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DRUG DISCOVERY
Novartis recalibrates its drug engine A month after revealing a significant pruning of its pipeline, Novartis is providing details about the two-year evolution of its research agenda. In an interview with C&EN, Novartis Institutes for BioMedical Research (NIBR) President Jay Bradner explains the tough decisions and the renewed focus of the pharma giant’s R&D engine. “Outside our walls, there’s a footrace for the lowest-hanging fruit,” Bradner says. Novartis might participate in that race on occasion, he concedes, but his research organization is squarely focused on first-in-class molecules or drugs that offer more than just an incremental improvement over existing treatments. As one of the rare big pharma companies devoting significant time and money toward early research, he says, “we have the luxury to reach for the highest-hanging fruit.” The portfolio review that took place between July and September aimed to weed out programs that didn’t jibe with that lofty ambition, belonged to a therapeutic area Novartis has decided to abandon, or were ones where the business rationale simply didn’t add up. In the end, Novartis cut 20% of its portfolio, or 90 projects. It also ended research in infectious diseases. It is the first major portfolio overhaul under the watch of Bradner, a chemical biologist who in early 2016 left Harvard Medical School to lead NIBR’s 6,000 researchers. That research organization has trained its sights on several risky, but potentially highly rewarding, areas of science. “We have made a significant investment and have focused recruitment in the field of chemical biology, believing that this is a field of science that has matured to the point of promising new types of drug molecules to overcome long-standing
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C&EN | CEN.ACS.ORG | NOVEMBER 26, 2018
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tractable,” he says, noting that NIBR has worked on historically inaccessible targets like nonenzymatic scaffolding proteins and transcription factors. Although he declined to provide a detailed timeline, Bradner expects Novartis and others will have their first protein degraders in the clinic in 2019. Another emerging area that has gathered momentum is designing small molecules to modulate splicing of RNA. The company already has one such compound, LMI070, in early clinNIBR ical trials to treat spinal musPresident cular atrophy and has since Jay Bradner worked internally and with collaborators to explore the idea of whether it’s possible to directly drug RNA. “If RNA is druggable, then nothing is undruggable,” Bradner says. Bradner says that of the 340 drug discovery projects that survived the pipeline review, small molecules targeting RNA and protein degradation are both “well represented.” As for the molecules that Novartis terminated, Bradner believes many will find homes outside Novartis. Over the past two years, Novartis has built a group within its business development unit working on targeted protein degradation, that is looking at opportunities to license a way of using complex small molecules products like the ones recently trimmed to tag errant proteins for the cellular trash from the pipeline. That could include bin. Although it’s unusual for a major conventional licensing deals like the one drug company’s R&D head to take such a reached last month with Boston Pharmahands-on approach, Bradner has a special ceuticals, which bought the rights to three attachment to the field: It was a focus of antibiotics, or enabling new company forhis academic lab, work that led to one of mation like with QED Therapeutics, which the first protein-degrader-focused biotech launched in January to develop a fibroblast companies, C4 Therapeutics. Moreover, the method of breaking down growth factor receptor inhibitor that Novartis had discontinued. proteins, rather than simply blocking their Now, with even more programs collectactivity, aligns with Bradner’s mandate that ing dust, “we will be working through 2019 NIBR scientists take on proteins that have long eluded drug hunters. “The community to start focused new biotech companies and/or partner with existing discovery should expect that the proteins targeted units,” Bradner says.—LISA M. JARVIS by protein degradation are otherwise inchallenges in discovery chemistry.” That has meant organizing teams of scientists around a few key concepts that include next-generation DNA-encoded library chemistry, small molecules that modulate RNA splicing, covalent chemoproteomics, targeted protein degradation, and what Bradner calls “a new brand of phenotypic drug discovery.” Bradner himself leads the sizable team
C R E D I T: N OVA RT I S
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R&D chief Jay Bradner discusses a recent portfolio overhaul and the evolution of its research operations
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