FDA Grants Fast-Track Designation to CX-5461 in Treatment of Certain Patients with Breast or Ovarian Cancer


The FDA has granted a fast-track designation to the G-quadruplex stabilizer CX-5461 for BRCA1/2, PALB2, or HRD mutations in their breast or ovarian cancer.

The FDA granted a fast-track designation to the first-in-class G-quadruplex stabilizer CX-5461 (Pindnarulex) for the treatment of patients with BRCA1/2PALB2, or other homologous recombination deficiency (HRD) mutations in their breast or ovarian cancer.1

CX-5461 is a G4-stablizing compound that acts in tandem with HR pathway deficiency, aiming to stabilize folded conformation and stall DNA replication forks to cause cancer cell death.2

According to the drug developers, in HRD tumors cancer cells can’t self-repair as well, which leads to genomically unstable tumors allowing for CX-5461 to exploit this vulnerability through a synthetic lethality approach that targets those DNA repair defects in HRD tumors.

"We are excited to receive Fast Track Designation and look forward to working closely with the US FDA to accelerate the development of Pidnarulex, aiming to bring a meaningful treatment to patients with breast and ovarian cancer whose tumors have BRCA1/2, PALB2, or other HRD mutations," said Mei-Hui Kuo, acting chief executive officer of Senhwa Biosciences, in a press release about the announcement.

This approach is currently being studied in a phase 1b (NCT04890613) open-label, multi-center expansion study, that looked at tolerable doses of CX-5461 in this patient population. In a previous phase 1 study (NCT02719977) results from the trial indicated durable benefits in patients with BRCA1/2 and PALB2 mutations that were resistant to previous platinum and other chemotherapies.

The current phase 1B trial is set to enroll patients 18 years of age or older who have a histologically, or cytologically confirmed, malignancy of the ovarian, fallopian tube, or primary peritoneal cancer, with a high grade serous or high-grade endometroid histology subtype, and documented evidence of a BRCA2 and/or a PALB2 mutation in an exploratory cohort. Moreover, patients must also have measurable disease per RECIST v1.1 criteria and be platinum sensitive with no evidence of disease progression within 6 months of their last dose of a platinum-based treatment.

Patients in the main cohort had to have a histologically or cytologically confirmed malignancy of the pancreas, prostate, breast, or ovary and documented evidence of a BRCA2 and/or PALB2 mutation based on RECIST v1.1 criteria. The primary end point of the study is to determine the suitable phase 2 dose, with secondary objectives to assess the safety and tolerability of late-onset toxicity, along with evaluating anti-tumor activity and health related quality of life outcomes for patients on this treatment.3

Exploratory objectives include evaluating the anti-tumor activity in patients with ovarian cancer and pathogenic BRCA1 mutation and/or other HRD-associated somatic mutation, characterizing the molecular profile of tumors and evaluating the predictive value of mutational signatures to predict the response, or resistance, to CX-5461. The researchers also plan to explore the significance of dynamic changes in circulating tumor DNA levels and plasma DNA levels.

“Addressing treatment resistant tumors continues to be an unmet medical need in cancer treatment,” Senhwa Biosciences concluded in their press release. “Pidnarulex has proven human efficacy across certain tumor types by accelerating dsDNA breaks. By targeting the G-quadruplex DNA structure instead, Pidnarulex has great potential as an alternative treatment for patients who have developed resistance to PAPRi or other chemotherapies.”


1. Senhwa’s Pidnarulex receives US FDA fast track designation for the treatment of solid tumors with BRCA1/2, PALB2 and other HR gene mutations. News release. Senhwa Biosciences, Inc.; January 24, 2022. Accessed January 26, 2022. https://bit.ly/3G47R7C

2. Pidnarulex CX-5461, G-quadruplex (stabilizer). Senhwa Biosciences, Inc. website. Accssed January 26, 2022. https://bit.ly/3fZVoHO

3. CX-5461-solid tumors and BRCA2 and/or PALB2 mutation. Senhwa Biosciences, Inc. website. Accessed January 26, 2022. https://bit.ly/3G3IaEp

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