Vonjo (pacritinib) / SOBI - LARVOL DELTA

Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis. (PubMed, Blood Adv) - "Pacritinib inhibited ACVR1 with greater potency (IC50 = 16.7 nM; Cmax:IC50 = 12.7) than momelotinib (IC50 = 52.5 nM; Cmax:IC50 = 3.2), fedratinib (IC50 = 273 nM; Cmax:IC50 = 1.0), or ruxolitinib (IC50 >1000; Cmax:IC50 <0.01). Among patients on PERSIST-2 who were not TI at baseline based on Gale criteria, a significantly greater proportion became TI on pacritinib compared to best available therapy (37% vs. 7%, P=0.001), and significantly more had a ≥50% reduction in transfusion burden (49% vs. 9%, P<0.0001). These data indicate that the anemia benefit of the JAK2/IRAK1 inhibitor pacritinib may be a function of potent ACVR1 inhibition."

Journal • Anemia • Hematological Disorders • Myelofibrosis • ACVR1 • IRAK1

A phase 2 study of canakinumab in patient with myelofibrosis: Results from part 1 (ASH 2025) - "Introduction Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) for which the only approved therapies are JAKinhibitors which improve splenomegaly and disease-related symptoms. Given the encouraging impact onMF symptoms, blood counts and reassuring safety profile, the study was amended to enroll pts on astable dose of a JAK inhibitor (ruxolitinib, fedratinib, momelotinib, or pacritinib) who have the potential tobenefit from additional therapy. Part 2 is currently enrolling at multiple sites and updated clinical andcorrelative data will be presented at the meeting."

Clinical • P2 data • Cardiovascular • Fibrosis • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Thrombocytopenia • CRP • IL1B

PROSPERA: Pacritinib vs. Hydroxyurea in Advanced Proliferative Chronic Myelomonocytic Leukemia (clinicaltrials.gov) - P2 | N=66 | Recruiting | Sponsor: Theradex | Not yet recruiting ➔ Recruiting

Enrollment open • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

MDS: Pacritinib With Aza for Upfront Myelodysplastic Syndrome (clinicaltrials.gov) - P1/2 | N=25 | Not yet recruiting | Sponsor: Thomas Jefferson University

New P1/2 trial • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology

Prospera (ABNL-MARRO 002): A randomized phase 2 study of pacritinib vs. hydroxyurea in patients with advanced proliferative chronic myelomonocytic leukemia (CMML) (ASH 2025) - P2 | "In the phase 3 DACOTA trial (Itzykson et al., JCO 2022),decitabine modestly delayed leukemic transformation compared to HU but did not improve event-free oroverall survival and was associated with increased early mortality. The primary endpoint is CBR at Week 24, defined by modified IWG MDS/MPNcriteria incorporating hematologic improvement, spleen volume reduction, and symptom response.Secondary endpoints include CBR at any time, duration of response, event-free survival, leukemia-freesurvival, and overall survival.Correlative studies will assess treatment-related changes in clonal dynamics, cytokine signaling, andhematopoietic composition using longitudinal peripheral blood and bone marrow sampling. Single-celltranscriptomic and immunophenotypic profiling will be employed to characterize pacritinib's impact onboth the malignant clone and the surrounding immune microenvironment."

Clinical • Metastases • P2 data • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Thrombocytopenia • IRAK1

Pacritinib Response Is Associated With Overall Survival in Myelofibrosis: PERSIST-2 Landmark Analysis of Survival. (PubMed, Eur J Haematol) - P3 | "In patients with myelofibrosis and platelets ≤ 100 × 109/L, achieving SVR on pacritinib, but not BAT (including ruxolitinib), was associated with significant OS benefit, suggesting that pacritinib may offer a unique survival advantage in patients with myelofibrosis and thrombocytopenia who achieve any SVR. Trial Registration: ClinicalTrials.gov number: NCT02055781."

Journal • Hematological Disorders • Myelofibrosis • Thrombocytopenia • ACVR1 • IRAK1 • JAK2

Preliminary Data from the Phase I/II Study of TP-3654, a Selective Oral PIM1 Kinase Inhibitor, in Patients with Myelofibrosis Previously Treated with or Ineligible for JAK Inhibitor Therapy (ASH 2022) - P1/2 | "TP-3654 showed less hematopoietic inhibition than Janus kinase (JAK) inhibitors (ruxolitinib, pacritinib and momelotinib) in in vitro human megakaryocyte and erythrocyte cell colony formation. The preliminary clinical data in dose escalation show: 1) encouraging signs of clinical activity in spleen volume reduction, symptom improvement, and cytokine reduction with TP-3654 monotherapy in patients previously treated with JAK inhibitors, 2) TP-3654 is well tolerated with limited myelosuppressive adverse events. The non-clinical findings and preliminary clinical safety/efficacy data support accelerated development and assessment of TP-3654 as the optimal partner for combination with JAK inhibitors."

