Reimagining chemistry

Chemist Robert Pulz could not help but feel a bit surprised when he learned that - the team he was about to join at the Novartis Biomedical Research immunology group in Basel in 2010 - his colleagues were starting to work on special types of molecules that had a somewhat shady reputation in the industry. The molecules in question were covalent inhibitors, molecules that can bind more strongly and for longer to a disease target. While this quality may sound convincing to a layperson, such molecules are more difficult to make because researchers need to ensure that these long-lasting compounds do not bind to other proteins and cause toxic reactions – a task that until then was rarely done. “Covalent inhibitors were not in fashion then, to say the least,” said Covalent inhibitors were not in fashion then, to say the least,” said Robert Pulz, Director at Global Discovery Chemistry Immunology at Novartis in Basel. “In the early days, the mere mention of covalent inhibitors in drug discovery circles could raise eyebrows,” he added.

Irreversible hurdle When Robert Pulz joined the team, his colleagues had already been working on the program for several years. Initially, they were trying to discover and develop a reversible small-molecule inhibitor to block the Bruton’s tyrosine kinase (BTK) protein, which is a key regulator of B cells, as well as of other immune cells like mast cells in allergy and urticaria. At the time, the internal team focused on BTK inhibitors for autoimmune and allergic diseases, including rheumatoid arthritis, chronic spontaneous urticaria, and multiple sclerosis, areas in which Novartis had considerable experience. In parallel, several external companies were searching for BTK inhibitors for cancer patients suffering from B cell lymphomas. “Initially, we were following up on findings in external literature, which suggested that BTK inhibitors may be efficacious in inflammatory conditions,” said Bruno Cenni, Executive Director in the biology space in the immunology department at Novartis Biomedical Research, who was part of the early research group that launched the project back in 2007. “We were working on different series of reversible inhibitors, each based on distinct structures with their own characteristics,” Cenni said. “In the early stages, you pursue multiple scaffolds in parallel to identify the most promising one. But initially, we had no plans whatsoever to work with covalent inhibitors.” The team found an ideal scaffold – an early core structure– that had a unique binding mode and clear selectivity advantages. But the resulting compounds were too large and lipophilic, which was not ideal for a clinical candidate. “The real challenge was combining all the necessary properties into one molecule, which proved to be extremely difficult,” Bruno Cenni remembered. Leaders follow the team While the team worked hard for several years to identify a molecule that was smaller and would have better drug-like properties, general scientific research on covalent inhibitors had advanced in the meantime, putting these once shady compounds into the limelight. Data started to emerge that covalent molecules ata started to emerge that covalent molecules could be safely used in medicine. This is because scientists got a better grasp of the underlying biology and were able to create molecules with higher specificity that bind to only a very specific target and not anywhere else. They were also able to prove that, at least in oncology, such inhibitors could be turned into successful drugs. This proved to be an ideal route for Bruno Cenni and his colleagues. Given the roadblock they encountered with their large reversible molecules, the team suggested pursuing a hitherto untested avenue: They aimed to combine the advantages of their reversible scaffold with those of a covalent irreversible inhibitor. Although the approach was uncommon at the time, immunology disease area head Dhaval Patel, who has since retired, and the then immunology chemistry head Martin Missbach decided to approve the team’s proposal since this unique combination offered the promise of a best-in-class molecule – a strategic goal that Novartis attempts to reach in all of its projects.

More than technology, it was the team's eagerness to test new avenues that led it to pursue a new molecular mechanism in the realm of immunology.

