Tag Archives: mf

Azacitidine Plus Ruxolitinib Demonstrates ‘Promising’ Efficacy in Myelofibrosis

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Amber Denham

05/31/2024

Azacitidine in combination with ruxolitinib demonstrates promising efficacy for patients with myelofibrosis (MF), according to long-term follow-up results from a phase 2 clinical trial presented at the 2024 American Society of Clinical Oncology (ASCO) Annual meeting.

The trial included adult patients aged ≥18 years with MF intermediate 1 to 2 or high-risk disease, measured by the Dynamic International Prognostic Scoring System (DIPSS). From March 2013 to October 2021, a total of 61 patients were treated in the trial. Patients had a median age of 66 years (46 to 87). The median hemoglobin was 10.1 g/dl (6.8 to 16.2) and bone marrow blasts 2% (0 to 14%). Overall, 14 (23%) patients had BM blasts ≥5%. Furthermore, JAK2 was mutated in 35 (57%) patients and 38 (62%) patients had intermediate-2 or high-risk DIPSS disease.

Study results showed an International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) response occurred in 44 (72%) patients. A clinical improvement was noted in 37 (61%) patients, including IWG-MRT spleen reduction >50% in 28 (61%) of 46 patients with baseline length ≥5 cm below left costal margin, and 31 (61%) of 51 patients with baseline total symptom score (TSS) >12 having a >50% improvement in TSS 50. In addition, a partial response was seen in 4 patients and cytogenetic complete remission in 3 patients.

With a median follow-up of 93 months, median overall survival (OS) was 46 months (95% confidence interval [CI], 25 to 66), median event-free survival was 33 months (95% CI, 24 to 43), and median duration of any objective response was 43 months (95% CI, 24 to 62). It was noted that disease transformation to AML occurred in 14 (23%) patients with a median time to transformation of 19 months. In addition, 20 (33%) patients received a stem cell transplant (SCT), and 11 (55%) patients had intermediate-2/high-risk DIPPS disease. It was observed that patients in the Intermediate-2/high-risk DIPPS group who received a SCT showed a trend towards improved median OS vs those who did not receive a transplant (38 vs 27 months, P = .2).

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JAK Inhibitor–Based Combinations Could Represent the Next Frontier in Myelofibrosis

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Ryan Scott

In an interview with OncLive® following the Vanderbilt Stem Cell Transplant and Cellular Therapy Symposium, Ashwin Kishtagari, MD, discussed advancements in the treatment of patients with intermediate-risk to high-risk myelofibrosis and highlighted recent data from the 2023 ASH Annual Meeting for combination therapies using JAK inhibitors.

Studies presented at the meeting included the phase 3 TRANSFORM-1 clinical trial (NCT04472598) evaluating navitoclax plus ruxolitinib (Jakafi), as well as the phase 3 MANIFEST-2 trial (NCT04603495) investigating pelabresib (CPI-0610) in combination with ruxolitinib.1,2

Kishtagari, who serves as an assistant professor of medicine in the Department of Hematology and Oncology at Vanderbilt University Medical Center, as well as a clinical research fellow in Bick Lab at Vanderbilt University School of Medicine in Nashville, Tennessee, provided further updates on JAK inhibitors for the treatment of patients with myelofibrosis in another interview with OncLive.

OncLive: How do you see the treatment paradigm for myelofibrosis evolving in the future?

Kishtagari: We have 4 JAK inhibitors which are FDA approved for the treatment of [patients with] myelofibrosis, with the first being ruxolitinib. Fedratinib [Inrebic] was the second agent approved in 2019. Pacritinib [Vonjo] was approved by the FDA in 2022, and momelotinib [Ojjaara]was approved in 2023.

We are moving toward combination therapies because our goal is to have a more significant improvement in splenomegaly response and symptom improvement. The whole field of myelofibrosis is moving toward combination therapy, especially for patients with higher- or intermediate-risk myelofibrosis.

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Sobi to present new myelofibrosis data at the ASCO 2024 Annual Meeting

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WALTHAM, Mass., May 24, 2024 (GLOBE NEWSWIRE) — Sobi North America, the North American affiliate of Swedish Orphan Biovitrum AB (Sobi®), today announced the presentation of three abstracts that highlights data from its myelofibrosis treatment option at the American Society of Clinical Oncology (ASCO) Annual Meeting taking place in Chicago from May 31 – June 4, 2024.

Sobi’s commitment to delivering innovative treatments for people living with hematological diseases is seen in global studies spanning multiple rare disorders, including myelofibrosis.

