From opening new therapeutic mechanisms to repairing neuronal damage, investigational molecules from Ventyx Therapeutics, AC Immune, Gain Therapeutics and more could shape the future of Parkinson’s disease treatment.
Last month, the Parkinson’s disease space celebrated a breakthrough: For the first time, an active immunotherapy—developed by AC Immune—appeared to slow the progression of the disease in a mid-stage trial. But despite this, and the hundreds of millions of dollars being invested in Parkinson’s disease research, consensus is that we have only just scratched the surface.
There remains a “strong need” to develop new medicines and explore alternative therapeutic pathways for the neurodegenerative condition, Pinky Agarwal, professor of neurology at the University of Washington, told BioSpace in an email.
Agarwal explained that the current approach to Parkinson’s is to supplement the body’s dopaminergic pathway. One way to do this, she continued, is by dosing patients with levodopa, a precursor of dopamine, which in turn supplements concentrations of the neurotransmitter in the body.
The clinical benefits of synthetic levodopa were first established in the late 1960s, shortly after scientists identified dopamine depletion as a key driver of Parkinson’s. The industry took the drug and ran with it, testing it as part of various combination regimens to improve its efficacy and ease its side effects. One such combination, with the decarboxylase inhibitor carbidopa, hit the market in 1975.
Since then, other treatment options have emerged, including the use of drugs that activate dopamine receptors in the brain, such as Boehringer Ingelheim’s Mirapex, and those that inhibit enzymes that degrade dopamine, like Supernus Pharmaceuticals’ Xadago.
Still, these approaches only temporarily alleviate motor symptoms but do not halt disease progression, Agarwal said. “Over time, patients experience motor fluctuations, dyskinesias, and increasing non-motor symptoms that dopaminergic therapies do not adequately address.”
These shortcomings highlight the need for novel therapies for Parkinson’s, especially those that apply a precision approach to the disease and target its underlying biology, Kelly Mills, director of the Parkinson’s Disease and Movement Disorder Center at Johns Hopkins Medicine, told BioSpace in an email.
“I suspect that therapies may need to be targeted for ‘predominant’ mechanisms in individuals,” he said. By way of an example, Mills pointed to a popular emerging approach to the disease, which is to modulate or tamp down the immune response to limit damage to the brain.
“For instance, trials using immunomodulation or immunosuppression may first screen for imaging or blood/CSF-based biomarkers,” Mills explained.
Other strategies target Parkinson’s-linked cellular pathways to ease oxidative stress, reverse mitochondrial dysfunction or repair the cell’s faulty recycling system.
Drugmakers that seek to leverage these underlying mechanisms, Mills continued, would do well to enrich their study samples with patients carrying certain biomarkers, making them more likely to respond to specific interventions. In turn, “I think [Parkinson’s treatment] will be more personalized at the mechanistic level even when a known risk factor gene is not found,” he said.
Here, BioSpace looks at five investigational Parkinson’s therapies that penetrate pathologic pathways in search of a disease-modifying treatment.
Ventyx’s NLRP3 Program Attracts $1.2B Bid From Lilly
Kicking off this list is a Parkinson’s player that has already made big waves this year. Ventyx Therapeutics commanded a $1.2 billion buyout bid earlier this month from pharma giant Eli Lilly.
At the core of Lilly’s takeover is Ventyx’s NLRP3 program, which includes the oral drug VTX3232, currently in mid-stage development for Parkinson’s disease. NLRP3 is what is known as an inflammasome, a complex of several proteins that come together in response to certain molecular signals, such as infections, irritants or injuries.
NLRP3 is the most prominent inflammasome, according to Ventyx, and is specifically assembled in relation to chronic inflammation and tissue damage. The activation of NLRP3 triggers a signaling cascade that culminates in the release of molecules that promote inflammation, in turn aggravating the pathology in neurodegenerative disorders like Parkinson’s.
VTX3232 works by targeting and inhibiting NLRP3, disrupting this pro-inflammatory cascade. This mode of action, along with its ability to cross into the central nervous system, gives the drug its “best-in-class potential” for various neuroinflammatory conditions, the company claims. In June last year, Ventyx released Phase II data showing that VTX3232 significantly reduces levels of NLRP3, validating its mechanism.
The drug also lowered concentrations of downstream inflammatory markers, such as IL-6, hsCRP and SAA. In a note at the time, Jefferies analysts said these results support continued trials in Parkinson’s, “and perhaps Alzheimer’s, too.”
Aside from Parkinson’s, VTX3232 is also being tested for cardiometabolic diseases.
AC Immune Targets Immune System To Stem Neurodegeneration
Like Ventyx, AC Immune is looking to address the underlying dysfunction in Parkinson’s by targeting the immune system.
Parkinson’s disease is “multisystem and heterogeneous,” CEO told BioSpace in an email, “which suggests a need to address the major mechanistic drivers, for disease modification and neuroprotection.”
With ACI-7104.056, AC Immune is aiming to tackle a key molecular driver of the disease. ?The active immunotherapy is designed to target alpha-synuclein (a-syn), a protein abundant in the brain that under healthy conditions helps modulate the transmission of signals between neurons. In Parkinson’s, a-syn is misfolded, causing it to stick together and form toxic clumps, which ultimately lead to the destruction of neurons.
