TAK-071

Therapeutic potential of TAK-071, a muscarinic M1 receptor positive allosteric modulator with low cooperativity, for the treatment of cognitive deficits and negative symptoms associated with schizophrenia

The selective activation of the muscarinic M1 receptor (M1R) may be a promising approach for treating cognitive impairment associated with cholinergic dysfunction. We previously reported that low cooperativity (α-value) is associated with a favorable cholinergic side effect profile of M1R positive allosteric modulators (M1 PAMs), as well as being a crucial factor for the cognitive improvement observed after combining M1 PAMs with donepezil, in rodents. In this study, we preclinically characterized TAK-071, a novel M1 PAM with low cooperativity (α-value = 199), as a new therapy for schizophrenia. We tested TAK-071 in the offspring of polyriboinosinic-polyribocytidylic acid-treated dams, which is a maternal immune activation model of schizophrenia. TAK-071 improved sociability deficits and working memory in this model. In a genetic mouse model of schizophrenia, miR-137 transgenic (Tg) mice, TAK-071 improved deficits in working memory, recognition memory, sociability, and sensorimotor gating. Patients with schizophrenia usually take several antipsychotics to treat positive symptoms. Thus, we also investigated the combined effects of TAK-071 with currently prescribed antipsychotics. Among the 10 antipsychotics tested, only olanzapine and quetiapine showed M1R 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 D2 receptor antagonists. In conclusion, TAK-071 can exert beneficial effects on social behavior and cognitive function and could be a new therapy for schizophrenia.

Safety, pharmacokinetics and quantitative EEG modulation of TAK-071, a novel muscarinic M1 receptor positive allosteric modulator, in healthy subjects

Aims: TAK-071 is a muscarinic M₁ receptor positive allosteric modulator designed to have low cooperativity with acetylcholine. This was a first-in-human study to evaluate the safety, pharmacokinetics, and pharmacodynamics of TAK-071.
Methods: TAK-071 was administered as single and multiple doses in a randomized, double-blind, placebo-controlled, parallel-group design in healthy volunteers alone and in combination with donepezil. Laboratory, electrocardiogram (ECG) and electroencephalogram (EEG) evaluations were performed. Cerebrospinal fluid and blood samples were taken to evaluate the pharmacokinetics (PK), relative bioavailability and food effect.
Results: TAK-071 was safe and well tolerated, and no deaths or serious adverse events occurred. TAK-071 demonstrated a long mean (% coefficient of variation) half-life of 46.3 (25.2%) to 60.5 (51.5%) hours and excellent brain penetration following oral dosing. Coadministration with donepezil had no impact on the PK of either drug. There was no food effect on systemic exposure. Quantitative EEG analysis revealed that TAK-071 40-80 mg increased power in the 7-9 Hz range in the posterior electrode group with eyes open and 120-160 mg doses increased power in the 16-18 Hz range and reduced power in the 2-4 Hz range in central-posterior areas with eyes open and eyes closed. Functional connectivity was significantly reduced after TAK-071 at high doses and was enhanced with coadministration of donepezil under the eyes-closed condition.
Conclusions: 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.

TAK-071, a novel M1 positive allosteric modulator with low cooperativity, improves cognitive function in rodents with few cholinergic side effects

The muscarinic M₁ receptor (M₁R) is a promising target for treating cognitive impairment associated with cholinergic deficits in disorders such as Alzheimer's disease and schizophrenia. We previously reported that cooperativity (α-value) was key to lowering the risk of diarrhea by M₁R positive allosteric modulators (M₁ PAMs). Based on this, we discovered a low α-value M₁ PAM, TAK-071 (α-value: 199), and characterized TAK-071 using T-662 as a reference M₁ PAM with high α-value of 1786. Both TAK-071 and T-662 were potent and highly selective M₁ PAMs, with inflection points of 2.7 and 0.62 nM, respectively. However, T-662 but not TAK-071 augmented isolated ileum motility. TAK-071 and T-662 increased hippocampal inositol monophosphate production through M₁R activation and improved scopolamine-induced cognitive deficits in rats at 0.3 and 0.1 mg/kg, respectively. TAK-071 and T-662 also induced diarrhea at 10 and 0.1 mg/kg, respectively, in rats. Thus, taking into consideration the fourfold lower brain penetration ratio of T-662, TAK-071 had a wider margin between cognitive improvement and diarrhea induction than T-662. Activation of M₁R increases neural excitability via membrane depolarization, reduced afterhyperpolarization, and generation of afterdepolarization in prefrontal cortical pyramidal neurons. T-662 induced all three processes, whereas TAK-071 selectively induced afterdepolarization. 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 M₁R expression, while minimizing peripheral cholinergic side effects.

TAK-071, a muscarinic M1 receptor positive allosteric modulator, attenuates scopolamine-induced quantitative electroencephalogram power spectral changes in cynomolgus monkeys

Activation of the muscarinic M1 receptor is a promising approach to improve cognitive deficits associated with cholinergic dysfunction in Alzheimer's disease, dementia with Lewy bodies, and schizophrenia. TAK-071 is an M1-selective positive allosteric modulator that improves cognitive deficits induced by scopolamine, a non-selective muscarinic receptor antagonist, with reduced side effects on gastrointestinal function in rats. In this study, we explored changes in quantitative electroencephalography (qEEG) power bands, with or without scopolamine challenge, as a non-invasive translational biomarker for the effect of TAK-071 in cynomolgus monkeys. Scopolamine has been reported to increase theta and delta power bands and decrease alpha power band in healthy volunteers. In line with the clinical observations, scopolamine (25-100 μg/kg, subcutaneous administration [s.c.]) increased theta and delta power bands in cynomolgus monkeys in a dose-dependent manner, whereas it had the opposite effect on alpha power band. The effects of TAK-071 on scopolamine (25 μg/kg, s.c.)-induced qEEG spectral changes were examined using an acetylcholinesterase inhibitor donepezil and a muscarinic M1/M4 receptor agonist xanomeline as comparative cholinomimetics. 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.

Reduction of falls in a rat model of PD falls by the M1 PAM TAK-071

Rationale: In addition to the disease-defining motor symptoms, patients with Parkinson's disease (PD) exhibit gait dysfunction, postural instability, and a propensity for falls. These dopamine (DA) replacement-resistant symptoms in part have been attributed to loss of basal forebrain (BF) cholinergic neurons and, in interaction with striatal dopamine (DA) loss, to the resulting disruption of the attentional control of balance and complex movements. Rats with dual cholinergic-DA losses ("DL rats") were previously demonstrated to model PD falls and associated impairments of gait and balance.
Objectives: We previously found that the muscarinic M1-positive allosteric modulator (PAM) TAK-071 improved the attentional performance of rats with BF cholinergic losses. Here, we tested the hypotheses that TAK-071 reduces fall rates in DL rats.
Results: Prior to DL surgery, female rats were trained to traverse a rotating straight rod as well as a rod with two zigzag segments. DL rats were refamiliarized with such traversals post-surgery and tested over 7 days on increasingly demanding testing conditions. TAK-071 (0.1, 0.3 mg/kg, p.o.) was administered prior to daily test sessions over this 7-day period. As before, DL rats fell more frequently than sham-operated control rats. Treatment of DL rats with TAK-071 reduced falls from the rotating rod and the rotating zigzag rod, specifically when the angled part of the zigzag segment, upon entering, was at a steep, near vertical angle.
Conclusions: 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.