BPN14770 · program
Zatolmilast for Fragile X syndrome
- FDA Orphan Drug Designation (Fragile X Syndrome; 2018)
- FDA Rare Pediatric Disease Designation (Fragile X Syndrome; Granted 2023-09-27)
Indications for BPN14770: Fragile X syndrome · Phase 3 Alzheimer's disease · Phase 2
Zatolmilast (BPN14770), a first-in-class selective PDE4D negative allosteric modulator, for cognitive impairment in fragile X syndrome — the lead indication and the furthest any FXS-specific cognitive drug has advanced. After a 30-patient Phase 2 crossover study in adult males (Nat Med 2021) showed language-domain cognitive and daily-function improvements, Tetra/Shionogi ran the pivotal EXPERIENCE Phase 2b/3 program: EXPERIENCE-204 (NCT05163808, adolescent males 9–17, n=163, Phase 2/3), EXPERIENCE-301 (NCT05358886, adult males 18–45, n=171, Phase 3), and the EXPERIENCE-302 open-label extension (NCT05367960, n=314). On 2026-05-13 Shionogi reported to the FXS community that the primary endpoints were not met in either pivotal study — EXPERIENCE-301 on the NIH Toolbox Crystallized Cognition Composite and EXPERIENCE-204 on FXS-NRS language/communication and daily function (key secondary CGI-I of Language also not met) — with treatment generally well tolerated and no new safety concerns. In the adult study, significant differences on the caregiver-rated FXS-NRS language/communication and daily function were observed, which Shionogi calls 'suggestive of an efficacy signal' but not conclusive. The program is not discontinued: EXPERIENCE-302 continues for enrolled participants, exploratory analyses of 301/204 plus 302 are underway, and Shionogi plans to engage the FDA and update the community in the second half of 2026.
Development timeline
- UpcomingProgram-decision update on zatolmilast in fragile X syndrome: Shionogi plans to analyze the EXPERIENCE-302 open-label extension alongside exploratory analyses of EXPERIENCE-301/-204, engage the FDA, and update the FXS community in the second half of 2026 — effectively the program's go/no-go catalyst.↗
- missedEXPERIENCE-301 (adult) missed its primary endpoint: zatolmilast did not improve the NIH Toolbox Crystallized Cognition Composite vs placebo at Week 13 in adult males with fragile X syndrome, though significant caregiver-rated FXS-NRS language/communication and daily-function differences were observed ('suggestive of an efficacy signal', not conclusive).↗
- missedEXPERIENCE-204 (adolescent) missed its primary endpoints (FXS-NRS language/communication and daily function) and its key secondary (CGI-I of Language) in male adolescents with fragile X syndrome; generally well tolerated, no new safety concerns.↗
- Phase 3 EXPERIENCE-301 (NCT05358886) started: randomized, double-blind, placebo-controlled study of zatolmilast 25 mg BID in male adults aged 18–45 with FXS (final enrollment 171). The EXPERIENCE-302 open-label extension (NCT05367960) started the same day. Protocol amendments announced 2024-07-18 widened access (minimum age lowered to 9, weight floor lowered to 55 lb, remote visits, OLE extended to two years).
- Pivotal EXPERIENCE program opened with EXPERIENCE-204 (NCT05163808), a randomized, double-blind, placebo-controlled two-part Phase 2/3 study in male adolescents aged 9–17 (zatolmilast 15 or 25 mg BID vs placebo; final enrollment 163).
- Phase 2 randomized, double-blind, placebo-controlled two-period crossover study of BPN14770 25 mg BID in 30 adult males with fragile X syndrome started (NCT03569631, Tetra Discovery Partners; completed 2020-07-31). Published as Berry-Kravis et al., Nat Med 2021: primary endpoint was safety; exploratory efficacy showed cognitive improvement in language domains (picture vocabulary, oral reading recognition) and clinically meaningful daily-function gains.
Readouts
- 2H 2026AnticipatedFull resultsNCT05367960
Program-decision update on zatolmilast in fragile X syndrome: Shionogi plans to analyze the EXPERIENCE-302 open-label extension alongside exploratory analyses of EXPERIENCE-301/-204, engage the FDA, and update the FXS community in the second half of 2026 — effectively the program's go/no-go catalyst. ↗
- 2026-05-13ReportedTopline datamissedNCT05358886
EXPERIENCE-301 (adult) missed its primary endpoint: zatolmilast did not improve the NIH Toolbox Crystallized Cognition Composite vs placebo at Week 13 in adult males with fragile X syndrome, though significant caregiver-rated FXS-NRS language/communication and daily-function differences were observed ('suggestive of an efficacy signal', not conclusive). ↗
- 2026-05-13ReportedTopline datamissedNCT05163808
EXPERIENCE-204 (adolescent) missed its primary endpoints (FXS-NRS language/communication and daily function) and its key secondary (CGI-I of Language) in male adolescents with fragile X syndrome; generally well tolerated, no new safety concerns. ↗
Clinical trials in Fragile X syndrome
NCT05367960BPN14770-CNS-302Phase 3Activen=314
An Open-Label Extension Study of BPN14770 in Subjects With Fragile X Syndrome (EXPERIENCE-302)
NCT05358886BPN14770-CNS-301Phase 3Completedn=171
A Randomized, Double-blind, Placebo-controlled, Parallel Group Study of BPN14770 in Male Adults (Aged 18 to 45) With Fragile X Syndrome (EXPERIENCE-301)
missedprimaryNIH Toolbox Cognitive Battery Crystallized Cognition Composite (NIH-TCB-CCC), change from baseline to Week 13
Primary cognition endpoint not met in the adult study. Significant differences were observed on the caregiver-rated FXS Numerical Rating Scale (NRS) language/communication and daily function — described by Shionogi as 'suggestive of an efficacy signal' but not conclusive given the primary miss. Generally well tolerated; no new safety concerns.
