BOSTON—In the opening keynote presentation at SLAS 2024, Juliet Williams, PhD, head of research at Kymera Therapeutics, presented clinical updates touting the systemic advantages of targeted protein degraders compared to biologics and/or small molecules for a range of indications, especially in immunology and oncology.
Williams was the featured speaker in the opening session of the Society of Lab Automation and Screening (SLAS), which is being held this week in Boston. Williams is an experienced biopharma scientist, having previously led oncology research and small molecule drug discovery at the Novartis Institutes of BioMedical Research (NIBR), as well as stints at Sanofi-Aventis and Millennium Pharmaceuticals. Her talk was entitled: “Solving Big Problems with Small Molecule Degraders.”
Targeted protein degradation (TPD) offers “a game-changing novel modality,” Williams said, by harnessing natural biochemical pathways to abolish proteins that might be misfolded or overly abundant. The platform is also disease-agnostic, although the initial focus, based in Watertown, Mass., centers on applications in immunology and oncology. Several of those programs are moving successfully into the clinic.
In biology, cells clean out misfolded or accumulated proteins via the E3 ubiquitin pathway. TPD involves the tagging of protein targets by small molecule degraders, sometimes called PROTACs (proteolysis targeting chimeras). These consist of bifunctional linkers shaped like molecular dumbbells—the ligand at one end binds to the target, while the other ligand binds to E3 ubiquitin ligase. When in close proximity, the ligase tags the target protein with chains of ubiquitin, marking the protein for destruction by the proteasome.
TPD features “exquisitely potent compounds,” Williams said, that could in principle bind anywhere on a target protein. The field is showing signs of commercial maturation— “exponential growth” in Williams’ words—after more than two decades of research. Arvinas, a biotech based in New Haven, CT, was the first to take the technology into the clinic.
The best scenarios for TPD are cases where “we have proteins that can’t be drugged well by other modalities,” Williams said. By some estimates, 80 percent of protein targets are undruggable—and in many instances, small molecule inhibitors cannot fully exploit what TPD can do. Williams added that TPD can remove all scaffolding functions and result in “deep pathway suppression.” Moreover, these orally administered drugs can offer biologic-like activity in the form of a pill.
“We don’t want this modality to fail in the clinic because we’ve chosen the wrong targets,” she said. “There needs to be a clear path of early clinical differentiation” with existing drugs or therapies. In addition, Kymera (and presumably other TPD companies) want to choose diseases where they can make “a huge impact on patients.”
Williams offered the SLAS audience—albeit below capacity due to lengthy early-morning registration check-in lines that left some attendees visibly irritated—several vignettes of Kymera’s progress in the clinic. These programs use a large toolbox of integrated approaches to drug discovery, including machine learning to facilitate hit identification and optimization, cyro-EM validation, careful study of pharmacodynamics, and virtual screening against novel targets. Seeking to replicate the promise of preclinical results in patients, Williams said her colleagues see a “high fidelity of translation” across all four programs that have progressed into the clinic.
KT474 is the first TPD candidate in the clinic for an immunological target—in this case, a master regulator called IRAK4, an “obligate node” in interleukin-1R and toll-like receptor (TLR) signaling. Humans with null mutations in IRAK4 are healthy, suggesting it should be safe to remove this protein. “It took years to make this degrader,” Williams said, but after successful testing on healthy volunteers, Kymera moved to patients. High concentrations were reached in the skin, with patients with the chronic skin condition hidradentis suppurativa (HS) as well as atopic dermatitis showing a robust clinical benefit after four weeks of dosing.
A preclinical program, KT-621, targets a transcription factor called STAT6. Gain-of-function mutations in this gene cause severe allergic diseases. Current drugs include Dupixent and Dupilimab. “Imagine a pill that could reach a wider population that biologics?” Williams posed, touting the potential advantage of TPD compared to an “occupancy-driven biologic.” KT-621 appears to be highly potent at picomolar concentrations, exhibiting degradation in vivo in blood, spleen, skin, and the lungs. It also targets STAT6 specifically, leaving other homologous STAT proteins untouched.
In oncology, Williams also mentioned KT-253, which targets a protein called MDM2, a well-known p53 modulator. Scientists have been trying to develop small-molecule inhibitors for MDM2 for more than 20 years, but they have been hampered by toxicity, Williams said. The early results show that low doses for KT-253 are well tolerated in patients.
In her closing remarks, Williams said, “We’re trying to expand a range of targets for degrader therapies” in order to build a broad, deep, disease-agnostic pipeline.
Responding to an audience member question, Williams acknowledged that the biggest challenge in developing TPDs is chemistry, manufacturing and controls, or CMC, before adding that with the benefit of many years of experience, her team is able to overcome those challenges. Improving oral bioavailability is another aspect where experience is paying dividends.
SLAS 2024 continues this week in Boston.