Ojjaara (momelotinib)

Momelotinib-approved for treatment of myelofibrosis in adults with anemia-and its major active metabolite, M21, were assessed as drug-drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple-dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single-dose rifampin), and a strong CYP3A4 inducer (multiple-dose rifampin). Momelotinib DDI perpetrator potential (multiple-dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively)...Safety findings were mild in this short-term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments.

Recent years have seen the emergence of novel therapeutic agents, notably ruxolitinib and fedratinib, which target the Janus kinases (JAK) pathway. Due to its mechanism of action, MMB represents a valuable therapeutic option in MF, addressing the clinical challenge of anemia and potentially improving outcomes for patients with hematologic malignancies. Ongoing research explores MMB's potential in acute myeloid leukemia and combination therapies.

No abstract available

No new or unexpected safety signals were identified. Overall, momelotinib provides spleen, symptom, and anemia benefits to JAK inhibitor-naive patients with myelofibrosis regardless of baseline hemoglobin level, and greater anemia-related benefits vs. ruxolitinib in patients with hemoglobin <12 g/dL.

Here we apply our experiences in the phase III trials of momelotinib, a JAK1/JAK2/ACVR1 inhibitor and the first therapy indicated by the US FDA for myelofibrosis patients with anemia, to highlight how application of different criteria impacts the anemia-related benefits reported for any potential treatment in myelofibrosis. We advocate for a convention of a new expert consensus panel to bring consistency and transparency to the definition of anemia-related response in myelofibrosis.

P1/2, N=20, Not yet recruiting, M.D. Anderson Cancer Center

Six drugs (abrocitinib, baricitinib, deucravacitinib, ritlecitinib, tofacitinib, upadacitinib) are used for the treatment of inflammatory diseases (atopic dermatitis, rheumatoid arthritis, psoriasis, alopecia areata, and ulcerative colitis)...The following seven drugs received FDA approval in 2023: capivasertib (HER2-positive breast cancer), fruquintinib (metastatic colorectal cancer), momelotinib (myelofibrosis), pirtobrutinib (mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma), quizartinib (Flt3-mutant acute myelogenous leukemia), repotrectinib (ROS1-positive lung cancer), and ritlecitinib (alopecia areata). All of the FDA-approved drugs are orally effective with the exception of netarsudil, temsirolimus, and trilaciclib. This review summarizes the physicochemical properties of all 80 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, polar surface area, potency, solubility, lipophilic efficiency, and ligand efficiency.

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.

The primary objective of treatment in myelofibrosis (MF) is prolongation of life, which is currently accomplished only by allogeneic hematopoietic stem cell transplantation (AHSCT). Pacritinib and fedratinib provide alternative options in the presence of severe thrombocytopenia or ruxolitinib-resistance/intolerance, respectively. Splenectomy remains a viable option for drug-resistant symptomatic splenomegaly and cytopenia.

This review summarizes novel and promising treatments for anemia in myelofibrosis including transforming growth factor-β inhibitors luspatercept and KER-050, JAK inhibitors momelotinib, pacritinib, and jaktinib, BET inhibitors pelabresib and ABBV-744, antifibrotic PRM-151, BCL2/BCL-XL inhibitor navitoclax, and telomerase inhibitor imetelstat. Standard approaches to treat myelofibrosis-related anemia have limited efficacy and are associated with toxicity. New drugs have shown positive results in myelofibrosis-associated anemia when used alone or in combination.

Despite the current standard of care, the JAK1/2 inhibitor (JAKi) ruxolitinib (RUX), a significant unmet need remains for patients (pts) with MF, due to lack of response or JAKi resistance... JAK2V617F mutant cell lines HEL ( TP53M113K), UKE-1 ( TP53WT), MUTZ-8 ( TP53WT), and JAK2WT ELF-153 ( TP53I251N) cells were treated with SEL alone or in combination with RUX, pacritinib (PAC), momelotinib (MMB), pelabresib (PELA), or navitoclax (NAV)... In a panel of MPN-derived cells with or without JAK2V617F, SEL showed single-agent antiproliferative activity, and synergism with other MF therapeutics at clinically achievable concentrations through regulation of XPO1, JAK/STAT signaling, and apoptosis/senescence regulators. In addition to positive Phase 1 clinical data in pts with JAKi-naïve MF who received SEL with RUX, these preclinical data support synergistic activity between SEL and other MF therapies, suggesting the potential for SEL as a backbone for novel treatment combinations for MF.

