zatolmilast (BPN14770) / Shionogi - LARVOL DELTA

Jiao-tai-wan suppresses ferroptosis induced by heart-kidney disharmony insomnia by regulating the PDE4D/BDNF signaling pathway. (PubMed, Phytomedicine) - "JTW inhibits hippocampal neuronal ferroptosis through multi-target regulation, ameliorating insomnia-related neuronal damage and providing a molecular basis for its traditional efficacy in restoring Heart-Kidney communication."

Journal • CNS Disorders • Cognitive Disorders • Insomnia • Nephrology • Renal Disease • Sleep Disorder • ACSL3 • BDNF • FTH1 • GPX4 • PACERR • PTGS2

From Bench to Clinic: Zatolmilast and the Translation of Neurobiology Research into a Targeted Therapy for Fragile X Syndrome (CINP 2026) - "This session will provide a comprehensive overview of the translational, preclinical, and early clinical research, including key methodological considerations, that has helped to propel zatolmilast into a registrational, Phase 2/3 clinical development program in FXS. By sharing both the experience and learnings from this foundational work, we aspire to inform future interventional clinical trials in FXS."

Fragile X Syndrome • Genetic Disorders

SCNP-Selected Symposium 5: Translational Therapeutic Discovery in Autism and Fragile X Syndrome (CINP 2026) - "Currently, only aripiprazole and risperidone are approved for clinical use, and both target irritability rather than core symptoms of autism (1, 2).Similarly, despite major advances in understanding the genetic and molecular mechanisms underlying Fragile clinical trials (3-10)...The session will also illustrate how basic science discoveries can evolve into clinical development programs, as exemplified by the path leading to zatolmilast for FXS.Mr...Ilse Gantois will present her research on the therapeutic effects of metformin, an FDA-approved drug, in treating symptoms associated with ASD, using mouse models of FXS and Phelan-McDermid syndrome (PMS; Shank3 knockout mice) in both males and females. Their mechanistic studies have implicated the ERK/MAPK and mTOR pathways, which control mRNA translation, and are overactivated in several brain areas of these mouse models.Together, these talks integrate molecular, circuit-level, and pharmacological perspectives to identify..."

Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Fragile X Syndrome • Genetic Disorders

Study of Zatolmilast (BPN14770) in Participants With PPP2R5D Neurodevelopmental Disorder (Jordan's Syndrome [JS]) (clinicaltrials.gov) - P2 | N=30 | Active, not recruiting | Sponsor: Shionogi | Trial completion date: Jan 2030 ➔ Dec 2027 | Trial primary completion date: Jan 2030 ➔ Dec 2027

Trial completion date • Trial primary completion date • CNS Disorders • Developmental Disorders • Psychiatry

Study of BPN14770 in Participants With Severe Renal Impairment and Healthy Controls (clinicaltrials.gov) - P1 | N=14 | Completed | Sponsor: Shionogi | Recruiting ➔ Completed

Trial completion • Renal Disease

Phase 1 Study of BPN14770 in Participants With Hepatic Impairment and Healthy Controls (clinicaltrials.gov) - P1 | N=32 | Completed | Sponsor: Shionogi | Recruiting ➔ Completed

Trial completion • Hepatology

A Randomized Study of BPN14770 in Male Adolescents (Aged 9 to < 18 Years) With Fragile X Syndrome (clinicaltrials.gov) - P2/3 | N=163 | Completed | Sponsor: Tetra Discovery Partners | Active, not recruiting ➔ Completed | Trial completion date: Dec 2025 ➔ Sep 2025

Trial completion • Trial completion date • Fragile X Syndrome • Genetic Disorders • FMR1

Study of Zatolmilast (BPN14770) in Participants With PPP2R5D Neurodevelopmental Disorder (Jordan's Syndrome [JS]) (clinicaltrials.gov) - P2 | N=30 | Active, not recruiting | Sponsor: Shionogi | Enrolling by invitation ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Developmental Disorders • Psychiatry

Intracellular β1AR-Phosphodiesterases 4D Axis Control Local ER Stress in HFpEF (AHA 2025) - "Treatment with the PDE4D inhibitor Zatolmilast significantly reduced E/E' compared to saline-treated HFpEF controls, indicating improved diastolic function... These findings identify PDE4D as a key mediator of ER stress and cardiac dysfunction in HFpEF. Inhibition or genetic deletion of cardiac PDE4D alleviates ER stress, improves calcium handling, and restores diastolic function, highlighting PDE4D as a promising therapeutic target in HFpEF."

Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • ATF4 • PDE4D

Lessons Learned and Improved Paths to Development of Targeted Therapeutics in Fragile X Syndrome (AACAP 2025) - "Work to improve trials for targeted treatment development in FXS has helped circumvent previous trial design issues and appears to have been critical for more successful trials.GS, ND, RCT"

Fragile X Syndrome • Genetic Disorders

The Emerging Role of Phosphodiesterase Inhibitors in Fragile X Syndrome and Autism Spectrum Disorder. (PubMed, Pharmaceuticals (Basel)) - "BPN14770 (a PDE4 inhibitor) has shown promising efficacy in FXS patients while cilostazol, pentoxifylline, resveratrol, and luteolin have showed improvements in children with ASD. However, challenges such as isoform-specific targeting, optimal therapeutic window, and timing of intervention remain. Collectively, these findings highlight PDE inhibition as a novel therapeutic avenue with the potential to restore cognitive and socio-behavioral functions in ASD and FXS, for which effective targeted treatments remain unavailable."

