PharmaEssentia Initiates Phase 2b Trial of ropeginterferon alfa-2b-njft for Essential Thrombocythemia (ET) in North America

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Single-arm trial to expand body of evidence supporting treatment with novel monopegylated interferon among adults with ET living in the U.S. and Canada

BURLINGTON, Mass.–(BUSINESS WIRE)–PharmaEssentia USA Corporation, a subsidiary of PharmaEssentia Corporation (TPEx:6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology and oncology, today announced that the first patients are now being dosed in a Phase 2b clinical study evaluating ropeginterferon alfa-2b-njft for the treatment of adults with essential thrombocythemia (ET).

ET is a rare blood cancer characterized by a genetic mutation triggering the overproduction of platelets in the blood. It is part of a group of disorders called myeloproliferative neoplasms (MPNs), for which there are few therapeutic options today. Without proper treatment, ET often progresses toward myelofibrosis or secondary acute myeloid leukemia (sAML). Based on an improved understanding of the disease etiology, clinical guidelines recommend the use of systemic therapies that can move beyond symptom management toward more complete control of the disease.

“Clinicians who treat ET patients recognize the need for more effective and more tolerable treatment options to gain greater control over the effects of this progressive cancer and help more patients reach their goals,” said Lucia Masarova, M.D., Assistant Professor, Department of Leukemia at UT MD Anderson Cancer Center, Houston Texas. “This important study will provide useful insights into the role of this novel interferon to overcome the limitations of the current options available today and potentially represent a real advancement in the care of these patients.”

This single-arm study will assess the efficacy of ropeginterferon alfa-2b-njft in approximately 64 eligible adults with ET at 20-25 treatment centers in the United States and Canada. The study will include assessments of hematologic response rate as well as changes in the JAK2 and CALR mutation to understand their role in treatment response, and will capture additional safety and tolerability assessments, quality of life impact, and other evaluations. The study will include a 12-month primary treatment phase during which participants will receive treatment subcutaneously every two weeks (starting dose 250 mcg, target optimal dose 500 mcg) followed by a 28-day follow up. Those who respond to treatment will be eligible to participate in an extension phase of the study. More information on the study including eligibility criteria can be found by visiting www.ExceedET.com or www.clinicaltrials.gov and searching for the trial identifier NCT05482971.

“Years of ongoing research have demonstrated that there is an important role for a monopegylated interferon to improve the care paradigm for people who suffer from chronic, progressive myeloproliferative neoplasms. We’ve delivered on this through our first indication in polycythemia vera, and now we are expanding our focus into ET,” said Raymond Urbanski, M.D., Ph.D., U.S. Head of Clinical Development and Medical Affairs. “Our goal through this research is to provide a clear, comprehensive view of the clinical profile for this treatment in ET that could support registration.”

This study will build upon the insights generated as part of the ongoing global SURPASS ET study, a Phase 3 pivotal clinical trial of ropeginterferon alfa-2b for the treatment of ET. Topline data for both trials are expected in 2024.

About BESREMi® (ropeginterferon alfa-2b-njft)

BESREMi is an innovative monopegylated, long-acting interferon. With its unique pegylation technology, BESREMi has a long duration of activity in the body and is aimed to be administered once every two weeks (or every four weeks with hematological stability for at least one year), allowing flexible dosing that helps meet the individual needs of patients.

BESREMi has orphan drug designation for the treatment of polycythemia vera (PV) in adults in the United States. The product was approved by the European Medicines Agency (EMA) in 2019, in the United States in 2021, and has recently received approval in Taiwan and South Korea. The drug candidate was invented by PharmaEssentia and is manufactured in the company’s Taichung plant, which was cGMP certified by TFDA in 2017 and by EMA in January 2018. PharmaEssentia retains full global intellectual property rights for the product in all indications.

BESREMi was approved with a boxed warning for risk of serious disorders including aggravation of neuropsychiatric, autoimmune, ischemic and infectious disorders.

Please see full Prescribing Information, including Boxed Warning.

About Essential Thrombocythemia

Essential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN) characterized by an overproduction of platelets in the blood that results from a genetic mutation; data indicates a JAK2 gene mutation is present in approximately half of diagnosed patients. ET is estimated to affect up to 57 per 100,000 people in the U.S. The disease is most commonly diagnosed through routine blood work and is most common in people over the age of 50, with women 1.5 more times more likely to be diagnosed than men. As a chronic, progressive disease, ET requires regular monitoring and appropriate treatment. Over time, the disease may progress into more deadly conditions such as myelofibrosis or acute leukemia.1,2

About PharmaEssentia

PharmaEssentia (TPEx: 6446), headquartered in Taipei, Taiwan, is a global and rapidly growing biopharmaceutical innovator. Leveraging deep expertise and proven scientific principles, PharmaEssentia aims to deliver effective new biologics for challenging diseases in the areas of hematology and oncology, with one approved product and a diversifying pipeline. Founded in 2003 by a team of Taiwanese-American executives and renowned scientists from U.S. biotechnology and pharmaceutical companies, today PharmaEssentia is expanding its global presence with operations in the U.S., Japan, China, and Korea, along with a world-class biologics production facility in Taichung, Taiwan.

