Stopping Shape-Shifting Tumors with a First-in-Class Epigenetic Drug

Episode Summary

Executive Summary: Terry Connolly of K36 Therapeutics describes the company’s strategy to target NSD2, an epigenetic enzyme that can drive or sustain cancer by reprogramming gene expression. K36 is advancing KTX1001 in multiple myeloma and KTX2001 in metastatic castration-resistant prostate cancer, aiming to restore treatment sensitivity and create durable combination regimens.

Main Topics: Epigenetics as cancer’s operating system (Priority: 5/5): Connolly explains epigenetics as reversible gene regulation that controls cell identity and behavior without altering DNA sequence, making it a therapeutic opportunity in cancer. NSD2 biology and oncogenic dependency (Priority: 5/5): NSD2 modifies chromatin via H3K36 dimethylation and can drive malignancy, resistance, and lineage plasticity; K36 sees it as both a cancer driver and a dependency across disease contexts. KTX1001 in multiple myeloma (Priority: 5/5): K36’s lead asset, licensed from Novartis, is being developed first in genetically defined multiple myeloma patients, especially those with t(4;14), with biomarker-guided clinical development. Combination strategy to resensitize tumors (Priority: 4/5): After monotherapy dose escalation established safety and target engagement, K36 shifted focus to combinations with standard myeloma agents to restore sensitivity and deepen responses. KTX2001 for prostate cancer (Priority: 4/5): A next-generation, internally developed NSD2 inhibitor is being tested in metastatic castration-resistant prostate cancer, including combinations with darolutamide, to address lineage plasticity and resistance. Partnerships and clinical collaboration (Priority: 3/5): K36 highlights collaborations with Bristol Myers Squibb and Bayer as practical enablers for supply, development, and potential registrational pathways. Financing and future expansion (Priority: 3/5): The company says it has raised about $100 million and has runway for key milestones over the next 12 to 18 months, with plans to expand into broader biomarker-defined and solid tumor populations.

Key Arguments: Epigenetic changes are reversible, unlike genetic mutations, so they are attractive drug targets for cancer therapy. NSD2 is not a peripheral pathway; it reshapes the transcriptional landscape and can drive survival, resistance, and identity changes in cancer cells. KTX1001 was worth building a company around because strong biology, testable biomarkers, and a clinical patient population aligned. In multiple myeloma, the best initial population is t(4;14) patients, but NSD2-high non-t(4;14) patients may also benefit. K36 believes NSD2 inhibition is best deployed in combinations because the target helps tumors evade therapy and combination treatment may restore sensitivity. KTX2001 extends the platform into solid tumors, especially prostate cancer, where NSD2 is linked to lineage plasticity and treatment-emergent neuroendocrine disease. The company’s partnerships are designed to accelerate clinically meaningful combinations and support future registrational strategies. K36 views NSD2 as a broad cancer dependency that could matter across multiple hematologic and solid tumor indications.

Data Points: Approximate patient subgroup in multiple myeloma: 20% - Connolly said NSD2 is overexpressed in about 20% of multiple myeloma cases. Translocation name: t(4;14) - Primary genetically defined multiple myeloma population targeted for KTX1001. Biology evidence base: More than 25 years - Connolly cited more than 25 years of biology supporting NSD2’s role in cancer. Capital raised: Approximately $100 million - Total funding raised by K36 to date. Runway: 12 to 18 months - Existing capital is expected to cover key inflection points over the next year and a half. Combination cohorts planned for KTX1001: Three - K36 plans to advance KTX1001 into three combination cohorts in multiple myeloma. Clinical stage of KTX2001: First-in-human phase 1 - KTX2001 is now in early clinical testing in metastatic castration-resistant prostate cancer.

Pivotal Quotes: "epigenetics is more like the software where we call it reprogramming that tells the cell what programs to run." — Terry Connolly: Explaining epigenetics as a reversible regulatory layer that can be therapeutically targeted. "We're not just trying to kill the cells directly, we're reprogramming them out of a malignant state" — Terry Connolly: Describing the intended mechanism and therapeutic logic of NSD2 inhibition. "It wasn't just a belief in the molecule. It was really a convergence of validated biology, enabling chemistry, and execution capability" — Terry Connolly: Summarizing why K36 was built around KTX1001.

Implications: K36 is betting that targeting a cancer epigenetic dependency can both select patients better and restore response to existing drugs. If successful, the approach could expand beyond myeloma into prostate and other tumors.