DALLAS & CHICAGO--(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, presented first-in-human Phase 1 clinical data on its lead investigational candidate, PT2385, at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, IL. PT2385 is the first clinical stage antagonist of hypoxia inducible factor-2α (HIF-2α), a transcription factor implicated in the development and progression of kidney and other cancers.
In an oral presentation titled “A Phase 1 Dose-Escalation Trial of PT2385, a first-in-class oral HIF-2α Inhibitor, in Patients with Advanced Clear Cell Renal Cell Carcinoma," it was shown that PT2385 was well tolerated with no dose-limiting toxicities and had pharmacologic activity with encouraging clinical efficacy.
Patients with advanced clear cell renal cell carcinoma (ccRCC) and at least one prior therapy with a VEGF inhibitor were treated with PT2385 to determine the recommended Phase 2 dose and evaluate safety, pharmacokinetics and pharmacodynamics.
Twenty-six patients were enrolled in dose escalation and received PT2385 from 100 to 1800 mg twice per day. Patients were heavily pretreated prior to study entry, with greater than 50 percent having four or more prior therapies. Exposure increased with doses up to the 800 mg cohort without a further increase from 800 to 1800 mg. No dose limiting toxicities were observed at any dose level. Circulating plasma levels of the HIF-2α transcriptional target erythropoietin (EPO) rapidly decreased with treatment with PT2385 and remained suppressed. Based on safety, pharmacokinetic and EPO pharmacodynamic data, 800 mg twice per day was selected as the recommended Phase 2 dose. An additional 25 patients were enrolled in an expansion cohort at the recommended Phase 2 dose.
Among the 51 patients in total, the most common all-grade adverse events (AEs) were anemia, peripheral edema and fatigue. No cardiovascular AEs were noted. To date, one patient had a complete response, three patients had a partial response, and 16 patients had stable disease for 16 or more weeks. Ten percent of patients remain in this ongoing clinical trial for at least one year.
“Research at our institution has shown that HIF-2α is strongly implicated in renal cell carcinoma. PT2385 is the first agent to target this transcription factor and is very well tolerated. Its efficacy in patients with advanced clear cell renal cell carcinoma is promising,” said Toni Choueiri, M.D., from the Dana-Farber Cancer Institute and Harvard Medical School, the senior author of the study.
“We are encouraged by the initial efficacy results in this heavily pretreated population and the fact that PT2385 does not have the cardiovascular toxicities of most other kidney cancer treatments, most notably VEGFR tyrosine kinase inhibitors. In light of this favorable safety profile and preclinical evidence of synergistic activity of our HIF-2α antagonists in combination with immune checkpoint inhibitors shown at the recent AACR conference, we have opened a clinical trial of PT2385 in combination with nivolumab (Opdivo®). Additionally, we are planning clinical studies of PT2385 as monotherapy and with other combination regimens,” said John Josey, Ph.D., Peloton’s Chief Executive Officer.
PT2385 is a first-in-class small molecule inhibitor 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). 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 responsible for unrestrained cancer cell growth and proliferation, tumor angiogenesis, and suppression of anti-tumor immune responses characteristic of ccRCC.
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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