zatolmilast (BPN14770) / Shionogi - LARVOL DELTA

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 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

A Study of BPN14770 in Male Adults (Aged 18 to 45) With Fragile X Syndrome (clinicaltrials.gov) - P3 | N=150 | Recruiting | Sponsor: Tetra Discovery Partners | Trial completion date: Jul 2024 ➔ Sep 2025 | Trial primary completion date: Feb 2024 ➔ Jun 2025

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

An Open-Label Extension Study of BPN14770 in Subjects With Fragile X Syndrome (clinicaltrials.gov) - P3 | N=300 | Enrolling by invitation | Sponsor: Tetra Discovery Partners | Trial completion date: Dec 2025 ➔ Dec 2027 | Trial primary completion date: Feb 2024 ➔ Sep 2027

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

Auditory N1 event-related potential amplitude is predictive of serum concentration of BPN14770 in fragile X syndrome. (PubMed, Mol Autism) - "These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of a significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS."

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

Behavioral effects of phosphodiesterase 4D inhibition in a mouse model of Houge-Janssens Syndrome 1, an autosomal dominant neurodevelopmental disorder, caused by de novo mutations in a protein phosphatase 2A regulatory subunit (Neuroscience 2024) - "Because our biochemical data show enhanced PP2A activity in HJS1, we therefore explored if zatolmilast or BPN14770, a PDE4D inhibitor, offers therapeutic benefits in our mouse model of HJS1, potentially by boosting the cAMP-mediated PKA activity...Our findings suggest acute and chronic phosphodiesterase 4D inhibition exerts different behavioral effects in our HJS1 mice. Further examination of the neuroanatomical changes in response to acute or chronic phosphodiesterase 4D inhibition may help to understand the different behavioral effects observed in our HJS1 mice."

Neurodevelopmental • Preclinical • CNS Disorders • Cognitive Disorders • Epilepsy • Mental Retardation • Psychiatry

Clinical Trials in Fragile X Syndrome (NFXF-FXC 2024) - "Trials to be covered include: single-dose EEG-focused challenge studies (in home and in clinic), ergoloid mesylates/5HTP, metformin, cannabidiol, and BPN 14770. A basic explanation of how each medication works and the results in trials previously conducted will be discussed. For each trial currently recruiting, requirements for participation, sites where patients can participate, and logistical information will be given, and presenters will answer any questions about trials."

Clinical • Fragile X Syndrome • Genetic Disorders

Tetra Therapeutics/Shionogi Group Company - Update on the development of Zatolmilast (BPN14770) for Fragile X Syndrome (NFXF-FXC 2024) - No abstract available

Fragile X Syndrome • Genetic Disorders

Auditory N1 event-related potential amplitude is predictive of bioavailability of BPN14770 in fragile x syndrome (NFXF-FXC 2024) - "A recent phase 2 clinical trial assessing BPN14770, a first-in-class phosphodiesterase 4D inhibitor, in 30 adult males with FXS demonstrated cognitive improvements including language and daily functioning and marginal decreases in N1 auditory event-related potential (ERP) amplitude from an auditory habituation task. Reductions in N1 ERP amplitude were associated with bioavailability of BPN14770 (via pharmacokinetic sampling), raising confidence in the validity of the original results, in favor of neural processing improvements with BPN14770."

Fragile X Syndrome • Genetic Disorders

Auditory N1 event-related potential amplitude is predictive of serum concentration of BPN14770 in fragile x syndrome. (PubMed, Res Sq) - "These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS."

Journal • CNS Disorders • Developmental Disorders • Fragile X Syndrome • Genetic Disorders • Mental Retardation • Psychiatry • FMR1

Robust Quantification of Phosphodiesterase-4D Using Carbon-11 Pet Radioligands in Monkey Brain Without Radiometabolite Contamination (SOBP 2024) - "The carbon-11 labelled (t1/2=20.4 min) radioligands were injected intravenously and imaged with PET for 120 minutes at baseline and 90 minutes with rolipram (0.2 mg/kg, i.v.) or a PDE4D-selective inhibitor (BPN14770, 3 mg/kg, i.v.) as a blocking agent... Phosphodiesterase-4D was quantified in monkey brain without radiometabolite contamination using PET imaging of carbon-11 labelled ligands. The findings warrant further evaluation of [11C]JMJ-81 and [11C]JMJ-129 in human subjects, with [11C]JMJ-129 first due to its higher signal-to-background ratio."

Preclinical • CNS Disorders • Mental Retardation • Psychiatry