Matching degrader chemistry to the problem: The BioCentury Show

Kymera CEO Nello Mainolfi on glues vs. heterobifunctional degraders, and how to prove a new modality on a new target without incurring biology risk

Kymera has a clear mission: to transform immunology with targeted protein degraders that enable “oral drugs with biologics-like activity,” CEO and medicinal chemist Nello Mainolfi told The BioCentury Show.

A pioneer in one of biopharma’s most closely watched new therapeutic modalities, Kymera Therapeutics Inc. (NASDAQ:KYMR) is now over nine years into its story, with multiple pharma partnerships and a wholly owned pipeline, including STAT6 degrader KT-621, which produced promising safety and biomarker results in a healthy volunteer study in June.

In the interview, Mainolfi sketched a clear rubric for building drugs that work by targeted protein degradation, and for choosing when to favor heterobifunctional degraders over molecular glues. Both types of degraders add a ubiquitin tag to a target, sending it to the proteasome for degradation, but they have different physicochemical properties.

Although molecular glues have been attracting more dealmaking and investment enthusiasm in recent years, Mainolfi believes heterobifunctional molecules are the rational choice when a target has a ligandable surface.

“We will always go after [such targets] with a heterobifunctional degrader approach because we believe it’s the most rational drug design, where you have absolute control of specificity, potency, and molecular properties,” he said.

For Kymera, glues come into play when the target protein is highly disordered or has a binding site shared by another class member.

“Human nature tends to gravitate to the lowest activation barrier,” Mainolfi said. “The activation barrier for a molecular glue is apparently lower, but for actually making the final drug, it is technically higher, because the rules are very different and the risks are generally higher.”

Although heterobifunctional degraders are larger and less inherently drug-like than glues, Mainolfi says mature playbooks now exist to deliver stability, half-life, and once-daily oral profiles. Kymera has helped codify those rules so the molecules “behave like active pharmaceutical agents.”

Kymera’s philosophy of matching the chemistry to the problem also guides target selection. Its STAT6 program shows how targeted protein degradation can tackle a historically “undruggable” transcription factor — one of the modality’s core promises — while keeping biology risk low. That’s a difficult needle to thread for a new-modality company; most offset technology risk by starting with validated targets,  which increases the bar for differentiation.

In Kymera’s case, picking intracellular nodes in validated biological pathways lowers biology risk while opening new avenues for differentiation, such as tissue access and oral convenience. STAT6, for example, sits downstream of IL-4 and IL-13, the cytokines targeted by Dupixent dupilumab, one of immunology’s most successful biologics. Kymera aims to replicate the pathway’s validated clinical benefit with an oral small molecule instead of an injectable antibody.

Mainolfi outlines Kymera’s translational strategy for ensuring STAT6 degradation is mechanistically similar to IL-4 and IL-13 inhibition. In addition to investigating the human genetics of STAT6 variants and the effects of STAT6 manipulation in human cell models, the company is maximizing its learning from Phase I studies with comprehensive molecular exploration.

In its Phase Ib BroADen study in atopic dermatitis patients, which is due to read out this quarter, Kymera is not only tracking STAT6 degradation and key biomarkers of Th2 inflammation in blood and skin, but also conducting whole transcriptome analyses on skin lesions to get a fuller mechanistic picture of the downstream effects of STAT6 degradation.

“I always tell my team,” they must have “the sense of urgency and the focus of small biotech” but “the rigor of larger pharmaceutical companies,” Mainolfi said.

His advice for today’s platform founders: “You have to earn the right to grow.” Capital alone isn’t a reason to hire or expand; reproducibility of the innovation engine is. Be transparent about both strengths and challenges, and avoid optimism that breeds timeline misalignment. Above all, marry technology to the clinical problem. “The field of protein degradation has suffered from ‘let’s degrade the protein because we can’ versus ‘let’s degrade the protein because we want to’.”

Kymera is well-capitalized, with runway into 2H28. It raised $250.8 million in a follow-on after its June data and has active partnerships with multiple pharma companies, positioning it to set a high bar for out-licensing core immunology assets, which Mainolfi said is unlikely before Phase IIb proof of concept.

Although its heterobifunctional platform is, in his words, “perfected as much as one can say on this earth,” he’s open to adding new technologies. Here too, solving a specific problem is the guiding principle.

“I like thinking about extracellular bispecific molecules to enable other types of protein clearance. I like the concept of sequestration of particular targets in particular cell types via bispecific, heterobifunctional molecules.”