Tag Archives: mf

Lower Pharmacy Costs Give Ruxolitinib Edge for Patients With MF and Anemia

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November 9, 2024

Author(s): Mary Caffrey

The clinical benefits and lower transfusion costs of momelotinib (Ojjaara) are not enough to offset its higher pharmacy costs compared with an older therapy for patients with myelofibrosis (MF) and anemia who rely on transfusions, according to a recent cost-effectiveness analysis.

The results were presented in a poster at the 16th International Congress on Myeloproliferative Neoplasms, held in Brooklyn, New York, October 24-25, 2024.1

Aaron T. Gerds, MD, MS | Image Credit: Cleveland Clinic

Led by Aaron T. Gerds, MD, MS, assistant professor of Medicine, Cleveland Clinic Taussig Cancer Institute, the authors presented data based on a predictive model that computed per-patient total cost of care for 6-month, 1-year, and 2-year periods, comparing the Janus kinase (JAK) inhibitors ruxolitinib (Jakafi), and momelotinib (Ojjaara). Both inhibit the JAK/STAT pathway, with momelotinib additionally targeting a pathway that can result in improved iron-restricted anemia.

As the poster authors stated, ruxolitinib is indicated for patients with intermediate- or high-risk MF, including those with primary MF, post-polycythemia vera MF, post–essential thrombocythemia MF. Momelotinib is indicated for patients with intermediate- or high-risk MF, including those with primary MF, post-polycythemia vera MF, and post–essential thrombocythemia MF in in adult patients with anemia.1

The SIMPLIFY-2 study showed that patients switching from ruxolitinib to momelotinib took less time to achieve transfusion in dependence.2

This analysis presented in Brooklyn was based on the SIMPLIFY-1 study, which compared ruxolitinib and momelotinib in patients who had not previously received a JAK inhibitor.3 The authors, many of whom worked SIMPLIFY-1, found that the difference in pharmacy costs is $11,095 per month, with momelotinib being more expensive. Although transfusion costs for ruxolitinib were projected to cost an additional $10,854 over a 6-month period, the total cost of care still favored ruxolitinib, Results were as follows:

  • At the 6-month mark, the total cost of care favored ruxolitinib by$46,388.
  • At the 1-year mark, the total cost of care favored ruxolitinib by $84,239.
  • At the 2-year mark, the total cost of care favored ruxolitinib by $144,539.

Assumptions in the model. Authors wrote that the model assumed patients remained on therapy for the entire duration of the study or until death. It was limited to pharmacy- and transfusion-related costs, “to isolate costs associated with reductions in transfusion; other costs of care were assumed similar between ruxolitinib and momelotinib.”

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Inrebic May Reduce Spleen Volume in Myelofibrosis

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October 31, 2024

Author(s): Alex Biese

Fact checked by: Spencer Feldman

Among patients with myelofibrosis who have been previously treated with Jakafi (ruxolitinib), treatment with Inrebic (fedratinib) was beneficial, particularly regarding spleen volume reduction (SVR) when compared to treatment with otherwise best-available therapy (BAT), researchers have found.

Findings from the phase 3 FREEDOM2 trial were published in The Lancet Hematology.

“In the FREEDOM2 trial, patients with myelofibrosis previously treated with [Jakafi] showed superior SVR and symptom response when treated with [Inrebic] compared with BAT (predominantly [Jakafi]),” researchers concluded in the study. “The safety profile of [Inrebic] was consistent with previous trials, and mitigation measures effectively managed known adverse events. Overall, the results indicate that [Inrebic] is a promising option for second-line JAK inhibitor treatment of myelofibrosis.”

Inrebic, a type of tyrosine kinase inhibitor, works by blocking JAK2 and other proteins — which, as defined by the National Cancer Institute, may help keep abnormal blood cells or cancer cells from growing. It was approved by the Food and Drug Administration for the treatment of patients with myelofibrosis in 2019.

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Karyopharm to Host Investor Event with Leading Myelofibrosis KOLs and Provide a Favorable Study Design Update on October 31, 2024

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NEWTON, Mass., Oct. 30, 2024 /PRNewswire/ — Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, today announced it will host a conference call and audio webcast at 8:00 a.m. ET on Thursday, October 31, 2024 to provide a favorable study design update on the Company’s pivotal Phase 3 SENTRY study in JAKi naive myelofibrosis.

The call will feature leading myelofibrosis key opinion leaders Dr. Raajit Rampal, Director of the Center for Hematologic Malignancies and Director of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center and Dr. John Mascarenhas, principal investigator of the Phase 3 SENTRY trial, Professor of Medicine at the Icahn School of Medicine at Mount Sinai and Director of the Center of Excellence for Blood Cancers and Myeloid Disorders.

