INCB160058 / Incyte - LARVOL DELTA

INCB160058 selectively targets JAK2V617F-driven hematopoiesis in diverse and drug-resistant models of myeloproliferative neoplasms (ASH 2025) - P1 | "Furthermore, currently approved JAK2inhibitors for MPNs induce paradoxical hyperphosphorylation of the JAK2 activation loop (Y1007/1008)associated with withdrawal syndrome; in contrast, INCB160058 reduced activation loop phosphorylation,consistent with its binding to the JH2 domain of JAK2V617F. These findings support the potential ofINCB160058 to overcome ruxolitinib resistance and mitigate withdrawal-related signaling effects inclinical settings.In conclusion, our findings demonstrate that INCB160058 selectively targets JAK2V617F-mediatedpathways and inhibits constitutive differentiation of CD34+ cells driven by the mutation, while preservingcytokine-dependent signaling for normal hematopoietic differentiation across numerous clinicallyrelevant in vitro and ex vivo MPN models."

Essential Thrombocythemia • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Polycythemia Vera • Thrombocytosis • ASXL1 • CD34 • CXCL8 • PIM1 • STAT5

A multicenter, open-label phase 1 study of INCB160058, a first-in-class JAK2V617F mutant–selective inhibitor, in patients with myelofibrosis, polycythemia vera, or essential thrombocythemia (ASH 2025) - P1 | "Preclinically, INCB160058inhibited aberrant signaling and proliferation in JAK2V617F+ cells with minimal impact on signaling andgrowth of wild-type counterparts, offering the potential to eradicate malignant clones while minimizingtreatment-associated adverse events related to broader wild-type JAK inhibition.Study Design and The INCB160058-101 phase 1, multicenter, global, open-label, dose-escalation/expansion study will investigate the safety, tolerability, pharmacokinetics (PK),pharmacodynamics, and preliminary clinical efficacy of INCB160058 in pts with JAK2V617F-positive MF,PV, or ET (NCT06313593).The study is open and enrolling adults with MF, PV, or ET for treatment with INCB160058 monotherapy; itwill enroll pts with MF for treatment with INCB160058 as an add-on to ruxolitinib after suboptimalresponse to ruxolitinib (MF SubOpt R). Change in JAK2V617F variant allelefrequency is an exploratory endpoint. This study will explore the potential of this novel..."

Clinical • P1 data • Bone Marrow Transplantation • Essential Thrombocythemia • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Polycythemia Vera • Thrombocytosis • Thrombosis

Ernest Beutler Lecture and Prize (ASH 2025) - "The ensuing years have also shown benefit of ruxolitinib on survival for MF. Subsequently, three additional JAK inhibitors — each with their own incremental benefits — have been approved (fedratinib in 2019, pacritinib in 2022, and momelotinib in 2023). A new generation of more mutant selective JAK2 inhibitors (INCB160058, AJ1-11095) is currently in early clinical trials...Radek C. Skoda will describe how the JAK2-V617F mutation drives hematopoiesis causing MPNs and recent advances in understanding of how this mutation activates the JAK2 kinase, opening new ways to find candidate drugs preferentially targeting the mutated JAK2 protein.Dr. Ruben Mesa will summarize how the single-agent JAK inhibitors significantly helped decrease the burden of MPNs and the role of current agents, the next generation of new inhibitors, and combination approaches, as well as the impact JAK inhibitors have had on non-neoplastic inflammatory disorders."

Atopic Dermatitis • Chronic Graft versus Host Disease • Dermatitis • Dermatology • Essential Thrombocythemia • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Polycythemia Vera • Thrombocytosis • Vitiligo • CALR • TET2

Details on Incyte data presentations at ASH include: Poster Presentations (Incyte Press Release)

Clinical data • Acute Graft versus Host Disease • Anemia • Chronic Graft versus Host Disease • Essential Thrombocythemia • Follicular Lymphoma • Myelofibrosis • Myeloproliferative Neoplasm • Polycythemia Vera

Preclinical Evaluation of INCB160058 – a Novel and Potentially Disease-Modifying Therapy for JAK2V617F Mutant Myeloproliferative Neoplasms (ASH 2023) - "Approved therapies for MPNs such as ruxolitinib, which act by directly inhibiting activity of the kinase domain (JH1) of JAK2, have demonstrated impressive clinical efficacy and safety in patients with MPNs; however, they do not address JAK2V617F allelic burden or achieve molecular remission of disease. Extended treatment with INCB160058 at low therapeutic doses results in the specific elimination of mutant JAK2V617F-harboring cells in mouse models and human cancer cells with minimal impact on WT counterparts. Clinical testing of INCB160058 may allow patients with MPNs to achieve molecular remission by eliminating cells with the main genetic aberration and afford an opportunity to overcome the disease."

