What Comes After Levodopa?

Parkinson’s disease affects around 12 million people and is the fastest growing neurological condition worldwide. To date, there is no cure or disease-modifying treatment.

“Patients are challenged with motor symptoms, gastrointestinal problems, and sleep disturbances, all of which significantly impact their quality of life,” said Ben Kraemer, PhD, Translational Science Liaison at SPARK NS.

For decades, the gold standard of care has been levodopa (L-DOPA), a dopamine precursor that replenishes depleted neurotransmitter levels in the brain and alleviates hallmark motor symptoms. “Levodopa helps manage symptoms but is not effective long-term, as patients eventually become less responsive,” added Dr. Kraemer.

While highly effective in early disease, L-DOPA does not address underlying neurodegeneration, and many patients experience complications such as dyskinesia, a movement disorder. As a result, therapeutics that can modify disease biology to slow or halt progression remain one of the most pressing unmet needs in Parkinson’s disease research. “Unfortunately, identifying patients in the early phase of the disease is challenging because patients do not present with motor symptoms until a large number of neurons have degenerated, which is an irreversible process,” said Dr. Kraemer.

Parkinson’s disease research is undergoing a significant shift, moving beyond dopamine replacement therapies toward approaches that target the underlying mechanisms of disease progression. “This is where the field is gaining substantial momentum,” said Opher Kornfeld, PhD, Managing Director of Translational Research and Development at SPARK NS.

The field is pushing drugs against established targets further into clinical development. Examples include prasinezumab, a monoclonal antibody designed to reduce the buildup of toxic alpha-synuclein proteins that damage dopamine-producing neurons in the brain, as well as small molecules such as BIA 28-6156 and DNL15, which target the proteins encoded by the Parkinson’s-associated genes GBA1 and LRRK2, respectively.^1-3 At the same time, as researchers gain a deeper understanding of the disease’s heterogeneity through expanded patient profiling, new hypotheses about its underlying biology are emerging and being tested. As noted by Dr. Kraemer, “The field has learned from its past failures and the scope of potential drug targets has diversified as more molecular pathways that contribute to disease progression have been uncovered.”

The same is true for different treatment approaches. “While traditional modalities such as antibodies and small molecules remain prominent in late-stage clinical development, the pipeline has expanded to include a breadth of modalities, including gene therapies, oligonucleotide-based approaches, cell therapies, and bifunctional small molecules," noted Dr. Kornfeld.

Bemdaneprocel, a stem cell–derived dopaminergic neuron replacement therapy, is one such example.⁴ Although still experimental, such approaches hold promise for addressing the underlying neurodegeneration more directly than traditional pharmacological interventions.

In addition to efforts developing brand new therapeutics are those looking to find a new use for existing drugs. Repurposed and repositioned drugs that modulate inflammation, mitochondrial function, or metabolic pathways are being revisited for potential disease-modifying effects. For example, ambroxol, which is already used to treat respiratory conditions, is currently in a Phase 3 trial to evaluate whether the drug can slow down the progression of Parkinson’s disease.⁵

“It is possible that one single therapy will not be effective in all Parkinson’s patients, which is why it is critical for SPARK NS projects to think with the end in mind about which subpopulation will be responsive to their therapeutic,” said Dr. Kraemer.

At the forefront of this shift, SPARK NS is working to bridge the gap between academic discovery and clinical impact.

“SPARK NS is advancing the development of novel treatments for Parkinson’s disease by providing support and guidance to advance academic discoveries that may otherwise get lost in the ‘Valley of Death’,” said Dr. Kraemer. “Our unique status as a nonprofit enables us to fund new projects each year that focus on a diverse set of drug targets and encompass multiple modalities in a noncompetitive environment.”

Of the 25 projects currently in the SPARK NS Translational Research Program, 19 are focused on developing novel, disease-modifying therapies for Parkinson’s disease. One of these efforts has advanced to a Phase 2b clinical trial (D-SPARK), which is evaluating whether the repurposed nutraceutical D-Serine can improve symptoms or delay disease progression. “D-Serine plays a vital role in synaptic plasticity—the brain's ability to rewire and repair itself,” said Ravi Ponnusamy, PhD, Senior Project Manager at SPARK NS. “Our hypothesis is that by modulating this pathway, we can enhance neuronal resilience and perhaps even encourage the recovery of dopaminergic pathways.”

This trial also highlights another advantage of SPARK NS: its willingness to fund and develop projects that may have limited commercial appeal and, as a result, attract little interest from the pharmaceutical industry.

“Developing drugs takes a large team, and SPARK NS is able to pull in expertise along the entire spectrum of drug development for our projects from the beginning of their time in our program,” said Dr. Kraemer. “Our ability to provide funding, education, and guidance for all of our projects is truly unique and will lead to new therapies and improve patients’ lives.”

Together, these efforts underscore a broader shift in the Parkinson’s disease therapeutic landscape from symptomatic control to disease modification. While significant challenges remain, including the need for robust biomarkers and a deeper understanding of disease heterogeneity, the expanding pipeline reflects growing momentum. For patients, this evolution offers the possibility of treatments that do more than manage symptoms. As awareness continues to grow, both on screen and in the clinic, so too does the hope that Parkinson’s disease may one day be slowed, halted, or even prevented.