For more information, visit our website or find us on LinkedIn and Twitter.

Forward Looking Statement

This press release may contain forward-looking statements. For those statements, we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995 and similar legislation and regulations under Taiwanese law. These forward-looking statements are based on management expectations and assumptions as of the date of this press release, and actual results may differ materially from those in these forward-looking statements as a result of various factors. These factors include risks and uncertainties related to the initiation, timing, progress and results of our research and development programs, preclinical studies, clinical trials, and regulatory submissions. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof.

1 Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma. 2014 Mar;55(3):595-600
2 “What is Essential Thrombocythemia?” MPN Research Foundation. 2020. Available at: http://www.mpnresearchfoundation.org/Essential-Thrombocythemia

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Discussing Currently Available Therapies for Patients With MPNs

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Andrew Kuykendall, MD

Andrew Kuykendall, MD, an assistant member at the H. Lee Moffitt Cancer Center of University of South Florida in Tampa, FL, discusses some of the recent changes there have been for patients with myeloproliferative neoplasms (MPNs).

The MPN field has expanded over the past few years with a number of clinical developments. Some of these novel treatments include ruxolitinib (Jakafi), fedratinib (Inrebic), and pacritinib (Vonjo).

In August 2019, the FDA approved fedratinib for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis, including post-polycythemia vera or post-essential thrombocythemia myelofibrosis based on data from multiple studies.

Then in February 2022, pacritinib, an oral macrocyclic member of the JAK family, was granted an accelerated approval by the FDA for the treatment of myelofibrosis for patients with severe thrombocytopenia. The basis of pacritinib’s approval comes from results of the phase 3 PERSIST-1 (NCT01773187), the phase 3 PERSIST-2 (NCT02055781), and phase 2 dose-finding PAC203 trial.

Currently, investigators are evaluating treatment with momelotinib, which has previously shown clinically significant improvements vs danazol for patients with anemia and intermediate-risk or high-risk myelofibrosis in the phase 3 MOMENTUM (NCT04173494) study.

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Managing Anemia in Myelofibrosis — New Treatment Options

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Medical Source: Dr. Muneeb Niazi

Updated February 17th, 2023

 

New Treatment Options for Myelofibrosis-Related Anemia

  • Myelofibrosis is a form of blood cancer where the blood-producing bone marrow is slowly replaced by scar tissue.
  • Janus kinase (JAK) inhibitors are an effective treatment for myelofibrosis. However, they carry side effects and can cause a symptomatic decrease in patients’ red blood cell counts, which is called anemia.
  • Many new medications are being developed to combat this anemia. Lusapatercept, imetelstat, and pacritinib have shown promise, but are not yet Food and Drug Administration (FDA) approved for anemia. However, they are already being used as an off-label treatment in clinical practice.

Myelofibrosis (MF) belongs to a group of blood cancers called myeloproliferative neoplasms (MPNs). These cancers originate in the myeloid tissue, commonly known as the bone marrow, which lines the inside of large bones, such as the vertebral column or the hip bones.

 

“The [abnormal] cell of origin [for these cancers] is in the bone marrow… There are three classical MPNs, essential thrombocytosis, which is too many platelets, polycythemia vera, which is too many red cells, and MF, which is a condition in which there is a proliferation of cells in the bone marrow. But there’s also a significant amount of scarring or fibrosis in the bone marrow,” explains Dr. James Mangan, Hematologist/Medical Oncologist at the University of California San Diego.

A common side effect of a type of MF treatment called janus kinase (JAK) inhibitors is anemia, or a decrease in a patient’s red blood cell count (which can cause issues like fatigue, weakness, dizziness, etc.) There are some promising new treatment options for myelofibrosis-related anemia, but before we get into those, it’s important to understand how the disease works. 

It Starts Within the Bone Marrow

Bone marrow is a red, spongy tissue that contains the mother cells, known as the stem cells, which generate all the life-sustaining products of the blood, including red blood cells (RBCs), white blood cells (WBCs), and platelets. The bone marrow produces these cells day in, day out. Yet if the marrow starts to produce one or more of these cells at an abnormal rate, cancers can develop. 

