KTX-1001 / K36 Therap, Novartis - LARVOL DELTA

Highlights of JTCC Research to be presented at ASH 2025: Multiple Myeloma (PRNewswire) - "Phase 1 study of ktx-1001, a first-in-class oral MMSET/NSD2 inhibitor, demonstrates clinical activity in relapsed/refractory multiple myeloma (ABSTRACT 25-2077); Phase 2 registrational study of anitocabtagene autoleucel for the treatment of patients with relapsed and/or refractory multiple myeloma: Updated results from iMMagine--1 (ABSTRACT 25-4541); Talquetamab, a GPRC5D×CD3 bispecific antibody, in combination with pomalidomide in patients with Relapsed/Refractory multiple myeloma: Updated safety and efficacy results from the Phase 1b monumental-2 study (ABSTRACT 25-11949)."

Clinical data • Multiple Myeloma

Phase 1 study of ktx-1001, a first-in-class oral MMSET/NSD2 inhibitor, demonstrates clinical activity in relapsed/refractory multiple myeloma (ASH 2025) - P1 | "Preclinically, KTX-1001synergistically inhibited cell viability in MM cell lines when combined with a proteasome inhibitor (PI),immunomodulatory drug (IMiD), or cereblon E3 ligase modulator (CELMoD™). Pairedbone marrow samples further confirmed on-target PD effects, with a marked reduction in H3K36me2levels in MM cells at Cycle 2 Day 1 with observed anti-MM effect of reduced proliferation of MM cells withconcomitant increased proliferation in immune cells in pts achieving clinical benefit. ConclusionsKTX-1001 is a novel agent showing tolerable safety profile in RRMM and demonstrating promising singleagent activity in heavily pretreated, triple class refractory RRMM including those with high-risk features.KTX is currently evaluated in ongoing study in combination with carfilzomib and the investigationalCELMoD™ mezigdomide in t(4; 14) RRMM pts."

Clinical • IO biomarker • P1 data • Febrile Neutropenia • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Targeted Protein Degradation • Thrombocytopenia • CRBN • NSD2

Trial in Progress: A Phase 1 Study of KTX-1001, an Oral, First-in-Class, Selective MMSET Inhibitor in Patients with Relapsed and Refractory Multiple Myeloma (ASH 2023) - P1 | "This Phase 1 study will evaluate a potential treatment for RRMM utilizing KTX-1001, which is a novel, first-in-class, potent, oral small-molecule MMSET inhibitor. The study is open and actively enrolling patients at centers in the United States, Spain, France, and Canada."

Clinical • IO biomarker • P1 data • CNS Disorders • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • Plasma Cell Leukemia • NSD2

A Mass Cytometry-Based Clinical Pharmacodynamic Assay for Histone 3 Lysine 36 Dimethyl (H3K36me2) Levels in Myeloma Cells and Peripheral Blood for Implementation in NSD2 Inhibitor Ktx-1001 First in Human Trial in Relapsed and Refractory Multiple Myeloma (ASH 2024) - P1 | "The KMS11/BTZ (JCRB1642) t(4; 14)+ MM cell line is a derivative of KMS11 cells that are resistant to the proteasome inhibitor bortezomib (Ri M, et al. In KMS11/BTZ MM cells, a decrease in H3K36me2 signal was also observed with KTX-1001 treatment versus DMSO treated cells (1 uM 37.6% decrease; 3.0 uM 38.6% decrease).Conclusions : We found that the anti-H3K36me2 antibody is highly sensitive and specific in detecting Lysine 36 dimethyl Histone 3 marks in healthy PBMC and a MM cell line in vitro. In addition, the ability to detect the signal in multiple cell types in PBMC (B, T or NK cells and monocytes) and in MM cell lines in a range of drug concentrations suggest the potential utility of the assay to test planned clinical samples (eg, PBMC or bone marrow aspirates) to interrogate the correlation between dose, pharmacokinetics and pharmacodynamic effects of KTX-1001 in the dose escalation phase of the clinical trial."

Clinical • First-in-human • IO biomarker • P1 data • PK/PD data • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • CD8 • CEACAM8 • IL2RA • ITGAX • NCAM1 • NSD2 • PTPRC

First Results from the Dose Escalation Part of the Phase 1 Study of KTX1001, an Oral, First-in-Class, Potent Inhibitor of MMSET/NSD2 for Relapsed/Refractory Multiple Myeloma (RRMM) (ASH 2024) - P1 | "These PD data support the targeted mechanism of action of KTX-1001 to selectively inhibit MMSET and break the t(4; 14) histone code. Given KTX-1001's promising safety profile, single-agent and combination expansion cohorts with standard-of-care MM agents/classes will begin in 2025 to further optimize doses and provide proof of concept in Part B of the Phase 1 study."

