FDA Grants Fast Track Designation to 225Ac-FL-020 for mCRPC

Steffen Heeger, MD, MSc

The FDA has granted fast track designation to the prostate-specific membrane antigen (PSMA)–targeted radiopharmaceutical ²²⁵Ac-FL-020 for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).¹

²²⁵Ac-FL-020 is a novel, next-generation PSMA-targeting radionucleotide drug conjugate (RDC) that uses targeted alpharadiotherapy to selectively attack cancer cells and simultaneously reduce the damage to healthy tissues. The RDC utilizes the targeting vector FL-020, which allows for improved drug uptake in the tumor and the maintenance of fast systemic clearance.

“The FDA fast track designation for ²²⁵Ac-FL-020 underscores the critical need for innovative and effective treatments for mCRPC,” Steffen Heeger, MD, MSc, chief medical officer of Full-Life Technologies, stated in a news release. “This designation will enable us to collaborate more closely with the FDA throughout the development process, potentially accelerating the availability of ²²⁵Ac-FL-020 to patients.”

At the 2024 AACR Annual Meeting, investigators presented findings from a preclinical study of ²²⁵Ac-FL-020. This study was conducted based on a need for improved clinical benefits and safety profiles of PSMA-targeted radiotherapy.² For instance, lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly ¹⁷⁷Lu-PSMA-617) was FDA approved in 2022 for the treatment of patients with progressive, PSMA-positive mCRPC.³ However, the complete response rate in the pivotal phase 3 VISION trial (NCT03511664) was 9.2%, and 38.8% of patients had grade 1/2 xerostomia.⁴

In this preclinical study, investigators determined the binding affinity of FL-020 by competing it with Cy5-labeled PSMA ligands on LNCaP cells and evaluated the selectivity of FL-020 through Safety Panel screening.² LNCaP cell internalization was measured by ¹⁷⁷Lu-labeled FL-020 on LNCaP cells at different time points. Investigators assessed in vivo biodistribution of 111In-labeled FL-020 by SPECT/CT on LNCaP xenograft models at various time points. Ex vivo cut-and-count of ¹⁷⁷Lu-labeled FL-020 on these models was also evaluated.

The in vivo efficacy of ²²⁵Ac-FL-020 was compared with that of ²²⁵Ac-PSMA-617 in mice with LNCaP tumors. Investigators assessed the safety profile of ²²⁵Ac-FL-020 by body weight measurements and hematology parameters in these mice. Moreover, the mechanism of action of ²²⁵Ac-FL-020 was defined using a quantitative image analysis of yH2AX and cCASP3 in tumor tissues after treatment with the radiopharmaceutical.

Radiolabeled FL-020 generated a potent in vivo biodistribution profile, including fast systemic clearance and high-sustained tumor uptake. Furthermore, ²²⁵Ac-FL-020 yielded antitumor activity in LNCaP xenograft mice. FL-020 bound to LNCaP cells with an IC50 value of 51.55 nM. Off-target screening revealed that FL-020 at 10 µM was highly selective, with less than 50% inhibition of binding or activity against 85 targets, including ion channels, receptors, transporters, and enzymes. When compared with ²²⁵Ac-PSMA-617, ²²⁵Ac-FL-020 had superior antitumor activity at the same dose level (10 KBq per mouse) in LNCaP xenograft models. 225Ac-FL-020 also had a favorable safety profile per hematological and body weight parameters.

Investigators observed no significant irreversible hematology changes (including in platelets, red blood cells, white blood cells, lymphocytes, and neutrophils) or loss of body weight with all evaluated dose levels of ²²⁵Ac-FL-020 compared with the group of models that received a control vehicle. Moreover, findings from a mechanistic study in ²²⁵Ac-FL-020–treated LNCaP tumor samples showed tumor cell apoptosis and DNA double-strand breaks, which confirmed the mechanism of action of the agent’s alpha emitters.

In May 2024, the FDA cleared the investigational new drug application for clinical trials evaluating ²²⁵Ac-FL-020.¹ A phase 1 trial will investigate the safety, tolerability, and antitumor activity of the radiopharmaceutical.

References

1. Full-Life Technologies granted FDA Fast Track Designation for 225Ac-FL-020 for the treatment of metastatic castration-resistant prostate cancer. News release. July 3, 2024. Accessed July 3, 2024. https://www.full-life.com/media/press-releases/27
2. Liu F, Zhang J, Yang J, et al. 225Ac-FL-020 is a novel PSMA-targeting radionucleotide drug conjugate (RDC) with superior in vivo anti-tumor activity. Cancer Res. 2024;84(suppl_6):6023. doi:10.1158/1538-7445.AM2024-6023
3. FDA approves Pluvicto for metastatic castration-resistant prostate cancer. FDA; March 23, 2022. Accessed July 3, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer?utm_medium=email&utm_source=govdelivery

• Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi: 10.1056/NEJMoa2107322