Small Molecule · BPN14770

Zatolmilast

Phase 3Tetra Discovery Partners
  • FDA Orphan Drug Designation (Fragile X Syndrome; 2018)
  • FDA Rare Pediatric Disease Designation (Fragile X Syndrome; Granted 2023-09-27)

Oral, first-in-class selective phosphodiesterase-4D (PDE4D) negative allosteric modulator (BPN14770) originated by Tetra Discovery Partners/Tetra Therapeutics and developed by the Shionogi Group since its 2020 acquisition of Tetra. Zatolmilast binds a primate-specific N-terminal region of PDE4D, partially inhibiting cAMP hydrolysis to raise neuronal cAMP — a pathway suppressed downstream of FMR1 silencing in fragile X syndrome — with the aim of promoting synaptic maturation and improving cognition. A 30-patient Phase 2 crossover study in adult males with FXS (Berry-Kravis et al., Nat Med 2021) showed improvements in language-domain cognition and daily function, triggering the pivotal EXPERIENCE Phase 2b/3 program. On 2026-05-13 Shionogi reported that both pivotal studies missed their primary endpoints (adult EXPERIENCE-301 on the NIH-TCB Crystallized Cognition Composite; adolescent EXPERIENCE-204 on FXS-NRS language/communication and daily function), with a significant caregiver-rated FXS-NRS language/communication and daily-function signal in the adult study; the open-label extension continues while Shionogi analyzes the data and engages the FDA. Holds FDA Orphan Drug Designation (2018) and Rare Pediatric Disease Designation (2023) for FXS. Previously missed its Phase 2 primary endpoint in early Alzheimer's disease (PICASSO AD, 2020). Also in Phase 2 for PPP2R5D neurodevelopmental disorder (Jordan's syndrome).

Also known as: BPN14770, BPN-14770, zatolmilast, 1606974-33-7, 2-[4-[[2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl]methyl]phenyl]acetic acid

Data current as of

Key facts

Modality
Small molecule
Chemical class
trifluoromethylpyridine, arylpyridine, phenylacetic acid
Chemistry
Achiral
Mechanism
PDE4D NAM
Highest phase
Phase 3
Lead indication
Fragile X syndrome
Developer
Tetra Discovery Partners
Designations
FDA Orphan Drug Designation (Fragile X Syndrome; 2018), FDA Rare Pediatric Disease Designation (Fragile X Syndrome; Granted 2023-09-27)
Trials
5 tracked · 93 sites
Next catalyst
2H 2026 — Full results (Fragile X syndrome)

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.

TargetActionAffinity
PDE4DprimaryPDE4DNAM—ⓘ

Formulations#

FormulationRouteRegimenPharmacokinetics
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.
OralTwice daily—

Development timeline#

2020202220242026TodayPhase 331 Dec 2026 — upcoming — 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.13 May 2026 — readout (missed) — 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).13 May 2026 — readout (missed) — 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.1 Nov 2022 — phase change — 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).1 Jan 2018 — Orphan Drug — FDA grants Orphan Drug Designation to zatolmilast (BPN14770) for fragile X syndromePhase 227 Sept 2023 — phase change — Program dormant: by the date of Shionogi's Rare Pediatric Disease Designation press release — which describes the zatolmilast clinical program as the fragile X EXPERIENCE studies plus a preclinical PDE4B asset, with no mention of Alzheimer's disease — the AD indication had been absent from sponsor communications for over three years and no new AD trial had been registered. No formal discontinuation statement is citable, so the status token is 'unknown' rather than 'discontinued'; a sponsor statement either way is the re-trigger to update this row.31 May 2020 — readout (missed) — PICASSO AD Phase 2 missed its primary endpoint: BPN14770 did not separate from placebo on the RBANS Delayed Memory Index at Week 13 in 255 patients with early Alzheimer's disease (~+10 points in all arms); disclosed alongside Shionogi's acquisition of Tetra in May 2020.1 May 2020 — Acquisition — Shionogi acquires Tetra Therapeutics, taking ownership of zatolmilast (BPN14770)4 Feb 2020 — phase change — PICASSO AD reached primary completion. The primary endpoint (RBANS Delayed Memory Index change at Week 13) was missed — all three arms improved by ~10 points (10.1 / 9.9 / 9.7 for 10 mg / 25 mg / placebo per the posted results) — disclosed in May 2020 alongside the announcement of Shionogi's acquisition of Tetra. No safety issues were observed. A CDR-SB subgroup signal in the 25 mg arm was described at the time as warranting further development, but no further Alzheimer's study was ever registered.30 Apr 2019 — phase change — PICASSO AD (NCT03817684) started: randomized, double-blind, placebo-controlled 3-arm Phase 2 study of BPN14770 10 mg and 25 mg BID vs placebo for 13 weeks in 255 patients with early Alzheimer's disease, run by Tetra Discovery Partners at ~60 US sites, under the December 2018 development collaboration with Shionogi.9 Jul 2018 — phase change — 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.Phase 2/329 Mar 2022 — phase change — 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 change Readout Event UpcomingHover a marker for details.
Phase 3Jan 2018 – Dec 2026
  1. 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.Fragile X syndrome↗
  2. 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).Fragile X syndrome↗
  3. 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.Fragile X syndrome↗
  4. 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).Fragile X syndrome
  5. Orphan DrugFDA grants Orphan Drug Designation to zatolmilast (BPN14770) for fragile X syndromeFragile X syndrome↗
Phase 2Jul 2018 – Sept 2023
  1. Program dormant: by the date of Shionogi's Rare Pediatric Disease Designation press release — which describes the zatolmilast clinical program as the fragile X EXPERIENCE studies plus a preclinical PDE4B asset, with no mention of Alzheimer's disease — the AD indication had been absent from sponsor communications for over three years and no new AD trial had been registered. No formal discontinuation statement is citable, so the status token is 'unknown' rather than 'discontinued'; a sponsor statement either way is the re-trigger to update this row.Alzheimer's disease↗
  2. missedPICASSO AD Phase 2 missed its primary endpoint: BPN14770 did not separate from placebo on the RBANS Delayed Memory Index at Week 13 in 255 patients with early Alzheimer's disease (~+10 points in all arms); disclosed alongside Shionogi's acquisition of Tetra in May 2020.Alzheimer's disease↗
  3. AcquisitionShionogi acquires Tetra Therapeutics, taking ownership of zatolmilast (BPN14770)↗
  4. PICASSO AD reached primary completion. The primary endpoint (RBANS Delayed Memory Index change at Week 13) was missed — all three arms improved by ~10 points (10.1 / 9.9 / 9.7 for 10 mg / 25 mg / placebo per the posted results) — disclosed in May 2020 alongside the announcement of Shionogi's acquisition of Tetra. No safety issues were observed. A CDR-SB subgroup signal in the 25 mg arm was described at the time as warranting further development, but no further Alzheimer's study was ever registered.Alzheimer's disease↗
  5. PICASSO AD (NCT03817684) started: randomized, double-blind, placebo-controlled 3-arm Phase 2 study of BPN14770 10 mg and 25 mg BID vs placebo for 13 weeks in 255 patients with early Alzheimer's disease, run by Tetra Discovery Partners at ~60 US sites, under the December 2018 development collaboration with Shionogi.Alzheimer's disease
  6. 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.Fragile X syndrome
Phase 2/3Mar 2022
  1. 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).Fragile X syndrome

Zatolmilast for Fragile X syndrome#

Phase 3ActiveFragile X syndrome indication →

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.

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. ↗

Zatolmilast for Alzheimer's disease#

Phase 2UnknownAlzheimer's disease indication →

Zatolmilast (BPN14770) for early Alzheimer's disease — a completed, negative Phase 2 program with no development activity since. The PICASSO AD study (NCT03817684; 255 patients with early AD at ~60 US sites; BPN14770 10 mg or 25 mg twice daily vs placebo for 13 weeks) missed its primary endpoint, change from baseline in the RBANS Delayed Memory Index at Week 13: per the posted results, the 10 mg arm improved 10.1 points, the 25 mg arm 9.9 points, and placebo 9.7 points — no separation from placebo, a pattern consistent with practice effects. The miss was disclosed in May 2020, at the same time Shionogi's acquisition of Tetra was announced; a subgroup analysis (25 mg patients with above-median baseline CDR-SB improving on CDR-SB) was floated as warranting further development, but no subsequent Alzheimer's trial was ever registered and Tetra/Shionogi communications since 2023 describe zatolmilast exclusively as a fragile X syndrome (and later Jordan's syndrome) program. Status is recorded as 'unknown' (dormant) rather than 'discontinued' because no formal discontinuation statement is citable.

Readouts

  • 2020-05-31ReportedTopline datamissedNCT03817684

    PICASSO AD Phase 2 missed its primary endpoint: BPN14770 did not separate from placebo on the RBANS Delayed Memory Index at Week 13 in 255 patients with early Alzheimer's disease (~+10 points in all arms); disclosed alongside Shionogi's acquisition of Tetra in May 2020. ↗

Clinical trials#

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)

Started Nov 2022· Primary completion Jul 2025· 17 sites across 1 country

United States

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.

NCT05367960BPN14770-CNS-302Phase 3Activen=314

An Open-Label Extension Study of BPN14770 in Subjects With Fragile X Syndrome (EXPERIENCE-302)

Started Nov 2022· Primary completion Sept 2027· 17 sites across 1 country

United States

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)

Started Mar 2022· Primary completion Sept 2025· 17 sites across 1 country

United States

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.

NCT03817684Phase 2Completedn=255

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 (PICASSO AD)

Started Apr 2019· Primary completion Feb 2020· 41 sites across 1 country

United States

missedprimaryChange from baseline in RBANS Delayed Memory Index (RBANS-DMI) at Week 13 — RBANS-DMI change: +10.1 (10 mg BID), +9.9 (25 mg BID), +9.7 (placebo) — no separation from placebo

Primary endpoint missed: all three arms, including placebo, improved by roughly ten points on the RBANS Delayed Memory Index, consistent with practice effects and leaving no drug-placebo separation. No safety issues were observed. A subgroup analysis (25 mg patients with above-median baseline CDR-SB) suggested a CDR-SB improvement signal, but no further Alzheimer's development followed. Results posted to ClinicalTrials.gov 2025-02-18.

NCT03569631Phase 2Completedn=30

A Randomized, Double-blind, Placebo-controlled, 2-period Crossover Study of BPN14770 in Adult Males With Fragile X Syndrome

Started Jul 2018· Primary completion Jul 2020· 1 site across 1 country

United States

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).

Sources#

  1. 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)
  2. 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)
  3. 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)
  4. 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)
  5. 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)
  6. 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)
  7. 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)
  8. 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)
  9. 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.
  10. Zatolmilast, CID 90111638 — identity: CAS 1606974-33-7, UNII G786V328X6, ChEMBL4541964; PDE4D negative allosteric modulator — PubChem (NCBI, U.S. National Library of Medicine)