actinium (225Ac) zadavotide guraxetan

Overview

FPI-2265 (225Ac-PSMA-I&T) is an investigational, small‑molecule radioconjugate that targets prostate‑specific membrane antigen (PSMA) and delivers the alpha‑emitter actinium‑225. It is being developed for metastatic castration‑resistant prostate cancer (mCRPC), including patients previously treated with 177Lu‑based PSMA radioligand therapy. Phase 2/3 studies are ongoing and actively enrolling. (fusionpharma.com)

Mechanism of action

• Target: PSMA, highly expressed on most prostate cancer cells.
• Modality: PSMA‑I&T small‑molecule ligand linked to actinium‑225, an alpha‑particle emitter with short path length and high linear energy transfer, designed to induce clustered DNA double‑strand breaks while limiting off‑target tissue exposure. (fusionpharma.com)

Efficacy

Interim Phase 2 (TATCIST) poster (data cutoff March 1, 2024; 35 treated, 25 with ≥12 weeks’ follow‑up; 20 efficacy‑evaluable after prespecified exclusions):
- PSA50 response (≥50% decline by week 12): 50% (10/20) overall; 54–61% in lutetium‑naïve and 42–43% in prior‑lutetium patients.
- Exploratory subset with baseline PSMA SUVmean >6 (n=13; 6 with prior lutetium): PSA50 in 69% (9/13).
- RECIST v1.1 (independent review; n=9 with measurable soft‑tissue disease): partial response 33% (3/9); stable disease 44% (4/9).
- PCWG3 composite: non‑progressive disease in 70% (14/20).
These findings indicate antitumor activity in heavily pretreated patients, including after prior 177Lu‑PSMA radioligand therapy. (fusionpharma.com)

Earlier, small prospective/retrospective experiences with 225Ac‑PSMA‑I&T in advanced mCRPC reported PSA50 responses in 7/14 patients and manageable hematologic toxicity, supporting biological activity of this construct. (pubmed.ncbi.nlm.nih.gov)

Safety

In the TATCIST interim analysis (safety population n=25):
- Most treatment‑related adverse events (TRAEs) were grade 1–2.
- Xerostomia was the most common TRAE; the poster describes predominantly grade 1–2 events, and the sponsor’s summary specifies 62% grade 1 and 24% grade 2.
- Hematologic TRAEs (anemia, thrombocytopenia), fatigue, and dry eye were also observed.
- One treatment‑related death (cerebral hemorrhage) occurred in a patient with a superscan pattern; superscan patients were excluded from efficacy analyses after a protocol amendment. (fusionpharma.com)

A prospective Phase I dose‑escalation study of 225Ac‑PSMA‑I&T (NCT05902247) is separately assessing tolerability and dosimetry to inform dosing; the published protocol underscores the need to define optimal activity due to xerostomia and hematologic risks observed with alpha‑PSMA agents. (bmccancer.biomedcentral.com)

Ongoing trials

• TATCIST Phase 2/3, randomized, open‑label, multicenter study in PSMA‑positive mCRPC previously treated with 177Lu‑PSMA RLT; currently enrolling at multiple centers (e.g., MD Anderson). (mdanderson.org)

Further reading

• Preliminary efficacy and safety results from the TATCIST trial (AACR 2024 poster; PDF). (fusionpharma.com)
• Sponsor summary of TATCIST interim data (AACR 2024 press release). (prnewswire.com)
• First clinical results for 225Ac‑PSMA‑I&T in advanced mCRPC (retrospective series). (pubmed.ncbi.nlm.nih.gov)
• 225Ac‑PSMA‑I&T Phase I dose‑escalation protocol (BMC Cancer; NCT05902247). (bmccancer.biomedcentral.com)

Note: Phase 2/3 development is ongoing; efficacy and safety data are interim and may evolve with larger, controlled cohorts. (fusionpharma.com)

Last updated: Oct 2025