Dr. Mangan explains, “the cell of origin [for these cancers] is in the bone marrow… There are three classical MPNs, essential thrombocytosis, which is too many platelets, polycythemia vera, which is too many red cells, and MF, which is a condition in which there is a proliferation of cells in the bone marrow. But there’s also a significant amount of scarring or fibrosis in the bone marrow.” 

Primary MF: A Scarring Bone Marrow

Primary MF is the replacement of healthy bone marrow cells with its namesake fibrous tissue, commonly known as scar tissue. This tissue is produced by fibroblasts. Over a period, these cells take over the bone marrow. Since they are incapable of producing normal blood products, the population of healthy blood cells starts to decline.

Cause

The specific cause of MF is unknown. However, many patients carry JAK2 mutations. JAK2 genes (JAK1 and JAK2) code for a protein enzyme that promotes the growth and proliferation of normal bone marrow cells. Mutations in this gene can rev up cell production within the marrow, which can ultimately result in cancers such as MF. This mutation is not required, and almost half of the patients may lack such mutations. Overall, there is an increase in chemicals that stimulate fibroblasts, cells that form connective tissues from collagen but not blood products. These cells slowly take over and replace the normal marrow cells, resulting in a decreased production of RBCs, WBCs, and platelets. This process is termed fibrosis.

Symptoms

Symptoms of MF result from a lack of RBCs and platelets. Of note, as RBC production decreases within the bone marrow, the body compensates for it by increasing production in other areas of the body, such as the spleen and the liver, causing them to enlarge. Symptoms may include:

  • Profound Fatigue (tiredness)
  • Shortness of breath
  • Night sweats
  • Fever
  • Itching
  • Unintentional weight loss
  • Splenomegaly (enlarged spleen)
  • Hepatomegaly (enlarged liver)
  • Abdominal fullness due to splenomegaly and/or hepatomegaly
  • Abnormal blood work

Around 20% of people with this disorder may have no symptoms and are only incidentally diagnosed based on lab work obtained for some other reason. “MF can [be diagnosed] sometimes through labs or sometimes through symptoms. I’ve seen patients present both ways,” recalls Dr. Mangan.

How is MF Treated?

There are several different treatments for MF, such as watchful waiting, targeted therapies, chemotherapy, immunotherapy, and allogenic stem-cell transplantation (ASCT). ASCT is the only curative treatment, but it comes at the cost of significant, sometimes life-threatening complications.

RELATED: How Does a Stem Cell Transplant Work?

“We’re only curing maybe 50 to 55% of patients with a transplant. [And] the decision to get a transplant is a big decision that carries risk … I’m actually very optimistic about some of the [other] treatment tools we have for treating MF. I tend to manage [my patients] with medical therapies or symptom-directed therapies [first],” Dr. Mangan says. “Patients may live for five, six, or seven years with a good quality of life before they must subject themselves to the risks of a transplant. [Therefore], we defer transplants in MF.”

Targeted therapies exploit unique features of cancer cells and use drugs that target these features. Janus-associated kinase-1 and 2 (JAK1 and JAK2) are two enzymes that are involved in the aberrant production of cells in MF. Targeting these enzymes using JAK inhibitors, such as ruxolitinib, can help control MF. While they can be extremely effective, they carry their own side effects and can especially increase the risk of symptomatic anemia and low platelet counts in patients.

“Unfortunately, the JAK inhibitors [can make] the anemia a little bit worse and [become] a drag on platelet counts,” notes Dr. Mangan. “Thus, we must turn to alternative therapies to improve the anemia in [such] patients.”

Luspatercept: A Promising Potential Treatment For Anemia in Myelofibrosis

Luspatercept (tradename Reblozyl) is a first-in-its-class medication, which serves to enhance the production of RBCs within the blood. Technically, it binds to proteins from the transforming growth factor-beta (TGFβ) and diminishes the TGFβ-assisted cascade of events that regulates RBC production. In doing so, it enhances RBC numbers and alleviates anemia. It has been approved by the Food and Drug Administration (FDA) for treatment in patients with β-thalassemia who require regular blood transfusions and certain myelodysplastic syndromes (a group of diseases resulting in abnormal blood cell production).

It has not been approved for MF-related anemia just yet. But that does not mean it is not effective. In fact, preliminary clinical trials in MF patients have shown significant promise. Their findings have greenlit an ongoing phase 3 clinical trial, called INDEPENDENCE, the results of which could mean FDA approval for luspatercept for MF-associated anemia.

