The story of Xofigo: Norwegian excellence in radiopharmacy

For more than 25 years, Norwegian scientists have pioneered the use of nuclear medicine to diagnose and treat various diseases. In particular, Norway has excelled in the field radiopharmaceuticals, drugs that contain radioactive forms of chemical elements known as radioisotopes. Norwegian radiopharma expertise has come from ongoing cooperation between private industry, academia and the Norwegian Government.

One major advantage of radiopharmaceuticals is that they enable a personalised approach to medicine in which only malignant cells are targeted and killed, leaving healthy cells unharmed. Perhaps the best known of these drugs is Xofigo®, prescribed worldwide for men with prostate cancer that has spread to the bones. Studies show that the drug has a high rate of efficacy.

Xofigo® is Norwegian through and through. In the 1990s, scientists and serial entrepreneurs Roy Larsen and Øyvind Bruland developed radium 223 dichloride, a type of internal radiotherapy treatment. Given the brand name Xofigo, radium 223 is a mildly radioactive form of the metal radium that shrinks areas of cancer cells that have spread to the bones, reducing pain and improving quality of life.

In 1997, Dr Larsen and Dr Bruland founded the company Anticancer Therapeutic Inventions AS (ATI, later named Algeta AS). ATI asked the Norwegian Institute for Energy Technology (IFE) if it could produce a radium 223 injectable drug solution for clinical trials. IFE agreed, and the two organisations collaborated closely to produce the product at IFE’s facilities just outside Oslo. In 2001, the first patient received a trial dose of Xofigo. From then on IFE produced all the doses for clinical trials until 2023, when its spin-off Agilera Pharma AS was founded and took over.

“As you know, developing a new drug takes a long time, so Algeta was doing clinical trials until about 2010,” adds Silje Sivesind, Sector Director of Radiopharmaceutical Production at Agilera.

A decisive moment for the development of Xofigo was when Bayer and Algeta entered into an agreement worth USD 800 billion in 2009. This agreement was crucial to enabling the successful Phase III clinical study that started in 2011, which very quickly confirmed positive findings and became the foundation for the approval of Xofigo in 2013.

Xofigo® had its commercial launch in 2013, and one year later the global pharmaceutical giant Bayer acquired Algeta for USD 2.9 billion, giving Bayer sole control of Xofigo. Around this same time, the European Medicines Agency and the US Food and Drug Administration (FDA) approved Xofigo for use, opening up huge markets for the drug.

When Algeta looked around for a European site for commercial production, it selected Norway and Agilera (then a division of IFE). Algeta, with the support of Bayer, and in close collaboration with IFE/Agilera, began work on establishing a new production line tailormade for Xofigo.

“This was a huge project for us at IFE to take on at the time,” states Bente Tange Harbø, Sector Director for Radiopharmaceutical R&D at Agilera. “We did groundbreaking work to establish such a large commercial-scale manufacturing facility for radiopharmaceuticals.”

“It’s also important to remember that Xofigo was the world’s first alpha therapy product, and it had never been produced on a commercial scale before,” she adds.

Today Agilera has supplied more than 500 000 doses of Xofigo for commercial use around the world. As the sole manufacturer, Agilera delivered 100 000 doses per year to Bayer at the peak of production. In the radiopharma field, this is regarded as a large production volume. In 2017, Bayer opened a second manufacturing facility in the US, and production is divided between the two sites.

Compared to other drugs, radiopharmaceuticals are difficult to handle because of their radioactive component and short shelf life. Xofigo, for instance, has a shelf life of 28 days, with radioactivity decaying each passing day.

This means the drug must be delivered fresh, in a safe, appropriate and timely manner. Moreover, a network of global agents must be available to handle the radioactivity properly and distribute the drug around the world.

“We’re proud that we are able to manufacture and distribute the drug efficiently. I think we have paved the way for the export of radiopharmaceuticals to many difficult destinations, thousands of kilometres from the production site,” adds Sivesind.

