zilurgisertib (INCB00928) / Incyte - LARVOL DELTA

To Assess the Efficacy, Safety, and Tolerability of INCB000928 in Participants With Fibrodysplasia Ossificans Progressiva (clinicaltrials.gov) - P2 | N=98 | Recruiting | Sponsor: Incyte Corporation | N=60 ➔ 98 | Trial completion date: Apr 2028 ➔ Dec 2032

Enrollment change • Trial completion date

Emerging Pathogenetic Mechanisms and New Drugs for Anemia in Myelofibrosis and Myelodysplastic Syndromes. (PubMed, Am J Hematol) - "These include TGF-β ligand traps (luspatercept, elritercept), activin A receptor type 1 (ACVR1)/activin receptor-like kinase 2 (ALK2) inhibitors (momelotinib, zilurgisertib), and anti-hemojuvelin antibody-based therapies (DISC-0974). Luspatercept and momelotinib are approved for anemia related to lower-risk MDS and MF, respectively, and represent an important addition to the treatment armamentarium, along with imetelstat, a telomerase inhibitor, recently ratified for anemia in lower-risk MDS. A promising strategy to overcome the limitations of existing anemia-directed therapies includes the use of drug combinations with complementary mechanisms (luspatercept + erythropoiesis stimulating agents, luspatercept + momelotinib, DISC-0974 + momelotinib), and harnessing the erythropoietic potential of sodium-glucose co-transporter-2 inhibitors (SGLT-2I). Future research should address the complex pathophysiology of anemia, standardize definitions for anemia with gender-specified..."

Journal • Review • Anemia • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Myelofibrosis • Oncology • ACVR1 • SMAD2 • SMAD4 • TGFB1

LIMBER: INCB000928 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Anemia Due to Myeloproliferative Disorders (clinicaltrials.gov) - P1/2 | N=84 | Active, not recruiting | Sponsor: Incyte Corporation | Recruiting ➔ Active, not recruiting | N=206 ➔ 84

Enrollment change • Enrollment closed • Monotherapy • Anemia • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Thrombocytosis

Pharmacokinetics of Zilurgisertib With and Without Food from Single and Multiple Ascending Dose Phase 1 Studies in Healthy Adults. (PubMed, Eur J Drug Metab Pharmacokinet) - "Zilurgisertib exhibited a favorable pharmacokinetic profile amenable to once-daily dosing that can be administered without regard to food. Study results support further clinical development of zilurgisertib in patients."

Journal • P1 data • PK/PD data • Hematological Disorders • ACVR1

MODULE 4: Future Directions in the Management of MF (ASH 2024) - "This program is supported by educational grants from CTI BioPharma, a Sobi Company, Geron Corporation, GSK, Incyte Corporation and Karyopharm Therapeutics.Mechanism of antitumor activity of navitoclax and biological rationale for its evaluation for MF Available efficacy and safety findings from the Phase III TRANSFORM-1 study of navitoclax in combination with ruxolitinib versus ruxolitinib alone for patients with previously untreated MF Potential role of navitoclax in the up-front setting and ongoing evaluation for relapsed/refractory (R/R) disease in the Phase III TRANSFORM-2 study Rationale for the evaluation of BET inhibitors for MF; updated findings from the Phase III MANIFEST-2 study combining pelabresib to ruxolitinib for JAK inhibitor-naïve disease Scientific justification for the evaluation of selinexor for MF; early efficacy and safety findings with selinexor as monotherapy and in combination with ruxolitinib Ongoing evaluation of the combination of..."

Oncology

INCB 00928-105: To Assess the Safety and Tolerability of INCB000928 in Participants With Myelodysplastic Syndromes or Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=22 | Completed | Sponsor: Incyte Corporation | Active, not recruiting ➔ Completed

Trial completion • Anemia • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Myelodysplastic Syndrome • Oncology

ALK2 AND JAK2 INHIBITION FOR IMPROVED TREATMENT OF ANEMIA IN MYELOFIBROSIS PATIENTS: PRECLINICAL PROFILE OF AN ALK2 INHIBITOR ZILURGISERTIB IN COMBINATION WITH RUXOLITINIB (EHA 2024) - P1/2 | "Zilurgisertib is a potent and selective ALK2 inhibitor that can reduce hepcidin levels and improve anemia. Zilurgisertib directly inhibits ALK2 activity, reducing phosphorylation of the direct target SMAD1, and levels ofthe SMAD target gene hepcidin. These data suggest JAK2 inhibition does not inhibit erythropoiesis restoredfollowing ALK2 inhibition."

