For years, the hunt for a Parkinson's disease-modifying drug came down to one protein: alpha-synuclein. Clear it out, the thinking went, and you slow the disease. That bet hasn't paid off yet. Now a growing slice of the industry is chasing a different culprit: inflammation in the brain itself.
A new research note from Jefferies lays out why. The bank isn't abandoning alpha-synuclein, but it's telling clients that neuroinflammation has become one of the field's most important storylines, and one worth watching closely heading into 2027.
The opportunity, in Jefferies' view, is too large to ignore, even with the field's track record of disappointment. According to analysts, Parkinson’s remains one of the largest untapped opportunities in neuroscience, with the addressable early population across the US and EU expected to exceed two million patients by 2035. That represents a potential disease-modifying therapy market approaching $8 billion, the bank's analysts noted.
"(D)espite decades of investment, no therapy has convincingly demonstrated an ability to slow neurodegeneration,” analysts wrote. “With several late-stage and emerging programmes now approaching important clinical milestones, we believe the field is entering a pivotal period that could determine whether disease modification becomes a commercial reality.”
Roche and Prothena's prasinezumab, Parkinson's most advanced disease-modifying antibody, has missed its primary endpoint twice, though both trials hinted at slower motor decline, enough for Roche to push it into Phase III. Denali's LRRK2 drug BIIB122 fared worse, failing outright in broad Parkinson's patients, and is now being tested only in a genetically defined subgroup.
Jefferies reads both results not as target failures but as evidence that Parkinson's is driven by multiple mechanisms at once, alpha-synuclein, cellular cleanup breakdown, and neuroinflammation, meaning single-pathway drugs likely won't be enough on their own.
“Given much of the pathological protein resides intracellularly, we believe next-generation modalities may ultimately prove better suited to targeting the underlying biology,” analysts wrote.
“The field is increasingly focused on next-gen modalities that could more effectively address the underlying biology of PD.”
Among the approaches drawing the most attention are drugs that target alpha-synuclein inside cells, vaccine candidates, and treatments aimed at neuroinflammation. Analysts group neuroinflammatory drugs with next-generation vaccines and intracellular alpha-synuclein approaches, rather than treating them as a separate, competing bet.
The logic isn't that inflammation replaces alpha-synuclein as a target. It's that the two likely feed each other. Quiet the inflammation, the theory goes, and you may blunt the damage alpha-synuclein is doing at the same time.
Who's actually building these drugs
There are a handful of companies that sit closest to the exact mechanism Jefferies is highlighting. Ventyx Biosciences (NASDAQ:VTYX) is developing oral inhibitors of NLRP3, the inflammasome pathway the bank calls out by name, and is one of the more advanced pure-play programs in that space. Olatec Therapeutics, a private biotech, is chasing the same target with its drug dapansutrile.
A couple of smaller names show how far the inflammation thesis can stretch. BioVie Inc (NASDAQ:BIVI, NASDAQ:BIVIW) has spent years developing bezisterim, a pill that crosses into the brain and dials down inflammatory signaling through the NFκB and TNF-alpha pathways, while also improving insulin sensitivity. The company just reported topline data from its Phase 2 SUNRISE-PD trial in early Parkinson's patients this week, with patients showing improvements in blood-based inflammatory markers and a range of clinical outcomes compared with placebo. Patients with higher baseline inflammation saw the greatest benefit.
Tiziana Life Sciences Ltd (NASDAQ:TLSA) is running a smaller trial of its own, testing an intranasal antibody called foralumab in Multiple System Atrophy, a Parkinson's-related disorder with no approved disease-modifying treatment. The goal is to calm overactive brain immune cells called microglia. Early PET scans have shown drops in brain inflammation in the handful of patients treated so far.
The bottom line
Companies targeting inflammation are riding the same wave: the idea that calming the brain's immune response could do as much for Parkinson's patients as chasing alpha-synuclein ever did.
Whether that idea holds up is still unproven, butut it's exactly the kind of bet Jefferies thinks is worth making right now, in a field it believes is finally approaching a real turning point.