IO biomarker • P1 data • Constipation • Fatigue • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Multiple Myeloma • Oncology • NSD2

Ktx-1029, a Potent, Selective MMSET/NSD2 Inhibitor Is Effective in t(4; 14) Multiple Myeloma Preclinical Models (ASH 2024) - P1 | "The KMS11/BTZ line is also cross-resistant to carfilzomib and addition of KTX-1029 to carfilzomib resulted in synergistic inhibition of cell viability (IC50 : carfilzomib alone=15.27 nM, KTX-1029 alone=5104 nM, 1000 nM KTX-1029+bortezomib= 7.87 nM). KTX-1029 compliments the orally-available clinical candidate, KTX-1001 that is being evaluated in an ongoing clinical trial for relapsed/refractory MM patients. Preclinical data with KTX-1029 adds to the body of evidence for targeting MMSET in MM patients with t(4; 14) and for further exploration of combination regimens with MM standards of care."

Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology • IGH • NSD2

Ectopic NSD2 Remodels H3K36me2 and DNA Methylation to Promote Oncogenic Gene Expression in Multiple Myeloma (ASH 2024) - P, P1 | "Currently, KTX-1001 is a first-in-class catalytic NSD2 inhibitor in a phase 1 clinical trial (NCT05651932)...We will present these results alongside data from extended NSD2 inhibitor treatments. We posit that elevated NSD2 in t(4; 14) MM causes excessive H3K36me2 leading to relative DNA hypermethylation and transcriptional dysregulation which can be reversed through extended pharmacologic inhibition of NSD2."

Epigenetic controller • Hematological Malignancies • Multiple Myeloma • Oncology • DNMT3B • KRAS • NSD2

Characterization of the Biochemical Activity of Ktx-1001, a Selective Small Molecule NSD2 Inhibitor, in Surface Plasmon Resonance (SPR) (ASH 2024) - P1 | "These data also identify that SPR in "reverse" mode is a useful tool to characterize small molecule binding events not amenable to standard SPR format. A Phase 1 study evaluating KTX-1001 in relapsed/refractory multiple myeloma is ongoing (NCT05651932)."

Acute Lymphocytic Leukemia • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • Prostate Cancer • Solid Tumor • NSD2

K36 Therapeutics…has initiated patient dosing in an expansion cohort evaluating KTX-1001, its first-in-class NSD2/MMSET inhibitor, in combination with carfilzomib and dexamethasone (PRNewswire) - "In addition, K36 has begun dosing patients in a separate cohort evaluating KTX-1001 in combination with mezigdomide, a novel investigational therapy from Bristol Myers Squibb...To enable this study, the companies have entered into a clinical trial supply agreement, under which K36 will sponsor and run the trial to evaluate the novel triplet of KTX-1001, mezigdomide and dexamethasone in patients with relapsed and refractory MM (EUCTR: 2022-500801-41-00)....The company anticipates reporting initial data in mid-2026."

Licensing / partnership • P1 data • Trial status • Multiple Myeloma

K36 Therapeutics to Present New Preclinical Data Supporting Ongoing Phase 1 Clinical Trial of KTX-1001 at the 22nd Annual International Myeloma Society Meeting (PRNewswire) - "The new data presented at IMS highlight the mechanism of action and potential clinical utility of KTX-1001. The data include bone marrow analyses from patients enrolled in the Phase 1 trial that support its clinical relevance. Additional findings from large multi-omics datasets identify a subgroup of newly diagnosed patients with high NSD2 expression in the absence of the t(4;14) translocation, highlighting the opportunity to expand investigation of NSD2 inhibition in patients that lack the translocation."

P1 data • Preclinical • Multiple Myeloma

Anti-adhesion Properties of KTX-1001, a Selective NSD2/MMSET Inhibitor, Enhance Carfilzomib Sensitivity in Multiple Myeloma (IMS 2025) - P1 | "We find KTX1001's role in disrupting adhesion of MM cells by regulating CD44, CD56 and N-cadherin levels and driving synergy with carfilzomib (CFZ) in a bortezomib-resistant highly adherent cell line. Inhibition of NSD2 by KTX1001 led to disruption of adhesive properties of MM cells that were mediated by CD44 and N-Cadherin in cell lines and patient samples. Further, the effects of KTX1001 on adhesion sensitized BTZ-resistant cells to combination treatment with CFZ. Analysis of patient samples from the ongoing trial that includes combination of KTX1001+CFZ would help ascertain synergy and the proposed molecular mechanism in the clinic."