Preclinical • Essential Thrombocythemia • Hematological Disorders • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Thrombocytosis • CD34 • CXCL8 • IL6 • PTPRC • STAT5

INCB160058-101: A Study to Evaluate the Safety, Tolerability of INCB160058 in Participants With Myeloproliferative Neoplasms (clinicaltrials.gov) - P1 | N=186 | Recruiting | Sponsor: Incyte Corporation | Trial completion date: Mar 2028 ➔ Oct 2028 | Trial primary completion date: Mar 2027 ➔ Oct 2028

Trial completion date • Trial primary completion date • Essential Thrombocythemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of INCB160058 When Administered Orally to Healthy Adult Participant (clinicaltrials.gov) - P1 | N=137 | Completed | Sponsor: Incyte Corporation | Recruiting ➔ Completed

Trial completion

Is Combination Therapy Here for MPN? (SOHO 2025) - "2 Outside of the potential benefit of type 2 (AJ1-11095) and JAK2 V617F-selective (INCB160058) inhibitors under phase 1 evaluation, the research community has focused efforts on developing rational JAK inhibitor-based combination therapy regimens...3 Data from prospective and retrospective studies suggest a correlation between spleen reduction and OS with ruxolitinib and pacritinib...Nevertheless, the combination of pelabresib and ruxolitinib was well tolerated, and biomarkers of disease modification — including reduction in bone marrow fibrosis, driver mutation allele frequency, and inflammatory cytokine expression levels — all favored the combination, supporting the proposed mechanism of action and published preclinical synergy...11 The phase 3 trial will aim to confirm this activity in patients who have received at least 18 weeks of ruxolitinib therapy and meet rigorously defined criteria for suboptimal response, after which these patients will be randomized to..."

Combination therapy • IO biomarker • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • CD34 • XPO1

Incyte...Provides Updates on Key Clinical Programs (Businesswire) - "The Phase 1 data in patients with myelofibrosis (MF) as monotherapy and in combination with ruxolitinib are anticipated in the second half of 2025...A Phase 1 study evaluating JAK2V617Fi in MPNs is ongoing. Initial proof of concept data are anticipated in the first half of 2026...Incyte plans to initiate Phase 3 studies for its potentially first-in-class CDK2 inhibitor (INCB123667), in ovarian cancer in 2025 and is also evaluating INCB123667 in combination with other treatments; The Phase 3 study evaluating tafasitamab as first-line treatment for diffuse large B-cell lymphoma (DLBCL) is ongoing. The Phase 3 data are anticipated in the second half of 2025; The Phase 1 studies evaluating KRASG12D and TGFßR2×PD-1 in solid tumors are ongoing. Initial proof of concept data for both studies are anticipated in the second half of 2025."

Clinical data • New P3 trial • Diffuse Large B Cell Lymphoma • Myelofibrosis • Myeloproliferative Neoplasm • Ovarian Cancer • Solid Tumor

A MULTICENTER, OPEN-LABEL PHASE 1 STUDY OF INCB160058, A FIRST-IN-CLASS JAK2 V617F MUTANT-SPECIFIC INHIBITOR, IN PATIENTS WITH MYELOPROLIFERATIVE NEOPLASMS (MPN) (EHA 2025) - "The INCB160058-101 phase 1 study is exploring the potential of INCB160058, a first-in-class JAK2 V617F mutant-specific inhibitor, in pts with MF and should provide important insight into the safety and preliminary efficacy of this targeted approach. A planned protocol amendment will include pts with JAK2 V617F-positive ET and PV."

