anle138b oligomer modulator (prion mouse data; MODAG clinical development in synucleinopathies)

Key facts

• Origin: a screen at the Groschup lab in Riems, Germany, for molecules that block formation of protease-resistant prion protein led to a pyrazole compound class covered by US patent application US20110293520, filed in 2009.
• Mechanism claim: the 2013 authors propose that it acts on pathological oligomers and shifts aggregates toward smaller forms; direct binding was shown for aggregated alpha-synuclein but not for prion protein.
• Prion mouse result: in RML-infected C57BL/6 mice, daily oral dosing from the day of infection roughly doubled median survival (355 versus 180 days), and dosing from day 80 or day 120 still extended survival (242 versus 168 and 224 versus 172 days, per a commentary on the paper).
• Strain breadth: cell-free amplification assays showed activity against two other rodent strains and human sporadic and variant CJD material, but living-animal data cover only RML; the authors' suggestion for human prion disease is an extrapolation.
• Normal prion protein was not reduced by treatment, unlike PrP lowering approaches.
• Genetic prion models: a 2023 J Virol study (NINDS funded) confirmed that anle138b doubled survival in RML-infected mice, but in D178N and E200K knock-in mouse models no clear disease endpoint could be found, so efficacy could not be tested.
• First-in-human: a 68-participant randomised placebo-controlled phase 1 in healthy adults (December 2019 to August 2020, Nottingham) found mostly mild adverse events similar to placebo at 50 to 300 mg, a half-life near 12 hours, and exposure at 200 mg daily at the level cited as effective in a mouse Parkinson model.
• The phase 1a report notes that nearly all participants were male, repeat dosing lowered exposure (suspected enzyme induction), and several authors work for MODAG or the contract research organisation and hold related patents or shares.
• Parkinson phase 1b: 70 patients with mild to moderate disease received 150 to 300 mg per day for 7 to 28 days; a 2023 abstract reports no severe adverse events and patient pharmacokinetics similar to healthy volunteers. The registry shows no posted results.
• Efficacy trial: TOPAS-MSA (NCT06568237), a Teva-sponsored phase 2 in multiple system atrophy, began 2 October 2024, compares oral TEV-56286 with placebo over 48 weeks, lists 349 enrolled across 61 sites in 8 countries, and is active, not recruiting with estimated completion 15 September 2027.
• Commercial status: Teva and MODAG announced worldwide licensing and joint development in October 2021 with no public financial terms; MODAG's homepage lists the Teva partnership and does not mention prions.
• Planned enrollment is given as 200 on Alzforum and MODAG's page but 349 on the registry; the registry figure is used here.

Timeline

1. 2009Patent application US20110293520 filed covering the compound class.
2. 2013Wagner et al publish the oligomer modulator paper in Acta Neuropathologica, with prion and Parkinson mouse data.
3. 2019Healthy-volunteer first-in-human study starts in Nottingham.
4. 2020Healthy-volunteer study completes.
5. 2020Parkinson phase 1b starts.
6. 2021Teva and MODAG announce a licensing and development collaboration.
7. 2022Phase 1a results published in eBioMedicine.
8. 2022Parkinson phase 1b study completion.
9. 2023J Virol study of anle138b in genetic prion mouse models published online.
10. 2024TOPAS-MSA phase 2 starts.
11. 2026TOPAS-MSA registry record last updated; status active, not recruiting.