225Ac-PSMA-R2

225Ac-PSMA-R2 is an investigational radiopharmaceutical developed by Novartis for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC). It is a targeted alpha therapy (TAT) combining actinium-225 (225Ac), an alpha-emitting radionuclide, with PSMA-R2, a small-molecule ligand targeting prostate-specific membrane antigen (PSMA), a protein overexpressed in prostate cancer cells. The therapy delivers high-energy alpha radiation to induce DNA damage in cancer cells, leveraging the short tissue range of alpha particles to minimize damage to healthy tissues. As of May 2025, 225Ac-PSMA-R2 is in Phase I/II clinical trials and has not received regulatory approval.[1][2]

## Contents

* 1 Mechanism of action
* 2 Clinical development
* 3 Safety and tolerability
* 4 References

## Mechanism of action

225Ac-PSMA-R2 targets PSMA, a transmembrane protein highly expressed on prostate cancer cells, particularly in advanced mCRPC. The PSMA-R2 ligand binds PSMA with high affinity, delivering 225Ac to tumor sites. Actinium-225, with a 9.92-day half-life, emits four alpha particles in its decay chain, causing complex DNA double-strand breaks that lead to cancer cell death. The alpha particles' short penetration range (47–85 μm) enhances tumor selectivity compared to beta-emitting therapies like lutetium-177 (177Lu)-PSMA-617. A chelator in the PSMA-R2 molecule ensures stable 225Ac binding, optimizing tumor targeting and reducing off-target radiation.[3][2][4]

## Clinical development

The SatisfACtion trial (NCT04597411), a Phase I/II, open-label, multi-center study by Novartis, is evaluating 225Ac-PSMA-R2 in patients with mHSPC and mCRPC. The trial includes dose escalation and expansion phases to determine the maximum tolerated dose (MTD) or recommended dose for expansion (RDE). Patients must have PSMA-positive disease, confirmed by 68Ga-PSMA-11 PET/CT, and documented disease progression. The study includes cohorts with prior 177Lu-PSMA radioligand therapy, assessing safety, tolerability, and preliminary anti-tumor activity. As of March 2025, the trial is recruiting, with no published efficacy data.[1][5]

Combination approaches, such as with androgen receptor inhibitors (e.g., darolutamide), are being explored to enhance outcomes. Challenges include the limited global supply of 225Ac, produced via thorium-229 decay or cyclotron methods, and the need for advanced imaging to monitor treatment response. Further trials are essential to establish 225Ac-PSMA-R2's clinical role and address supply constraints.[1][6]

## Safety and tolerability

The safety profile of 225Ac-PSMA-R2 is under investigation, with preclinical and related 225Ac-PSMA therapies (e.g., 225Ac-PSMA-617) suggesting potential toxicities. Xerostomia (severe dry mouth) is a notable risk due to salivary gland uptake, often dose-limiting in 225Ac-based PSMA therapies. Other adverse effects may include myelosuppression (e.g., anemia, leukopenia, thrombocytopenia) and renal toxicity, though these are less common. The PSMA-R2 ligand incorporates improved linker technology to enhance tumor uptake and reduce off-target effects compared to earlier PSMA ligands like PSMA-617. The SatisfACtion trial is optimizing dosing to balance efficacy and toxicity.[3][7]

## References

1. ↑ 1.0 1.1 1.2 "Phase I/II Study of [225AcAc-PSMA-R2 in PSMA-positive Prostate Cancer, With/Without Prior 177Lu-PSMA RLT"]. Novartis. 2025-02-14. https://www.novartis.com/clinicaltrials/study/nct05983198.
2. ↑ 2.0 2.1 "Delving into the Latest Updates on 225 Actinium PSMA 617 (Novartis Pharma AG)". Synapse. 2024-06-26. https://synapse.patsnap.com/drug/5f0f4d1f549e4891b0c5484d39692415.
3. ↑ 3.0 3.1 "In vitro dose effect relationships of actinium-225- and lutetium-177-labeled PSMA-I&T". European Journal of Nuclear Medicine and Molecular Imaging 49 (11): 3627–3638. 2021-08-02. doi:10.1007/s00259-022-05821-w. PMID 35556158.
4. ↑ "Design of 225Ac-PSMA for targeted alpha therapy in prostate cancer". Annals of Translational Medicine 12 (4): 67. August 2024. doi:10.21037/atm-23-1842. PMID 39118950.
5. ↑ "A Study of [225Ac-PSMA-R2 in Men With PSMA-positive Prostate Cancer"]. ClinicalTrials.gov. 2024-10-15. https://clinicaltrials.gov/study/NCT04597411.
6. ↑ "Multiple Production Methods Underway to Provide Actinium-225". National Isotope Development Center. 2022-04-05. https://www.isotopes.gov/information/actinium-225.
7. ↑ "ACCEL: [Ac-225-PSMA-62 phase Ia/Ib/II clinical trial"]. Journal of Clinical Oncology. 2025-02-01. doi:10.1200/JCO.2025.43.5_suppl.TPS282. https://ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.TPS282.

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Therapeutic radiopharmaceuticals (ATC: V10)

Pain palliation|

* 153Sm
* Lexidronam
* 89Sr (Strontium chloride)

Adrenergic tumors|

* 131I
* Iobenguane

CD20 antibodies|

* 90Y
* Ibritumomab tiuxetan
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Radionuclides|

| alpha emitters|

* 223Ra (Radium chloride)

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beta emitters|

* 32P
* 89Sr
* 90Y
* 131I
* 153Sm
* 165Dy
* 169Er
* 177Lu (Oxodotreotide)
* 186Re
* 198Au

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