Background

Verdiperstat is an irreversible inhibitor of myeloperoxidase. This enzyme catalyzes the generation of reactive oxygen species by activated microglia and other immune cells. The hypothesized mechanism of action of verdiperstat includes reduction of oxidative stress and neuroinflammation, and countering cell death due to pathological microglia activation. Taken in tablet form, verdiperstat has been shown to enter the brain (Johnström et al., 2015).

Verdiperstat was tested in a mouse model of multiple system atrophy (MSA), a rare and rapidly progressing α-synucleinopathy. In the model, induction of oxidative stress with 3-nitroproprionic acid (3-NP) in animals overexpressing α-synuclein in oligodendrocytes leads to microglia activation, synuclein inclusions, neuron loss, and movement deficits. Treating mice with verdiperstat before and during 3-NP exposure reduced microglial activation, α-synuclein aggregation, and neurodegeneration, and improved motor function (Stefanova et al., 2012). Delaying treatment until mice had developed full-blown pathology still reduced microglial activation and α-synuclein aggregation, but did not improve neuron loss or motor impairments (Kaindlstorfer et al., 2015).

Findings

Between 2008 and 2013, AstraZeneca completed multiple Phase 1 studies of AZD3241/verdiperstat, and a Phase 2 safety and tolerability study in people with Parkinson’s disease (PD). In these trials, verdiperstat was reported to dose-proportionally reduce MPO activity in plasma (Tong et al., 2018).

In 2012, the company used PET imaging to assess the effects of verdiperstat on microglia activation in the brains of 24 people with Parkinson’s disease. The study used ^11-CPBR28 tracer, a tracer that binds to the transporter protein (TSPO) in activated glia. Results are published, showing that eight weeks of treatment with 600 mg twice daily verdiperstat led to a reduction in the PET TSPO signal (Jucaite et al., 2015). No serious adverse events were reported in this small trial; the most common side effects in the treated group were headache, nausea, and insomnia. 

In 2015-2016, a Phase 2 trial tested a 12-week course of verdiperstat or placebo against a primary outcome of change in microglial activation in the striata in people with MSA. The 59 participants took 300 or 600 mg twice daily or placebo, and underwent the ^11CPBR28 PET. Secondary outcomes included myeloperoxidase inhibition in plasma, and exploratory efficacy outcomes including change in the Unified MSA Rating Scale (UMSARS). Results are posted at clinicaltrials.gov. No significant changes from baseline, or between groups, were detected.

In 2018, Biohaven licensed verdiperstat from AstraZeneca. At that time, the company disclosed some results on the exploratory efficacy outcomes of the Phase 2 MSA trial (press release). Among 52 people who completed the trial, Biohaven reported a dose-related trend for slowing disease worsening with verdiperstat, which was not statistically significant. The placebo group registered a 4.6-point decrease on the 104-point scale. The 300 mg group declined by 3.7 points; the 600 mg group lost 2.6 points. The drug significantly decreased MPO activity in plasma, the company claimed.

In July 2019, Biohaven began enrolling 336 people with MSA for a 48-week, Phase 3 trial. The study compared 600 mg twice daily to placebo on primary endpoints of a subset of measures from UMSARS, and safety and tolerability. Secondary endpoints included Clinical Global Impression of Improvement, quality of life, and total UMSARS. The trial was to run through September 2022, but on September 27, 2021, Biohaven announced that the trial had been completed at full enrollment, and that it had failed on its primary outcome and on key secondary efficacy measures (press release). Biohaven stopped an expanded access program, and discontinued development for MSA.

In July 2020, a Phase 2/3 trial began testing verdiperstat in ALS. This study is part of the Healey ALS platform trial, a multicenter clinical collaboration testing four different interventions in parallel against a common placebo group. As with all interventions in the Healey trial, verdiperstat was selected by an independent review board, based on evidence for the role of oxidative damage and microglia activation in ALS, including an observed elevation of TSPO-PET signals in ALS patients (Zürcher et al., 2015; Ratai et al., 2018). One hundred and sixty ALS patients were to receive 600 mg verdiperstat twice daily for 24 weeks. The primary outcome was disease progression on the ALS Functional Rating scale, with secondary outcomes spanning breathing function, muscle strength, and survival. The trial ended in April 2022, with a final enrollment of 167. On September 29, 2022, the company announced that verdiperstat had failed to show any difference from placebo on the primary or key secondary measures of disease progression (press release). Verdiperstat has been removed from the company pipeline.

In December 2020, Biohaven began a small study assessing the newer TSPO PET ligand ^18FPBR06, before and after verdiperstat treatment (Fujimura et al., 2010). This study enrolled 19 people with MSA who will have a scan at baseline and after six months of verdiperstat. Eight of the patients had previous scans during a six- to nine-month observational phase to establish the trajectory of changes in ^18FPBR06 signal, followed by six months of verdiperstat and a final scan. The study was completed in January 2022.

In March 2022, a Phase 1 began recruiting 64 people with semantic variant primary progressive aphasia (svPPA) due to frontal temporal lobal degeneration with TDP-43 pathology. Called Veri-T, this trial will randomize patients 3:1 to 600 mg verdiperstat daily or placebo for 24 weeks. The primary outcome is adverse events. Secondary outcomes include CSF and plasma pharmacokinetics, and exploratory biomarkers of CSF neurofilament light chain, and imaging, as well measures of dementia, cognitive function, and neuropsychiatric symptoms. Participants cannot have evidence of amyloid or tau pathology, or a clinical diagnosis of Alzheimer’s disease or an FTLD-associated clinical syndrome other than svPPA. The single-site study, at the University of California, San Francisco, will finish in June 2026.

Verdiperstat has fast-track and orphan-drug designations by the U.S. FDA and the European Medicine Agency for MSA.

For details on verdiperstat trials, see clinicaltrials.gov.