Therapeutics

TAK-341

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Overview

Name: TAK-341
Synonyms: MEDI1341
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: alpha-synuclein
Condition(s): Parkinson's Disease, Multiple System Atrophy
U.S. FDA Status: Parkinson's Disease (Phase 1), Multiple System Atrophy (Phase 2)
Company: AstraZeneca, Takeda Pharmaceutical Company

Background

This is a high-affinity monoclonal antibody to a C-terminal epitope on monomeric and aggregated α-synuclein, originally developed by AstraZeneca. Genetic and pathological evidence implicates α-synuclein in the pathogenesis of Parkinson's disease (PD) and other α-synucleinopathies such as dementia with Lewy bodies (DLB).

In preclinical studies, MEDI1341 entered the brain after intravenous administration to rats or monkeys, where it was reported to lower concentrations of free α-synuclein in cerebrospinal fluid and brain interstitial fluid. The antibody intercepted cell-to-cell spreading of human α-synuclein fibrils in cell culture and in a mouse model of α-synuclein pathology propagation in brain. A version of the antibody with diminished Fc receptor binding was equally potent in the mouse model, suggesting that antibody-mediated immune mechanisms are not required for its activity (Schofield et al., 2019).

MEDI1341 is one of several α-synuclein antibodies being investigated for PD. Others include ABBV-0805cinpanemabLU AF82422prasinezumab, and UCB7853.

Findings

In October 2017, Astra Zeneca began a Phase 1 single-ascending-dose study in 48 healthy volunteers age 18 to 65. Each volunteer was to receive a one-hour intravenous infusion of MEDI1341 or placebo, followed by three months of observation. The study planned to test up to six doses, safety data permitting. Starting with the lowest dose, each cohort of eight volunteers was to be completed before the trial moved to the next-higher dose in a new group of volunteers. Primary outcomes are adverse events; secondary outcomes include pharmacokinetics, quantification of α-synuclein in blood and CSF, and detection of anti-drug antibodies in serum. In August 2019, the sponsor updated the qualifying criteria to exclude anyone with a significant eye disorder, and added assessment of vision and eye health to the primary outcomes. The trial, run by the CRO Covance in Dallas; Madison, Wisconsin; and Leeds, U.K., ended in March 2021.

From August 2020 to January 2022, the sponsor ran a second Phase 1 trial, assessing multiple ascending doses in people with Parkinson’s disease. The study enrolled 25 participants who received antibody or placebo three times over eight weeks, with 13 weeks of follow-up. Three increasing doses had been planned in successive cohorts of 12 volunteers each, but the study ended after only two. Primary outcomes were adverse events and clinical and lab safety measures, electrocardiogram, plus ophthalmic assessments and measures of cognitive impairment, suicidal ideation and behavior.

In November 2022, Takeda took over development, with a Phase 2 trial in 138 people with multiple systems atrophy. Participants will receive infusions of antibody or placebo every four weeks for one year. An early PK cohort will receive an unspecified dose; the main cohort will receive a different dose. The primary outcome is change in the Unified Multiple System Atrophy Rating Scale Part 1 after one year. This scale assesses activities related to motor disability and autonomic function. Secondary outcomes include PK, other clinical measures, survival time, adverse events, and antidrug antibodies. The study will run in 56 locations in North America, Europe, and Asia through August 2025.

For details, see clinicaltrials.gov.

Last Updated: 17 Jan 2023

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References

Therapeutics Citations

  1. Exidavnemab
  2. LU AF82422
  3. Prasinezumab
  4. UCB7853

Paper Citations

  1. . Preclinical development of a high affinity α-synuclein antibody, MEDI1341, that can enter the brain, sequester extracellular α-synuclein and attenuate α-synuclein spreading in vivo. Neurobiol Dis. 2019 Dec;132:104582. Epub 2019 Aug 21 PubMed.

Other Citations

  1. cinpanemab

External Citations

  1. clinicaltrials.gov.

Further Reading

Papers

  1. . Immunotherapies for Parkinson's disease: Progression of Clinical Development. CNS Neurol Disord Drug Targets. 2021 May 26; PubMed.