Clinical • P1/2 data • Hematological Disorders • Immunology • Myelofibrosis • CALR • IL18 • MMP9 • PIM1 • TIMP1

Post-FDA Approval Experience With Momelotinib in JAK Inhibitor-Naïve Myelofibrosis: Focus on Anemia Response and Treatment-Emergent Nephropathy and Peripheral Neuropathy. (PubMed, Am J Hematol) - "Real-world experience using momelotinib as first-line JAK2 inhibitor therapy in myelofibrosis. Anemia response was moderate (23%) while treatment-emergent adverse events included nephropathy (29%) and peripheral neuropathy (20%)."

FDA event • Journal • Anemia • Hematological Disorders • Myelofibrosis • Pain • Renal Disease

PACRIMYEL: Pacritinib For Bone Marrow Fibrosis In Patients With Myelofibrosis Who Have Thrombocytopenia (clinicaltrials.gov) - P2 | N=30 | Not yet recruiting | Sponsor: Grupo Español de Enfermedades Mieloproliferativas Crónicas PH Negativas

New P2 trial • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Thrombocytopenia

Pacritinib Is a Potent ACVR1 Inhibitor with Significant Anemia Benefit in Patients with Myelofibrosis (ASH 2022) - "The subgroup of BAT that received erythroid support (erythropoiesis stimulating agents, danazol, thalidomide or analogs, or corticosteroids) was also analyzed...The inhibitory activity of pacritinib, momelotinib, fedratinib, and ruxolitinib against ACVR1 was assessed using a HotSpot assay (Reaction Biology Corporation)... Baseline characteristics of patients who were not TI (SIMPLIFY criteria) were similar between pacritinib (n=42) and BAT (n=44), including median hemoglobin (8.7 vs. 8.6 g/dL), median platelet count (43 vs. 41 x109/L), and percentage who received prior JAK2 inhibitor therapy (55% vs."

Clinical • Anemia • Hematological Disorders • Myelofibrosis • Thrombocytopenia • ACVR1 • IRAK1

Risk-adjusted safety analysis of the oral JAK2/IRAK1 inhibitor pacritinib in patients with myelofibrosis. (PubMed, EJHaem) - "To account for longer treatment durations on the pacritinib arms compared to best available therapy (BAT), we present a risk-adjusted safety analysis of event rates accounting for different time on treatment. While the rate of overall events was higher on pacritinib compared to BAT, the rate of fatal events was lower, and there was no excess in bleeding, cardiac events, secondary malignancy, or thrombosis on pacritinib, including in patients with severe thrombocytopenia."

Journal • Cardiovascular • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Thrombocytopenia • Thrombosis • IRAK1 • JAK2

Consistency of pacritinib for spleen and symptom reduction in patients with myelofibrosis regardless of cytopenias. (ASCO 2023) - P3 | "Pacritinib demonstrates consistent efficacy for spleen and symptom response in patients with MF regardless of blood counts. This consistent effect may be related to pacritinib’s unique kinome profile and its ability to be delivered at full dose in patients regardless of cytopenias. Clinical trial information: NCT01773187, NCT02055781."

Clinical • Hematological Disorders • Immunology • Myelofibrosis • Thrombocytopenia • ACVR1 • IRAK1

A phase Ib/II study of pacritinib, an interleukin 1 receptor associated kinase 1 (IRAK1) inhibitor, in patients (pts) with solid tumors harboring the 1q21.3 copy number amplification (CNA). (ASCOBT 2024) - P1/2 | "Pacritinib at 200mg BID is safe and tolerable in pts with solid tumors. IRAK1 inhibition appears to modulate immune cell populations both in the tumor microenvironment and systemic circulation. Dose expansion is underway, with potential signal of disease control in HPB tumors."

Clinical • P1/2 data • Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Immune Modulation • Immunology • Lung Cancer • Myelofibrosis • Oncology • Pancreatic Cancer • Solid Tumor • CD4 • CD8 • FLT3 • IRAK1 • JAK2 • PD-1

Development and Validation of a Simultaneous Quantification Method for 12 Targeted Therapies and 3 Active Metabolites in Human Plasma Using Liquid Chromatography-Tandem Mass Spectrometry: An Application to Therapeutic Drug Monitoring in Patients With Hematological Malignancies. (PubMed, Ther Drug Monit) - "We developed and validated a sensitive liquid chromatography-tandem mass spectrometry method requiring only 50 µL of plasma volume for the quantification of 12 targeted oral anticancer drugs and 3 active metabolites. This multianalyte assay offers strong potential for TDM in patients receiving contemporary anticancer treatments."

