Scenic Biotech joins Michael J. Fox LRRK2 consortium with a novel lysosomal bet on Parkinson’s

Instead, the Amsterdam-based company aims to inhibit a different related target, the enzyme PLA2G15, in order to harness the lipid biochemistry that keeps lysosomes working. This is a novel and differentiated bet that arrives just as two prominent candidates against the disease’s common genetic risk factors have failed in phase 2b trials within weeks of each other.

Last month, Biogen and Denali’s BIIB122 successfully inhibited LRRK2 – by more than 90% – but a roughly 640-patient trial in idiopathic Parkinson’s failed to deliver clinical benefit. Earlier this week, BIAL registered a similar disappointment: its candidate BIA 28-6156, designed to activate GCase and boost lysosomal function, missed its goals in a 273-patient trial in GBA-associated Parkinson’s disease.

Unfazed by those failures, Scenic is looking to chart its own path, arguing that while the case for genetic involvement in disease progression is solid, a better approach may be to target the interactions of different genes further downstream.

“Rather than targeting a single genetic driver upstream, Scenic is focused on a lysosomal pathway that may be relevant across multiple forms of Parkinson’s disease, including LRRK2-associated PD,” Scenic told European Biotechnology Magazine. “The recent setback in LRRK2 reinforces the need for complementary approaches that can address the cellular consequences of impaired lysosomal biology through differentiated mechanisms.”

A new approach

The science behind that claim is fairly recent. PLA2G15, also known as lysosomal phospholipase A2, breaks down bis(monoacylglycero)phosphate (BMP),a lysosomal lipid that supports the activity of GCase (the enzyme encoded by the risk-associated gene GBA1) and other waste-clearing enzymes inside the lysosome. By inhibiting PLA2G15, Scenic aims to raise BMP levels and indirectly enhance a broader lysosomal lipid-clearing programme, rather than activating GCase alone, as BIAL attempted with BIA 28-6156. A team including Scenic’s founders Sebastian Nijman and Thijn Brummelkamp reported the mechanism in Nature last year.

The collaboration, announced on 11 June, brings Scenic into the foundation’s LRRK2 Investigative Therapeutics Exchange (LITE), giving it access to the Parkinson’s models in the Dundee laboratory of Dario Alessi, a leading LRRK2 researcher. Scenic will supply its brain-penetrant small-molecule PLA2G15 inhibitors for testing in those models; positive results, the company says, would open a path to trials in patients with LRRK2-mutation Parkinson’s.

“The PLA2G15-BMP axis offers a compelling way to explore how lysosomal biology intersects with LRRK2-linked Parkinson’s disease,” Alessi commented in a joint press release.

There is still a fair amount of work ahead to prove their thesis, or even to initiate clinical trials with a specific candidate. “Scenic is performing IND-enabling studies with the lead PLA2G15 inhibitor SC6177, plans to file an IND by year-end, and enter the clinic in 2027,” the company told us.

The Michael J. Fox Foundation’s LITE program

Scenic is far from the only team that refuses to give up on the therapeutic value of lysosomal pathways in the face of recent setbacks. According to the World Health Organization, the prevalence of Parkinson’s disease has increased by about 100% over the past quarter century.

No cure currently exists, while therapies on the market mostly seek to address the debilitating symptoms. The lysosomal pathways have been validated in a number of recent studies as promising targets.

Even in the clinic, there has been some, if tentative, positive news. In late May, for example, Gain Therapeutics, whose GT-02287 targets GCase directly, reported that the drug moved a lysosomal biomarker in patients with elevated baseline levels in a phase 1b trial.

Meanwhile, the LITE cohort is rapidly growing. In recent days, the Michael J. Fox Foundation announced collaborations with two other teams, US-based Arvinas and UK-based Harness Therapeutics, aimed at targeting different steps in the same processes.

“Programs like LITE and PPMI [Parkinson’s Precision Medicine Initiative] are helping build the translational and biomarker infrastructure needed to better understand LRRK2 biology, support more precise therapeutic development, and advance the field toward more personalized approaches to Parkinson’s disease,” a foundation representative said in a press release last month.