinical trial designs. As with the Auvelity case study, clinical testing of any combinations would require extensive dose-ranging and pharmacokinetic studies, where potential pharmacodynamic interactions as well as overlapping toxicity could also be addressed. For later tests of efficacy, clinical trials are likely to be large, investigating each drug as a monotherapy, as well as incorporating the drugs in combination and including a placebo group. This situation could represent an opportunity to be explored on the new multi-arm, multi-stage (MAMS) platform trials that are currently in development for PD.
An additional challenge is patient heterogeneity. Workshop attendees discussed possible patient stratification protocols and whether this might help improve outcomes in clinical trials. While genotyping is currently being employed in clinical trials investigating potential DMTs, stratification of the idiopathic community remains unclear. There are ongoing efforts to redefine PD based on specific biomarkers such as alpha-synuclein (搜索) seeding assays and aromatic L-amino acid decarboxylase (AADC) levels in cerebrospinal fluid, as well as inflammatory signals pointing towards different at-risk subtypes; however, validation of these groupings in DMT clinical trials is still required. Thus, the design of a combination therapy targeting specific subtypes of PD should be carefully considered.