The current, and only approved, standard therapy for the treatment of myelofibrosis, a myeloproliferative neoplasm, characterized by splenomegaly constitutional symptoms, bone marrow fibrosis, and a propensity towards transformation to acute leukemia, include Janus kinase (JAK-) inhibitors. These agents have been successful in reducing spleen and symptom burden.
However, JAK inhibitors do not significantly impact disease progression, In addition, many patients are ineligible due to coexisting cytopenias. Furthermore, patients who are refractory to JAK inhibition also have a poor survival. Therefore, non-JAK inhibitor-based therapies are being explored in pre-clinical and clinical settings.
New data from two of its LIMBER (Leadership In MPNs and GVHD BEyond Ruxolitinib) trials evaluating monotherapy and combination strategies using ruxolitinib (Jakafi®; Incyte) with parsaclisib (INCB050465), an investigational phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, and zilurgisertib (INCB00928), its activin receptor-like kinase (ALK2) inhibitor, in patients with myelofibrosis (MF).
These Phase 2 and Phase 1/2 trials (Abstract #236 and Abstract #1714, respectively) were presented at the 64th American Society of Hematology (ASH) Annual Meeting, held December 10-13, 2022, in New Orleans and virtually. 
“Despite the significant advances we have made in the treatment of myeloproliferative neoplasms (MPNs) like MF, a need for additional options remains for those who have an inadequate response to or are unable to tolerate current therapies,” said Peter Langmuir, M.D., Vice President, Oncology Drug Development, Incyte.
“The parsaclisib and ruxolitinib data presented at ASH demonstrate the clinical potential of the combination to improve upon the standard of care and continue to support the safety profile. We look forward to building on these results through our Phase 3 LIMBER-304 and LIMBER-313 trials evaluating parsaclisib as an add-on to ruxolitinib and in the frontline setting, both of which are currently underway,” Langmuir added.
Parsaclisib + ruxolitinib
Final results from the Phase 2 trial (Abstract #236; NCT02718300) evaluating the efficacy and safety of add-on parsaclisib to ruxolitinib for patients with MF who had a suboptimal response to ruxolitinib resulted in additional spleen volume reduction and improvement in symptom burden with add-on parsaclisib. Patients in the trial received parsaclisib daily for eight weeks in combination with stable dose ruxolitinib and then daily or weekly thereafter. Patients who received an all daily parsaclisib dosing schedule appeared to have a more durable efficacy profile compared with daily followed by weekly dosing of parsaclisib. Specifically:
- At 12 weeks of treatment, 59.5% (25), 21.4% (9) and 4.8% (2) of patients who received all daily dosing experienced ≥10%, ≥25% and ≥35% reduction in spleen volume, respectively.
- Comparatively, 28.1% (9), 3.1% (1) and 0% of patients who received daily followed by weekly dosing experienced ≥10%, ≥25% and ≥35% reduction in spleen volume, respectively.
- At 24 weeks of treatment the reduction was maintained, with 50% (21), 28.6% (12) and 7.1% (3) patients who received all daily dosing experiencing ≥10%, ≥25% and ≥35% reduction in spleen volume, respectively.
- Comparatively, 12.5% (4), 12.5% (4) and 3.1% (1) of patients who received daily followed by weekly dosing experienced ≥10%, ≥25% and ≥35% reduction in spleen volume, respectively.
- Addition of parsaclisib to ruxolitinib was generally well-tolerated, with limited grade 3 or 4 adverse events and treatment-emergent adverse event (TEAE)-related discontinuations. TEAEs common to PI3Kδ inhibitors in lymphoma (e.g., hepatotoxicity, rash, colitis) were infrequent or absent with the addition of parsaclisib.
- Serious TEAEs occurring in ≥2 patients overall included pneumonia (n=6; 2 daily/weekly, 1 all daily), fall (n=3; 2 daily/weekly, 1 all daily) and pyrexia (n=2; 1 daily/weekly, 1 all daily).
- Overall, 9 patients (5 daily/weekly, 4 all daily) had a TEAE leading to parsaclisib discontinuation, and 4 patients (2 daily/weekly, 2 all daily) had a TEAE leading to ruxolitinib discontinuation.
“MF is a rare, chronic blood cancer, and despite the advancements made in treatment, additional options are needed,” said Abdulraheem Yacoub, MD, Associate Professor, Hematologic Malignancies and Cellular Therapeutics, University of Kansas Cancer Center.
“I am encouraged by these findings and the potential of parsaclisib and ruxolitinib to be an efficacious combination therapy to help improve outcomes for certain patients living with MF,” Yacoub further noted.
Additionally, data from a Phase 1/2 open-label, dose escalation and expansion study (Abstract #1714; NCT04455841) assessing the safety and tolerability of zilurgisertib (INCB00928), a potent and selective ALK2 inhibitor, as monotherapy or in combination with ruxolitinib in patients with anemia due to MF were presented at annual ASH meeting.
Anemia occurs in more than one-third of patients at MF diagnosis and can be exacerbated during treatment. 
Initial results of the study observed reduction in post-dose hepcidin levels at all dose levels and observed improvements in anemia among patients treated in both the monotherapy and combination cohorts, which suggest the potential for therapeutic activity. The data also support once-daily dosing of INCB00928 and continued dose escalation to achieve optimal exposure.
Treatment with INCB00928 monotherapy and in combination with ruxolitinib resulted in predominantly grade 1/2 TEAEs and no dose-limiting toxicities (DLTs). Few grade ≥3 TEAEs were observed, including thrombocytopenia in two patients with baseline grade 2 thrombocytopenia, and neutropenia in one patient with baseline grade 2 neutropenia. No TEAEs led to study drug discontinuation.
A Study of INCB050465 in Combination With Ruxolitinib in Subjects With Myelofibrosis – NCT02718300
INCB000928 Administered as a Monotherapy or in Combination With Ruxolitinib in Participants With Anemia Due to Myeloproliferative Disorders – NCT04455841
Highlights of Prescribing Information
Ruxolitinib (Jakafi®; Incyte) [Prescribing Information]
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 Yacoub A, Borate U, Rampal RK, Ali H, Wang E, Gerd AT, Hobbs GS, et al. Efficacy and Safety of Add-on Parsaclisib to Ruxolitinib Therapy in Myelofibrosis Patients With Suboptimal Response to Ruxolitinib: Final Results From a Phase 2 Study. Abstract 236. Presented at the 64th ASH Annual Meeting, December 10-13, 2022.
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Featured image: The American Society of Hematology 64th Annual Meeting at the Georgia World Congress Center. Photo courtesy: © 2022 ASH/Zach Boyden-Holmes. Used with permission.