Combination therapy • Preclinical • Anemia • Hematological Disorders • Hematological Malignancies • Lymphoma • Multiple Myeloma • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • ACVR1 • ALK1

THE ACTIVIN RECEPTOR-LIKE KINASE-2 INHIBITOR ZILURGISERTIB (INCB000928) AS MONOTHERAPY OR WITH RUXOLITINIB IN PATIENTS WITH ANEMIA DUE TO MYELOFIBROSIS: PHASE 1/2 STUDY RESULTS (EHA 2024) - P1/2 | "Zilurgisertib as monotherapy or in combination with RUX had a favorable tolerance profile, with predominantlygrade 1/2 TEAEs and only 1 DLT. Greater hepcidin control over time was observed at higher zilurgisertib dosesin both treatment groups. Preliminary improvements in anemia were observed in non–transfusion-dependentpts during dose escalation, suggesting potential for therapeutic activity."

Clinical • Monotherapy • P1/2 data • Anemia • Hematological Disorders • Myelofibrosis • Oncology • ACVR1

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 • Diffuse Large B Cell Lymphoma • Myelofibrosis • Polycythemia Vera

Incyte Reports 2024 First Quarter Financial Results and Provides Updates on Key Clinical Programs (Businesswire) - "Jakafi (ruxolitinib) net product revenues of $572 million in Q1'24, total paid patients increased +5% Y/Y; reiterating full year 2024 guidance of $2,690 - $2,750 million....Phase 3 study for BETi is anticipated to initiate in the second half of 2024 and clinical proof-of-concept for zilurgisertib is anticipated by mid-2024."

New P3 trial • Sales • Hematological Malignancies • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera

LIMBER: INCB000928 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Anemia Due to Myeloproliferative Disorders (clinicaltrials.gov) - P1/2 | N=206 | Recruiting | Sponsor: Incyte Corporation | N=100 ➔ 206 | Trial completion date: Apr 2024 ➔ Jun 2026 | Trial primary completion date: Apr 2024 ➔ Nov 2025

Combination therapy • Enrollment change • Monotherapy • Trial completion date • Trial primary completion date • Anemia • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Thrombocytosis

To Assess the Efficacy, Safety, and Tolerability of INCB000928 in Participants With Fibrodysplasia Ossificans Progressiva (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Incyte Corporation | Trial completion date: Dec 2024 ➔ Apr 2028 | Trial primary completion date: Dec 2023 ➔ Apr 2025

Trial completion date • Trial primary completion date

ACVR1: A Novel Therapeutic Target to Treat Anemia in Myelofibrosis. (PubMed, Cancers (Basel)) - "Among the approved JAK inhibitors (ruxolitinib, fedratinib, momelotinib, and pacritinib) for MF, momelotinib and pacritinib are preferably used in cytopenic patients; both agents are potent ACVR1 inhibitors that suppress hepcidin expression via the BMP6/ACVR1/SMAD pathway and restore iron homeostasis/erythropoiesis...Zilurgisertib (ACVR1 inhibitor) and DISC-0974 (anti-hemojuvelin monoclonal antibody) are evaluated in early phase clinical trials in patients with MF and anemia. Luspatercept (ACVR2B ligand trap) is assessed in transfusion-dependent MF patients in a registrational phase 3 trial. Approved ACVR1 inhibitors and novel agents in development are poised to improve the outcomes of anemic MF patients."

Journal • Review • Anemia • Hematological Disorders • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • ACVR1 • ACVR2B • BMP6

INCB 00928-105: To Assess the Safety and Tolerability of INCB000928 in Participants With Myelodysplastic Syndromes or Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=22 | Active, not recruiting | Sponsor: Incyte Corporation | Recruiting ➔ Active, not recruiting | N=80 ➔ 22

Enrollment change • Enrollment closed • Monotherapy • Anemia • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Myelodysplastic Syndrome • Oncology

Phase 1/2 Study of the Activin Receptor-like Kinase-2 Inhibitor Zilurgisertib (INCB000928, LIMBER-104) As Monotherapy or with Ruxolitinib in Patients with Anemia Due to Myelofibrosis (ASH 2023) - P1/2 | "Treatment with zilurgisertib monotherapy or in combination with RUX in this pt population was generally well tolerated, with predominantly grade 1/2 TEAEs. Reduced hepcidin levels were observed at all dose levels with both monotherapy and in combination with RUX, with greater control of hepcidin over time observed at higher zilurgisertib doses. Preliminary improvements in anemia were observed in non–transfusion-dependent pts during dose escalation, suggesting potential for therapeutic activity."