A retrospective analysis will be presented that demonstrates the efficacy of pacritinib in spleen volume reduction, symptom benefit and red blood cell transfusion response, compared with best available therapy, in patients with myelofibrosis who have both thrombocytopenia and anemia.

An additional retrospective analysis will be presented that shows the substantial symptom benefit pacritinib provides compared with best available therapy or low-dose ruxolitinib, specifically in patients who required red blood cell transfusion at the time of pacritinib initiation. The number of patients experiencing treatment emergent Grade 3 anaemia was similar between pacritinib and BAT groups.

New real-world data will be presented that demonstrates treatment with pacritinib provides stability or improvement in thrombocytopenia and/or anemia in patients with myelofibrosis, regardless of baseline counts, and has favorable overall survival similar to other JAK inhibitor historical controls.

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JAK Inhibitor–Based Combinations Could Represent the Next Frontier in Myelofibrosis

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Ryan Scott

In an interview with OncLive® following the Vanderbilt Stem Cell Transplant and Cellular Therapy Symposium, Ashwin Kishtagari, MD, discussed advancements in the treatment of patients with intermediate-risk to high-risk myelofibrosis and highlighted recent data from the 2023 ASH Annual Meeting for combination therapies using JAK inhibitors.

Studies presented at the meeting included the phase 3 TRANSFORM-1 clinical trial (NCT04472598)evaluating navitoclax plus ruxolitinib (Jakafi), as well as the phase 3 MANIFEST-2 trial (NCT04603495) investigating pelabresib (CPI-0610) in combination with ruxolitinib.1,2

Kishtagari, who serves as an assistant professor of medicine in the Department of Hematology and Oncology at Vanderbilt University Medical Center, as well as a clinical research fellow in Bick Lab at Vanderbilt University School of Medicine in Nashville, Tennessee, provided further updates on JAK inhibitors for the treatment of patients with myelofibrosis in another interview with OncLive.

OncLive: How do you see the treatment paradigm for myelofibrosis evolving in the future?

Kishtagari: We have 4 JAK inhibitors which are FDA approved for the treatment of [patients with] myelofibrosis, with the first being ruxolitinib. Fedratinib [Inrebic] was the second agent approved in 2019. Pacritinib [Vonjo] was approved by the FDA in 2022, and momelotinib [Ojjaara]was approved in 2023.

We are moving toward combination therapies because our goal is to have a more significant improvement in splenomegaly response and symptom improvement. The whole field of myelofibrosis is moving toward combination therapy, especially for patients with higher- or intermediate-risk myelofibrosis.

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Ajax Therapeutics Announces FDA Clearance of IND Application for AJ1-11095, a First-in-Class Type II JAK2 inhibitor, for the Treatment of Myelofibrosis

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

– Phase 1 dose escalation study expected to begin in 2H 2024 –

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 that it has received clearance for its Investigational New Drug (IND) application from the U.S. Food and Drug Administration (FDA) to initiate a Phase 1clinical study of AJ1‑11095, a first-in-class Type II JAK2 inhibitor, for the treatment of patients with myelofibrosis.

“This is an important milestone for our company and our first program to enter the clinic and the first clinical study to ever evaluate a Type II JAK2 inhibitor in patients.”

“We are thrilled to obtain clearance to advance AJ1-11095 into the clinic and excited to bring this innovative new medicine to patients with myelofibrosis,” said Martin Vogelbaum, co-founder and CEO of Ajax Therapeutics. “This is an important milestone for our company and our first program to enter the clinic and the first clinical study to ever evaluate a Type II JAK2 inhibitor in patients.”

“We look forward to the clinical development of AJ1-11095 in myelofibrosis and to initiating our Phase 1 dose escalation study, AJX-101, later this year,” said David Steensma, MD, FACP, Chief Medical Officer at Ajax. “As a first-in-class therapy with a unique mechanism as a Type II inhibitor of JAK2, AJ1-11095 was developed to provide a much-needed new treatment for patients with myelofibrosis by offering the potential for improved efficacy with disease modifying effects compared to existing therapies.”

About AJ1-11095

AJ1-11095 was designed by Ajax, through our collaboration with Schrödinger, to be a next generation JAK2 inhibitor by using structure-based drug design and computational methods at scale to selectively bind the Type II conformation of the JAK2 kinase and to provide greater efficacy with disease modification compared to all currently approved JAK2 inhibitors which bind the Type I conformation of JAK2. Additionally, AJ1-11095 has been shown in preclinical studies to reverse marrow fibrosis, reduce mutant allele burden and maintain efficacy against MPN cells that become resistant to chronic Type I JAK2 inhibition.