Reductions in transfusion dependence and transfusion visits for MMB vs RUX were associated with projected healthcare system savings in transfusion costs and transfusion-related time burden in JAK inhibitor–naive pts with MF, including in subgroup analyses of pts aged ≥65 years.

In September 2023, momelotinib was approved in the USA for the treatment of intermediate or high-risk MF, including primary MF or secondary MF &lsqb;post-polycythemia vera (PV) and post-essential thrombocythemia (ET)], in adults with anemia. This article summarizes the milestones in the development of momelotinib leading to this first approval for MF.

Post hoc analyses herein evaluated the efficacy and safety of momelotinib in patients with MF and thrombocytopenia (platelet counts <100 × 10/L) from randomized phase 3 studies: MOMENTUM (momelotinib versus danazol; JAK inhibitor experienced); SIMPLIFY-1 (momelotinib versus ruxolitinib; JAK inhibitor naïve); and SIMPLIFY-2 (momelotinib versus best available therapy; JAK inhibitor experienced); these studies were not statistically powered to assess differences in thrombocytopenic subgroups, and these analyses are descriptive. The safety profile of momelotinib in thrombocytopenic patients was also consistent with the overall study population. In summary, momelotinib represents a safe and effective treatment option for patients with MF and moderate-to-severe thrombocytopenia.

In cytopenic MF patients from PERSIST-2, TI-R on pacritinib was associated with BMF improvement. Though these results are based on a small sample size, they contrast with recent data suggesting no correlation between BMF reduction and TI-R on the JAK1/2 inhibitors momelotinib and ruxolitinib (Oh ST, et al. Blood 2022; 140 (Supp 1):821-23).

Introduction: Three Janus kinase 2 (JAK2) inhibitors (JAKinibs) have been approved by the FDA for the treatment of myelofibrosis (MF): ruxolitinib, fedratinib, and pacritinib; a fourth one, momelotinib, is currently under FDA review. JAKinibs clinically evaluated for treatment of MF exhibit distinct kinase inhibition profiles and cellular activities. Amongst the agents tested in this study, ruxolitinib was the most potent and selective JAK2 inhibitor. At concentrations several fold above clinically relevant concentrations, ruxolitinib had no observable effects on the health of cells not reliant on JAK/STAT mediated signaling.

Reductions in transfusion dependence and transfusion visits for MMB vs RUX were associated with projected healthcare system savings in transfusion costs and transfusion-related time burden in JAK inhibitor–naive pts with MF, including in subgroup analyses of pts aged ≥65 years.

FDA-approved JAKi for the treatment of MF include ruxolitinib, fedratinib, and pacritinib. CALR-1 mutation is the most important risk factor for both drug survival and longevity without AHSCT, in momelotinib-treated patients with MF. Such information might help identify MF patients who might benefit from treatment with momelotinib and in whom AHSCT might be deferred or not.

Momelotinib (MMB) is a Janus kinase (JAK) 1/JAK2/activin A receptor type 1 (ACVR1) inhibitor that has demonstrated spleen, symptom, and anemia benefits, including increases in hemoglobin (Hb) and reduction or elimination of red blood cell (RBC) transfusion requirements in pts with MF...Analyses were performed in the safety populations of S1 (N=430; MMB vs ruxolitinib [RUX], JAK inhibitor [JAKi] naive), S2 (N=156; MMB vs best available therapy [88.5% RUX], JAKi experienced), and MOMENTUM (N=195; MMB vs danazol, JAKi experienced)... These data demonstrate that when accounting for differences in known prognostic factors and effect modifiers as well as changes in RBC transfusion status over time, a consistent and statistically significant relationship was observed between transfusion status and OS across all 3 phase 3 MMB trials. Consistent with inclusion of transfusion status in DIPSS-plus risk assessment, these data validate TI status as a clinically relevant and meaningful endpoint that is prognostic for survival in JAKi-naive and JAKi-experienced disease settings.