To access the conference call, please dial (800) 836-8184 (local) or (646) 357-8785 (international) at least 10 minutes prior to the start time and ask to be joined into the Karyopharm Therapeutics call. A live audio webcast of the call, along with accompanying slides, will be available under “Events & Presentations” in the Investor section of the Company’s website, http://investors.karyopharm.com/events-presentations. An archived webcast will be available on the Company’s website approximately two hours after the event.

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Ajax Therapeutics Announces First Patient Dosed in Phase 1 Clinical Trial Evaluating AJ1-11095, a First-in-Class Type II JAK2 inhibitor, for the Treatment of Myelofibrosis

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October 30, 2024

– AJ1-11095 is the first Type II JAK2 Inhibitor to enter the clinic –

– Preclinically, AJ1-11095 has demonstrated superior efficacy to Type I JAK2 inhibitors, such as ruxolitinib, with disease modifying effects on mutant allele burden and fibrosis –

NEW YORK & CAMBRIDGE, Mass.–(BUSINESS WIRE)–Ajax Therapeutics, Inc., a biopharmaceutical company developing next generation JAK inhibitors for patients with myeloproliferative neoplasms (MPNs), today announced the first patient has been dosed in its Phase 1 clinical trial evaluating AJ1‑11095, a first-in-class Type II JAK2 inhibitor, for the treatment of patients with myelofibrosis.

“We’re excited to announce dosing of the first patient enrolled in our first-in-human study with AJ1-11095” said David Steensma, MD, FACP, Chief Medical Officer at Ajax. “As a first-in-class therapy with a unique mechanism of action as a Type II inhibitor of JAK2, AJ1-11095 was developed to provide a much-needed new treatment for patients with myeloproliferative neoplasms by offering the potential for improved efficacy compared to existing therapies.”

AJ1-11095 is the first JAK2 inhibitor to enter the clinic that binds the Type II conformation of the JAK2 kinase as opposed to all the other approved JAK2 inhibitors, including ruxolitinib, that bind the Type I conformation. The advancement of AJ1-11095 into this Phase 1 clinical trial was based on preclinical studies in which AJ1-11095 showed superior efficacy when compared to Type I JAK2 inhibitors with significant disease modifying effects on mutant allele burden and fibrosis, two of the main hallmarks of myelofibrosis.

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Mutated Calreticulin Could Lead to MF Onset

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Brian Murphy, PhD

Mutations in the CALR gene, including a 52 base pair (bp; CALR Del52) deletion and 5 bp insertion (CALR Ins5), affect several signaling pathways in cells leading to the pathogenesis of myelofibrosis (MF) and other myeloproliferative neoplasms (MPNs), according to a study published in the International Journal of Molecular Sciences.

Cells carrying CALR Del52 and CALR Ins5 mutations had increased activation of the Janus kinase/signal transducer and activator of the transcription (JAK/STAT) and the phosphatidylinositol 3-kinase/Protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathways which have been previously implicated in the pathogenesis of MPNs. These effects were still present in a cell culture model lacking MPL gene (thrombopoietin receptor) expression.

The CALR mutations resulted in reduced functionality of calreticulin proteins. Calreticulin generally functions as a major chaperone in the endoplasmic reticulum and is involved in several processes, including control of protein folding, calcium homeostasis, and responses to cellular stress.

The study found cells with CALR Del52 mutations had statistically significant higher levels of DNA damage compared to controls when exposed to hydrogen peroxide. Cells with CALR Ins5 had significantly higher levels of phosphorylated ATM and H2AX than controls. Both cell types were not able to repair DNA damage after 24 hours following oxidative stress.

Apoptosis levels were also significantly higher in cells with the CALR Ins5 mutation compared to controls. Those with CALR Del52 also had higher rates of apoptosis, but it did not reach significance. Further analysis found that the CALR mutations not only led to increased apoptosis after hydrogen peroxide exposure-induced oxidative stress but also tended to arrest the cells in the G2/M phase.

“Functional analysis revealed that the accumulation of G2/M-CALR-mutated cells indicates that oxidative stress-induced DNA damage is difficult to repair. The mentioned cell cycle delay has not been shown in other studies analyzing mutated calreticulin,” the authors said.

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INCA033989 May Address Need for Disease-Modifying Therapies in Myelofibrosis

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October 25, 2024

Author(s): Courtney Flaherty

Fact checked by: Megan Hollasch

Unlike the array of JAK inhibitors available for the treatment of patients with myelofibrosis, the novel monoclonal antibody INCA033989 may have disease-modifying potential among those expressing CALR type 1 mutations, potentially addressing an area of need in myeloproliferative neoplasm (MPN) management, according to Daniel J. DeAngelo MD, PhD.

