Background

Minzasolmin is a small-molecule α-synuclein aggregation inhibitor. Oligomerization and aggregation of α-synuclein is implicated in Parkinson’s disease, dementia with Lewy bodies, and multiple-system atrophy. Minzasolmin was discovered at Neuropore, licensed to UCB in 2014, and licensed for co-development to Novartis in 2021.

Neuropore scientists and collaborators have described a series of cyclic peptidomimetic compounds designed to interact with the C-terminal domain of α-synuclein and prevent it from binding to membranes and oligomerizing there. One compound was reported to reduce α-synuclein aggregation in vitro and in α-synuclein transgenic mouse models, where it also normalized neural and inflammatory markers, and ameliorated motor deficits. In vivo imaging showed a reduction in cortical synaptic α-synuclein within one hour of dosing in the mice (Wrasidlo et al., 2016).

Minzasolmin is a second-generation compound, optimized for oral bioavailability and brain entry. It is the purified R enantiomer of the racemic mixture NPT-200-11. In preclinical work, NPT-200-11 reduced retinal α-synuclein pathology over two months of daily administration in mice expressing human α-synuclein. It also lessened cortical α-synuclein pathology and astrogliosis, normalized striatal dopamine transporter levels, and improved motor function (Price et al., 2018). Similar results were subsequently reported for minzasolmin (Price et al., 2023). A high-resolution structure of oligomeric, membrane bound α-synuclein suggests that minzasolmin interacts with the protein to increase its flexibility and impair its embedding into the membrane. In this way, minzasolmin interferes with fibril growth and toxic pore formation, and promotes the release of synuclein monomers in their soluble, random coil form (Schwarz et al., 2023). This study showed that the enantiomers interacted identically with membrane-bound α-synuclein.

Findings

In April 2021, UCB presented the results of a Phase 1b study at the American Academy of Neurology Annual Meeting (Genius et al., 2021). According to a news report, the study enrolled 31 people with early stage Parkinson’s disease, who received 90 or 180 mg UCB0599 or placebo twice daily for 28 days. Most adverse events were mild to moderate, occurring at similar frequency in treated and placebo groups. Two participants treated with UCB0599 showed mild hypersensitivity reactions. Overall, the drug raised no safety concerns, according to the investigators. The company subsequently published this data, along with results of single and multiple ascending doses in 73 healthy volunteers (Smit et al., 2022). At 90, 180, 360, and 450 mg, pharmacokinetics were linear and predictable, including in CSF. Food effects were minimal. Co-administration of the cytochrome P450 inhibitor itraconazole doubled plasma exposure, but did not change short term safety. Two volunteers in this study had moderately severe hypersensitivity reactions.

In December 2020, UCB began an 18-month, Phase 2, placebo-controlled study in 300 people with early PD and mild symptoms. In late 2021, enrollment was increased to 450, split evenly among high-dose, low-dose, and placebo arms, delivered as granules in capsules.. The primary outcome is change in the Unified Parkinson’s Disease Rating Scale (UPDRS), Parts I-III. Secondary outcomes include UPDRS individual parts I, II, and III, time to disease worsening, change in Montreal cognitive assessment, dopamine transporter imaging, time to start of symptomatic treatment, symptomatic treatment intake, adverse events, and events leading to withdrawal. The trial enrolled 496 participants at more than 100 sites in the U.S., Canada, France, Germany, Italy, Poland, Spain, the Netherlands and the U.K., and was completed in September 2024. A long-term extension has enrolled 428 participants, at either high or low dose.

A Phase 1 study evaluated 11[C]-labeled UCB0599 as a PET ligand. Four participants were scanned before, and two hours after, a 360 mg oral dose of unlabeled UCB0599. The radioligand distributed throughout the brain, and steady-state brain concentrations were approximately half of plasma levels. Prior administration of unlabeled compound did not change the amount of tracer entering the brain (Mercier et al., 2023).

In May 2023, a Phase 1 began to compare the bioavailability of two new formulations of UCB0599 under normal and elevated gastric pH. A second part of the study assesses pharmacokinetics in healthy Japanese and Chinese participants. This study was completed in April 2024.

In July 2024, the company registered a Phase 1 study to assess the bioavailability of a new tablet formulation, and the effect of food. The trial plans to enroll 18 healthy adults, and run until October 2024.

For details on minzasolmin/UCB0599 trials, see clinicaltrials.gov.