Bial drops pariceract after Phase IIb failure in GBA-associated Parkinson’s
Portuguese drugmaker BIAL has discontinued development of BIA 28-6156, also known as pariceract, after a Phase IIb study failed to show that the oral therapy could slow progression in patients with GBA-associated Parkinson’s disease. The readout marks a setback for one of the more advanced attempts to turn Parkinson’s genetics into a disease-modifying therapy.
The Phase IIb ACTIVATE study enrolled 273 genetically confirmed GBA-PD patients across 85 clinical sites in 11 countries in Europe and North America. According to Bial, the randomised trial did not meet its primary endpoint or key secondary efficacy endpoints, with pariceract failing to demonstrate significant differentiation from placebo. The company said the drug was generally well tolerated and no unexpected safety concerns emerged, but it will stop further development of the programme in this indication.
Pariceract was designed as a once-daily oral activator of beta-glucocerebrosidase, or GCase, a lysosomal enzyme encoded by the GBA1 gene. Pathogenic variants in GBA1 are among the most important genetic risk factors for Parkinson’s disease. Reduced GCase activity is thought to impair lysosomal function and glycosphingolipid metabolism, contributing to the accumulation of alpha-synuclein, a hallmark of Parkinson’s pathology.
The rationale was therefore different from Bial’s established Parkinson’s therapy opicapone, marketed as Ongentys, which is used as an add-on to levodopa, the main dopamine-replacing treatment used to control motor symptoms in Parkinson’s disease, in patients with end-of-dose motor fluctuations. Opicapone extends the effect of levodopa by inhibiting catechol-O-methyltransferase, an enzyme involved in levodopa breakdown. This is a mechanism aimed at symptomatic control. Pariceract, by contrast, was developed as a potential disease-modifying intervention for a genetically defined subgroup of patients.
Failed acquisition
The compound came to Bial through its 2020 acquisition of Parkinson’s research programmes from Lysosomal Therapeutics, a Cambridge, Massachusetts-based company founded with the backing of former Genzyme chief executive Henri Termeer. Lysosomal Therapeutics had developed LTI-291, the molecule that later became BIA 28-6156/pariceract, as a small-molecule activator of GCase. The deal also formed the basis for Bial Biotech, the company’s US research presence in Cambridge, led by former LTI executives and scientists.
At the time, the acquisition, reported to be worth up to $130 million in milestone payments, was presented as a strategic move beyond symptomatic Parkinson’s care. Bial said the lead asset had completed Phase I testing and could enter Phase II studies in 2021. The company’s ambition was to move from treating motor complications to intervening in the disease mechanism itself.
GCase challenge
That ambition has now met the same translational challenge that has affected several other Parkinson’s programmes targeting lysosomal and glycosphingolipid biology. Sanofi’s venglustat, a glucosylceramide synthase inhibitor that approached the pathway from the substrate-reduction side rather than by activating GCase, previously failed to demonstrate clinical benefit in GBA-associated Parkinson’s. The failure of pariceract does not close the field, but it adds another cautionary datapoint.
Other companies are still pursuing related strategies. Gain Therapeutics is developing GT-02287, an oral small molecule designed to restore GCase activity and improve lysosomal function. Recent Phase Ib data reported in Parkinson’s patients suggested stable motor function over five months and biomarker changes, including effects on glucosylsphingosine and DOPA decarboxylase in cerebrospinal fluid. However, that study was small and open-label, and remains far from the kind of placebo-controlled efficacy test that pariceract has now failed.
The ACTIVATE result therefore leaves the GCase hypothesis in a more difficult position. The genetic and biological rationale remains strong: GBA1 variants are clearly linked with Parkinson’s risk and often with faster disease progression, but the clinical question is whether boosting GCase activity with a small molecule is sufficient, at the right stage of disease, to alter the trajectory of neurodegeneration in a measurable way.
For Bial, the failure narrows its Parkinson’s portfolio back toward its established symptomatic franchise. Ongentys remains an approved add-on therapy for patients whose levodopa benefit wears off before the next dose but pariceract was the company’s more ambitious attempt to enter disease modification in Parkinson’s disease, and also the only asset in development listed on its website’s portfolio.
Bial said it will share the ACTIVATE data through scientific meetings and peer-reviewed publications. For the Parkinson’s field, the key issue is not only why pariceract failed, but whether the result reflects the limitations of one molecule, one trial design, or a broader problem with trying to correct GBA-related biology after disease has already taken hold.