Journal • Hematological Disorders • Hematological Malignancies • Immunology • Oncology • Oral Cancer

A Study to Assess the Effectiveness and Safety of Pacritinib in Patients With VEXAS Syndrome (PAXIS) (clinicaltrials.gov) - P2 | N=78 | Active, not recruiting | Sponsor: Swedish Orphan Biovitrum | Trial completion date: Aug 2027 ➔ May 2028 | Trial primary completion date: Aug 2027 ➔ Dec 2026

Trial completion date • Trial primary completion date

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

Current treatments, practical management, and emerging investigational therapies for myelofibrosis. (PubMed, Expert Rev Hematol) - "Equally, there is a major focus on next generation JAK inhibitors and mutant calreticulin antibodies. There is also increasing conversation around the need for novel endpoints, as the limitations of symptom assessment, in particular, become apparent and candidate biomarkers of disease modification emerge."

Journal • Review • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Transplantation • CALR

Prescribing patterns in MDS/MPN syndromes (ASH 2025) - "Additionally, the prescribing patterns of Hydroxyurea, Hypomethylating Agents (HMA)- Azacitidine/Decitabine and JAK inhibitors Ruxolitinib/Cedazuridine/Pacritinib/Momelotinib/Fedratinib were analyzed in these patients. In this real-world analysis, our data demonstrate that over 90% of patients diagnosed with MDS/MPN overlap syndromes do not receive any treatment in routine clinical practice. The most prescribed medication in this cohort of patients with MDS/MPN was hydroxyurea, followed by hypomethylating medications (decitabine and azacitidine). Being untreated was associated with a significant decrement in survival, with untreated patients having up to twice the risk of death than those treated."

Atypical Chronic Myeloid Leukemia • Bone Marrow Transplantation • Chronic Myeloid Leukemia • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Juvenile Myelomonocytic Leukemia • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm

Selinexor alone and in combination with JAK inhibitors suppresses pro-inflammatory cytokine secretion from primary myelofibrosis cells ex vivo (ASH 2025) - P3 | "In combination with ruxolitinib (RUX), SEL has shown rapid, deep, and sustained spleenand symptom responses including disease modifying potential in patients with JAK inhibitor(JAKi)–naïve myelofibrosis (MF), with associated reductions in proinflammatory cytokines(Tantravahi SK, et al...JAKis used in MF therapy, including RUX, momelotinib (MOM), and pacritinib(PAC), have limited impact on cytokine modulation... XPO1 inhibition is a potentially fundamental mechanism that addresses keyinflammatory and pathobiological features of MF. Here we demonstrate that SEL effectivelysuppresses ex vivo NF-κB–regulated pro-inflammatory cytokine production in PBMCs derivedfrom patients with MF, both as a single agent and in combination with JAKi, further validating thepotential of disease modification. The combinatory activity of XPO1 inhibition and JAK/STATinhibitors supports the clinical use of SEL plus RUX in JAKi-naïve MF, which is being evaluated inthe ongoing Phase..."

Combination therapy • IO biomarker • Preclinical • Fibrosis • Immunology • Myelofibrosis • CALR • IL6 • JAK2 • TLR8 • XPO1

Pacritinib in transplant-eligible myelofibrosis: Final analysis of the phase 2 HOVON-134 trial (ASH 2025) - "Prior treatment with ruxolitinib (RUX) was allowed if tapered and discontinued beforeinclusion...Per protocol alloHSCT was done witha matched related donor (MRD) or 10/10 matched unrelated donor (MUD) and a standardized reduced-intensity conditioning protocol: intravenous busulfan 3.2 mg/kg adjusted ideal body weight (days -7 to -6)and 1.6 mg/kg adjusted ideal body weight (day -5), fludarabine 30 mg/m2 (days -7 to -2) and anti-Tlymphocyte globulin 10 mg/kg (days -3 to -1) for MRD and 20 mg/kg (days -3 to -1) for MUD. Prophylaxisfor graft-versus-host disease (GVHD) consisted of mycophenolate mofetil (days 0 to 28) and cyclosporineA (days -3 to 100, followed by tapering)... PAC is a feasible and effective symptomatic treatment in transplant-eligible MF-patients andits pre-transplant use does not limit higher-risk patients in proceeding to their intended alloHSCT. Ours isone of few studies in MF showing outcome of alloHSCT by intent-to-transplant."

