Objective: To present first-in-patient data of the oligomer modulator anle138b (TEV-56286, emrusolmin) in patients with Parkinson’s disease (PD).

Background: Synucleinopathies such as PD and Multiple System Atrophy are characterized by deposition of misfolded and aggregated α-synuclein. Anle138b, an orally bioavailable small molecule compound targets mainly these aggregate species and shows strong disease-modifying effects in animal models (1,2,3). A first-in-human study in healthy volunteers has shown safety and tolerability of anle138b with exposure concentrations comparable to levels showing therapeutic activity in animal models (4).

Method: A single-centre, double-blind, randomised, placebo-controlled multiple ascending dose study in patients with mild-to-moderate PD was performed. Participants were randomly assigned to placebo or anle138b (150-300 mg/day for 7-28 days), respectively. Primary endpoints were safety and tolerability; the secondary endpoint was pharmacokinetics. Exploratory endpoints related to the effect of food on the pharmacokinetics of anle138b in PD patients were examined, to study potential effects of longer gastrointestinal passage time in PD patients. Additional pharmacodynamic endpoints assessed to the potential effects on patients’ functional status when co- administered with PD symptomatic treatments. Treatment was administered orally in hard gelatine capsules containing anle138b or excipient only. Clinicaltrials.gov: NCT04685265. EudraCT: 2020-004869-38.

Results: 70 participants were enrolled in cohorts A-E. Apart from one patient that was withdrawn due to a SARS-CoV2 infection, all patients completed the study per protocol. There were no major protocol violations. No compound-related adverse events leading to early termination and no severe adverse events were observed. No abnormal trends seen in any system organ class. Pharmacokinetics of anle138b in PD patients was comparable to the pharmacokinetics previously observed in healthy volunteers.

Conclusion: In patients with PD across a wide range of disease severity, anle138b was safe and well tolerated when administered 7-28 days. Exposures were reached above the minimally effective plasma levels seen in animal models. Efficacy trials in patients with synucleinopathies are planned.

References: 1) Wagner J, Ryazanov S, Leonov A, Levin J, Shi S, Schmidt F, et al. Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson’s disease. Acta Neuropathol. 2013;125(6):795-813.
2) Levin J, Schmidt F, Boehm C, Prix C, Botzel K, Ryazanov S, et al. The oligomer modulator anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset. Acta Neuropathol. 2014;127(5):779-80.
3) Wegrzynowicz M, Bar-On D, Calo L, Anichtchik O, Iovino M, Xia J, et al. Depopulation of dense alpha-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model. Acta Neuropathol. 2019;138(4):575-95.
4) Levin J, Sing N, Melbourne S, Morgan A, Mariner C, et al. Safety, tolerability and pharmacokinetics of the oligomer modulator anle138b with exposure levels sufficient for therapeutic efficacy in a murine Parkinson model: A randomised, double-blind, placebo-controlled phase 1a trial. EBioMedicine. 2022 Jun;80:104021.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/anle138b-p1-02-a-randomised-double-blinded-placebo-controlled-phase-1b-study-to-investigate-safety-tolerability-pharmacokinetics-and-pharmacodynamics-of-the-oligomer-modulator-anle138b-in-parkins/