Category Archives: Myelofibrosis

Ojjaara (momelotinib) approved in Canada for the treatment of myelofibrosis in adults who have moderate to severe anemia

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  • Ojjaara (momelotinib) is the only approved treatment for newly diagnosed and previously treated myelofibrosis patientsi who have moderate to severe anemia and other key manifestations associated with the disease.ii
  • This approval underscores GSK’s commitment to help drive progress for people living with complex blood cancers.

MISSISSAUGA, ON, Nov. 12, 2024 /CNW/ – GSK announced today that Health Canada has approved Ojjaara (momelotinib) for the treatment of splenomegaly and/or disease-related symptoms, in adult patients with intermediate or high-risk primary myelofibrosis (MF), post polycythemia vera MF or post essential thrombocythemia MF who have moderate to severe anemia.iii Ojjaara is the first and only approved medication globally, and now in Canada, that treats both the anemia and other key manifestations of myelofibrosis (newly diagnosed and previously treated).iv

“Treatment options for myelofibrosis-related anemia have been limited. We are proud to offer this treatment alternative for Canadian patients to address this critical unmet need and other myelofibrosis symptoms. With most myelofibrosis patients becoming anemic over time, Ojjaara’s approval represents a significant milestone to improve the outcomes of these patients while also highlighting GSK’s commitment to making an impact in Canada’s hematology oncology space through innovative new treatments,” said Michelle Horn, Interim Country Medical Director, GSK Canada.

Myelofibrosis is a rare blood cancer part of the broader myeloproliferative neoplasms (MPNs) diseases. MPNs have an incidence rate of 2.05 new cases per 100,000 Canadians.v Currently there are between 1,400-2,177 estimated people living with this type of disease in Canada.vi Anemia is a common symptom of myelofibrosis and a major unmet needvii, but awareness among Canadians is low. A 2024 survey shows that 90% of Canadians have heard of anemia but almost 50 per cent do not know about blood cancer related anemia.viii Canadians also have low knowledge of anemia with over 40 per cent of the same respondents saying they know little to nothing about this condition.ix

“Anemia and related transfusions significantly affect the quality of life, prognosis and survival for anemic myelofibrosis patients,” said Cheryl Petruk, CEO of HEAL Canada. “We are excited to witness progress in this rare disease space and to see Ojjaara approved in Canada. This new treatment has the potential to help improve the lives of patients while addressing the disease’s main challenges, namely anemia and other major symptoms.”

Ojjaara is the only once-a-day, oral JAK1/JAK2 and activin A receptor type 1 (ACVR1) inhibitor.x The approval of Ojjaara by Health Canada is supported by data from the pivotal MOMENTUM Phase III trial, which demonstrated significant improvements in Total Symptom Score (TSS), Transfusion Independence, and Splenic Response Rate.xi Additional support came from a subset of patients in the SIMPLIFY-1 Phase III trial, reinforcing Ojjaara’s efficacy in treating moderate to severe anemia and related symptoms in myelofibrosis patients.xii

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Dr DeAngelo on the Integration of JAK Inhibitors in Myelofibrosis Management

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November 11, 2024

Author(s): Daniel J. DeAngelo, MD, PhD

Daniel DeAngelo, MD, PhD, professor, medicine, Harvard Medical School, chief, Division of Leukemia, institute physician, Dana-Farber Cancer Institute, discusses the integration of JAK inhibitors into clinical practice for patients with myelofibrosis. Lower third needs to be updated

When incorporating JAK inhibitors, such as ruxolitinib (Rituxan), into clinical practice, it is essential to understand both their benefits and the challenges they present, particularly regarding anemia, DeAngelo begins. The phase 3 COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) trials, which initially sought to address symptom control and spleen reduction, demonstrated a notable survival advantage with ruxolitinib over placebo in patients with intermediate-2 or high-risk myelofibrosis, or intermediate-1 disease with symptomatic splenomegaly, he reports. These results led to ruxolitinib becoming the standard of care for high-risk or symptomatic patients, especially as allogeneic transplantation remains limited to select candidates, DeAngelo shares.

A primary consideration with ruxolitinib is its tendency to induce a hemoglobin level drop of approximately 2 points during the first 2 months of treatment due to on-target JAK2 inhibition, which affects erythropoiesis, he continues. Although newer agents are now approved by the FDA specifically for patients with baseline anemia, clinicians using ruxolitinib should anticipate this hemoglobin level decline, he states. Importantly, the initial drop in hemoglobin level does not indicate treatment failure but is a manageable effect that is often misunderstood, leading some oncologists to discontinue or reduce dosing with the drug prematurely, DeAngelo notes.

He goes on to state that his advice for integrating JAK inhibitors into myelofibrosis management plans is to proactively address these expected effects with patients. Patients can be supported through transfusions, growth factors, or alternative JAK inhibitors if needed, according to DeAngelo. In most cases, hemoglobin levels tend to stabilize and improve after the first few months, typically between months 3 and 4, he notes. Setting clear treatment expectations helps ensure patient adherence to therapy and optimizes outcomes when using JAK inhibitors in clinical practice, DeAngelo concludes.

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Frequent Testing for Driver Mutations Critical in Myelofibrosis

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Nov 12, 2024

Researchers from the Munich Leukemia Laboratory in Germany have developed a model that uses 12 genetic markers to accurately stratify patients with myeloproliferative neoplasms (MPNs), according to a study published online ahead of print in Leukemia.

The WHO categorizes classical MPNs—using cytomorphology, bone marrow biopsy, grading of fibrosis, blood counts, and a handful of molecular markers—into four individual entities: chronic myeloid leukemia (CML) and the BCR::ABL1 negative MPNs polycythemia vera (PV), primary myelofibrosis (PMF), and essential thrombocythemia (ET).

“However, overlaps, borderline findings, or transitions between MPN subtypes occur, and incomplete clinical data often complicates diagnosis,” Manja Meggendorfer, PhD, and the study coauthors wrote.

The researchers analyzed 355 patients with MPN to use the results to stratify MPN entities and provide prognostic information. The investigation revealed the presence of genetically distinct subgroups with different cytogenetic abnormalities, mutations, and JAK2 allele statuses.

“Notably, differences in JAK2 allele status (heterozygous/homozygous) correlated with diverse EFS [event-free survival] and OS [overall survival] outcomes, potentially due to additional prognostic mutations,” the researchers reported. “In contrast, groups with cytogenetic aberrations and additional mutations generally had shorter EFS and poorer OS regardless of the diagnosed entity, aligning with studies on the impact of karyotype and mutation count on survival.”

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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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