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Three researchers have been jointly awarded the Nobel Prize for Physiology or Medicine for their work in understanding how changing oxygen levels, including hypoxia or low oxygen levels, affects cellular metabolism.

Sir Peter Ratcliffe of the Francis Crick Institute in the UK and William G Kaelin Jr of Harvard University and Gregg L Semenza of John Hopkins University in the US were awarded for their research, the Nobel committee announced on 7 October. 

Decades on from when they first conducted their research, the work is still proving fruitful in helping biopharma companies to develop novel drugs.

This includes the new class of hypoxia-inducible factor prolyl hydroxylase (HIF-PH)  inihbitors, led by FibroGen’s roxadustat, which has just received its first approvals via licensing deals with Astellas Pharma Inc. in Japan and AstraZeneca PLC in China. (Also see "Approval Positions Roxadustat As Japan HIF-PHI Pioneer" - Scrip, 25 Sep, 2019.)

The trio’s research, carried out independently from each other, has helped piece together the molecular machinery that regulates gene activity in response to varying levels of oxygen. 

This includes Semenza’s work to map out the hormone erythropoietin (EPO) gene, which leads to increased production of red blood cells, and pinpoint the specific DNA segments which mediate the response to hypoxia.

Ratcliffe and Semenza’s discovery of a protein complex, the hypoxia-inducible factor (HIF) has implications for a range of diseases where low oxygen levels play a role, including cancer, diabetes and coronary artery disease.

Kaelin’s work on the inherited disorder von Hippel-Lindau's disease (VHL disease) and its link to increased risk for certain cancers with VHL mutations has also directly inspired new drug treatments.

The discoveries were integral to the development of the angiogenesis inhibitors such as Roche’s Avastin (bevacizumab), which works by blocking formation of new blood vessels which supply oxygen and nutrients to the tumor.

"It turns out that because oxygen is so critical to life, many of the common human diseases have derangements in the ability to maintain proper oxygen levels." Semenza said after the prize was announced.

"So for example in a cancer, the cancer cells divide very rapidly, consumer a lot of oxygen, and become very hypoxic. And what we've learned is that when they become hypoxic, they turn on genes that enable them to invade, metastasize, and spread throughout the body."

HIF-PH Inhibitors
The hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors which piggybacked on this basic research are now reaching global markets. 

The medicines work by mimicking the body’s physiological response to low levels of oxygen that leads to the production of red blood cells.

The first in the class is roxadustat, which as developed by FibroGen and licensed to Astellas in Japan, the EU, Russia and the Middle East and with AstraZeneca in the US, China and other global markets.

The drug is tipped for blockbuster status, with revenues expected to peak above $2bn a year.

Astellas gained approval for the drug in Japan in September, where it is known as Evrenzo for the treatment of renal anemia associated with chronic kidney disease (CKD) in dialysis patients. SC125918

Roxadustat is also in Phase III trials for anemia in patients with myelodysplastic syndromes (MDS).

A slew of other drugs in the same class are close behind, including Mitsubishi Tanabe Pharma Corp.’s vadadustat, Japan Tobacco Inc. and commercial subsidiary Torii Pharmaceutical Co. Ltd.’s enarodustat and GlaxoSmithKline PLC/Kyowa Hakko Kirin Co. Ltd.’s daprodustat.

Mene Pangalos, executive vice president, BioPharmaceuticals R&D at AstraZenecea congratulated the three winners of the prize.

“Their discoveries on HIF pathways served as the foundation for us to explore the mechanisms of HIF-PHIs and take the science forward. HIF-PHIs are a new class of medicines in development for the treatment of anaemia caused by chronic kidney disease that work by co-ordinating erythropoiesis.”

AstraZeneca expects to launch the drug in China before the end of 2019.

“Roxadustat is a first-in-class HIF-PHI and we are merely steps away from bringing this medicine to CKD patients with anaemia. This would never have been possible without early breakthroughs of this year’s Nobel winners and we thank them for their contributions,” Pangalos said.

Another emerging drug class based on the science are the HIF2a inhibitors.

This modality is being researched by Peloton Therapeutics as a renal cell carcinoma treatment, and led Merck & Co. to pay $1.05bn for the company in May this year. (Also see "Merck Buys Peloton On Eve Of IPO, Expands Kidney Cancer Portfolio" - Scrip, 21 May, 2019.)

Patent Disputes
However rows over intellectual property have sometimes marred relations between academic scientists and pharma companies, and held up progress on translating these discoveries into new medicines.

Last year’s Nobel Prize in Physiology and Medicine went to Japanese doctor Tasuku Honjo and US physician James Allison for their research that led to development of PD-1 checkpoint inhibitors for immune-oncology.

There is, however, an ongoing dispute over who should properly claim credit for the discovery, and related patents.

Honjo is mounting legal action against Ono Pharma in relation to its PD-1 blockbuster Opdivo (nivolumab, co-marketed with BMS) claiming he is entitled to unpaid royalties related to his research.

He claims he is entitled to 10% or about ¥15.4bn ($143m) of the amount Ono Pharmaceutical and BMS received from Merck & Co. when they settled a patent infringement lawsuit. 

However a rival claim by Dana-Farber Cancer Institute in the US has also claimed that two other researchers, Gordon Freeman and Clive Wood, should be named as the inventors of six key patents.

A US court rule in the cancer institute’s favor in May, though the decision will be challenged by BMS.

Ground-breaking research in the field of CRISPR gene-editing has been tipped for a Nobel Prize recognition for several years, and the first clinical trials of the technology now underway. 

However ongoing legal disputes over patents is making crediting individuals problematic, and the Nobel committee may well be waiting for these wrangles to be settled before recognizing the field.

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