First-in-class HIF-2a inhibitor could revolutionise renal cell carcinoma treatment algorithm

GlobalData Healthcare 13th September 2019 (Last Updated September 13th, 2019 16:29)

MK-6482 is under development by Merck for the treatment of clear-cell renal cell carcinoma (RCC), metastatic RCC and glioblastoma multiforme.

First-in-class HIF-2a inhibitor could revolutionise renal cell carcinoma treatment algorithm
Elacytarabine and its main metabolites.

Following the acquisition of Peloton Therapeutics in July 2019, Merck is accelerating the development of the first-in-class oral, selective hypoxia-inducible factor (HIF)-2a inhibitor, MK-6482 (previously PT2977).

MK-6482 is under development for the treatment of clear-cell renal cell carcinoma (RCC), metastatic RCC and glioblastoma multiforme. However, MK-6482 will be tested before nephrectomy in von Hippel-Lindau (VHL) disease-associated advanced, but not metastatic, RCC in the neo-adjuvant therapy setting. This opens up the potential for MK-6482 to revolutionize the treatment algorithm of RCC.

The current treatment paradigm in RCC proposes nephrectomy for Stages I, II, III, and systemic drug treatment only for Stage IV metastatic RCC. In the US, only Pfizer’s Sutent (sunitinib malate), a tyrosine kinase inhibitor (TKI), is approved for adjuvant therapy following nephrectomy, and no drug is approved for adjuvant use in Europe.

The RCC pipeline currently consists of six ongoing clinical trials in late-stage development for adjuvant therapy with varying combinations of the immune checkpoint inhibitors: Roche’s Tecentriq (atezolizumab), AstraZeneca’s Imfinzi (durvalumab), Bristol-Myers Squibb’s Yervoy (ipilimumab), Bristol-Myers Squibb’s Opdivo (nivolumab), Merck’s Keytruda (pembrolizumab), AstraZeneca’s/MedImmune’s tremelimumab, and Novartis’ mammalian target of rapamycin (mTOR) inhibitor Afinitor (everolimus).

However, Merck’s Phase II clinical trial (Peloton Therapeutics, NCT03401788) will be the first to investigate a drug candidate for neo-adjuvant use. Primary endpoint completion is expected in March 2020. If successful, MK-6482 could revolutionise the treatment landscape of RCC by moving systemic drug therapy up the treatment algorithm to earlier disease stages.

VHL disease is a disorder caused by a rare, autosomal dominant mutation in the VHL gene that leads to a dysfunctional or non-functional VHL protein (pVHL). pVHL is required to mark HIF-1a and HIF-2a for destruction under normal oxygen level conditions. HIF-1a and HIF-2a upregulate vascular endothelial growth factor (VEGF), which promotes angiogenesis, a hallmark of solid tumours. Therefore, loss of function of pVHL causes accumulation of HIF-1a and HIF-2a, promoting angiogenesis and exacerbating cancer development. The VHL gene is inactivated in over 90% of clear-cell RCC cases, the most common form of RCC.

Merck will be presenting data from its first-in-human Phase I/II trial of MK-6482 for advanced solid tumours including RCC (Peloton Therapeutics, NCT02974738) at the European Society of Medical Oncology (ESMO) 2019 Congress in September.

Merck’s key drug, Keytruda, is the best-selling programmed cell death protein 1 (PD-1) inhibitor in the RCC market, with sales of $4.9m in H1 2019, a 57% increase compared to $3.1m in H1 2018. Merck also benefits from two recent approvals of its combinatorial therapies for first-line treatment for patients with metastatic RCC: Keytruda + Pfizer’s Inlyta (axitinib) in April 2019 and its Bavencio (avelumab) with Inlyta in May 2019.

With these marketed immune checkpoint inhibitor combinations and novel agents in the pipeline, such as MK-6482, Merck is set to dominate the RCC market.

The company’s knowledge and experience in cancer therapeutics provide confidence in this novel approach of systemic drug treatment in earlier stages of RCC. If successful, GlobalData believes the use of MK-6482 in the neo-adjuvant setting will give Merck an advantage over competitors that leverage their products exclusively in the metastatic setting.

Related report
GlobalData (2014) EpiCast Report: Renal Cell Carcinoma – Epidemiology Forecast to 2023, August 2014, GDHCER032-14.