About Myelofibrosis

Myelofibrosis (MF) is a rare blood cancer that affects approximately 20,000 patients in the United States. The disease is characterized by spleen enlargement, scarring (fibrosis) in the bone marrow, progressive anemia, and debilitating symptoms, such as fatigue, night sweats, itching, and abdominal discomfort, which can impair a patient’s’ quality of life. The most widely used treatment for MF patients are Type I JAK2 inhibitors which can reduce spleen size and provide symptomatic improvement but have little effect on the underlying cause of disease. Over time, most MF patients stop Type I JAK2 inhibitor therapy. The most common causes for treatment discontinuation include a lack of benefit or loss of response, adverse events, and disease progression, leaving significant unmet treatment needs for these patients.

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Novel Targets Beyond the JAK-STAT Pathway Aim to Push Myelofibrosis Treatment Forward

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Jax DiEugenio

Ongoing research in myelofibrosis continues to focus on agents directed at novel targets with the hope of expanding treatment options beyond the host of JAK inhibitors used in this treatment paradigm, according to Anthony M. Hunter, MD.

“[There are] a lot of novel agents on the horizon [that could] work in combination with JAK inhibitors to hopefully continue to move that bar forward for patients [with myelofibrosis,” said Hunter, who is an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine and the medical director of the Immediate Care Center at Winship Cancer Institute of Emory University in Atlanta, Georgia.

In an interview with OncLive®, Hunter explained the evolving understanding of the biology of myelofibrosis, detailed the growth of JAK inhibitors being used for the treatment of these patients, and expanded on novel targets and agents currently being tested in clinical trials.

OncLive: How has our understanding of the pathology of myelofibrosis evolved in recent years as more research studies have been conducted?

Hunter: What has been well documented for years now is that the key biologic pathway or cell-signaling pathway actually involved in myeloproliferative neoplasms [MPN] or myelofibrosis is the JAK-STAT pathway. That [understanding] was advanced in 2005 when we found out about the JAK2 mutation in a large percentage of these patients, [and we] subsequently [found out about] the MPL and CALR mutations, as well. We find that in all patients with MPN or myelofibrosis, irrespective of those mutations, we see activation of this JAK-STAT signaling pathway, which has a lot of different effects and we can break those up into effects on hematopoiesis, or how they affect sort of blood cell production.

Then we also see increases in inflammatory cytokine signaling. The JAK/STAT pathway signals through a lot of cytokine and inflammatory receptors, so we see a lot of inflammatory signaling increase in a number of different cytokine levels and in myelofibrosis, which impacts the disease and the symptoms that we see. That has been key to [understanding] the biology [of myelofibrosis] and has led to the development of JAK inhibitors.

We’ve started to move beyond [the JAK-STAT] pathway a little bit, as well. A lot of the research now and new agents that are being explored in clinical trials are largely looking at non–JAK inhibitor agents, combining other pathways such as BET inhibitors, various other signaling molecules, and anti-fibrotic type compounds. All of those have additional roles, along with the JAK-STAT pathway in myelofibrosis.

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Momelotinib Improves Anemia in JAK Inhibitor-Naive Myelofibrosis

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Sabrina Serani

Treatment with momelotinib (Ojjaara) delivered benefits to anemia among patients with myelofibrosis who were naive to JAK inhibitors, regardless of their baseline hemoglobin level. Further, momelotinib provided significant anemia benefits compared with ruxoltinib (Jakafi), according to an analysis from the phase 3 SIMPLIFY-1 study (NCT01969838).

SIMPLIFY-3 randomized 432 patients with myelofibrosis who had not received JAK inhibitors toreceive momelotinib or ruxolitinib.In patients who were anemic and received momelotinib, mean hemoglobin levels increased by weeks 2 to 4 of treatment, and hemoglobin levels remained stable among patients who were not anemic.

Comparatively, patients who were anemic and nonanemictreated with ruxolitinib experienced an initial decrease in mean hemoglobin. This decrease stabilized after weeks 4 to 6 as patients received red blood cell transfusions. Patients receiving ruxolitinib were permitted to cross over to the momelotinib group, and mean hemoglobin levels increased after this change.

The study also evaluated patients at different levels of anemia. Among patient who were mildly anemic, with ahemoglobin levelbetween 10 and 12 g/dL, 90.4% of patients were transfusion-free at baseline, 93.9% of these patients remained transfusion-free while receiving momelotinib. Four patients who were not transfusion-free at baseline became transfusion-free while on treatment. In contrast, patients who were mildly anemic in the ruxolitinib arm became more dependent on transfusion; 50% of patients who were transfusion-free at baseline required a transfusion while on ruxolitinib.

