zilurgisertib (INCB00928) / Incyte, Mirum Pharmaceuticals - LARVOL DELTA

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

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

Mirum Pharmaceuticals and Incyte Announce Positive Pivotal Phase 2 Results from PROGRESS Study of Zilurgisertib in Fibrodysplasia Ossificans Progressiva (Businesswire) - "Results from Cohort 1 of the PROGRESS study demonstrated a consistent treatment effect across measures of disease activity and durability through Week 48....During the open-label extension, no new HO lesions were observed among patients who continued to receive zilurgisertib or among placebo-treated patients who crossed over to active treatment at Week 24....Fewer patients receiving zilurgisertib developed new HO lesions at Week 24, with an 81% reduction versus placebo....99.9% reduction in total volume of new HO lesions in patients receiving zilurgisertib versus placebo at Week 24....The U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for zilurgisertib for the treatment of FOP in patients 12 years of age and older and granted Priority Review....The Prescription Drug User Fee Act (PDUFA) target action date for zilurgisertib is September 26, 2026."

FDA filing • P2 data • PDUFA • Priority review • Genetic Disorders • Musculoskeletal Diseases

Zilurgisertib in Patients With Fibrodysplasia Ossificans Progressiva: Interim Results From the PROGRESS Study (ENDO 2026) - P2 | "ZGB demonstrated fewer new HO lesions, reduced volume of total HO lesions, and fewer flares vs placebo. Improvements were maintained or further improved in the open-label extension. Treatment was generally well tolerated."

Clinical • Infectious Disease • Musculoskeletal Pain • Respiratory Diseases • ACVR1

Zilurgisertib in Patients With Fibrodysplasia Ossificans Progressiva: Interim Results From the PROGRESS Study (ENDO 2026) - P2 | "ZGB demonstrated fewer new HO lesions, reduced volume of total HO lesions, and fewer flares vs placebo. Improvements were maintained or further improved in the open-label extension. Treatment was generally well tolerated."

Clinical • Late-breaking abstract • Infectious Disease • Musculoskeletal Pain • Respiratory Diseases • ACVR1

U.S. FDA accepted the New Drug Application (NDA) for zilurgisertib in FOP patients 12 years and older and granted Priority Review with a Prescription Drug User Fee Act (PDUFA) date of September 26, 2026 (Businesswire) - "Entered into an exclusive license agreement with Incyte for worldwide rights to zilurgisertib, an ALK2 inhibitor in development for fibrodysplasia ossificans progressiva (FOP)."

Licensing / partnership • PDUFA • Priority review • Genetic Disorders

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 final results (ASH 2025) - P1/2 | "Zilurgisertib monotherapy or in combination with ruxolitinib had a favorable tolerabilityprofile, with few DLTs and no apparent correlation between dose and TEAE frequency. However, despiteevidence of on-target hepcidin suppression, zilurgisertib provided minimal improvements for anemia.These findings highlight the multifactorial nature of anemia in MF and suggest that selective inhibition ofALK2/ACVR1 may not be sufficient to effectively ameliorate MF-related anemia."

Clinical • Monotherapy • P1/2 data • Anemia • Infectious Disease • Myelofibrosis • Septic Shock • 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..."

Myelofibrosis • Oncology

Effects of Renal and Hepatic Impairment on the Pharmacokinetics of Zilurgisertib. (PubMed, Br J Clin Pharmacol) - P2 | "Zilurgisertib exposure was unchanged with mild renal or moderate hepatic impairment, but increased by 30%-70% with moderate or more severe renal impairment and by 25% with severe hepatic impairment. These findings, alongside the therapeutic index, to be defined by the ongoing pivotal FOP trial (NCT05090891), will guide dosing in these populations."

Journal • PK/PD data • Chronic Kidney Disease • Hepatology • Nephrology • Renal Disease • ACVR1

To Assess the Efficacy, Safety, and Tolerability of INCB000928 in Participants With Fibrodysplasia Ossificans Progressiva (clinicaltrials.gov) - P2 | N=98 | Recruiting | Sponsor: Incyte Corporation | Trial primary completion date: Feb 2025 ➔ Jul 2027

Trial primary completion date

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

Discovery and Characterization of Zilurgisertib, a Potent and Selective Inhibitor of Activin Receptor-like Kinase‑2 (ALK2) for the Treatment of Fibrodysplasia Ossificans Progressiva. (PubMed, ACS Med Chem Lett) - "Zilurgisertib fully suppresses HO in a pediatric mouse model of injury-induced FOP and therefore holds great potential as a novel targeted disease-modifying therapy for FOP. The candidate is being evaluated in clinical trials."

Journal • Pediatrics • 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

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

Evaluation of clinical cardiac safety of zilurgisertib, an activin receptor-like kinase-2 (ALK2) inhibitor, in healthy participants. (PubMed, Clin Pharmacol Drug Dev) - "No clinically meaningful effects on cardiac conduction (PR and QRS intervals) or any categorical PR or QRS outliers were observed. These data support further clinical development of zilurgisertib."

Journal • ACVR1

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 | Terminated | Sponsor: Incyte Corporation | Completed ➔ Terminated; Strategic Business Decision

Monotherapy • Trial termination • Anemia • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Myelodysplastic Syndrome • Oncology

To Assess the Efficacy, Safety, and Tolerability of INCB000928 in Participants With Fibrodysplasia Ossificans Progressiva (clinicaltrials.gov) - P2 | N=98 | Recruiting | Sponsor: Incyte Corporation | Trial primary completion date: Jul 2025 ➔ Feb 2025

Trial primary completion date

INCB 00928-104: 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 | Trial completion date: Oct 2025 ➔ Nov 2027

Monotherapy • Trial completion date • Anemia • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Thrombocytosis

Effect of Itraconazole or Rifampin on Zilurgisertib Pharmacokinetics When Administered Orally in Healthy Participants. (PubMed, Clin Pharmacol Drug Dev) - "No dose-limiting toxicities occurred in either cohort, and all treatment-emergent adverse events were Grade 1 in severity. Zilurgisertib dose adjustment may be necessary with concomitant administration of strong CYP3A4 inhibitors, and coadministration of zilurgisertib with strong CYP3A4 inducers is not recommended."

Journal • PK/PD data • ACVR1

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 | Trial completion date: Jun 2026 ➔ Oct 2025 | Trial primary completion date: Nov 2025 ➔ Apr 2025

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=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

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