Hematological Malignancies • Multiple Myeloma • CD44 • CDH2 • NCAM1 • NSD2 • TWIST1

Characterization of the activity of KTX-1001, a small molecule inhibitor of multiple myeloma SET domain (MMSET) using surface plasmon resonance (SPR). (PubMed, J Biol Chem) - "These data identify the utility of SPR in a "reverse" format, where immobilization of KTX-1001 allowed for the interrogation of binding to a protein target that may be challenging if conformation changes are induced in the coupling of that biologic target to a chip surface. Collectively, this analysis demonstrates the specific potent biochemical activity of KTX-1001 against MMSET and supports the ongoing evaluation of KTX-1001 in the clinic."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • NSD2

NSD2 inhibition as a therapeutic approach for treatment-induced neuroendocrine prostate cancer. (ASCO-GU 2025) - P1 | "Furthermore, genetic depletion of NSD2 has been shown to reverse AR(-) NEPC to an AR(+) adenocarcinoma phenotype and re-sensitize the prostate cancer cells to enzalutamide treatment. K36 Therapeutics has developed a selective NSD2 inhibitor KTX1001 that is currently undergoing clinical evaluation in multiple myeloma (NCT05651932)... These data support our hypothesis that NSD2 inhibition can reverse NEPC to AR(+) adenocarcinoma lineage and restore sensitivity to standard-of-care ARPI. Given these mechanistic insights and the safety profile observed with our NSD2 inhibitor in the clinic, evaluation of NSD2 inhibition in NEPC patients is warranted."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CHGA • FOXA2 • KLK3 • NKX3-1 • NSD2 • SYP

KTX-MMSET-001: A Study of an MMSET Inhibitor in Patients with Relapsed and Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=125 | Recruiting | Sponsor: K36 Therapeutics, Inc. | N=60 ➔ 125 | Trial completion date: Oct 2025 ➔ Jun 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Enrollment change • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology • NSD2

K36 Therapeutics Announces Multiple Poster Presentations Highlighting the First Clinical Data for KTX-1001...at the 66th American Society of Hematology (ASH) Annual Meeting (PRNewswire) - P1 | N=60 | NCT05651932 | Sponsor: K36 Therapeutics, Inc. | "The KTX-1001 presentations will feature the first results from the dose escalation part of the Phase 1 study and characterization of the asset's biochemical activity....The dose-escalation phase of the clinical trial demonstrates an increase in KTX-1001 exposure by dose and a corresponding decrease in H3K36me2 biomarker, reflecting clear target engagement that is consistent with preclinical models....In 2025, we will combine our oral investigational drug with standard of care agents, starting with a proteasome inhibitor and IMiDS to continue the development of KTX-1001 for the treatment of t(4;14) patients."

P1 data • Trial status • Hematological Malignancies • Multiple Myeloma • Oncology

NSD family proteins: Rising stars as therapeutic targets. (PubMed, Cell Insight) - "The reversibility of epigenetic modifications makes them promising targets for therapeutic intervention and drugs targeting epigenetic regulators (e.g., tazemetostat, targeting the H3K27 methyltransferase EZH2) have been applied in clinical therapy for multiple cancers. The NSD family of H3K36 methyltransferase enzymes-including NSD1 (KMT3B), NSD2 (MMSET/WHSC1), and NSD3 (WHSC1L1)-are now receiving drug development attention, with the exciting advent of an NSD2 inhibitor (KTX-1001) advancing to Phase I clinical trials for relapsed or refractory multiple myeloma...Multiple studies have implicated NSD proteins in human disease, noting impacts from translocations, aberrant expression, and various dysfunctional somatic mutations. Here, we review the biological functions of NSD proteins, epigenetic cooperation related to NSD proteins, and the accumulating evidence linking these proteins to developmental disorders and tumorigenesis, while additionally considering prospects for..."

Journal • Review • CNS Disorders • Developmental Disorders • Gene Therapies • Hematological Malignancies • Multiple Myeloma • Oncology • Psychiatry • NSD1 • NSD2 • NSD3

K36 Therapeutics Announces Presentation on KTX-1001 for Relapsed and Refractory Multiple Myeloma at the 65th American Society of Hematology (ASH) Annual Meeting (GlobeNewswire) - "K36 Therapeutics, Inc...today announced that its abstract evaluating KTX-1001 in relapsed and refractory multiple myeloma has been accepted for presentation at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition, which will be held December 9-12, 2023, in San Diego, California, and online."

