Following a strong scientific concept into a new territory

Novartis researcher Rene Hersperger, who today heads Global Discovery Chemistry in Immunology, still remembers the times when he and his chemistry colleagues would regularly meet in the cafeteria on the second floor of the Food tower on the Campus in Basel and discuss the latest research challenges in a relaxed and cozy atmosphere. It was during one of the impromptu meetings around 15 years ago that he and his colleagues – among them today’s Global Discovery Chemistry Head Basel, Martin Missbach, and Laszlo Revesz, who has since retired, were discussing the future of an immunology project that had hit an impasse. The Bruton Tyrosin Kinase (BTK) team – named after the target they wanted to reach – had been working on a reversible molecule that was designed to hit BTK, a disease-triggering enzyme, in a highly specific and safe manner, a prerequisite for treating autoimmune diseases. At that time, highly potent but not very selective inhibitors were already in advanced clinical testing for oncology indications. But the team`s lead series and front runner molecules were far from ideal to make it all the way to the patient. They were too big and too greasy and would face insurmountable challenges if they were to be formulated into a safe drug. The risk was that, due to its modest potency and lack of solubility, a large amount of the drug dose would be needed to produce any reasonable clinical benefit. A cafeteria meeting This is when the cafeteria gatherings opened the possibility to think outside the box and formulate questions that might have not been discussed in regular leadership meetings. One of those taboo questions was whether the team should consider working on a covalent inhibitor, which could potentially solve the existing challenges of potency and drug-like properties. But the idea came with a big caveat because covalent molecules create a much stronger, in fact irreversible bond, with the target enzyme. If a covalent molecule is not specific enough, it could permanently modify additional wrong proteins and could lead to serious side effects the team wanted to avoid. In the oncology space, where covalent BTK inhibitors were already in advanced clinical studies, side effects such as rashes or diarrhoea were tolerable, but not in immunology. A ray of hope, which appeased some of the side-effect fears and made the idea look less risky, was the fact that some well-known medicines were in fact covalent molecules, such as Aspirin®, Penicillin and others, even though researchers had not been aware of this fact long after these medicines were developed. “This actually gave us the courage that we could try out a covalent modality in immunology,” Hersperger said. The initial molecule, a reversible compound, the team had been working on exceled in one key point: it had high selectivity. Its weakness – low potency and unfavourable druglike properties, so the thinking went, could be addressed by a covalent structure. The idea was to bring together two worlds – the reversible structure with its high selectivity and the special bonding mode of a covalent molecule, which would form a lasting bond with the target enzyme and thus high potency and a long duration of action.

Combining two worlds “I still remember distinctly that I asked Laszlo during one of our cafeteria meetings why no one was following up such an idea and concept,” Hersperger said, adding that this was not just an idea that came out of the blue but was the result of the quest to come up with safer next generation molecules that would help Novartis differentiate itself from competitors. “We were already some years behind with our research,” Hersperger said. “A highly specific covalent molecule could allow us, while not being first-in-class, to become best-in-class – an idea which we believed would also convince our commercial colleagues to continue to support the project.” What happened then was like something out of a fairy tale. Shortly after the meeting in the cafeteria Laszlo Revesz, an experienced medicinal chemist, put together a hybrid molecule containing a covalent principle as well as the high selectivity of the original large reversible molecule. And, to the surprise of almost everyone, it worked, and already first in vitro assays confirmed our working hypothesis. This was the proof-of-concept the team had needed, said Martin Missbach, who together with Hersperger was on the leadership team for this project. “It was an untested route, but it seemed to have a very valid basis.”

High scepticism Still, due to its novelty and potential for unwanted side effects, scepticism was high, Missbach added. “But what we said to ourselves is that if there was any preferred indication, we could test this covalent concept in, it would be immunology due to its immune-tempering mode of action since a BTK inhibitor would reduce unwanted inflammatory effects in case the molecule bound anywhere else.” Although it would still take several years before the team could hope to see the experimental compound develop into a drug, Hersperger and Missbach believed that they were on the right track. “It really energized the entire team, from biologists to chemists, to work on this new type of molecule,” said Rene Hersperger. “With this new molecule, we were able to carve out our own territory and work on something that was truly unique”, Hersperger said. “We had a compound that was highly potent, druglike, and, thanks to its selectivity, was also safe. This made a huge difference,” he said. Hersperger and Missbach are fully cognizant of the heavy lift their colleagues from Novartis Biomedical Research and Development put in to turn the molecule into a success. “It was really hard work. But I think a key point was that we had the right concept,” Hersperger said. Following your idea To this day, Hersperger uses the compound’s development journey as a key lesson learned when talking to his younger colleagues. “Really, what you have to do is to believe in your concept, and then do everything to test your concept against reality and have the data make the final call.” Hersperger is convinced that such clear strategic thinking gives research teams more clout to defend a project in the long-term. “In this case, we were able to show that our compound enabled us to stand out against competitors and, if successful, make a difference to patients. This is what counts in the end.” Missbach said the compound also led the team to cement the concept of being best-in- class in this field. “Competition is very high in the pharmaceutical space and often the race is won by an outsider company when it comes to being first-in-class. But, if we can’t achieve first-in-class, being best-in- class with a molecule that can make a difference, has a very high value,” he said.