Covalent strength Chances, according to Bruno Cenni, looked good as the team became more familiar with the idea of decoupling pharmacokinetics (PK) from pharmacodynamics (PD) – meaning the exposure levels of a drug and its activity in the body – giving the team enough confidence to work on a covalent inhibitor. Covalent inhibitors, although they come with some risks, have convincing, long-lasting binding properties compared to reversible inhibitors, which only bind to a target for as long as the drug concentration stays above a certain threshold. Covalent inhibitors work by binding in the usual way at first, but then form a permanent, covalent bond with the target protein. Once that bond, which is created by atoms sharing electrons, is formed, it does not break even if the drug is cleared from the bloodstream. This means that a short and low exposure can his means that a short and low exposure can be enough if the compound manages to bind all target molecules in the body Successful prototype Robert Pulz was initially skeptical of the covalent concept. But he started to trust it once he was convinced of the underlying science as well as the fact that the first covalent compounds were successfully used in the oncology space. Furthermore, the high selectivity of the existing reversible compound gave him confidence that a potential covalent version could include this quality too and thus avoid the fate of other covalent inhibitors that were unspecific and led to various unwanted effects. But given that such covalent compounds were ut given that such covalent compounds were not widely used in the industry at that time, the team had to figure out everything from the ground up. “Due to the novelty, there was some skepticism,” Robert Pulz remembered. “But we never gave up because we felt that the science was leading us in the right direction.” Luck was on their side, though. Already by 2010, when the team started to work on the covalent compound, they were able to create an irreversible scaffold with high specificity. “The first prototype did exactly what it was supposed to do – that rarely happens,” Robert Pulz remembered. Challenges emerge The initial success in the in vitro tests, however, would soon hit a barrier in the follow-up in vivo studies, giving researchers quite a headache. The chemistry team, including Daniela Angst, François Gessier, and Anna Vulpetti, had already significantly improved their initial starting point. They had enhanced the molecule’s potency and further refined its selectivity. But when they tested the compound in animals, the molecule failed to deliver any measurable effect. The issue was not with the compound’s ability to bind to BTK, but rather with how quickly it was cleared from the animals,” Robert Pulz explained. “We didn’t fully understand why the scaffold was behaving the way it did in animal studies,” he added. “So, we asked ourselves: What can we do when the concept is strong, but the chemistry doesn’t work?” This is when the he answer was to diversify: This is when the chemists started to develop new compound variants that could do the trick. The team kept the key features – covalent binding and high selectivity – but began modifying the chemical structure in multiple ways. In the end, one n the end, one distinct change to the scaffold made all the difference. “That was our eureka moment,” Robert Pulz said.

Persuasion and scientific data While the team went through several pivotal moments – the project came close to termination at least two times during the long discovery phase – they also had to guard themselves against persistent skepticism and muster strong scientific arguments for their cause. “It was a challenging time that required a lot of It was a challenging time that required a lot of persuasion and internal alignment. I often joke that 50 percent of my job wasn’t science – it was convincing people that this program made sense,” Robert Pulz said. His colleague Bruno Cenni agreed: “We had to advocate hard across many teams to justify taking this risk. The doubts peaked when the formulation wasn’t yet stable, and concerns resurfaced just as we were moving toward Phase I.” The trick that eventually helped Bruno Cenni, Robert Pulz, and the team to win over the last skeptics came from their colleagues in Technical Research and Development, who devised a new way of formulating the compound. By milling down the active ingredient into very small particles, they were able to increase the overall surface and thus eventually enhance the drug’s exposure in the body, thereby enabling toxicology studies in animals and the Phase I human trial. ” “Once we showed clean toxicology in animals and no safety signals in Phase I, those concerns finally quieted down,” Bruno Cenni said. The rest, as the saying goes, is history. Marry your biologist “Personally, it was a major milestone, the first program I worked on that made it to the clinic,” Robert Pulz said. “Yes, there were challenges. But this compound overcame every one of them. I’m still amazed and incredibly proud. Because what the team achieved here is extraordinary. It’s the kind of outcome you hope for but rarely see.” For Robert Pulz the collaboration with Bruno Cenni from the biology team was also a key driver. “A former GDC head once told us chemists: ‘Marry your biologist, it’s the most important partnership you’ll have.’ Well, I didn’t marry Bruno,” Robert Pulz said laughingly, “but our collaboration was built on total trust, openness, and mutual respect.” Bruno Cenni agrees: “No matter how tough things got scientifically, we never had difficulties working together. We aligned on strategy, made decisions together, and always pulled in the same direction. That relationship made all the difference.” For both scientists, as well as for the rest of the team, their long and hard work has paid off not only in the fact that the drug is now approved in a skin indication. The innovative molecule could also prove to be beneficial in other immunological areas such as food allergies and multiple sclerosis, where studies are currently ongoing. “It is a researcher’s dream come true to work on something that can change people’s lives. So often, our projects lead nowhere, and we must start anew. Seeing one’s work reach patients is more than gratifying and it justifies all the hard work,” Bruno Cenni said. “The fact that this is a highly innovative compound, which is first- and best-inclass, feels all the more satisfying to us all.”