Already active in Norway for 60 years, the pharmaceutical giant Bayer made big waves in 2014 when it acquired Algeta, and therefore Xofigo®. Today Bayer Norway has 150 employees across the entire value chain from research to sales, focusing largely but not exclusively on radiopharma.

“The acquisition of Algeta has been a cornerstone of Bayer’s oncology strategy,” states Thomas Birger Eden-Jensen, Head of External Supply Management (ESM) Radiopharmaceuticals at Bayer’s Oslo office.

Innovation Norway estimates that Bayer has invested almost NOK 4 billion (roughly USD 384 million) in Norway since 2014. “Bayer has continually invested in Norway, establishing a Centre of Excellence for Radiopharmaceuticals for Bayer and creating added value in Norway rather than removing it,” he adds, noting that Bayer is active in Norway’s radiopharma ecosystem around Oslo, which has seen tremendous growth in recent years.

“We collaborate with the University of Oslo, Oslo University Hospital and the Norwegian Radium Hospital, as well as with various cluster organisations such as Oslo Cancer Cluster, the Life Science Cluster and Oslo Science City,” he says. “The Association of the Pharmaceutical Industry in Norway (LMI) and the Confederation of Norwegian Enterprise (NHO) are important as well.”

In addition, he highlights the role of Norway’s other radiopharmaceutical companies, from innovative startups to larger contract development and manufacturing organisations (CDMO).

Two of Norway’s innovators are ARTBIO and Oncoinvent, both founded by the developers of Xofigo, Drs Bruland and Larsen. ARTBIO is a clinical-stage radiopharmaceutical company creating a new class of alpha radioligand therapies (ARTs) for cancer care, while Oncoinvent, also a clinical-stage radiopharma company, has developed Radspherin®, a novel alpha radiation therapy candidate designed for the local treatment of cancers that have spread to body cavities.

Other cutting-edge companies are Node Pharma, a preclinical radiopharma company developing new therapies for patients with limited treatment options due to metastatic cancer, and Thor Medical, an emerging supplier of alpha-emitters for next-generation precision cancer treatment. Its production process is based on separation of naturally occurring radioactive decay products from thorium (Th-232), which the company will supply to ARTBIO, among many others.

In addition, the Norwegian Medical Cyclotron Centre delivers established and new isotopes and radiopharmaceuticals. The centre focuses on the international market, increasing capacity and establishing new diagnostic and therapeutic radiopharmaceuticals. It also ensures access to important medical isotopes. Founded in 2003, the Cyclotron Centre is the largest single investment in advanced medical research and diagnostics carried out in Norway.

While drug development is always a slow process, Norway’s many radiopharma companies are moving radiopharmaceuticals along the value chain at a promising pace. Bayer Norway, for instance, has developed a new product platform based on the actinium-225 nuclide. Now in the clinical phase, these products are being trialled for the treatment of prostate cancer and liver cancer.

Moreover, the experts at Agilera are optimistic about the future following the company’s recent acquisition by PharmaLogic, a North American radiopharma CDMO, for an undisclosed sum. Agilera’s activities will remain in Norway with no reorganisation.

“In recent years, we have seen big pharma show increasing interest in acquiring smaller Norwegian companies such as Agilera and investing in their development,” states Silje Sivesind at Agilera.

“There is a growing need for specialised production facilities and laboratories for handling radioactivity and radiopharmaceuticals, and this acquisition presents good opportunities for us. Our ambitions going forward are to be a leading CDMO partner for radiopharma companies both for development projects and for clinical production.”

Finally, an especially promising area for personalised oncology is theranostics, which is being pioneered within Oslo’s radiopharma ecosystem. In nuclear medicine, theranostics involves diagnostic imaging using radioactively labelled tracers to identify a biological target structure, followed by internal radiation therapy using the same tracer. Not every patient will benefit from theranostics, but for those who cross the target-detected line, the likelihood of response is very high.