Peloton Therapeutics Phase I Study of PT2385 Published in the Journal of Clinical Oncology Validates HIF-2α Antagonism for the Treatment of Kidney Cancer
DALLAS--(BUSINESS WIRE)-- Peloton Therapeutics today announced that results from a Phase 1 study evaluating PT2385 in patients with advanced kidney cancer were published online in the Journal of Clinical Oncology (JCO). These data demonstrated PT2385, the first clinical stage antagonist of hypoxia inducible factor-2α (HIF-2α), has a favorable safety profile and is active in patients with heavily pretreated clear cell renal cell carcinoma (ccRCC), validating HIF-2α antagonism for the treatment of patients with ccRCC. HIF-2α is a transcription factor implicated in the development and progression of kidney and other cancers.
“There is a great need for more effective therapies in kidney cancer, especially given the poor prognosis in patients with metastatic disease,” said Toni Choueiri, M.D., from the Dana-Farber Cancer Institute and Harvard Medical School, the senior author of the study. “These findings offer unique scientific insights that may further help the research community turn the corner on this disease.”
The von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in the majority of kidney cancer cases, leading to stabilization of HIF-2α and upregulation of the expression of genes that are important to tumor growth and metastasis. While many currently available therapies for ccRCC inhibit a single pathway, inhibition of the transcriptional activity of HIF-2α has the potential to inhibit a number of pathways that contribute to tumor growth in this disease.
“To date, targeting protein-protein interactions with small molecule approaches has proven to be challenging,” said Kevin Courtney, M.D., Ph.D. from The University of Texas Southwestern Medical Center, the corresponding author. “This study provides clinical evidence of the potential of targeting HIF-2α, a protein widely believed to be an oncogenic driver in VHL-deficient ccRCC that previously has been seen as intractable.”
Mohammad Hirmand, M.D., Peloton’s Chief Medical Officer, pointed out that currently there are no HIF-2α inhibitors available for therapeutic applications. “PT2385 is the first HIF-2α inhibitor to be tested in humans and to show activity in patients with ccRCC. We are encouraged by the compelling anti-tumor activity and safety profile seen in this trial as we continue to progress our HIF-2α programs in oncology and other diseases,” said Dr. Hirmand.
Peloton has succeeded in creating a series of orally-available small molecules that bind to HIF-2α and inhibit its transcription of disease-promoting genes. These include a second HIF-2α antagonist PT2977, a structurally-related compound that is more potent and affords enhanced exposure relative to PT2385. PT2977 is currently being investigated in Phase 1 clinical trials for the treatment of solid tumors and ccRCC, and in a Phase 2 clinical trial for the treatment of patients with VHL disease.
About the Phase 1 Study
This Phase 1 open-label, multi-center, dose-escalation study was designed to determine the recommended Phase 2 dose, evaluate the safety, pharmacokinetics (PK), pharmacodynamic (PD) profiles, and to assess the anti-tumor activity of PT2385. Twenty-six heavily pretreated patients with locally advanced or metastatic ccRCC and at least one prior therapy with vascular endothelial growth factor (VEGF) inhibitor were enrolled in dose escalation and received PT2385 from 100 to 1800 mg twice per day. Based on safety, PK, and PD data, 800 mg twice per day was selected as the recommended Phase 2 dose and subsequently administered to an additional 25 patients enrolled in an expansion cohort.
PT2385 was well tolerated, with anemia (grade 1-2, 35%; grade 3, 10%), peripheral edema (grade 1-2, 37%; grade 3, 2%), and fatigue (grade 1-2, 37%; no grade 3), being the most common treatment-emergent adverse events. No treatment-emergent cardiovascular toxicities were reported. No patients discontinued treatment due to AEs. Complete response, partial response, and stable disease as best response were achieved by 2%, 12%, and 52% of patients, respectively. At data cutoff, 13 patients had remained on study for at least one year. At a median follow-up of 17.5 months, 25% of patients had progression-free survival of greater than 14 months.
Peloton Therapeutics, Inc. presented these data, in part, as an oral presentation at the 51st Annual Meeting of the American Society of Clinical Oncology in 2016.
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. Loss of the von Hippel-Lindau tumor suppressor (VHL) is the key oncogenic event in up to 95% 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 Renal Cell Cancer
The American Cancer Society estimates that nearly 64,000 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 pharmaceutical company that is translating groundbreaking scientific insights into first-in-class oral medicines for patients with cancer and other serious or life-threatening conditions. The Company’s lead clinical programs are evaluating the first highly-specific, orally-available small-molecule inhibitors of hypoxia inducible factor-2α (HIF-2α), a transcription factor implicated in the development and progression of kidney cancer and a wide variety of other disorders. Peloton is also building a research platform to identify novel small-molecules capable of harnessing the ubiquitin ligase system to degrade target proteins, another promising cancer treatment approach. To learn more about Peloton Therapeutics, visit www.pelotontherapeutics.com.
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Source: Peloton Therapeutics, Inc.