Breakthroughs in basic research have been key to creating new therapeutic paradigms. In October, the 2019 Nobel Prize in Physiology or Medicine was awarded jointly to William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza, for their discoveries of how cells sense and adapt to oxygen availability. This is an important breakthrough in the understanding of an essential aspect of cellular metabolism. Oxygen sensing plays an important role in anemia, cancer, stroke, infection, wound healing, and myocardial infarction, and the prize-winning research will have a major impact on how these and certain other diseases can be treated.
Both Semenza, Director of the Vascular Research Program at the Johns Hopkins Institute for Cell Engineering, and Ratcliffe, based at the Francis Crick Institute in London and the Target Discovery Institute in Oxford, looked at how erythropoietin (EPO) levels change in response to different concentrations of oxygen. They independently found that the oxygen-sensing mechanism is active in all cells, including those that do not normally produce EPO. This led to Semenza’s discovery of the hypoxia-inducible factors (HIF), transcription factors that allows cells, including cancer cells, to adapt to oxygen-poor environments. Semenza published some of his key findings in 1995, including identification of the genes encoding HIF.
Kaelin, from the Dana-Farber Cancer Institute and Harvard Medical School, helped to further detail the molecular pathway used by cells to sense oxygen levels through his work on von Hippel-Lindau’s disease, a genetic disorder that increases the risk of cancer. His group linked VHL (Von Hippel-Lindau tumor suppressor) to HIF, showing that VHL mediates the degradation of HIF at normal oxygen levels. When cells become oxygen-starved, however, HIF prolyl hydroxylase inhibitors (HIF-PHI) no longer function, disabling VHL binding to, and ultimately degradation of, HIF. This allows HIF to activate EPO and promote erythropoiesis, thus improving iron regulation and reducing hepcidin. Given the direct effect on erythropoiesis, several pharma and biotech companies have been working in this area, seeking to leverage HIF and related proteins to treat anemia.
The first drug emerging from this research, roxadustat, a HIF-PHI developed by Fibrogen, has already made it to market in China, where it will be known as Ai Rui Zhuo. The Chinese approval was obtained through a partnership with AstraZeneca, which also holds rights in the United States, other markets in the Americas, Australia, New Zealand and Southeast Asia. Astellas has rights in Japan, Europe, the Commonwealth of Independent States, the Middle East and South Africa.
Fibrogen is in global Phase 3 trials with roxadustat for the treatment of anemia associated with chronic kidney disease (CKD). Clinical trial results, including Phase 3 pooled data analyses, have shown that the drug corrects and preserves hemoglobin levels, increases red blood cell count, and maintains normal or near-normal plasma EPO levels in subpopulations of CKD patients. Roxadustat is also moving beyond kidney disease and is currently being studied in anemia associated with myelodysplastic syndrome (MDS), with an ongoing Phase 3 trial in the United States and Phase 2/3 trials planned in China.
In parallel, Akebia Therapeutics is evaluating another HIF-PHI, vadadustat. The drug is in global Phase 3 clinical trials in anemia associated with CKD, and has been submitted for approval in Japan by its partner, Mitsubishi Tanabe Pharma. Otsuka Pharmaceutical has rights to vadadustat in the United States, Europe, China and a number of other territories. This has rapidly become a very competitive field, with other products not far behind in the pipeline. GlaxoSmithKline’s HIF-PHI, daprodustat, is in global Phase 3 trials for the treatment of anemia associated with CKD. Early results show that daprodustat is non-inferior to the standard of care. While Fibrogen’s HIF-PHI was first to market in China, a considerable race remains to get the first drug in the class approved in the United States and Europe.
The role of HIF has recently also been studied in other indications beyond nephrology and hematology. In neurology, for example, HIF may play a role in the pathogenesis of Parkinson’s disease, potentially giving HIF-PHIs a neuroprotective role. Other potential applications include ischemic hypoxic injury, infection, wound healing, atherogenesis, and inflammatory diseases including colitis.
In addition, HIFs are also being looked at in oncology. Clinical stage biopharma Peleton Therapeutics has developed a pipeline of small molecule therapeutics that target HIF-2α, and that have potential for the treatment of cancer and other conditions. Peleton’s lead oral HIF-2α inhibitor is in a Phase 2 clinical trial for VHL disease-associated renal cell carcinoma (RCC), a combination Phase 2 trial for metastatic RCC with the VEGFR-targeting agent cabozantinib, and a Phase 1/2 clinical trial for glioblastoma multiforme (GBM). HIF-2α has also been implicated in HER-positive breast cancer and other forms of cancer.
Bringing a new class of drugs to the market has its challenges. There have been some safety concerns with HIF-PHIs, including retinal disease, cancer, problems related to angiogenesis, thromboembolic complications and pulmonary hypertension. Whether these are going to be problems over the long term as roxadustat and the drugs that follow it become established on the market remains to be seen.
These targets show exciting potential for hard-to-treat diseases; however some concerns have been raised regarding serious adverse effects. People are wondering how this might impact the eventual use of these drugs if safety concerns are confirmed. Will they be limited to diseases with the highest unmet need? In severely ill patients only? Will this Nobel-prize winning research rival with the success stories that emerged from the discovery of cancer immunotherapy, which received the 2018 Nobel Prize in Physiology or Medicine?