Licence agreement with Swiss pharma firm for development of a cancer drug

The most expensive thing about a drug is its development. It takes years, sometimes decades, to get from the idea to the finished product. Chemist Martin Béhé of the Centre for Radiopharmaceutical Sciences CRS at the Paul Scherrer Institute PSI, under the leadership of Roger Schibli, had worked on a special active agent for more than ten years. This was meant to help against the especially malignant medullary thyroid cancer, which very easily forms secondary tumours and also affects children and young adults. At the beginning of 2016, the time had come: Béhé and his team at PSI had developed, radiolabelled, and finally patented a molecule consisting of 12 amino acids – a peptide. The peptide was able to bind to receptors on the surface of the tumour cells. It contained the radioactive substance lutetium-177, which destroyed the malignant cells in the thyroid with its radiation without damaging other tissues. Experiments in the laboratory showed this. The scientists were euphoric: Now the active agent could be tested in a first study on patients. The researchers planned this jointly with the doctors of the Clinic for Radiology and Nuclear Medicine at the University Hospital Basel. In 2016, with the permission of Swissmedic, the Swiss Agency for Therapeutic Products, and the Ethics Committee, the doctors were able to use the new active agent for the first time on study patients with a medullary thyroid carcinoma.

PSI blog elicited pharma industry interest

PSI published information about the new investigational drug and how time-consuming its development had been in a blog on its website (https://www.psi.ch/media/drug-against-thyroid-cancer). Just a few weeks later, Béhé's telephone rang. The researchers still recall this one phone call from just over two years ago. It was a member of the staff at the company Debiopharm, the chemist says. She wanted to know more about our agent and asked if she could meet with us at PSI. Researchers from other scientific institutions and from industry often contact PSI to get up-to-date information about its research facilities, service offerings, and possible cooperation projects – it's widely known that top research is being done in Villigen. But for a company to ask about a particular substance and arrange an extra visit just to find out more, that was new for us, Béhé recalls. The Lausannne-based company Debiopharm specialises in buying promising active agents from their developers or, in cases where there are existing patents, licencing them. It then develops the agents further and brings them to the point where they are approved as drugs and thus ready for the market.

Eye-level encounters

Several meetings between experts from Debiopharm and PSI followed that first call, all under the protection of a confidentiality agreement. Béhé and CRS pharmaceutical scientist Susanne Geistlich first told the industry representatives how they developed the peptide and altered it so that it only binds to cancer cells and not to healthy cells. They also explained how they coupled it with the radioactive lutetium isotope, because the production of a radioactive drug is anything but simple. Because the effective radiation decreases with every minute, it's a race against time. But the specialists at CRS have a lot of experience with that. In the cleanroom at PSI, Geistlich's team had already produced the new agent themselves twenty times and meticulously documented every step in the process (https://www.psi.ch/media/medicines-made-to-order-with-pinpoint-precision), as is customary in pharmaceutical manufacturing.

Successful patient study as decision-making aid

The study at the University Hospital of Basel was also of particular interest to Debiopharm. It would provide the first clinical data and should show if the drug also binds as expected to tumour cells in humans. At the time of the initial discussions between the pharma firm and PSI, the study had just been started with six patients. Both sides waited anxiously for the results. When these were in hand after a little more than a year, they confirmed the hope that the PSI drug could be used in an effective dosage to treat medullary thyroid carcinoma without causing severe side effects in other organs. These promising results convinced the business people in Lausanne. They wanted to licence the PSI-patented agent to further develop it and bring it to market.

Martin Béhé recalls: Our discussions with Debiopharm got bigger and the questions more concrete. The company sometimes sent up to eight specialists from all important areas of drug development. Each specialist from Debiopharm looked at the drug from a different angle. They were interested in the pharmacology of the drug and the elaborate manufacturing process; they discussed commercial and legal aspects and wanted to know which areas were covered by the PSI patent.

Contract negotiations supported by PSI Technology Transfer

Béhé and Geistlich confronted the questions confidently and laid all the data open on the table, because mutual trust between the partners was the foundation for the upcoming contract negotiations. The researchers received support from Christine Huber of PSI's technology transfer department. A molecular biologist, Huber looks after technology transfer in the life sciences area and therefore knows exactly what is important in negotiating with industry. In technology transfer, we have to be careful to keep many opportunities open to our researchers. They can't have their hands tied by a contract, because as a federal Swiss research institute, our job is fundamental research, Huber explains. Our developments must also benefit the population and the Swiss economy, as also in the case of Debiopharm. In the licence agreement, we have ensured that the drug won't disappear into the drawer if our partner loses interest in it. Lack of interest on the part of the Lausanne-based pharma firm is nothing to fear at the moment. On the contrary, from the start, Debiopharm wanted an exclusive licence for the PSI drug in the field of oncology, that is, the sole right to use it in the area of cancer diagnostics and treatment.

Several application areas for PSI agent

Béhé explains why the PSI agent is so interesting to the pharmaceutical industry: The peptide, which is labelled with the radioactive lutetium-177, is a so-called minigastrin, the researcher says. This is similar to the body's own hormone gastrin, which binds to the cholecystokinin-2 receptor. And this CCK-2 receptor is found not only in tumour cells of the thyroid, but also in those of the lungs and some other organs. That means, in principle, that all types of cancer that carry this receptor can be treated by our active agent. The business people at Debiopharm also recognised this potential and made the first proposal for a licence agreement to PSI in the summer of 2017. In December 2017, both partners signed the licence agreement. In July 2018 it finally came into force. Now the PSI agent, named 177LU-PSIG-2, belongs to the Lausanne-based pharmaceutical company, and PSI receives graduated royalties for it.

Debiopharm now wants to bring the drug to market not only for medullary thyroid carcinoma, but also for small-cell lung carcinoma. In Switzerland alone, several hundred patients are afflicted each year with this especially malignant tumour, which is caused mainly by smoking. Less than one-fifth of them are still alive five years later. Christine Huber: If Debiopharm brings the agent to market-readiness and the drug helps cancer patients to heal or survive longer, then PSI has once again made its contribution to the good of Swiss society.

Text: Sabine Goldhahn