balipodect (TAK-063) / Takeda - LARVOL DELTA

Potent and sustained enhancement of human sperm motility using novel cyclic AMP up-regulators. (PubMed, Reproduction) - "The enhancement of sperm motility persisted for 4 h after their removal, surpassing the effects of known cAMP analogs (8-bromo-adenosine-3', 5'-cAMP (8-Br-cAMP) or dibutyryl cAMP (db-cAMP)) or PDE inhibitors (3-isobutyl-1-methylxanthine (IBMX) or pentoxifylline (PTX)). In conclusion, cBiMPs and TAK-063 exhibit potent and sustained effects on human sperm motility, enhancing the efficiency of sperm preparation techniques. The ability to improve sperm motility holds significant implications for male infertility treatment, facilitating the use of low complexity techniques such as intrauterine insemination or in vitro fertilization, and may also aid in selecting viable testicular sperm for intracytoplasmic sperm injection."

Journal • Gynecology • Infertility • Sexual Disorders

Inhibition of Phosphodiesterase 10A Alleviates Pain-like Behavior in Mice. (PubMed, Anesthesiology) - "Collectively, our data support the idea that PDE10A is a suitable target for the development of efficacious analgesic drugs."

Journal • Preclinical • Pain • ACYP1 • LINC00473

Inhibition of phosphodiesterase 10A mitigates neuronal injury by modulating apoptotic pathways in cold-induced traumatic brain injury. (PubMed, Mol Cell Neurosci) - "Interestingly, TAK-063 treatment reduced levels of anti-apoptotic proteins or enzymes, including XIAP, Claspin, and HIF1α, without affecting Bcl-x, MCL-1, SMAC, HO-1, HO-2, HSP27, HSP60, and HSP70. The findings suggest that PDE10A regulates cellular signaling predominantly pro-apoptotic pathways, and inhibition of this protein is a promising approach for the treatment of acute brain injury."

Journal • CNS Disorders • Inflammation • Vascular Neurology • BCL2L1 • CASP3 • CLSPN, • FAS • HIF1A • HSPD1 • MCL1 • MMP9 • PTEN • TNFRSF10B • TNFRSF1A • XIAP

MK-8189, a PDE10A inhibitor, for the treatment of schizophrenia (ECNP 2023) - P2b | "Efficacy results from previous proof-of-concept clinical trials with PF-02545920 and TAK-063 in individuals with acute psychosis have been unimpressive but their enzyme inhibition over 24 hours was likely modest ( 80% trough EO. Consequently, doses up to 24mg, predicted to produce > 80% sustained EO, are being evaluated in an ongoing Phase 2b trial [NCT04624243]."

CNS Disorders • Dystonia • Psychiatry • Schizophrenia • ACYP1 • LINC00473

Functional Phenotypic Screening of Small Molecules in a human patient-derived cell model for Fragile X Syndrome (Neuroscience 2022) - "We compare the potential therapeutic effects of balipodect, mavoglurant, arbaclofen, and lovastatin in this model. We used a well-characterized iPSC cell line from an FXS patient and differentiated it into a glutamatergic neuronal cell culture. The neuronal cell cultures were cultivated on and studied using microelectrode array plates."

Clinical • CNS Disorders • Cognitive Disorders • Psychiatry

Phosphodiesterase 10A deactivation induces long-term neurological recovery, Peri-infarct remodeling and pyramidal tract plasticity after transient focal cerebral ischemia in mice. (PubMed, Exp Neurol) - "Herein, we evaluated the effects of PDE10A deactivation by TAK-063 (0.3 or 3 mg/kg, initiated 72 h post-stroke) in mice exposed to intraluminal middle cerebral artery occlusion...Liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed a set of dopamine receptor-related and neuronal plasticity-related PDE10A targets, which were elevated (e.g., protein phosphatase-1 regulatory subunit 1B) or reduced (e.g., serine/threonine protein phosphatase 1α, β-synuclein, proteasome subunit α2) by PDE10A deactivation. Our results identify PDE10A as a therapeutic target that critically controls post-ischemic brain tissue remodeling and plasticity."

Journal • Preclinical • Cardiovascular • TNS1

Phosphodiesterase 10A Is a Critical Target for Neuroprotection in a Mouse Model of Ischemic Stroke. (PubMed, Mol Neurobiol) - "In addition, liquid chromatography-tandem mass spectrometry revealed 40 proteins were significantly altered by TAK-063. Our study established PDE10A as a target for ischemic stroke therapy."

