TAK-418 / Takeda - LARVOL DELTA

Drug discovery strategy for TAK-418, a specific inhibitor of LSD1 enzyme activity, as a novel therapy for autism. (PubMed, Adv Pharmacol) - "A positron emission tomography tracer was discovered to potentially measure the occupancy of TAK-418 at the LSD1 active site in the brain to improve the translatability of its preclinical efficacy to therapeutic effects in humans. TAK-418-type LSD1 inhibitors may offer novel treatment options for neurodevelopmental disorders."

Journal • Review • Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Genetic Disorders • Hematological Disorders • Psychiatry

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy. (PubMed, J Med Chem) - "Over two decades, numerous LSD1 inhibitors have been reported, especially some of which have entered clinical trials, including eight irreversible inhibitors (TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, ORY-2001, TAK-418, and LH-1802) and two reversible inhibitors (CC-90011 and SP-2577)...LSD1 multitarget inhibitors have also been reported, exampled by clinical dual LSD1/histone deacetylases (HDACs) inhibitors 4SC-202 and JBI-802. Herein, we present a comprehensive overview of the combination of LSD1 inhibitors with various antitumor agents, as well as LSD1 multitarget inhibitors. Additionally, the challenges and future research directionsare also discussed, and we hope this review will provide new insight into the development of LSD1-targeted anticancer agents."

Combination therapy • Journal • Review • Oncology

Recent advances of LSD1/KDM1A inhibitors for disease therapy. (PubMed, Bioorg Chem) - "Nine LSD1 inhibitors including tranylcypromine, ORY-1001, ORY-2001, GSK-2879552, IMG-7289, INCB059872, TAK-418, CC-90011 and SP-2577 have entered clinical stage for disease treatment as either mono- or combinational therapy. The influence of the stereochemistry on the potency against LSD1 and its homolog LSD2 is briefly discussed. Finally, the challenges and prospects of LSD1-targeted drug discovery are also given."

Journal • Review • Hematological Disorders • Hematological Malignancies • Oncology

Design, synthesis, and structure–activity relationship of TAK-418, a novel LSD1 inhibitor with lowered risk of hematological side effects (ACS-Sp 2023) - P1 | "Here, we explain the design and synthesis of TAK-418 starting from (±)1 with focusing on the structure–activity relationship (SAR) for the lack of the impacts on LSD1-cofactor complex. We will also discuss the structural features responsible for the superior hematological safety profile based on X-ray co-crystal structure analysis."

Adverse events • Hematological Disorders • Thrombocytopenia

Drug discovery strategy of TAK-418, an LSD1 enzyme activity-specific inhibitor, for potential therapeutics of neurodevelopmental disorders (Neuroscience 2022) - "As LSD1 inhibition levels in the brain may be a good translation index to the efficacy of LSD1 inhibitors, we developed novel LSD1 PET tracer that has a potential to work as a clinical translation method. TAK-418 warrants further investigation as a novel therapeutic agent for neurodevelopmental disorders."

CNS Disorders • Psychiatry

Design, synthesis, and structure-activity relationship of TAK-418 and its derivatives as a novel series of LSD1 inhibitors with lowered risk of hematological side effects. (PubMed, Eur J Med Chem) - "We further confirmed that oral administration of TAK-418 at 0.3 and 1 mg/kg for 2 weeks ameliorated memory deficits in mice with NMDA receptor hypofunction, suggesting potential of efficacy in neurodevelopmental disorders. TAK-418 warrants further investigation as a novel class of LSD1 inhibitors with a superior safety profile for the treatment of CNS disorders."