Clinical • Monotherapy • P1/2 data • Anemia • Hematological Disorders • Myelofibrosis • Oncology • Thrombocytopenia • ACVR1

ALK2 and JAK2 Inhibition for Improved Treatment of Anemia in Myelofibrosis Patients: Preclinical Profile of an ALK2 Inhibitor Zilurgisertib in Combination with Ruxolitinib (ASH 2023) - P1/2 | "Taken together, the potent and selective on-target activity of zilurgisertib suggests that ALK2 inhibition could reduce hepcidin and improve anemia, and that the combination of zilurgisertib with ruxolitinib is a rational and attractive approach to mitigate anemia in patients with MF. The combination of ruxolitinib and zilurgisertib is currently being evaluated in a phase 1 clinical trial in patients with anemia due to myeloproliferative disorders (NCT04455841)."

Combination therapy • Preclinical • Anemia • Hematological Disorders • Hematological Malignancies • Lymphoma • Multiple Myeloma • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • ACVR1 • ALK1

Incyte Reports 2023 Third Quarter Financial Results and Provides Updates on Key Clinical Programs (Businesswire) - "Jakafi - Net product revenues for the quarter of $636 million: Net product revenues grew 3% compared with the third quarter of 2022. Channel inventory at the end of the third quarter of 2023 decreased by approximately $14 million versus the second quarter of 2023. Underlying demand in the third quarter of 2023 continued to grow both year-over-year and quarter-over-quarter....Combination trials of ruxolitinib twice daily (BID) with zilurgisertib (ALK2) and INCB57643 (BET) are ongoing and continue to enroll. Additional data from these studies are anticipated to be shared in the fourth quarter of 2023."

Clinical data • Sales • Trial status • Hematological Malignancies • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera

IDH1 R132H Mutation-specific Immunohistochemistry Reveals a Clonal Neutrophil- and Histiocyte-rich Panniculitic Infiltrate in a Patient with Primary Myelofibrosis (ASDP 2023) - "To our knowledge, panniculitis has not been reported as a cutaneous adverse event in association with luspatercept or INCB000928. Ultimately, these lesions were interpreted to represent primary involvement by his myeloid neoplasm. This case highlights the utility of IDH1 R132H immunohistochemistry to quickly confirm cutaneous involvement by myeloid neoplasia harboring this specific mutation."

Clinical • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Myelofibrosis • Oncology • CD34 • IDH1 • ITGB3 • KIT • SRSF2

Phase I/II Study of the Activin Receptor‑Like Kinase 2 (ALK2) Inhibitor Zilurgisertib (INCB000928, LIMBER‑104) as Monotherapy or With Ruxolitinib in Patients With Anemia Due to Myelofibrosis (SOHO 2023) - P1/2 | "Zilurgisertib monotherapy or with ruxolitinib was generally well tolerated, with predominantly grade 1/2 TEAEs and no DLTs. Hepcidin levels were reduced with zilurgisertib monotherapy and combination; preliminary improvements in anemia suggest potential for therapeutic activity."

Clinical • Monotherapy • P1/2 data • Myelofibrosis • Oncology • ACVR1

Addressing Anemia in Myelofibrosis (SOHO 2023) - "Two JAK inhibitors, momelotinib and pacritinib, have been demonstrated to inhibit ACVR1 in conjunction with providing anemia benefit in MF patients. Additional agents selectively targeting ACVR1/ ALK2 (e.g., INCB000928) are currently under investigation in MF. Preclinical and clinical data with these agents, as well as other modalities to address anemia in MF, will be covered in this presentation."