“With the 4 [FDA-approved] JAK inhibitors, we see clear improvements in symptoms, reduction in spleen [volume], and decreased counts for patients with polycythemia or essential thrombocytopenia, but we’re not seeing eradication and normalization of the bone marrow,” DeAngelo said in an interview with OncLive®. “We don’t know if this agent is going to change that, but the hypothesis is that [INCA033989] may be getting at the heart of the disease, although only for patients with CALR type 1 mutations.”

In engineered cell lines and primary CD34-positive cells from patients with MPN, INCA033989 was shown to antagonize mutant CALR–driven signaling and cellular proliferation. Moreover, in a mouse model of MPN with mutant CALR, administration of an INCA033989 mouse surrogate antibody prevented the development of thrombocytosis and accumulation of platelet-producing megakaryocytes in the bone marrow. The agent’s disease-modifying potential is supported by its reduction of pathogenic self-renewal among MPN cells expressing CALR mutations in both primary and secondary transplantations.1

These preclinical data support the agent’s ongoing investigation in a phase 1 study (NCT06034002) for patients with MPN.2

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FREEDOM2 Trial Shows Fedratinib’s Efficacy and Safety in Myelofibrosis

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By Jordyn Sava
Fact checked by Sabrina Serani

When given as a second-line JAK inhibitor option in patients with myelofibrosis, fedratinib (Inrebic) showed its effectiveness in achieving spleen volume reduction (SVR) while highlighting strategies for managing gastrointestinal adverse effects (AEs) and thiamine deficiency, according to findings from the FREEDOM2 study (NCT03952039).1

The FREEDOM2 study, a multicenter, open-label, randomized controlled trial, involved 316 patients with intermediate-2 or high-risk myelofibrosis who were either relapsed, refractory, or intolerant to ruxolitinib (Jakafi).2 The median follow-up for survival at the data cutoff on December 27, 2022, was 64.5 weeks (IQR, 37.9-104.9). The primary end point was the proportion of patients achieving an SVR of at least 35% (SVR35) at the end of cycle 6.

Results from the study demonstrated a significant difference in SVR35 between the fedratinib and best available therapy (BAT) groups, with 36% of patients in the fedratinib group achieving the primary end point compared with only 6% in the BAT group (30% difference; 95% CI 20%-39%; 1-sided P <.0001).1

“Findings from FREEDOM2 support fedratinib as a second-line Janus kinase inhibitor option to reduce spleen size after ruxolitinib failure or intolerance in patients with myelofibrosis,” wrote study authors in findings published in The Lancet Hematology.

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Dr Scandura on the SENTRY-2 Trial of Single-Agent Selinexor in JAK Inhibitor–Naive Myelofibrosis

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October 16, 2024

Author(s): Joe Scandura, MD, PhD

Fact checked by: Ryan Scott, Courtney Flaherty

Joseph M. Scandura, MD, PhD, associate attending physician, NewYork-Presbyterian Hospital; associate professor, medicine, Weill Cornell Medical College, Cornell University, discusses the phase 2 SENTRY-2 study (XPORT-MF-044; NCT05980806) evaluating single-agent selinexor (Xpovio) in JAK inhibitor–naive myelofibrosis.

The FDA granted fast track designation to single-agent selinexor for the treatment of patients with primary myelofibrosis, post-essential thrombocythemia myelofibrosis, and post-polycythemia vera myelofibrosis in July 2023. Notably, selinexor will be assessed in combination with ruxolitinib (Jakafi) in the phase 3 portion of the SENTRY trial (NCT04562389) and as a monotherapy in the phase 2 SENTRY-2 study for JAK inhibitor–naive patients.

The primary aim of the SENTRY-2 study is to evaluate the efficacy of selinexor as a standalone treatment for patients with myelofibrosis who have not previously been treated with a JAK inhibitor, Scandura begins. Currently, JAK inhibitors are the only FDA-approved class of drugs for this condition, complicating the ability to test alternative treatments like selinexor independently, he states. However, evidence suggests that selinexor demonstrates activity, prompting the FDA to permit the study’s initiation, Scandura says. In SENTRY-2, patients will start treatment with selinexor, and responses will be measured based on spleen volume reduction and symptom improvement, particularly anemia, he details.

An innovative aspect of the study is its flexibility, Scandura notes. If a patient shows some degree of response but it is not deemed significant, they may have a JAK inhibitor added to their treatment regimen, he explains. This could include ruxolitinib or newer agents such as pacritinib (Vonjoy), which does not suppress platelet counts, making it suitable for patients with low platelets. Momelotinib (Ojjaara), known for its efficacy in improving anemia, will be added if patients are anemic and maintain adequate platelet counts.