Adverse events • Journal • CNS Disorders • Developmental Disorders • Hematological Disorders • Psychiatry • Thrombocytopenia • GFI1

Investigating the Therapeutic Potential of LSD1 Enzyme Activity-Specific Inhibition by TAK-418 for Social and Memory Deficits in Rodent Disease Models. (PubMed, ACS Chem Neurosci) - "Thus, miR-137 modulation may be involved in memory improvement by LSD1 inhibition. TAK-418 warrants further investigation as a novel therapeutic agent for diseases with epigenetic dysregulation."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Hematological Disorders • Psychiatry • Thrombocytopenia • APP

Annual review of lysine-specific demethylase 1 (LSD1/KDM1A) inhibitors in 2021. (PubMed, Eur J Med Chem) - "In particular, two FDA-approved antihypertensive drugs raloxifene and fenoldopam were repurposed as reversible LSD1 inhibitors. The clinical candidate TAK-418 for treating neurodevelopmental disorders and PET imaging agent [F]30 for LSD1 were identified. Moreover, dual inhibitors targeting both LSD1 and HDAC6 or tubulin displayed enhanced anti-cancer effects than single agents. These compounds further enrich the structural types of LSD1 inhibitors."

Journal • Review • CNS Disorders • Developmental Disorders • Oncology • Psychiatry

Safety, pharmacokinetics and pharmacodynamics of TAK-418, a novel inhibitor of the epigenetic modulator lysine-specific demethylase 1A. (PubMed, Br J Clin Pharmacol) - P1 | "The brain-penetrant LSD1 inhibitor TAK-418 was well tolerated, with pharmacokinetic and pharmacodynamic effects that support further investigation."

Clinical • Journal • PK/PD data • CNS Disorders • Developmental Disorders • Psychiatry • KDM1A

Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome. (PubMed, Mol Ther Methods Clin Dev) - "After 2 weeks of TAK-418, Kmt2d mice demonstrated normalization of hippocampal memory defects. In summary, our data suggest that KDM1A inhibition is a plausible treatment strategy for KS and support the hypothesis that the epigenetic dysregulation secondary to KMT2D dysfunction plays a major role in the postnatal neurological disease phenotype in KS."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Mental Retardation • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • KMT2D

LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models. (PubMed, Sci Adv) - "These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders."

Journal • Autism Spectrum Disorder • CNS Disorders • Cognitive Disorders • Developmental Disorders • Genetic Disorders • Psychiatry

A Study With [18F]MNI-1054 to Determine Lysine -Specific Demethylase 1A (LSD1) Brain Enzyme Occupancy of TAK-418 After Single-Dose Oral Administration in Healthy Participants (clinicaltrials.gov) - P1; N=6; Completed; Sponsor: Takeda; Active, not recruiting ➔ Completed; N=16 ➔ 6; Trial completion date: May 2022 ➔ Mar 2020; Trial primary completion date: Apr 2022 ➔ Mar 2020

Clinical • Enrollment change • Trial completion • Trial completion date • Trial primary completion date

A Study With [18F]MNI-1054 to Determine Lysine -Specific Demethylase 1A (LSD1) Brain Enzyme Occupancy of TAK-418 After Single-Dose Oral Administration in Healthy Participants (clinicaltrials.gov) - P1; N=16; Active, not recruiting; Sponsor: Takeda; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

A Study With [18F]MNI-1054 to Determine Lysine -Specific Demethylase 1A (LSD1) Brain Enzyme Occupancy of TAK-418 After Single-Dose Oral Administration in Healthy Participants (clinicaltrials.gov) - P1; N=16; Recruiting; Sponsor: Takeda; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

A Study With [18F]MNI-1054 to Determine Lysine -Specific Demethylase 1A (LSD1) Brain Enzyme Occupancy of TAK-418 After Single-Dose Oral Administration in Healthy Participants (clinicaltrials.gov) - P1; N=16; Not yet recruiting; Sponsor: Takeda

Clinical • New P1 trial

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of Single and Multiple Oral Dose of TAK-418 in Healthy Female Participants (clinicaltrials.gov) - P1; N=32; Terminated; Sponsor: Takeda; Trial completion date: Apr 2019 ➔ Dec 2018; Active, not recruiting ➔ Terminated; Trial primary completion date: Apr 2019 ➔ Dec 2018; Business Decision; no human safety concern; evaluating preclinical toxicology finding

Clinical • Trial completion date • Trial primary completion date • Trial termination