zatolmilast (BPN14770) / Shionogi - LARVOL DELTA

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

A Randomized Study of BPN14770 in Male Adolescents (Aged 9 to < 18 Years) With Fragile X Syndrome (clinicaltrials.gov) - P2/3 | N=150 | Active, not recruiting | Sponsor: Tetra Discovery Partners | Recruiting ➔ Active, not recruiting

Enrollment closed • Fragile X Syndrome • Genetic Disorders • FMR1

A Study of BPN14770 in Male Adults (Aged 18 to 45) With Fragile X Syndrome (clinicaltrials.gov) - P3 | N=150 | Active, not recruiting | Sponsor: Tetra Discovery Partners | Recruiting ➔ Active, not recruiting

Enrollment closed • 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 | Not yet recruiting | Sponsor: Shionogi | Trial completion date: Sep 2026 ➔ Jan 2030 | Initiation date: Jan 2025 ➔ Mar 2027 | Trial primary completion date: Mar 2026 ➔ Jan 2030

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

Tetra PICASSO AD Trial: Study to Evaluate Effects of BPN14770 in Early Alzheimer's Subjects (clinicaltrials.gov) - P2 | N=255 | Completed | Sponsor: Tetra Discovery Partners | Unknown status ➔ Completed

Trial completion • Alzheimer's Disease • CNS Disorders

Shionogi and Jordan’s Guardian Angels Announce First-Ever Human Drug Study for Jordan’s Syndrome, an Ultra-Rare Genetic Neurodevelopmental Disorder (Businesswire) - "Shionogi & Co., Ltd...and Jordan’s Guardian Angels announced a research collaboration between their organizations and the first-ever clinical trial evaluating an investigational drug for PPP2 syndrome type R5D (Houge-Janssens syndrome 1, HJS1), commonly referred to as Jordan's Syndrome...The Phase 2 randomized, double-blind, placebo-controlled study will evaluate the safety and tolerability of zatolmilast (BPN14770), an investigational selective PDE4D inhibitor, in people with Jordan’s Syndrome. The study will also explore preliminary assessments of efficacy and obtain pharmacokinetic and biomarker data...The Phase 2 study of zatolmilast in Jordan’s Syndrome will enroll 30 participants in early 2025 aged 9-45 years with a confirmed/documented history of PPP2R5D neurodevelopmental disorder....The study is expected to conclude in late 2026."

Commercial • Enrollment status • Trial completion date • Developmental Disorders

Inhibition of the upregulated phosphodiesterase 4D isoforms improves SERCA2a function in diabetic cardiomyopathy. (PubMed, Br J Pharmacol) - "The current study identifies upregulation of specific PDE4D isoforms that selectively inhibit SERCA2a function in HFD-induced cardiomyopathy, indicating that this remodelling can be targeted to restore cardiac contractility in diabetic cardiomyopathy."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • PDE4D

Study of Zatolmilast (BPN14770) in Participants With PPP2R5D Neurodevelopmental Disorder (Jordan's Syndrome [JS]) (clinicaltrials.gov) - P2 | N=30 | Not yet recruiting | Sponsor: Shionogi

New P2 trial • CNS Disorders • Developmental Disorders • Psychiatry

A Randomized Study of BPN14770 in Male Adolescents (Aged 9 to < 18 Years) With Fragile X Syndrome (clinicaltrials.gov) - P2/3 | N=150 | Recruiting | Sponsor: Tetra Discovery Partners | Trial completion date: Jul 2024 ➔ Dec 2025 | Trial primary completion date: Feb 2024 ➔ Sep 2025

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