The importance of safety and rigorous science is emphasized in clinical trials, especially when evaluating new treatments, Scandura continues. With selinexor already recognized as safe, the focus shifts to optimizing its use in the treatment landscape of myelofibrosis, he says. If selinexor gains FDA approval for myelofibrosis, it could play a significant role in a more nuanced treatment approach, reflecting the complexities of managing this condition amidst financial considerations and the availability of multiple JAK inhibitors, Scandura concludes.

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Pacritinib Demonstrates Efficacy, Tolerability in Patients with Myelofibrosis and Thrombocytopenia

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October 16, 2024

Author(s): Alexandra Gerlach, Associate Editor

Pacritinib (Vonjo; CTI BioPharma Corp) demonstrated improved spleen volume reduction (SVR) and was tolerable in patients with myelofibrosis (MF) and thrombocytopenia, according to data published in the European Journal of Hematology. The findings offer deeper insights into the capabilities of Janus kinase (JAK) inhibitors to improve SVR and overall survival (OS), contradicting prior studies advising against use of JAK inhibitors for thrombocytopenia.1

Further studies are needed to identify the long-term safety and efficacy of the therapy.

Image Credit: © AkuAku – stock.adobe.com

Thrombocytopenia, a condition that occurs when blood platelet counts are too low, is a disease-related feature of MF that leads to poorer prognoses impacting both OS and leukemia-free survival. It can be caused by a variety of factors including ineffective hematopoiesis, splenic sequestration, and treatment-related effects. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curable treatment for MF but is only available for a minority of patients. However, the development of JAK inhibitors has expanded treatment options for patients with MF and may show promise for treatment of thrombocytopenia.2

Pacritinib is a JAK inhibitor used to treat intermediate or high-risk MF that targets JAK2 and FMS-like tyrosine kinase 3. It was approved by the FDA in 2022 for treatment of both primary and secondary MF in patients with platelet counts < 50 x 109/L. In the phase 3, randomized, controlled PERSIST-2 trial (NCT02055781), pacritinib demonstrated favorable efficacy and tolerability compared with best available therapy (BAT) in patients with MF and thrombocytopenia.3-5

In the study, approximately 300 patients with thrombocytopenia and primary or secondary myelofibrosis were randomized in a 1:1:1 ratio to receive either pacritinib 400 mg once daily, pacritinib 200 mg twice daily, or BAT. The primary end points included SVR of ≥ 35% reduction in spleen volume from baseline to week 24 as measured by MRI or computed tomography, as well as ≥ 50% reduction in the total symptom score from baseline to week 24 on the Myeloproliferative Neoplasm Symptom Assessment Form 2.0.1,5

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Dr Klisovic on a Case Discussion of Momelotinib in Myelofibrosis With Anemia

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October 16, 2024

Author(s): Rebecca Klisovic, MD

Fact checked by: Ashling Wahner, Ryan Scott

Rebecca Klisovic, MD, chief medical information officer, University Hospitals Seidman Cancer Center, discusses 3 case studies about patients with myelofibrosis that were presented during an OncLive® State of the Science Summit™ on hematologic oncology, which she chaired.

The first case that was discussed was on a 71-year-old male patient with newly diagnosed myelofibrosis with splenomegaly, mild anemia, a high symptom burden, and intermediate-2–risk disease, Klisovic begins. The consensus among the panelists was that this patient required treatment due to his spleen size, symptoms, and anemia, she says. Although some oncologists who participated in the discussion considered using ruxolitinib (Jakafi) because of its early survival data, the panel predominantly favored momelotinib (Ojjaara), given this agent’s potential benefit in patients with anemia, she explains.

The second case was on a 62-year-old female patient with myelofibrosis who had already received ruxolitinib and had comorbidities including symptom scoring and a large spleen, according to Klisovic. This patient also had anemia, with a hemoglobin level of 7.2 g/dL, she reports. Therefore, the focus on improving anemia made momelotinib a clear treatment choice in this setting, she adds. Whereas other case presentations prompted treatment debates between the panelists, this case was more clear cut, especially since this patient was refractory to ruxolitinib, Klisovic emphasizes.

The third case was on a 54-year-old female patient with newly diagnosed myelofibrosis that was characterized by both anemia and thrombocytopenia, as well as a platelet count of 34/µL, Klisovic says. This discussion centered around the use of pacritinib vs momelotinib, informed by the patient’s low platelet count, she explains. Some discussants raised concerns about the patient’s eligibility for momelotinib clinical trials, which have enrollment criteria with varying platelet cutoffs, she notes. Despite these concerns, most participants favored the use of pacritinib (Vonjo) due to this agent’s efficacy in managing thrombocytopenia, she reports. However, some discussants noted that momelotinib could also be a viable treatment option for patients similar to the one in this case, depending on clinical trial criteria and individual patient factors, she concludes.

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