P1 data • Hematological Malignancies • Multiple Myeloma • Oncology

Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2). (PubMed, J Med Chem) - "Excitingly, KTX-1001, a selective NSD2 inhibitor, has entered clinical trials. In this Perspective, the structures and functions of NSD2, its roles in various human diseases, and the recent advances in drug discovery strategies targeting NSD2 have been summarized. The challenges, opportunities, and future directions for developing NSD2 inhibitors and degraders are also discussed."

Journal • Review • Infectious Disease • Oncology • NSD2

K36 Therapeutics Announces $70 Million Series B Financing to Fund Clinical Proof of Concept of KTX-1001, First-in-class Inhibitor of MMSET for Treatment of Multiple Myeloma Patients with Genetic Translocation (4;14) (PRNewswire) - "K36 Therapeutics...developing KTX-1001, an investigational small molecule methyltransferase inhibitor of multiple myeloma SET (MMSET) domain, today announced a $70M Series B financing. The round was led by Nextech Invest, Ltd, a precision medicine focused investment firm, on behalf of one or more funds managed by it, with participation from Bristol Myers Squibb Company...and other undisclosed investors. All existing investors including Atlas Venture, F-Prime Capital, and Eight Roads Ventures participated in the round. The funds will support the ongoing Phase 1 study of KTX-1001, planned clinical studies of KTX-1001 in combination with existing standard-of-care agents in multiple myeloma, and the expansion of KTX-1001 into additional hematological and solid tumor indications."

Financing • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor

K36 Therapeutics announces dosing of first patient in KTX-1001 Phase 1 Clinical Trial for relapsed or refractory multiple myeloma and addition of Mr. Michael Heffernan as Independent Board Director (PRNewswire) - "K36 Therapeutics ('K36'), a privately held biotechnology company developing KTX-1001, an investigational small molecule methyltransferase inhibitor of multiple myeloma SET domain known as MMSET, announced today that the first patient has been dosed in its Phase 1 clinical trial earlier this year."

Trial status • Hematological Malignancies • Multiple Myeloma • Oncology

K36 Therapeutics announces dosing of first patient in KTX-1001 Phase 1 Clinical Trial for relapsed or refractory multiple myeloma and addition of Mr. Michael Heffernan as Independent Board Director (PRNewswire) - "The first patient has been dosed in Nashville, TN...Jesus Berdeja, MD, who stated, 'There still remains a need for new personalized therapies to treat multiple myeloma and novel precision therapeutics like KTX-1001 offer a potential solution to address the challenges seen in high-risk subsets like translocation t(4;14). We are delighted to be the first institution to advance this first-in-class agent into the clinic with K36.'"

Media quote

KTX-MMSET-001: A Study of an MMSET Inhibitor in Patients With Relapsed and Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: K36 Therapeutics, Inc.

New P1 trial • Hematological Malignancies • Multiple Myeloma • Oncology • NSD2

K36 Therapeutics Announces FDA Clearance of Investigational New Drug Application and Formation of Clinical Advisory Board for Lead Program KTX-1001 (PRNewswire) - "K36 also announced the formation of its Clinical Advisory Board comprised of...María-Victoria Mateos, Noopur Raje...Suzanne Trudel....'There remains a significant unmet need for new and more effective therapies that can benefit high-risk myeloma patients such as those with translocation t(4;14),' said Noopur Raje, M.D....'BCMA T cell redirecting therapies and the use of quadruplet therapy in myeloma are incredible advances but still have not leveled the playing field for high-risk multiple myeloma patients,' added Jesus Berdeja, M.D. 'There is still a need for novel precision therapeutics such as KTX-1001, and we are excited to be a part of bringing this first-in-class agent into Phase 1 testing.'"

Media quote • Regulatory

K36 Therapeutics Announces FDA Clearance of Investigational New Drug Application and Formation of Clinical Advisory Board for Lead Program KTX-1001 (PRNewswire) - "K36 Therapeutics, Inc...announced today that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) Application for the Company's lead program KTX-1001....K36 plans to initiate a Phase 1 clinical trial in the second half of 2022 to establish the safety, tolerability and preliminary efficacy of KTX-1001 in patients with relapsed and refractory multiple myeloma, enriching for patients who have the genetic translocation t(4;14)....K36 expects to enroll approximately 50 patients in the Phase 1 study, including an expansion cohort that will recruit patients with the genetic translocation t(4;14)."

IND • New P1 trial • Hematological Malignancies • Multiple Myeloma • Oncology