Journal • Review • Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Epilepsy • Fragile X Syndrome • Genetic Disorders • Inflammation • Mental Retardation • Mood Disorders • Psychiatry • FMR1

An Open-Label Extension Study of BPN14770 in Subjects With Fragile X Syndrome (clinicaltrials.gov) - P3 | N=314 | Active, not recruiting | Sponsor: Tetra Discovery Partners | Enrolling by invitation ➔ Active, not recruiting

Enrollment closed • Fragile X Syndrome • Genetic Disorders

Phase 1 Study of BPN14770 in Participants With Hepatic Impairment and Healthy Controls (clinicaltrials.gov) - P1 | N=32 | Recruiting | Sponsor: Shionogi | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatology

ROC Analysis of Biomarker Combinations in Fragile X Syndrome-Specific Clinical Trials: Evaluating Treatment Efficacy via Exploratory Biomarkers. (PubMed, Transl Psychiatry) - "Increased PAF from baseline was associated with drug but not placebo. Given the relationship between PAF and cognitive function among typically developed adults and those with intellectual disability, as well as previously reported reductions in alpha frequency and power in FXS, PAF represents a potential physiological measure of BPN14770 efficacy."

Biomarker • Clinical • Journal • CNS Disorders • Developmental Disorders • Fragile X Syndrome • Genetic Disorders • Immunology • Mental Retardation • Mood Disorders • Psychiatry • FMR1

A Study of BPN14770 in Male Adults (Aged 18 to 45) With Fragile X Syndrome (clinicaltrials.gov) - P3 | N=171 | Completed | Sponsor: Tetra Discovery Partners | Active, not recruiting ➔ Completed

Trial completion • Fragile X Syndrome • Genetic Disorders • FMR1

Study of BPN14770 in Participants With Severe Renal Impairment and Healthy Controls (clinicaltrials.gov) - P1 | N=16 | Recruiting | Sponsor: Shionogi | Not yet recruiting ➔ Recruiting

Enrollment open • Renal Disease

A Study to Assess the Effects of BPN14770 on Rosuvastatin (clinicaltrials.gov) - P1 | N=12 | Completed | Sponsor: Shionogi | Recruiting ➔ Completed

Trial completion

A Study to Assess the Effects of BPN14770 on Rosuvastatin (clinicaltrials.gov) - P1 | N=14 | Recruiting | Sponsor: Shionogi | Not yet recruiting ➔ Recruiting

Enrollment open

Study of Zatolmilast (BPN14770) in Participants With PPP2R5D Neurodevelopmental Disorder (Jordan's Syndrome [JS]) (clinicaltrials.gov) - P2 | N=30 | Enrolling by invitation | Sponsor: Shionogi | Not yet recruiting ➔ Enrolling by invitation | Initiation date: Mar 2027 ➔ May 2025

Enrollment open • Trial initiation date • CNS Disorders • Developmental Disorders • Psychiatry

Preclinical Evaluation of a Phosphodiesterase 4B Radioligand for Positron Emission Tomography Imaging (SNMMI 2025) - "Blocking studies with a selective PDE4B inhibitor PF-06445974 and a pan-PDE4 inhibitor rolipram reduced binding significantly, while a PDE4D inhibitor (zatolmilast) had no blocking effect, confirming target specificity... P4B-2412, which was first reported by Pfizer scientists, is a potent PDE4B inhibitor with high selectivity across other PDEs. [18F]P4B-2412 was synthesized with a radiochemical yield (RCY) of 27.2%, molar activity of 66.2 ± 2.5 GBq/μmol, and >99% radiochemical purity, making it suitable for biological evaluation (Figure 1A, 1B, and 1C). In vitro autoradiography revealed high and region-specific binding to PDE4B in the thalamus, cortex, and striatum, consistent with PDE4B distribution patterns (Figure 1D, 1E)."

Preclinical • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • Psychiatry • Schizophrenia

[11C]ZTP-1, an Effective Shorter-lived Radioligand for PET Imaging of Brain Phosphodiesterase-4B (SNMMI 2025) - "PET imaging with [11C]ZTP-1 of rhesus monkey and rat brain was performed at baseline and after administration of selective inhibitors (pan-PDE4 inhibitor: rolipram; PDE4B preferring inhibitor: PF-06445974; and PDE4D selective inhibitor: BPN14770)... [11C]ZTP-1 was obtained in ~10% decay-corrected yield (2.0–4.0 GBq), with high radiochemical purity (>99%) and with high molar activities (231±93 GBq/µmol). The logD7.4 of [11C]ZTP-1 was found to be 2.72, and expected to be conducive of good brain entry (Fig. 1A)."

Alzheimer's Disease • CNS Disorders • Depression • Inflammation • Psychiatry

Phase 1 Study of BPN14770 in Participants With Hepatic Impairment and Healthy Controls (clinicaltrials.gov) - P1 | N=32 | Not yet recruiting | Sponsor: Shionogi

New P1 trial • Hepatology

Study of BPN14770 in Participants With Severe Renal Impairment and Healthy Controls (clinicaltrials.gov) - P1 | N=16 | Not yet recruiting | Sponsor: Shionogi

New P1 trial • Renal Disease

A Study to Assess the Effects of BPN14770 on Rosuvastatin (clinicaltrials.gov) - P1 | N=14 | Not yet recruiting | Sponsor: Shionogi

New P1 trial

Individual contribution of PDE4B and PDE4D subfamilies to the prevention of object location memory impairments induced by sleep deprivation. (PubMed, Learn Mem) - "The results demonstrated that SD impaired the OLT performance, and both A-33 and zatolmilast protected against the negative consequences of SD when administered at the start and middle of the SD period. These findings suggest that both PDE4B and PDE4D subfamilies contribute to the beneficial effect of PDE4 inhibition against SD-induced memory consolidation impairment."

Journal • Alzheimer's Disease • CNS Disorders