NCT05163808BPN14770-CNS-204Phase 2/3Completedn=163
A Randomized, Double-blind, Placebo-controlled, Two-Part Study of BPN14770 in Male Adolescents (Aged 9 to < 18 Years) With Fragile X Syndrome (EXPERIENCE-204)
missedprimaryFXS-NRS language/communication and daily function (primary, per sponsor's 2026-05-13 results letter); key secondary CGI-I of Language
Primary endpoints not met in the adolescent study; the key secondary endpoint, Clinician Global Impression of Improvement (CGI-I) of Language, was also not met. Zatolmilast was generally well tolerated with no new safety concerns. NOTE: the ClinicalTrials.gov record and the 2023 RPD press release describe the primary as the NIH-TCB Crystallized Cognition Composite; the endpoints stated here follow Shionogi's own account of the final analysis in its 2026-05-13 community letter.
NCT03569631Phase 2Completedn=30
A Randomized, Double-blind, Placebo-controlled, 2-period Crossover Study of BPN14770 in Adult Males With Fragile X Syndrome
metprimarySafety and tolerability (primary); exploratory efficacy on NIH-TCB language domains and caregiver-rated daily function
Primary safety endpoint met: most common adverse events were vomiting and upper respiratory tract infection at rates similar to placebo, with no discontinuations for adverse events. Exploratory efficacy showed cognitive improvement in language domains (NIH Toolbox picture vocabulary and oral reading recognition) and clinically meaningful improvements in daily functioning (Berry-Kravis et al., Nat Med 2021).
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| Zatolmilast oral capsule (25 mg BID adult; 15 mg BID adolescent <43 kg) In Alzheimer's disease (PICASSO AD, NCT03817684): 10 mg or 25 mg twice daily for 13 weeks. In the fragile X program: 25 mg BID in adults, 15 or 25 mg BID in adolescents. | Oral | Twice daily | — |
Mechanism of action
Selective negative allosteric modulator (allosteric inhibitor) of phosphodiesterase-4D (PDE4D). Zatolmilast binds a primate-specific N-terminal (UCR-region) site of PDE4D rather than the catalytic site, partially inhibiting cAMP hydrolysis and thereby raising neuronal cAMP with a ceiling effect intended to avoid the emesis of full catalytic-site PDE4 inhibitors. In Alzheimer's disease the rationale was that raising cAMP would engage the same memory-formation pathway targeted downstream of cholinergic signaling — tested and not confirmed in the Phase 2 PICASSO AD study.
| Target | Action | Affinity |
|---|---|---|
| PDE4DprimaryPDE4D | NAM | —ⓘ |
← Full BPN14770 compound page (identity, identifiers, all indications)
Sources
- Berry-Kravis EM, Harnett MD, Reines SA, et al. Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial. Nat Med. 2021;27:862–870 — Nature Medicine (Springer Nature)
- BPN14770 — Therapeutics entry (PICASSO AD design and May 2020 primary-endpoint miss, CDR-SB subgroup signal, December 2018 Shionogi collaboration, May 2020 Tetra acquisition) — Alzforum (FBRI / Biomedical Research Forum)
- NCT03569631 — A Randomized, Double-blind, Placebo-controlled, 2-period Crossover Study of BPN14770 in Adult Males With Fragile X Syndrome — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT03817684 (PICASSO AD) — A Randomized, Double Blind, Placebo Controlled, 3-Arm Parallel Design Study to Evaluate the Effects of BPN14770 in Patients With Early Stage Alzheimer's Disease (with posted results, 2025-02-18) — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT05163808 (BPN14770-CNS-204, EXPERIENCE-204) — Two-Part Study of BPN14770 in Male Adolescents (Aged 9 to <18) With Fragile X Syndrome — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT05358886 (BPN14770-CNS-301, EXPERIENCE-301) — Parallel Group Study of BPN14770 in Male Adults (Aged 18 to 45) With Fragile X Syndrome — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT05367960 (BPN14770-CNS-302, EXPERIENCE-302) — An Open-Label Extension Study of BPN14770 in Subjects With Fragile X Syndrome — ClinicalTrials.gov (U.S. National Library of Medicine)
- Shionogi community letter to the U.S. Fragile X Syndrome Community: EXPERIENCE-301 and EXPERIENCE-204 primary endpoints not met; EXPERIENCE-302 continues; FDA engagement and 2H 2026 update (Juan Carlos Gomez, MD, CMO, 2026-05-13) — Shionogi Inc. (hosted by FRAXA Research Foundation)
- Zatolmilast Rare Pediatric Disease Designation press release (2023-09-27) — describes the zatolmilast clinical program as fragile X only, evidencing AD dormancy — Shionogi & Co., Ltd.
- Zatolmilast, CID 90111638 — identity: CAS 1606974-33-7, UNII G786V328X6, ChEMBL4541964; PDE4D negative allosteric modulator — PubChem (NCBI, U.S. National Library of Medicine)