Peloton Therapeutics, Inc. Announces Dual Publications of HIF-2α Antagonism in Kidney Cancer in the Journal Nature
- On-target efficacy of a HIF2α antagonist in preclinical kidney cancer models
(Cho et al., Nature, Advanced Online Publication, September 2016)
- Targeting renal cell carcinoma with a HIF-2 antagonist
(Chen et al., Nature, Advanced Online Publication, September 2016)
September 6, 2016, 8:00 AM Eastern Daylight Time
DALLAS, TX – (BUSINESS WIRE) – Peloton Therapeutics, Inc., a drug discovery and development company focused on advancing first-in-class, small molecule cancer therapies targeting unexploited molecular vulnerabilities, announced today two publications in the journal Nature that describe the application of Peloton-invented antagonists to advance the understanding of hypoxia-inducible factor-2α (HIF-2α) and its role in kidney cancer.
The first paper titled “On-target efficacy of a HIF2α antagonist in preclinical kidney cancer models” (Cho et al., Nature, Advanced Online Publication, September 2016, http://dx.doi.org/10.1038/nature19795) characterizes PT2399, an analogue of PT2385, Peloton’s first-in-class small molecule antagonist of HIF-2α that is in clinical development for the treatment of clear cell renal cell carcinoma (ccRCC). Using multiple techniques, the researchers demonstrated the high specificity of PT2399 for HIF-2α and its efficacy in orthotopic, metastatic, and patient-derived models of ccRCC. Their work also raises the possibility that sensitivity of ccRCC tumors to HIF-2α antagonism may depend on the status of the tumor suppressor protein p53.
In the second paper titled “Targeting renal cell carcinoma with a HIF-2 antagonist (Chen et al., Nature, Advanced Online Publication, September 2016, http://dx.doi.org/10.1038/nature19796), PT2399 was found to be more potent, active in a greater number of models, and less toxic than sunitinib in a large panel of patient-derived ccRCC xenografts. Additionally, a number of tumors that were completely insensitive to sunitinib regressed when transferred to PT2399. Importantly, genetic biomarkers that correlated with sensitivity to Peloton’s HIF-2α antagonists were identified.
“The work reported demonstrates the exquisite selectivity of Peloton’s antagonists that then enabled the further elucidation of the role of HIF-2α in kidney cancer and the potential value of our compounds in treating this disease,” said John A. Josey, Ph.D., Peloton’s Chief Executive Officer. “By causing regression in tumors that are resistant to standard-of-care drugs while minimizing cardiovascular and other toxicities, our hope is to provide patients with more attractive drug treatment options. Genetic biomarker development may also enable identification of patients best able to benefit from treatment with our HIF-2α antagonists. These biomarkers may also be particularly important as we expand indications beyond kidney cancer.”
PT2385 is a first-in-class small molecule antagonist of hypoxia-inducible factor-2α (HIF-2α), a transcription factor implicated in the development and progression of kidney cancer. It is currently being investigated in a Phase 1 clinical trial for the treatment of advanced or metastatic clear cell renal cell carcinoma (ccRCC) as monotherapy and in combination with the immuno-oncology agent nivolumab. Loss of the von Hippel-Lindau tumor suppressor (VHL) is the key oncogenic event in up to 95 percent of patients with ccRCC. With the loss of the VHL protein (pVHL), the transcription factor HIF-2α accumulates and drives the unbalanced expression of numerous gene products. Preclinical data indicate that orally bioavailable PT2385 disrupts HIF-2α activity in ccRCC and thereby blocks the expression of multiple tumorigenic factors. Clinical data in patients with advanced ccRCC has shown PT2385 to have encouraging efficacy, including a number of responses and a favorable tolerability profile, with no dose-limiting toxicities nor evidence of cardiovascular adverse events.
About Kidney Cancer
The American Cancer Society estimates that more than 62,000 new cases of kidney cancer will be diagnosed and more than 14,000 people will die from this disease this year. The National Cancer Institute reports that the prognosis for any treated renal cell cancer patient with progressing, recurring, or relapsing disease is poor, regardless of cell type or stage.
About Peloton Therapeutics
Peloton Therapeutics, Inc. is a clinical-stage biotechnology company that discovers and develops first-in-class, small molecule cancer therapies targeting unexploited molecular vulnerabilities. Peloton Therapeutics’ lead candidate, PT2385, is a first-in-class small molecule targeting hypoxia-inducible factor-2α (HIF-2α), a transcription factor implicated in the development and progression of kidney and other cancers. To learn more about Peloton Therapeutics, visit www.pelotontherapeutics.com.
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