On May 23, 2024 FibroGen, Inc. (NASDAQ: FGEN) reported positive interim results from the dose escalation portion of the investigator-sponsored Phase 1b/2 study conducted by the University of California San Francisco of FG-3246 (FOR46), a potential first-in-class anti-CD46 antibody drug conjugate (ADC) with a MMAE-containing payload, in combination with enzalutamide in patients with metastatic castration resistant prostate cancer (mCRPC) at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, FibroGen, MAY 23, 2024, View Source [SID1234643594]).

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"We are excited to announce that FG-3246 in combination with enzalutamide in patients with mCRPC demonstrated clinically meaningful early signals of efficacy," commented Deyaa Adib, M.D., Chief Medical Officer of FibroGen. "These data further validate and build upon the encouraging activity we observed in the recently reported Phase 1 monotherapy data of FG-3246, as well as in preclinical models where the combination of FG-3246 with enzalutamide enhanced its tumor cytotoxic activity. We look forward to continuing our collaboration with the University of California San Francisco and plan to provide additional clinical data from this trial when available."

The presentation includes data from 17 biomarker unselected patients in the dose escalation portion of the trial. Eligibility criteria for the trial included patients who received at least one prior androgen receptor signaling inhibitor (ARSI) while patients who were treated with prior chemotherapy in the castration resistant setting were excluded. Over 70% of the patients in the study received at least two prior ARSIs, which included prior enzalutamide treatment. Dose escalation was explored with and without prophylactic granulocyte colony-stimulating factor (G-CSF) support. The primary endpoint was determination of the maximally tolerated dose (MTD) of FG-3246 in combination with enzalutamide. The combination treatment demonstrated an encouraging preliminary estimate of median radiographic progression free survival (rPFS) of 10.2 months. The MTD was established at 2.1 mg/kg ABW, with primary G-CSF prophylaxis, in combination with enzalutamide 160 mg/day.

The most frequent adverse events were consistent with other MMAE-based ADCs and included fatigue, weight loss, elevated transaminases, neutropenia, and peripheral neuropathy.

Additionally, a baseline CD46-directed PET imaging probe utilizing the same antibody backbone as FG-3246 (89Zr-DFO-YS5) was obtained in a subset of patients and demonstrated tumor uptake in multiple lesions.

"I am very encouraged by the preliminary evidence of efficacy we have seen with FG-3246 and enzalutamide, specifically the potential for clinically meaningful prolongation of rPFS, as well as the safety profile," added Dr. Rahul Aggarwal, Professor of Medicine at the University of California San Francisco, and Principal Investigator of the study. "We will continue to evaluate this combination in the Phase 2 portion of the trial and further explore the potential of 89Zr-DFO-YS5 as a predictive biomarker of response."

The poster presentation, titled "A Phase 1b dose escalation study of FOR46, a novel antibody-drug conjugate targeting a tumor-specific epitope of CD46, in combination with enzalutamide (Enza) in patients with metastatic castration resistant prostate cancer (mCRPC)" is scheduled for the poster session taking place on June 2, 2024 from 9:00 am to 12:00 pm CDT.

The Company plans to meet with the U.S. Food and Drug Administration (FDA) to discuss the development pathway for FG-3246 and anticipates the initiation of the Phase 2 monotherapy dose optimization study of FG-3246 in mCRPC in the second half of 2024.

About the Phase 1b/2 Study of FG-3246 in Combination with Enzalutamide
This Phase 1b/2 study is an investigator-sponsored trial being conducted at the University of California San Francisco to evaluate FG-3246 (FOR46) in combination with enzalutamide in patients with metastatic castration resistant prostate cancer (mCRPC) after prior progression on at least one androgen receptor signaling inhibitor. The primary objective for the Phase 1b portion of the study is to determine the maximally tolerated dose (MTD) and recommended Phase 2 dose of FG-3246 in combination with enzalutamide in patients with mCRPC. The objectives of the Phase 2 portion of the study are to determine the composite response rate (CRR), proportion of participants with a greater than or equal to 50% change in prostate specific antigen (PSA50), objective response rate (ORR), median duration of response, median radiographic progression free survival (rPFS), and median overall survival (OS) of patients treated with FG-3246 in combination with enzalutamide. For more information about this study, which is currently enrolling, please visit www.clinicaltrials.gov (NCT05011188).

About FG-3246
FG-3246 (FOR46) is a potential first-in-class fully human antibody-drug conjugate (ADC), exclusively in-licensed from Fortis Therapeutics, and is being developed by FibroGen for metastatic castration-resistant prostate cancer and potentially other tumor types. FG-3246 binds to an epitope of CD46, a cell receptor target, that induces internalization upon antibody binding, is present at high levels in prostate cancer and other tumor types and demonstrates very limited expression in most normal tissues. FG-3246 is comprised of an anti-CD46 antibody, YS5, linked to the anti-mitotic agent, MMAE, which is a clinically and commercially validated ADC payload. FG-3246 has demonstrated anti-tumor activity in both preclinical and clinical studies. FG-3246 is currently in an ongoing Phase 1b/2 study being conducted at UCSF as an investigator-sponsored trial to evaluate FG-3246 in combination with enzalutamide, and another investigator-sponsored radiopharmaceutical marker trial using a PET with a zirconium tracer for CD46 using the same antibody backbone. The initiation of the Phase 2 monotherapy trial in metastatic castration-resistant prostate cancer is anticipated in the second half of 2024. FG-3246 is an investigational drug and not approved for marketing by any regulatory authority.