Journal • Preclinical • Cardiovascular • CNS Disorders • Immunology • Inflammation • Ischemic stroke • BCL2L1 • HIF1A • IFNG • MMP9 • TNFA

The PDE10A Inhibitor TAK-063 Reverses Sound-Evoked EEG Abnormalities in a Mouse Model of Fragile X Syndrome. (PubMed, Neurotherapeutics) - "Our data suggest that TAK-063 improves cortical auditory stimulus processing in Fmr1 KO mice, without significantly depressing baseline EEG power or causing any noticeable sedation or behavioral side effects. Thus, the PDE10A inhibitor TAK-063 has salutary effects on normalizing EEG biomarkers in a mouse model of FXS and should be pursued in further translational treatment development."

Journal • Preclinical • Anesthesia • CNS Disorders • Fragile X Syndrome • Genetic Disorders • Immunology • Mood Disorders • Psychiatry

Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities. (PubMed, CNS Spectr) - "Therapies targeting total symptoms include cannabidiol, D3 antagonist/5-HT1A partial agonist F17464, lumateperone (ITI-007), phosphodiesterase 10A (PDE10A) inhibitors MK-8189 and TAK-063, sodium nitroprusside, and trace amine-associated receptor-1 (TAAR1) agonist RO5263397 and SEP-363856. Treatments targeting negative symptoms include the PDE10A inhibitor LuAF-11167, 5-HT2A inverse agonist pimavanserin, sigma-2/5-HT2A antagonist roluperidone (MIN-101), and d-amino acid oxidase (DAAO) inhibitor TAK-831. Agents targeting primarily cognitive dysfunction are the glycine transporter-1 inhibitor BI-425809 and cannabidiol. Therapies targeting residual positive symptoms/treatment-resistant schizophrenia include pimavanserin, dopamine D1/D2 antagonist LuAF-35700, and DAAO inhibitor sodium benzoate. Two new long-acting injectable antipsychotic formulations, Aripiprazole Lauroxil NanoCrystal® and the first subcutaneous injectable LAI Perseris (RBP-7000), were recently approved..."

Journal • CNS Disorders • Schizophrenia

A randomized, placebo-controlled, phase 1 study to evaluate the effects of TAK-063 on ketamine-induced changes in fMRI BOLD signal in healthy subjects. (PubMed, Psychopharmacology (Berl)) - "Our results are consistent with non-clinical studies of ketamine and TAK-063 and clinical studies of ketamine and risperidone. It is unknown whether these data are predictive of potential antipsychotic efficacy, and further analyses are required."

Clinical • Journal • P1 data • CNS Disorders • Schizophrenia

Translational Development Strategies for TAK-063, a Phosphodiesterase 10A Inhibitor. (PubMed, Int J Neuropsychopharmacol) - "Overall, the phase 1 results showed some consistent evidence of antipsychotic activity. This translational strategy may be valuable for future development of novel therapeutic approaches, even when relevant nonclinical models are not available."

Journal • CNS Disorders • Schizophrenia • MRI

Phosphodiesterase 10A Inhibition Leads to Brain Region-Specific Recovery Based on Stroke Type. (PubMed, Transl Stroke Res) - "We tested a novel PDE10A inhibitor (TAK-063) for its effects on functional recovery...Inhibition of PDE10A improved recovery of function after striatal but not cortical stroke, consistent with its brain localization. This experiment is the first demonstration of brain region-specific enhanced functional recovery after stroke, and indicates that differential molecular signaling between brain regions can be exploited to improve recovery based on stroke subtype."

Journal

A phase 2, randomized, placebo-controlled study of the efficacy and safety of TAK-063 in subjects with an acute exacerbation of schizophrenia. (PubMed, Schizophr Res) - P2; "Although the study did not meet the primary endpoint (effect size = 0.308), the effects of TAK-063 on the primary and secondary endpoints may be suggestive of antipsychotic activity. Interpretation of these results is confounded by a relatively high placebo effect and a lack of dose-ranging or active reference."

Clinical • Journal • P2 data

TAK-063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia. (PubMed, CNS Neurosci Ther) - "TAK-063, with a faster off-rate property, could provide a unique opportunity as a novel therapeutic approach to treatment of psychosis and cognitive deficits in schizophrenia. TAK-063 also has a therapeutic potential in other basal ganglia disorders."

Journal • Review