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Utilization of Momelotinib for Myelofibrosis With Anemia Can Result in Small Savings

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Laura Joszt, MA

Although momelotinib to treat myelofibrosis (MF) with anemia has a higher acquisition cost, it is partially offset by savings when transfusion-related costs are reduced, according to a poster being presented at the AMCP Annual Conference, held April 15-18, 2024, in New Orleans, Louisiana.1

MF is a rare cancer in the bone marrow that disrupts the production of blood cells.2 MF causes anemia because of the extensive scarring to bone marrow. This extensive scarring also causes patients to have a low number of platelets, increasing their risk of bleeding. Patients may also have an enlarged spleen.

Momelotinib inhibits Janus kinase (JAK) 1, JAK2, and activin A receptor type 1. In September 2023, the FDA approved momelotinib to treat patients with intermediate- or high-risk MF with anemia.3

The approval of momelotinib was based on data from the phase 3 MOMENTUM trial, which found clinically significant improvements for patients treated with momelotinib vs danazol.4 A quarter of patients treated with momelotinib had a 50% or greater reduction in total symptom score compared with only 16% of patients on danazol.

Since the approval, the National Comprehensive Cancer Network (NCCN) has added momelotinib5 to its Clinical Practice Guidelines in Oncology for Myeloproliferative Neoplasms. Momelotinib was added as a category 2A treatment for patients with high-risk MF. It was also added as a 2B category treatment for patients with lower-risk MF.

Patients with MF who have anemia and are dependent on transfusions have increased medical costs and poor prognosis, the authors of the AMCP poster noted. JAK inhibitors may provide improvements in symptoms and spleen size, but they could worsen or induce anemia. However, momelotinib has been shown to reduce spleen size.4

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Ryvu Therapeutics Presents Preclinical Data on RVU120 and Synthetic Lethality Programs at the 2024 AACR Annual Meeting

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10 Apr, 2024

  • Ryvu PRMT5 inhibitors show potential best-in-class profiles, including a strong antiproliferative effect on MTAP-deleted cell lines and a good safety window versus MTAP WT cells.
  • Ryvu’s WRN inhibitor program has demonstrated target engagement and selective potency with a synthetic lethal effect; in vivo efficacy studies exhibited pronounced tumor growth inhibition in an MSI-H colorectal cancer xenograft model.
  • Ryvu’s proprietary ONCO Prime discovery platform, which recently received a PLN 26 million (approx. USD 6.6 million) grant from the Polish Agency for Enterprise Development, has identified novel drug targets in KRAS-mutant patient-derived cells (PDCs) with therapeutic potential in colorectal cancer; the ONCO Prime platform has broad potential across multiple tumor types.
  • RVU120 shows efficacy both as a monotherapy and synergistically in combination with ruxolitinib in preclinical models of myeloproliferative neoplasms, including myelofibrosis and polycythemia vera.
  • MEN1703 (SEL24), presented by partner Menarini Group, shows cytotoxic activity in myelofibrosis cell lines as a monotherapy and synergistically in combination with ruxolitinib.

KRAKOW, Poland, April 10, 2024 /PRNewswire/ — Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, presents preclinical data from its synthetic lethality pipeline, RVU120, and MEN1703 (SEL24) at the 2024 AACR Annual Meeting, April 5-10 in San Diego, California.

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Disease Progression for Patients With Low-Risk Myelofibrosis Participating in the MOST Study

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Grace Taylor

03/26/2024

A group of researchers presented data on disease progression for patients with low-risk myelofibrosis (MF) participating in the prospective observational Myelofibrosis and Essential Thrombocythemia Observational Study (MOST) at the 2023 ASH Annual Meeting & Exposition.

In order to qualify for the MOST study, participants were required to have a physician-reported diagnosis of MF (primary myelofibrosis [PMF], post progression of polycythemia vera [post-PV], or post essential thrombocythemia [post-ET). They also could not have any risk factors per the Dynamic International Prognostic Scoring System (DIPSS) criteria. However, participants could be aged 65 years or older. The number of patients with MF enrolled in the study was 232. Of this population, 205 met the study criteria and were included in cohort A. Although the remaining 27 patients had  ≥1 DIPSS risk factor, they were included in the study in a separate cohort B.

For the study, disease progression was defined by the worsening of clinical or laboratory parameters, which included one or more of the following criteria: hemoglobin (Hb) <10 g/dL, platelets <100×109/L, presence of constitutional symptoms (weight loss, fever, or sweats), new or worsening splenomegaly, blasts >1%, white blood cell count >25×109/L, death due to disease progression, leukemic transformation (LT), or >1 red blood cell transfusion. The median follow-up was 52.9 months (42-68).

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