Nordic Life Science 1
ivirikko, now emeritus, is still involved in Fibr
oGen, a company he cofounded based on his collagen work. Among FibroGen’s drugs is roxadustat, a small molecule inhibitor of HIF prolyl hydroxylase developed with AstraZeneca and Astellas. The drug is approved or pending approval in Asia for anemia in chronic kidney disease. The list of other diseases that might be treated with hypoxia-targeting drugs is vast. Candidates now in clinical Sir Peter Ratcliffe at the University of Oxford trials are in two categories, Ratcliffe explains. One type that includes roxadustat and drugs from GSK and Akebia augments the natural hypoxia response by inhibiting HIF prolyl hydroxylase. In addition to anemia, these drugs could help recover from low oxygen in ischemia and circulatory diseases. The other type inhibits HIF and has promise in early trials for kidney cancer. This is the direction that Jaakkola took after the Ratcliffe group. “I’m an oncologist,” he says, “so my interests are in the effects of the oxygen-sensing system in cancer cells, mainly kidney cancer.” Oulu researchers study another possible therapeutic indication: metabolic disease. In hypoxia, the body reprograms its metabolism, Kappinen explains. Early data suggest that drugs that imitate this response may have benefits for weight management, cholesterol levels, insulin sensitivity, and fatty liver disease. The hypoxia response is ubiquitous, so a clinical upside is many applications. The downside is the need for exquisite specificity. As Ratcliffe puts it, “We want to activate part but not all of the cascade in a given disease and it’s not always clear how to do that that.” Knowing more pathways in the hypoxia response could identify more drug targets. Ratcliffe’s collaborations with Oulu researchers include looking beyond HIF and its hydroxylases to other oxygenases. “The hypothesis,” Ratcliffe says, “is that these enzymes that directly use and incorporate oxygen into substrates are other candidates for oxygen sensing and control mechanisms. Those are the types of enzymes that we’re looking at.” From his experiences with a spinoff company and consulting, Ratcliffe says he has great respect for the work of generating safe, effective drugs based on research results. He tracks clinical developments that arise from his work but focuses on basic research. “It’s why I’m so passionate about the scientific discovery process,” he says. “It’s so satisfying that we described oxygen sensing that has been around since animal evolution. That’s a discovery for all time, so we’re just rejoicing in that. To put knowledge on the table and see how people use it in unexpected ways for the good of society. That’s what you hope when you put knowledge out there.” NLS 60 NORDICLIFESCIENCE.ORG PHOTO PAUL WILKINSON