Kymera Therapeutics (KYMR) Q4 FY25 earnings call: guidance and Q&A

What is Kymera's vision for the evolving AD treatment landscape, and what can be learned from the IRF5 healthy volunteer study beyond safety and target engagement?

Nello stated the AD market is early with significant unmet need (40-50M moderate-to-severe patients, only 2M treated), requiring new therapies. KT-621 targets a well-validated pathway (IL-4/13) with intracellular action, offering de-risking. Jared explained the IRF5 healthy volunteer study will show 90%+ knockdown and functional inhibition (50-80% reduction) of TLR-stimulated pathways (Type 1 interferons, pro-inflammatory cytokines, B cell autoantibodies) via ex vivo assays, which de-risks subsequent patient studies.

“And to be able to show an impact across those 3 pathways on ex vivo stim, we believe, significantly derisk our probability of success in subsequent patient studies, including the lupus studies.”

asked by Marc Frahm · answered by Jared Gollob

Will there be interim biomarker data for KT-621 Phase IIb studies, or only full results? How does unmet need inform IRF5 development priorities?

Nello stated they will wait for full study completion to unblind and share data for Phase IIb studies to protect integrity. For IRF5, indications like lupus and Sjogren's are prioritized due to strong genetic association, preclinical data, and significant unmet need for effective oral therapies. IBD is also an increasing focus.

“For starting a Phase III study, we need to complete Phase II. We need to have an FDA meeting post Phase II, and then we can start Phase III.”

asked by Geoffrey Meacham · answered by Nello Mainolfi

What are the gating factors for starting KT-621 Phase IIs outside of asthma/AD?

Nello clarified that the current Phase IIb studies in AD and asthma are designed to support late-stage development for all derm and respiratory indications, respectively. They do not plan to start new Phase II studies; future studies will be registrational, pending regulatory vetting.

“The new studies that you see us starting will be, we believe, all registrational studies. Now obviously, some of this still has to be vetted with the right authorities, but that's our current strategy.”

asked by Charles Ndiaye · answered by Nello Mainolfi

What triggers KT-621 Phase III initiation, what needs to be collected, and will it be one or multiple study starts?

Nello stated Phase III requires completing Phase II and an FDA meeting post-Phase II. He expects to start all Phase III studies (likely 3, following the current paradigm of 2 placebo-controlled and 1 with topical corticosteroid) as much in parallel as possible.

“I assure you that we will do our best as we always have, to do that as quickly as possible. But obviously, there are some things that we must do in order to move into Phase III.”

asked by Bradley Canino · answered by Nello Mainolfi

Where does KT-621 show most potential for efficacy improvements over dupilumab, based on clinical/preclinical data, and comparison of respiratory vs. AD preclinical models?

Nello noted KT-621 performed at least as well, often better, than dupilumab in preclinical asthma models, but AD preclinical models are less robust. Clinically, KT-621 showed robust activity and comparable/superior biomarker changes (e.g., IL-31, Eotaxin, FeNO) and clinical endpoints to injectable biologics at 4 weeks. The goal is biologics-like activity with oral convenience, which would be transformative regardless of marginal efficacy differences.

“But I think we delivered that ballpark scenario that we talked about for last year. And so for us to really know how it looks, we need to wait for the Phase II studies.”

asked by Eli Merle · answered by Nello Mainolfi

Comparison of IRF5 degradation vs. inhibition, and risk of pan-IRF inhibition (e.g., IRF8) with the degrader.

Nello explained that Kymera's molecule is highly selective, binding only to IRF5 (all splicing variants) and not other IRFs, ensuring utmost selectivity. Jared added that IRF5 expression is restricted to certain immune cells, and its activation is context-specific, allowing for deep and chronic degradation without broad immunosuppression or increased infection susceptibility, as supported by mouse knockouts and preclinical tox studies.

“Our selectivity is pristine because we've been able to find this molecule that is actually not functional. So it does not inhibit anything. It only binds to IRF5, all the IRF5s splicing variants, but not other IRFs.”

asked by Judah Frommer · answered by Nello Mainolfi

Thoughts on ITK as a target for AD and comparison to STAT6.

Nello acknowledged ITK as another mechanism but stated Kymera decided against it due to human genetics suggesting a link to lymphoma, which didn't meet their risk-benefit profile. He reiterated STAT6 targets the most validated IL-4/13 pathway with strong safety and efficacy data, and more mechanisms are good for patients.

“ITK is a target that we've looked extensively at Kymera. We decided not to work on it because the human genetics show that because of challenges with clearing ETV, I think all patients end up developing some form of lymphoma.”

asked by Jeet Mukherjee · answered by Nello Mainolfi