Clinical • P1 data • Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Thrombocytosis • JAK2

INCB160058-101: A Study to Evaluate the Safety, Tolerability of INCB160058 in Participants With Myeloproliferative Neoplasms (clinicaltrials.gov) - P1 | N=144 | Recruiting | Sponsor: Incyte Corporation | N=66 ➔ 144 | Trial completion date: Sep 2027 ➔ Mar 2028

Enrollment change • Trial completion date • Essential Thrombocythemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of INCB160058 When Administered Orally to Healthy Adult Participant (clinicaltrials.gov) - P1 | N=180 | Recruiting | Sponsor: Incyte Corporation | N=108 ➔ 180

Enrollment change

Incyte Reports 2024 Fourth Quarter and Year-End Financial Results, Provides 2025 Financial Guidance and Highlights 2025 R&D Milestones (Businesswire) - "Key Recent Company Updates: In December 2024, Incyte shared additional data from its BET inhibitor (INCB057643) in patients with relapsed or refractory myelofibrosis and other advanced myeloid neoplasms at the 2024 ASH Annual Meeting....Incyte plans to initiate a Phase 3 monotherapy study in the post Jakafi patient population in 2025. In December 2024, the supplemental Biologics License Application (sBLA) submission for retifanlimab (Zynyz) in advanced/metastatic squamous cell anal carcinoma was filed with the FDA with approval anticipated in the second half of 2025....The Phase 1 studies evaluating mutCALR in myelofibrosis (MF) and essential thrombocythemia (ET) and JAK2V617Fi in MF are ongoing and enrolling patients. Initial proof of concept data for both studies are anticipated in 2025."

FDA approval • FDA filing • New P3 trial • P1 data • Anal Carcinoma • Essential Thrombocythemia • Myelofibrosis • Squamous Cell Carcinoma

A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of INCB160058 When Administered Orally to Healthy Adult Participant (clinicaltrials.gov) - P1 | N=108 | Recruiting | Sponsor: Incyte Corporation | Trial completion date: Nov 2024 ➔ Sep 2025 | Trial primary completion date: Nov 2024 ➔ Sep 2025

Trial completion date • Trial primary completion date

Incyte Reports 2024 Third Quarter Financial Results and Provides Updates on Key Clinical Programs (Businesswire) - "Additional Pipeline Updates: A bioequivalence study of ruxolitinib extended-release (XR) is enrolling. The data are anticipated in the first half of 2025....Trials of ruxolitinib twice daily (BID) with BETi and zilurgisertib are ongoing. Additional data for BETi and zilurgisertib are anticipated in the fourth quarter of 2024. The Phase 1 studies evaluating mCALR and JAK2V617Fi are ongoing and enrolling patients. Initial data for both studies are anticipated in 2025."

Clinical data • P1 data • Myelofibrosis • Myeloproliferative Neoplasm

Incyte Reports 2024 Second Quarter Financial Results and Provides Updates on Key Clinical Programs (Businesswire) - "Jakafi: Net product revenues for the second quarter 2024 of $706 million (+3% Y/Y): Paid demand increased 9% in the second quarter of 2024 versus the same quarter in the prior year, with growth across all indications. Year over year net product revenue growth was lower than paid demand growth due to higher channel inventory levels at the end of the second quarter of 2023 versus the same period of 2024. Channel inventory at the end of the second quarter of 2024 was within the normal range....The Phase 1 studies evaluating mCALR and JAK2V617Fi are ongoing and enrolling patients. Initial data for both studies is anticipated in 2025."

P1 data • Sales • Graft versus Host Disease • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Polycythemia Vera

A Study to Evaluate the Safety, Tolerability of INCB160058 in Participants With Myeloproliferative Neoplasms (clinicaltrials.gov) - P1 | N=66 | Recruiting | Sponsor: Incyte Corporation | Not yet recruiting ➔ Recruiting

Enrollment open • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

PRECLINICAL EVALUATION OF INCB160058 - A NOVEL AND POTENTIALLY DISEASE-MODIFYING THERAPY FOR JAK2V617F MUTANT MYELOPROLIFERATIVE NEOPLASMS (EHA 2024) - "Our study demonstrates INCB160058 as a high-affinity JH2-binding inhibitor of JAK2V617F that blockscytokine-independent activity of JAK2V617F while preserving cytokine-dependent signaling. Extendedtreatment with INCB160058 results in the specific elimination of mutant JAK2V617F-harboring cells in mousemodels and human cancer cells, with minimal impact on WT counterparts. Clinical testing of INCB160058 mayallow patients with MPNs to achieve molecular remission and afford them an opportunity to overcome thedisease."