SIMPLIFY-1 included pts with JAK inhibitor–naive MF randomized (1:1) to receive MMB or ruxolitinib (RUX). In MOMENTUM, pts with symptomatic (Myelofibrosis Symptom Assessment Form Total Symptom Score ≥10), anemic (hemoglobin <10 g/dL), JAK inhibitor–experienced MF were randomized (2:1) to receive MMB or danazol (DAN)... These data demonstrate that MMB was associated with better maintenance of RBC transfusion intensity and zero RBC transfusion status vs RUX in pts with MF who were JAK inhibitor naive and showed greater reduction in RBC transfusion burden from baseline vs DAN in pts with MF who were JAK inhibitor experienced. Across both trials, ≥85% of pts treated with MMB maintained or improved transfusion intensity.

While Janus kinase (JAK) inhibitors such as ruxolitinib (RUX) and fedratinib (FED) may address symptoms and splenomegaly, they do not manage and may exacerbate anemia. Treatments for anemia include erythropoiesis-stimulating agents (ESAs), often in combination with RUX or FED, and androgens such as danazol; however, these have shown limited efficacy... In RUX/BAT-treated pts with MF who required RBC transfusions, continued treatment with RUX/BAT in most pts resulted in poor treatment outcomes compared with MMB. Specifically, treatment with MMB demonstrated an ability to deliver higher SVR, TI, and TSS response rates. The lower SVR35 rate in both arms, similar to the overall ITT population, was likely a result of lack of washout from prior JAK inhibitor treatment.

Sponsored by GSK

Momelotinib (MMB), a JAK1/JAK2/activin A receptor type 1 inhibitor, has demonstrated consistent anemia benefits, including increased transfusion independence and reduced transfusion burden, as well as spleen and symptom improvements across 3 phase 3 trials in MF... Analyses were performed in the safety populations, by treatment arm, over the randomized 24-wk treatment period of SIMPLIFY-1 (n/N=430/432; MMB vs ruxolitinib [RUX], JAKi naive) and SIMPLIFY-2 (N=156; MMB vs best available therapy [BAT; 88.5% RUX], JAKi experienced)... Pts treated with MMB spent less time reliant on RBC transfusions and more time free from transfusions and anemia events, without the cost of increased AEs, compared with those treated with RUX or BAT. Given the negative QOL and prognostic impact of RBC transfusion dependence, these analyses suggest that the anemia benefits of MMB lead to improved quality of survival for pts with MF.

P3, N=195, Completed, Sierra Oncology LLC - a GSK company | Active, not recruiting --> Completed | Trial completion date: Apr 2028 --> Dec 2022

Improvements favored momelotinib versus danazol for each MFSAF individual item, and greater improvements were observed for disease- and cancer-related fatigue and physical functioning at week 24, with significant results for multiple items/domains across the 3 assessments. These findings are consistent in demonstrating that momelotinib provides substantial symptom benefit.

Pacritinib inhibited ACVR1 with greater potency (half-maximal inhibitory concentration [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.

We also found that AXL-STAT3 inhibition can impede the recruitment of TAMs in a xenograft mouse model, thereby suppressing tumor growth. These findings suggest the potential application of AXL-STAT3-related markers to quantitatively assess metastatic potential and inform therapeutic strategies in lung cancer.

However, early JAK inhibitors (ruxolitinib and fedratinib) are often associated with cytopenias, particularly thrombocytopenia and anemia, which limit their tolerability. To address these complications, pacritinib has been developed and recently approved for patients with thrombocytopenia, while momelotinib is in development for those with anemia...In the near future, MF treatment strategies will involve selecting the most suitable JAK inhibitor based on individual patient characteristics and prior therapy. Ongoing and future clinical trials are crucial for advancing the field and expanding therapeutic options for MF patients.

Patients were randomised to receive MMB or ruxolitinib (RUX [S1]), best available therapy (S2; 89% RUX), or danazol (MOMENTUM). To date, this report represents the largest database of safety data from clinical trials for a JAKi in MF. No unexpected long-term or cumulative toxicity was observed with MMB.

OL MMB maintained symptom, TI, and spleen responses with continued good survival and safety in the ITT and low platelet populations. MMB may address an unmet need in anaemic patients with MF.

Jak1 inhibitor, CYT387 (2-16 micromolar), and ERK1/2 inhibitor, U0126 (5-80 micromolar), reduced CD40 expression in HLF cells under IFN-gamma stimulation. CD40 expression in poorly differentiated HCC cells is possibly regulated by CD4+T cells and IFN-gamma. A high level of soluble CD40 in the plasma of HCV-SVR patients may indicate the risk of HCC development.

Molecular characterization of mouse colorectal cancer cell lines with different metastatic potential identified AVIL as a potential therapeutic target in CRC patients with peritoneal metastasis. Regulation of AVIL expression by interferon gamma may suggest functional relevance of tumor immune microenvironment in the development of peritoneal metastasis in CRC.

Despite the fact that ruxolitinib and fedratinib have been clinically developed and approved, their use is limited due to adverse effects such as anemia and thrombocytopenia. Recently, pacritinib has been approved for a group of thrombocytopenic patients with significant unmet clinical needs. In symptomatic and anemic patients with prior JAK inhibitor exposure, momelotinib was superior to danazol in preventing exacerbation of anemia and in controlling MF-associated signs and symptoms, such as spleen size...In addition, several agents are being studied as monotherapies for ruxolitinib-resistant or -ineligible patients. We reviewed several new MF treatments in the advanced stages of clinical development and treatment options for cytopenic patients.

This non-specific activity resulted in clinically favorable effects on constitutional symptoms and splenomegaly and, consequently, FDA approval of three small molecule JAKi: ruxolitinib, fedratinib, and pacritinib. ACRV1 mediates SMAD2/3 signalling that contributes to upregulation of hepcidin production and iron-restricted erythropoiesis. Therapeutic targeting of ACRV1 raises therapeutic prospects in other myeloid neoplasms associated with ineffective erythropoiesis, such as myelodysplastic syndromes with ring sideroblasts or SF3B1 mutation, especially those with co-expression of JAK2 mutation and thrombocytosis.

Adult pts with high- and intermediate-risk MF were randomized to receive MMB or ruxolitinib (RUX; S1); MMB or best available therapy, which was RUX in 89% (S2) of patients; and MMB or danazol (MOMENTUM). We report the largest trial safety database to date for a JAK inhibitor in MF. MMB demonstrated a consistent safety profile without unexpected long-term or cumulative toxicity.

Introduction: Momelotinib (MMB), an oral ACVR1, JAK1 and JAK2 inhibitor, has previously demonstrated clinical activity on symptoms, anemia and spleen volume in JAK inhibitor (JAKi)-naïve and JAKi ‑experienced patients with myelofibrosis (MF)...Dynamic and time-to-event analyses have previously demonstrated MMB can reduce overall transfusion burden compared to ruxolitinib (RUX) in JAKi-naïve patients including in those who do not achieve TI-R (Mesa et al...To better understand the impact of MMB on TI-R, OS and transfusion burden in JAKi-experienced patients, similar analyses were applied to the ongoing Phase 3 MOMENTUM study which is investigating MMB vs danazol (DAN) in anemic, symptomatic patients with MF who have previously been treated with a JAKi... Mean duration of prior JAKi therapy was 139 weeks in the MMB arm and 125 weeks in the DAN arm. The study population was highly anemic with a mean Hgb of 8.1 g/dL in the MMB arm and 7.9 g/dL in the DAN arm; 48% and 49% of MMB and DAN patients respectively had baseline Hgb <8 g/dL. At baseline, 13% and 15% of MMB and DAN patients were TI, respectively, whereas a majority (49% MMB; 52% DAN) were TD.

In these initial analyses of response duration, OL MMB maintained symptom, TI, and spleen responses with continued good survival and safety in the ITT (symptomatic and anemic MF pts) and in those with low PLT. MMB may address a critical unmet need, particularly in MF pts with anemia, including those with severe thrombocytopenia.

Using available genetic atlas data, potential drug candidates for treatment of PDAC were identified based on differentially expressed genes, protein interaction analysis and connectivity mapping. These results may help focus efforts on identifying targeted agents with potential therapeutic efficacy for evaluation in prospective clinical trials of patients with PDAC.

Survival distributions were similar between JAKi-naïve patients randomized to momelotinib, or ruxolitinib then momelotinib, in SIMPLIFY-1 (OS HR = 1.02 [0.73, 1.43]; LFS HR = 1.08 [0.78, 1.50]). Week 24 TI response in JAKi-naïve, momelotinib-randomized patients was associated with improved OS in univariate (HR = 0.323; p < 0.0001) and multivariate (HR = 0.311; p < 0.0001) analyses. These findings underscore the importance of achieving or maintaining TI in myelofibrosis, supporting the clinical relevance of momelotinib's pro-erythropoietic mechanism of action, and potentially informing treatment decision-making.