P2 data • Acute Graft versus Host Disease • Bone Marrow Transplantation • Chronic Graft versus Host Disease • CNS Disorders • Graft versus Host Disease • Hematological Disorders • Immunology • Myelofibrosis • Transplantation • Ventriculomegaly • ACVR1 • CD34 • IRAK1 • JAK2

An independent, multi-center analysis of the post-approval utilization and efficacy of pacritinib and momelotinib in patients with myelofibrosis (ASH 2025) - "Early JAK inhibitors(ruxolitinib (RUX) and fedratinib) result in myelosuppression that often exacerbates disease-relatedanemia and thrombocytopenia. The magnitude ofthese differences warrants further investigation. Overall, this real-world study highlights clinical nuancesin JAK inhibitor selection and emphasizes the opportunity to personalize treatment approach."

Clinical • Myelofibrosis • Thrombocytopenia • CALR

Treatment patterns and outcomes in patients with myelofibrosis treated with pacritinib following a switch from ruxolitinib: The my-PAC study (ASH 2025) - "This real-world study demonstrated the utility of switching to PAC following RUX treatment. Amajority of pts had thrombocytopenia or anemia at the time of PAC initiation with most pts experiencingsymptom relief during PAC treatment, clinically meaningful benefits in spleen size and improvement inPLT and Hb following PAC treatment."

Clinical • Hematological Disorders • Myelofibrosis • Thrombocytopenia • ACVR1 • IRAK1

Real-world treatment duration of ruxolitinib and use of transfusion among 2268 patients with myelofibrosis: An analysis of the Medicare fee-for-service claims database (ASH 2025) - "Most pts were treatment naive (n=1564 [69%]); 659 ( hydroxyurea (HU) prior to RUX.During the baseline period, supportive medication for anemia was received by 277 (12%) pts overall(anemia Dx, n=197 [17%]; transfusion, n=102 [26%]), most commonly erythropoiesis-stimulating agents(n=251 [11%]) or danazol (n=43 [2%])...After RUXdiscontinuation, 25% received another MF treatment; the most common treatments were HU (n=256[11%]), fedratinib (n=186 [8%]), and pacritinib (n=115 [5%]). In this real-world study with long-term follow-up of approximately 4 years, median durationof RUX treatment was 3.1 years... In this real-world study with long-term follow-up of approximately 4 years, median durationof RUX treatment was 3.1 years. On average, pts started RUX early after MF diagnosis (median, 4.5 mo),and approximately one-third remained on RUX treatment at end of study period, regardless of age orbaseline anemia status. Most pts did not require transfusions at baseline."

Claims database • Clinical • HEOR • Medicare • Real-world • Real-world evidence • Reimbursement • US reimbursement • Acute Myelogenous Leukemia • Diabetes • Heart Failure • Hematological Disorders • Hematological Malignancies • Leukemia • Metabolic Disorders • Myelodysplastic Syndrome • Myelofibrosis • Nephrology • Peripheral Arterial Disease • Pulmonary Disease • Renal Disease • Respiratory Diseases

It's not yet time to abandon ruxolitinib in anemic myelofibrosis: Predictive factors of erythroid response to standard anemia-directed therapies combined with ruxolitinib (ASH 2025) - "However, on-target RUX-associated anemia represents a major therapeutic limitation,negatively affecting quality of life, prognosis, and treatment duration.Novel JAK1/2 inhibitors, such as momelotinib and pacritinib, also target ACVR1 and may ameliorateanemia both in RUX-naïve and -exposed pts. However, there is a number of standard anemia-directedtherapies (ADT), including erythropoietin (EPO), danazol, steroids and immunomodulatory agents (e.g.thalidomide), that have been used for a long time to manage anemia in MF...Proactive anemia management with EPO, initiated early before the establishment of TDA, isassociated with better RUX survival and favorable safety profile. These results support a personalizedapproach integrating early prognostic assessment with optimized anemia management strategies, inorder to maximize treatment benefits."

Biomarker • Anemia • Myelofibrosis • ACVR1 • CALR

Targeting HMGA1-driven leukemic transformation in myeloproliferative neoplasms with pacritinib (ASH 2025) - "This transcriptional reprogramming promotesproliferation, blocks differentiation, and accelerates leukemic progression in vivo.We discovered that HMGA1 overexpression confers resistance to ruxolitinib and fedratinib by sustainingE2F/G2-M programs. We identified HMGA1 as a critical driver and potent predictor of MPN-sAML transformation.HMGA1 protein expression, readily detectable by immunohistochemistry (IHC), demonstrated a stepwiseincrease from chronic MPN phases to sAML (P40.78%) in non-blast phase MPN predicted impending leukemic transformation within 12months (47% conversion rate), offering a median lead time of 6 months before overt blast crisis."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • CCNB1 • CD34 • CDK2 • E2F1 • FLT3 • HMGA1 • IRAK1 • JAK2 • KIT • TP53