Myelofibrosis • Oncology • ACVR1

MODULE 3: Future Directions in the Management of MF (SOHO 2023) - "This activity is supported through independent medical education grants from Bristol Myers Squibb, CTI Biopharma Corp, and GlaxoSmithKline. Mechanism of antitumor activity of navitoclax and biological rationale for its evaluation in patients with MF, Published research with navitoclax alone and in combination with ruxolitinib for MF; ongoing Phase III studies, Rationale for the inhibition of BET proteins in patients with MF; mechanisms of action of pelabresib and BMS-986158, Early clinical trial findings and ongoing research with BET inhibitors as monotherapy and in combination with JAK2 inhibitors for MF, Mechanism of action of, available data with and ongoing evaluation of luspatercept as monotherapy or combined with a JAK2 inhibitor for patients with MF and anemia; current role, if any, Published activity and safety data with and ongoing investigation of other novel agents and strategies (eg, bomedemstat, zilurgisertib, selinexor, navtemadlin) in MF,"

Oncology

PHASE 1/2 STUDY OF THE ACTIVIN RECEPTOR-LIKE KINASE 2 (ALK2) INHIBITOR ZILURGISERTIB (INCB000928, LIMBER-104) AS MONOTHERAPY OR WITH RUXOLITINIB IN PATIENTS WITH ANEMIA DUE TO MYELOFIBROSIS (EHA 2023) - P1/2 | "Treatment with zilurgisertib monotherapy or in combination with RUX in this patient population was generally well tolerated, with predominantly grade 1/2 TEAEs and no DLTs. Reduced hepcidin levels were observed with both monotherapy and in combination with RUX, and preliminary improvements in anemia were observed, which suggest potential for therapeutic activity. Anemia, Hepcidin, Myelofibrosis, Myeloproliferative disorder"

Clinical • Monotherapy • P1/2 data • Anemia • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Thrombocytopenia • ACVR1

Zilurgisertib With or Without Ruxolitinib Shows Early Tolerability, Activity in Anemic Myelofibrosis (OncLive) - P1/2 | N=100 | NCT04455841 | Sponsor: Incyte Corporation | "Administration of the selective ALK-2 inhibitor zilurgisertib alone or in combination with ruxolitinib (Jakafi) was safe, well tolerated, and showed preliminary signals of clinical activity in patients with primary or secondary myelofibrosis and disease-related anemia, according to data from the ongoing phase 1/2 INCB 00928-104 study (NCT04455841)....Analysis of zilurgisertib’s PK profile at steady state showed that the agent reached its time of peak plasma concentration 2 to 4 hours after administration across dose groups. The agent also was predicted to have a mean half-life ranging from 24 to 27 hours across the dose groups....Further safety analysis showed that 11 patients across both groups experienced treatment-emergent adverse effects (TEAEs) that were grade 3 or higher."

P1/2 data • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

Phase 1/2 study of the activin receptor-like kinase (ALK)-2 inhibitor zilurgisertib (INCB000928, LIMBER-104) as monotherapy or with ruxolitinib (RUX) in patients (pts) with anemia due to myelofibrosis (MF). (ASCO 2023) - P1/2 | "Treatment with zilurgisertib monotherapy or in combination with RUX in this patient population was generally well tolerated, with predominantly grade 1/2 TEAEs and no DLTs. Reduced hepcidin levels were observed with both monotherapy and in combination with RUX, and preliminary improvements in anemia were observed, which suggest potential for therapeutic activity. Clinical trial information: NCT04455841."

Clinical • Monotherapy • P1/2 data • Anemia • Hematological Disorders • Myelofibrosis • Thrombocytopenia • ACVR1

Data from Across Incyte’s Oncology Portfolio Accepted for Presentation at the 2023 ASCO Annual Meeting and EHA2023 Hybrid Congress (Businesswire) - "Incyte...today announced that multiple abstracts featuring data from across its oncology portfolio will be presented at the upcoming 2023 American Society of Clinical Oncology (ASCO) Annual Meeting held June 2-6 in Chicago, and at the European Hematology Association 2023 (EHA2023) Hybrid Congress held in Frankfurt, Germany, from June 8-11 and virtually from June 14-15."

Clinical data • P1 data • P1/2 data • P3 data • Chronic Graft versus Host Disease • Diffuse Large B Cell Lymphoma • Graft versus Host Disease • Hematological Malignancies • Myelofibrosis • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor