BPN14770 · program
Zatolmilast for Alzheimer's disease
Indications for BPN14770: Fragile X syndrome · Phase 3 Alzheimer's disease · Phase 2
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.
Development timeline
- 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.↗
- 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.↗
- 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.↗
- 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.
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 in Alzheimer's disease
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)
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.
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
- 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)
- 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)
- 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)