The U.S. Food and Drug Administration (FDA) has granted Fast Track designation for rinatabart sesutecan (Rina-S; PRO1184), a folate receptor alpha (FRα / FOLR1) targeted ADC, for the treatment of patients with FRα-expressing high-grade serous or endometrioid platinum-resistant ovarian cancer.  The novel ADC is being developed by ProfoundBio.

The Fast Track designation is intended to facilitate the development and expedited review of drugs with demonstrated potential to improve over available therapy for serious conditions with unmet medical need.

“Our receipt of Fast Track designation from the FDA underscores our belief in the tremendous promise of rinatabart sesutecan as a potential best-in-class FRα ADC to address the significant need for improved treatment options for advanced ovarian cancer,” said Naomi Hunder, Chief Medical Officer of ProfoundBio.

“FRα / FOLR1 is a highly prevalent antigen in ovarian cancer and Rina-S has shown encouraging antitumor activity and tolerability in our Phase 1 dose escalation study in ovarian and endometrial cancer patients across the full spectrum of FRα expression. We look forward to working closely with the FDA as we progress further clinical development and registrational studies for rinatabart sesutecan,” Hunder added.

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A FRα targeting ADC
Rinatabart sesutecan is a folate receptor-alpha (FRα / FOLR1) targeted ADC being developed as a novel treatment option for patients with ovarian and endometrial cancer, and potentially other FRα-expressing cancers. The investigational ADC is comprised of a human monoclonal antibody that selectively binds to FRα/FOLR1, a cleavable, hydrophilic linker,  conjugated to sesutecan, ProfoundBio’s novel, proprietary hydrophilic exatecan-based linker-drug*, at a homogeneous drug-to-antibody ratio (DAR) of 8.

Upon binding to FRα /FOLR1 on the surface of malignant cells, rinatabart sesutecan is internalized and exatecan released through enzymatic cleavage of the linker. Exatecan blocks the ligation step of the cell cycle and generates DNA single- and double-strand breaks, which leads to cell death. The mechanism of action and clinical potential of PRO1184 was tested in a series of studies.

Rinatabart sesutecan bound selectively and specifically to FRα / FOLR1 with nM affinity. In addition, rinatabart sesutecan was efficiently internalized and demonstrated cytotoxicity against multiple cell lines, in vitro.

In preclinical mouse carcinoma models, rinatabart sesutecan demonstrated robust anti-tumor activity across multiple tumor types that represent ovarian, non-small cell lung, and breast cancer. Also, rinatabart sesutecan was more potent with greater tumor growth inhibition than that of a DM4-conjugated ADC.

Trial design and results
A Phase 1/2 study of rinatabart sesutecan (PRO1184-001/ NCT05579366) to evaluate the safety, tolerability, PK, and antitumor activity of of the investigational drug in patients with selected locally advanced and/or metastatic solid tumors, including epithelial ovarian cancer, endometrial cancer, breast cancer, non-small cell lung cancer, and mesothelioma.

The study has two parts, Part A: Dose Escalation and Part B: Dose Expansion. Initial results from Part A were presented during the 38th annual meeting of the Society for Immunotherapy of Cancer (SITC 2023). The data confirmed encouraging antitumor activity for rinatabart sesutecan. [1] [2] The trial drug was also well tolerated doses in heavily pretreated ovarian and endometrial cancer patients unselected for FRα expression. Part B is currently enrolling patients at multiple sites in the U.S. and China.

The study enrolled 36 patients treated at dose levels from 60 mg/m2 to 180 mg/m2 administered every 21 days. These patients were diagnosed with ovarian cancer (n=17), endometrial cancer (n=9), breast cancer (n=3), non-small cell lung cancer (n=5), or mesothelioma (n=2). Patients in the study were heavily pretreated with a median of 4.5 prior therapies; patients with ovarian cancer had a median of 6 prior therapies and patients with endometrial cancer had a median of 4 prior therapies.

Safety and activity highlights include:

  • Rinatabart sesutecan was well tolerated at doses from 60 mg/m2 to 120 mg/m2, with 140 mg/m2 still under evaluation as a potential maximum tolerated dose; the most common treatment-related adverse events (TRAEs) included cytopenias, gastrointestinal adverse events, and fatigue and were both reversible and manageable. Most TRAEs were Grade 1 or 2.
  • No interstitial lung disease, pneumonitis, infusion-related reactions, or corneal toxicity were observed.
  • Among 21 response-evaluable patients with ovarian and endometrial cancer, unselected for FRα expression, an initial objective response rate of 38% was observed (1 complete response (CR), 7 partial responses (PR)); an additional 9 patients had stable disease (SD), including 7 with decreasing tumor measurements, for a disease control rate (CR+PR+SD) of 81%.
  • Antitumor activity was seen across the full spectrum of FRα expression, with objective responses observed in 8 out of 12 (67%) response-evaluable patients with ovarian and endometrial cancer having >1% FRα expression in their tumors, including 3 PRs in 3 patients with FRα expression below 25% 1+ IHC staining intensity.
  • Responses were observed across a wide dose range from 60 to 140 mg/m2, with responses deepening over time for most patients. One patient with ovarian cancer had prior treatment with Mirvetuximab soravtansine (Elahere™; ImmunoGen) and had a CR after receiving two doses of Rinatabart sesutecan.

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Note: * Exatecan is a highly potent, membrane permeable topoisomerase-1 inhibitor with strong bystander effect. Sesutecan is a highly hydrophilic, stable, cleavable linker designed to mask the hydrophobicity of conjugated exatecan on the ADC, enabling high DAR and efficient delivery of the exatecan payload to tumors while maintaining favorable physicochemical and pharmacokinetic properties of the ADC.

Clinical trial
PRO1184 for Advanced Solid Tumors (PRO1184-001) – ClinicalTrials.gov ID  NCT05579366

Highlights of prescribing information
Mirvetuximab soravtansine (Elahere™; ImmunoGen)[Prescribing Information]

Reference
[1] Baiteng Zhao, Lei Wang, Haidong Liu, Suping Huang, Xiao Shang, Tae Han. PRO1184, a novel folate receptor alpha-directed antibody-drug conjugate, demonstrates robust anti-tumor activity in mouse carcinoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1085.
[2] A Phase 1/2 Study of Rinatabart Sesutecan (PRO1184), a Novel Folate Receptor Alpha-Directed Antibody-Drug Conjugate, in Patients with Locally Advanced and/or Metastatic Solid Tumors. Abstracr 708 Presented by Justin A. Call, M.D., of START Mountain Region, West Valley City, UT, on Saturday, November 4, 2023, Exhibit Halls A and B1, 9 a.m. to 8:30 p.m. PDT; during the 38th annual meeting of the Society for Immunotherapy of Cancer (SITC 2023).

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