zatolmilast (BPN14770) / Shionogi - LARVOL DELTA

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

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 2024 ➔ Dec 2025

Trial completion date • Fragile X Syndrome • Genetic Disorders

Treatment with the selective PDE4B inhibitor A-33 or PDE4D inhibitor zatolmilast prevents sleep deprivation-induced deficits in spatial pattern separation. (PubMed, Behav Brain Res) - "Previous research showed that non-selective phosphodiesterase type 4 (PDE4) inhibitors like roflumilast can alleviate these deficits. The cognitive benefits of these inhibitors after SD may arise from alterations in relevant signaling pathways in the DG. This study provides initial evidence that inhibiting PDE4B or PDE4D holds promise for mitigating memory deficits due to SD."

Journal

Next Generation PDE4 Inhibitors that Selectively Target PDE4B/D Subtypes: A Narrative Review. (PubMed, Dermatol Ther (Heidelb)) - "Phosphodiesterase 4 (PDE4) inhibitors have been approved for both oral and topical use for inflammatory skin diseases. In this review, we present a summary of an emerging class of selective PDE4B/D inhibitors under clinical development and compare the differences in selectivity of this new generation of PDE4 inhibitors with the less selective currently approved PDE4 inhibitors."

Journal • Review • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation • Psoriasis • IL13 • IL17A • IL17RA • IL23A

Peak Alpha Frequency as a Potential Physiological Biomarker for Assessing Cognitive Effects of BPN14770 in Fragile X Syndrome: Insights from a Phase 2 Clinical Trial (Neuroscience 2023) - "Given the relationship between PAF and cognitive function among typically developed adults, PAF represents a successful physiological measure of BPN14770 efficacy supporting cognitive shifts noted in the original clinical trial analyses. Improvements in PAF with BPN14770 treatment for those with FXS suggests BPN14770 may enhance processing speed within the alpha range, a frequency band often reported to have low power in individuals with FXS."

Biomarker • Clinical • P2 data • CNS Disorders • Mental Retardation • Mood Disorders • Psychiatry • FMR1

Differential effects of two phosphodiesterase 4 inhibitors against lipopolysaccharide-induced neuroinflammation in mice. (PubMed, BMC Neurosci) - "These findings suggest that roflumilast, but not zatolmilast, has the potential for use as a therapeutic agent against neuroinflammatory diseases."

Journal • Preclinical • CNS Disorders • Inflammation • Oncology • ABCB1 • IL1B • IL6

A Randomized Study of BPN14770 in Male Adolescents (Aged 12 to < 18 Years) With Fragile X Syndrome (clinicaltrials.gov) - P2/3 | N=150 | Recruiting | Sponsor: Tetra Discovery Partners | Enrolling by invitation ➔ Recruiting

Enrollment status • 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 | Enrolling by invitation ➔ Recruiting | Trial completion date: Oct 2024 ➔ Jul 2024 | Initiation date: Mar 2022 ➔ Nov 2022

Enrollment status • Trial completion date • Trial initiation date • Fragile X Syndrome • Genetic Disorders • FMR1

A Randomized Study of BPN14770 in Male Adolescents (Aged 12 to < 18 Years) With Fragile X Syndrome (clinicaltrials.gov) - P2/3 | N=150 | Enrolling by invitation | Sponsor: Tetra Discovery Partners | Recruiting ➔ Enrolling by invitation | Trial completion date: Nov 2023 ➔ Jul 2024 | Trial primary completion date: Aug 2023 ➔ Feb 2024

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