A-syn represents the “hallmark proteinopathy” of Parkinson’s disease, Pfiefer said, making it a “particularly promising target” for therapies. ACI-7104.056 works by “[stimulating] the immune system to generate a specific antibody response against a-syn,” she explained, adding that “the aim is to slow neurodegeneration.”
In December, AC Immune released interim data from the Phase II VacSYn study, showing that its investigational immunotherapy stabilized a-syn levels, as well as concentrations of neurofilament light chain, an indicator of neuronal damage and neurodegeneration. Brain scans also showed “trends toward disease modification,” the Swiss biotech said at the time.
AC Immune is now seeking FDA feedback on a clinical development plan to potentially support a drug application, Pfeifer said. Final data from the first part of the VacSYn trial are expected in mid-2026.
Gain Therapeutics Eases Cellular Stress
“The most exciting progress in Parkinson’s right now is happening where deep biology and disease modification intersect,” Gene Mack, CEO of Gain Therapeutics, told BioSpace in an email, noting that the industry is now increasingly focusing on “upstream mechanisms that address the cellular dysfunction driving neurodegeneration.”
The Maryland-based biotech is participating in this progress through its lead asset GT-02287, a small-molecule drug that works by restoring the activity of glucocerebrosidase (GCase), a lysosomal enzyme that in Parkinson’s becomes misfolded, leading to the build-up of toxic proteins and the deterioration of neurons. GT-02287 is orally available and can penetrate the blood-brain barrier.
“Rather than simply trying to boost enzyme activity in the lysosome, GT-02287 stabilizes GCase folding and trafficking throughout the cell, restoring function across multiple compartments, including those critical to mitochondrial health,” Mack explained. “That matters because Parkinson’s can be seen as a disease of cellular stress, impaired waste clearance, and energy failure.”
Phase Ib data released in December showed that GT-02287 significantly lowered levels of glucosylsphingosine (GluSph) in the cerebrospinal fluid—a key marker of GCase dysfunction and indicator of synuclein buildup. Additional biomarker outcomes earlier this month further established the strength of the drug’s effects, with GluSph concentrations dropping 81% on average after 90 days of treatment.
The second part of this Phase Ib trial, consisting of a nine-month extension phase, is set to conclude in September this year.
Denali, Biogen Bet on Novel Protein Target
Denali Therapeutics and Biogen are also exploring a novel treatment mechanism for Parkinson’s disease with their candidate DNL151 (also known as BIIB122), looking to address the most common form of the disorder.
Designed to be available orally, DNL151 is a small-molecule inhibitor of LRRK2, a protein that can be found in the brain and serves a wide variety of functions, including forming part of the cell’s cytoskeleton, transmitting signals and exerting enzymatic activity. While its exact role in Parkinson’s pathology hasn’t yet been elucidated, mutations in LRRK2 have been linked to late-onset Parkinson’s, the most common form of the disease, according to MedlinePlus.
Working with Biogen, Denali is advancing DNL151 to block the activity of LRRK2 with the goal of slowing down disease progression, according to its website. Early-stage data released in May 2021 showed the drug elicited “robust reductions” in key disease biomarkers, including Rab10, a protein downstream of LRRK2.
A year later, the partners pushed DNL151 into late-stage development with the Phase IIb LUMA study, which launched in May 2022, and the Phase III LIGHTHOUSE study, which began in October of that year. However, owing to the “complexity” of LIGHTHOUSE, the companies in June 2023 axed the Phase III study. This decision, they insisted at the time, was “not based on any safety or efficacy” findings involving the candidate.
Currently, DNL151 is still being evaluated in LUMA alongside a Phase IIa study called BEACON. A readout from LUMA is expected this year.
Aspen Looks To ‘Rebuild’ Nerve Network With Cell Therapy
Capping off this list is Aspen Neuroscience, which is proposing a biologic approach to Parkinson’s disease.
Rather than simply supplementing and restoring dopamine levels in the brain, Aspen’s approach also involves rebuilding neural networks that have been destroyed by the disease, Revati Shreeniwas, chief medical officer, told BioSpace in an email. At the core of this push is ANPD001, an autologous investigational cell therapy consisting primarily of dopaminergic neuronal precursor cells.
ANPD001 is a “multi-cell composition,” Shreeniwas explained, that “generates a spectrum of neural precursors and mimics key aspects of the developing brain’s cellular environment,” thereafter integrating into the host networks. The objective, she continued, is to go “beyond one-off symptomatic treatments toward true circuit‑level repair.”
Aspen hopes that ANPD001’s circuit repair will translate into what Shreeniwas called “everyday outcomes: steadier mobility, better sleep, improved autonomic function, mood and voice.”
Aspen’s approach appears to be attractive to investors. Last November, the biotech made $115 million after closing its series C round co-led by big names such as OrbiMed, ARCH Venture Partners, Frazier Life Sciences and Revelation Partners. Cell therapy leader Gilead, through its Kite subsidiary, also participated in the round.
Currently, ANPD001 is being studied in the Phase I/IIa ASPIRO study, which in May last year found that delivering the cell therapy directly into the brain was safe overall, with no serious complications and toxicities reported. The intervention also led to improvements in both physician- and patient-reported outcomes.
Earlier this month, Aspen completed dosing in cohort three of ASPIRO, which will test a commercial-ready formulation of ANPD001.
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