IO biomarker • Preclinical • Essential Thrombocythemia • Hematological Disorders • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Thrombocytosis • CD34 • CD38 • CXCL8 • IL6 • PTPRC • STAT5

Incyte to Highlight Data From its Oncology Portfolio at the 2024 ASCO Annual Meeting and EHA2024 Congress (Businesswire) - "Incyte...announced that several abstracts featuring data from its oncology portfolio will be presented at the upcoming 2024 American Society of Clinical Oncology (ASCO) Annual Meeting held May 31 - June 4 in Chicago, and at the European Hematology Association 2024 (EHA2024) Congress held on June 13-16 in Madrid, Spain, and virtually."

Clinical data • Myelofibrosis • Myeloproliferative Neoplasm • Solid Tumor

A Study to Evaluate the Safety, Tolerability of INCB160058 in Participants With Myeloproliferative Neoplasms (clinicaltrials.gov) - P1 | N=66 | Not yet recruiting | Sponsor: Incyte Corporation

New P1 trial • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of INCB160058 When Administered Orally to Healthy Adult Participant (clinicaltrials.gov) - P1 | N=84 | Recruiting | Sponsor: Incyte Corporation | Not yet recruiting ➔ Recruiting

Enrollment open

Incyte Reports 2023 Fourth Quarter and Year-End Financial Results, Provides 2024 Financial Guidance and Highlights R&D Priorities (Businesswire) - P1 | N=340 | NCT05238922 | Sponsor: Incyte Corporation | "JAK2V617Fi (INCB160058), a potent and selective JAK2 pseudokinase domain binder, cleared the Investigational New Drug (IND) process with the FDA and a Phase 1 study is anticipated to initiate in the first half of 2024. In January 2024, Incyte highlighted promising early clinical efficacy data for its selective small molecule inhibitor of CDK2 (INCB123667), which demonstrated its potential use as monotherapy or combination therapy for late-stage cancers. In a Phase 1 study of INCB123667, early clinical activity was observed with several partial responses (PR) achieved in patients with amplification/over expression of CCNE1, a cell cycle regulator and potential predictive biomarker. Tumor shrinkage was observed across multiple tumor types, including CCNE1+ patients with ovarian cancer. The safety profile of for INCB123667 aligns with the mechanism of action. Additional data is expected to be presented in 2024."

IND • New P1 trial • P1 data • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of INCB160058 When Administered Orally to Healthy Adult Participant (clinicaltrials.gov) - P1 | N=84 | Not yet recruiting | Sponsor: Incyte Corporation

New P1 trial

Incyte to Spotlight More Than 40 Hematology and Oncology Abstracts Including a Plenary Presentation at the ASH Annual Meeting (Businesswire) - "Incyte...today announced that more than 40 abstracts highlighting data from eight of its hematology and oncology products will be presented at the upcoming 65th American Society of Hematology Annual Meeting 2023 (ASH 2023), held December 9-12, 2023, in San Diego and virtually."

Clinical data • Preclinical • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Myeloproliferative Neoplasm • Non-Hodgkin’s Lymphoma • Oncology • Polycythemia Vera

Incyte Reports 2023 Third Quarter Financial Results and Provides Updates on Key Clinical Programs (Businesswire) - "The Phase 1 study evaluating INCA033989 (mCALR) is ongoing and enrolling patients. In October, we announced the development of a new program targeting the JAK2V617F mutation, which is present in 55-60% of myelofibrosis (MF) and essential thrombocythemia (ET) patients, and in 95% of polycythemia vera (PV) patients. INCB100658 is a small molecule inhibitor, targeting the JAK2V617F mutation and we expected to file the IND by year-end 2023."

IND • Trial status • Essential Thrombocythemia • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera