TAK-071 / Takeda - LARVOL DELTA

Population Pharmacokinetic and Exposure-Response Analysis of the Cognitive Effects of TAK-071 in Participants With Parkinson Disease and Cognitive Impairment. (PubMed, Clin Pharmacol Drug Dev) - "As patients with PD can have an increased risk of falls, the relationship between cognitive function and risk of falls, as assessed by stride time variability, was explored. Cognition response for the attention domain score showed consistent and sustained improvement in stride time variability compared with when no response was observed, supporting further investigation of TAK-071 in PD for the risk of falls."

Journal • PK/PD data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Movement Disorders • Parkinson's Disease

M1 receptor positive allosteric modulators discovery approaches. (PubMed, Trends Pharmacol Sci) - "The development of M1 muscarinic acetylcholine-receptor-positive allosteric modulators has been hindered by their limited cognitive efficacy and cholinergic side effects. We discuss two unique approaches - low intrinsic agonism and low binding cooperativity - that were developed to address these issues and their therapeutic implications."

Journal

An Acetylcholine M1 Receptor-Positive Allosteric Modulator (TAK-071) in Parkinson Disease With Cognitive Impairment: A Phase 2 Randomized Clinical Trial. (PubMed, JAMA Neurol) - P2 | "Larger and longer studies in more diverse populations are needed to better understand the safety and efficacy of TAK-071 in broader populations. ClinicalTrials.gov Identifier: NCT04334317."

Clinical • Journal • P2 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Gastrointestinal Disorder • Movement Disorders • Parkinson's Disease

A Phase 2 Randomized Clinical Trial of TAK-071, an Acetylcholine M1 Receptor Positive Allosteric Modulator, in Parkinson Disease with Cognitive Impairment (MDS Congress 2024) - P2 | "In adults with PD with increased risk for falls and cognitive impairment, TAK-071 was generally safe and well-tolerated, did not improve gait parameters, but improved cognition compared with placebo."

Clinical • P2 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Parkinson's Disease

A Study of TAK-071 in People With Parkinson Disease (clinicaltrials.gov) - P2 | N=64 | Completed | Sponsor: Takeda | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders • Cognitive Disorders • Movement Disorders • Parkinson's Disease

A Study of TAK-071 in People With Parkinson Disease (clinicaltrials.gov) - P2 | N=64 | Active, not recruiting | Sponsor: Takeda | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Cognitive Disorders • Movement Disorders • Parkinson's Disease

Therapeutic Potential of TAK-071, a Muscarinic M Receptor Positive Allosteric Modulator with Low Cooperativity, For the Treatment of Cognitive Deficits and Negative Symptoms Associated with Schizophrenia. (PubMed, Neurosci Lett) - "We previously reported that low cooperativity (α-value) is associated with a favorable cholinergic side effect profile of MR positive allosteric modulators (M PAMs), as well as being a crucial factor for the cognitive improvement observed after combining M PAMs with donepezil, in rodents...Among the 10 antipsychotics tested, only olanzapine and quetiapine showed MR antagonistic effects, which were counteracted by TAK-071 at possible effective concentrations for cognitive improvement in vitro. Moreover, haloperidol did not affect the ability of TAK-071 to improve working memory in miR-137 Tg mice, suggesting a low risk of losing efficacy when combined with dopamine D receptor antagonists. In conclusion, TAK-071 can exert beneficial effects on social behavior and cognitive function and could be a new therapy for schizophrenia."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Safety, pharmacokinetics and quantitative EEG modulation of TAK-071, a novel muscarinic M1 receptor positive allosteric modulator, in healthy subjects. (PubMed, Br J Clin Pharmacol) - "PK and safety profiles of TAK-071 were favorable, including those exceeding expected pharmacologically active doses based on preclinical data. When administered without donepezil TAK-071 was largely free of cholinergic adverse effects. Further clinical evaluation of TAK-071 is warranted."

Clinical • Journal • PK/PD data • Alzheimer's Disease • CNS Disorders • Movement Disorders • Parkinson's Disease

Reduction of falls in a rat model of PD falls by the M1 PAM TAK-071. (PubMed, Psychopharmacology (Berl)) - "TAK-071 may benefit complex movement control, specifically in situations which disrupt the patterning of forward movement and require the interplay between cognitive and motor functions to modify movement based on information about the state of dynamic surfaces, balance, and gait."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease

A Study Of TAK-071 In People With Parkinson Disease (clinicaltrials.gov) - P2; N=74; Recruiting; Sponsor: Takeda; Trial completion date: Mar 2022 ➔ Nov 2022; Trial primary completion date: Mar 2022 ➔ Nov 2022

Clinical • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Movement Disorders • Parkinson's Disease

MJFF Announces 5 Parkinson’s Clinical Trials in Need of Recruits (Parkinson's News Today) - "One Phase 2 study (NCT04334317) is testing TAK-071, an investigational therapy that aims to ease cognitive impairment and reduce falls in people with Parkinson’s.... It aims to recruit 64 people with Parkinson’s who are experiencing mild cognitive impairment and have had at least two falls within the last six months. Recruitment is currently ongoing at sites in California, Florida, and Michigan, and more locations will be opening in the coming months....TEMPO-2 (NCT04223193), a Phase 3 study now recruiting, is investigating a medication called tavapadon....The trial aims to recruit 296 participants who have been diagnosed with Parkinson’s in the last three years and will be held at 12 sites across the U.S."

Enrollment status • CNS Disorders • Parkinson's Disease

Effect of TAK-071 on Falls in Participants With Parkinson Disease (PD) (clinicaltrials.gov) - P2; N=64; Recruiting; Sponsor: Takeda; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • CNS Disorders • Cognitive Disorders • Movement Disorders • Parkinson's Disease

T-495, a novel low cooperative M receptor positive allosteric modulator, improves memory deficits associated with cholinergic dysfunction and is characterized by low gastrointestinal side effect risk. (PubMed, Pharmacol Res Perspect) - "In fact, TAK-071, a novel M R PAM with low cooperativity (α-value of 199), improved scopolamine-induced cognitive deficits with a wider margin against GI side effects than a high cooperative M R PAM, T-662 (α-value of 1786), in rats. Here, we describe the pharmacological characteristics of a novel low cooperative M R PAM T-495 (α-value of 170), using the clinically tested higher cooperative M R PAM MK-7622 (α-value of 511) as a control...Additionally, in mice with reduced acetylcholine levels in the forebrain via overexpression of A53T α-synuclein (ie, a mouse model of dementia with Lewy bodies and Parkinson's disease with dementia), T-495, like donepezil, reversed the memory deficits in the contextual fear conditioning test and Y-maze task. Thus, low cooperative M R PAMs are promising agents for the treatment of memory deficits associated with cholinergic dysfunction."

Adverse events • Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Gastrointestinal Disorder • Lewy Body Disease • Movement Disorders • Parkinson's Disease

Rescuing the attentional performance of rats with cholinergic losses by the M1 positive allosteric modulator TAK-071. (PubMed, Psychopharmacology (Berl)) - "These findings suggest that TAK-071 may benefit the attentional performance of patients with partial cholinergic losses and specifically in situations that tax top-down, or goal-driven, attentional control."

Journal • Preclinical

Effect of TAK-071 on Falls in Patients With Parkinson Disease (clinicaltrials.gov) - P2; N=64; Not yet recruiting; Sponsor: Takeda

Clinical • New P2 trial

In Vivo Pharmacological Comparison of TAK-071, a Positive Allosteric Modulator of Muscarinic M Receptor, and Xanomeline, an Agonist of Muscarinic M/M Receptor, in Rodents. (PubMed, Neuroscience) - "Xanomeline suppressed both methamphetamine- and MK-801-induced hyperlocomotion in mice, whereas TAK-071 suppressed only MK-801-induced hyperlocomotion. When donepezil was co-administered to increase the levels of acetylcholine, the number of TAK-071-induced c-Fos-positive cells in these brain regions was increased. TAK-071, through induction of similar neural activation as that seen with xanomeline, may produce procognitive and antipsychotic effects with improved cholinergic side effects."

Journal • Preclinical

TAK-071, a novel M positive allosteric modulator with low cooperativity, improves cognitive function in rodents with few cholinergic side effects. (PubMed, Neuropsychopharmacology) - "Combining sub-effective doses of TAK-071, but not T-662, with an acetylcholinesterase inhibitor, significantly ameliorated scopolamine-induced cognitive deficits in rats. TAK-071 may therefore provide therapeutic opportunities for cognitive dysfunction related to cholinergic deficits or reduced MR expression, while minimizing peripheral cholinergic side effects."

Adverse events • Journal • Preclinical

TAK-071, a muscarinic M1 receptor positive allosteric modulator, attenuates scopolamine-induced quantitative electroencephalogram power spectral changes in cynomolgus monkeys. (PubMed, PLoS One) - "TAK-071 (0.3-3 mg/kg, oral administration [p.o.]), donepezil (3 mg/kg, p.o.), and xanomeline (1 mg/kg, s.c.) suppressed the scopolamine-induced increases in alpha, theta, and delta power bands. These results suggest that changes in specific qEEG power bands, in particular theta and delta power bands in the context of scopolamine challenge, could be used as translational biomarkers for the evaluation of TAK-071 in clinical studies."

Biomarker • Journal