Currently, the promising study results have led to luspatercept being used as an off-label treatment for these patients.

“I’ll disclose that this is an off-label use… there’s a drug called luspatercept, which has been effective in anemia in certain subtypes of myelodysplastic syndrome. [It] seems to work well in MF. And so, at our institution we have been putting a lot of [MF patients with anemia who are candidates for] JAK inhibition on a combination of ruxolitinib and Luspatercept,” notes Dr. Mangan.

Other Promising Treatment: Imetelstat, Pacritinib, and Momelotinib

Another first-in-its-class medication, Imetelstat works differently than Luspatercept. It inhibits telomerase, which is a naturally occurring enzyme that is active in proliferating cells but silent in mature, adult cells. It has been shown to aid in the development of many cancers, including MF. By inhibiting this enzyme, Imetelstat kills off malignant parent cells within the bone marrow which reduces the production of cancer cells.

“Imetelstat seems to be very promising, but it is currently [being tested] in clinical trials,” says Dr. Mangan. This means that it is also not yet FDA-approved for MF-related anemia.

Pacritinib is an inhibitor of JAK2 and some other proteins. It has previously been FDA-approved for the treatment of MF patients with low platelet counts based on the results of a large-scale clinical trial. However, further analyses of this same study demonstrate the benefits of this medication for anemia alleviation, as measured by a decrease in the frequency of blood transfusions required by MF patients. Like the previous two medications, it has not yet been explicitly greenlit by the FDA for MF-associated anemia, however, it is being used as an off-label drug for MF patients with anemia in clinical practice.

Momelotinib is an investigational drug for myelofibrosis that is a strong inhibitor of three proteins, including JAK1, JAK2, and Activin A receptor, type I (ACVR1). Its combative actions against anemia are mainly achieved through ACVR1 inhibition. ACVR1 inhibition reduces the levels of activin-like kinase-2 (ALK2), which is a protein present on the outside surface of liver cells. This prevents the generation of a hormone called hepcidin. Hepcidin decreases how much iron is available for use by the body. Its levels are often elevated in MF patients. By lowering these levels, Momelotinib increases the circulating iron within the body, making it readily available for bone marrow cells. This leads to increased production of hemoglobin, an iron-containing protein, and RBCs alleviating the anemia. Momelotinib was studied in a large-scale clinical trial with positive results. It is currently under review by the FDA for use in clinical settings.

The Future Holds Even More Promise

Dr. Mangan expresses optimism that these experimental but promising treatments will soon become part of the standard of care for the treatment of anemia in MF patients.

“[Currently] these therapies are a little bit more on the clinical trial spectrum than standard-of-care spectrum. Although I think soon that’s [going to change], especially with luspatercept and migalastat,” Dr. Mangan concludes.

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Potential Therapeutic Target for Blood Cancers Discovered

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By Melissa Rohman

Investigators have discovered that a specific complex drives cell proliferation in different forms of blood cancers called mutated myeloproliferative neoplasms (MPNs), suggesting the complex could serve as an ideal therapeutic target, according to a Northwestern Medicine study published in the Journal of Clinical Investigation. 

“This paper has set up a stepping stone for future drug development for patients with MPNs,” said Peng Ji, MD, PhD, ‘15 GME, professor of Pathology in the Divisions of Experimental Pathology and Hematopathology, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and senior author of the study.

MPNs occur when mutated stem cells in the bone marrow cause an overproduction of white cells, red cells and platelets. According to the Leukemia and Lymphoma Society, an estimated 100,000 people in the U.S. currently live with or are in remission from MPNs.

Patients with MPNs have increased risk of thrombosis, such as stroke or heart attack, and increased risk of the disease evolving into different types of MPNs, such as myelofibrosis — when blood cell production is disrupted altogether — or in more severe cases, acute myeloid leukemia (AML) can occur when myeloid (bone marrow) cells interfere with blood cell production.

Current therapies for MPNs include chemotherapy and drugs which can help reduce the risk of thrombosis, however these therapies are ineffective to reduce thrombosis and disease progression. Adverse side effects also occur in patients who undergo extended therapy, underscoring the need for new therapies for MPNs, Ji said.

Previous work has established that MPNs contain a genetic mutation in the JAK2-STAT pathway, which contains the protein-encoding gene called JAK2 and drives other downstream target genes promoting pathogenesis. One of these genes is Pleckstrin-2 (Plek2), which Ji’s laboratory had previously discovered is overexpressed in patients with MPNs, making this gene an attractive therapeutic target.

In the current study, Ji’s team used high-throughput screening and cell-based assays to identify the precise mechanisms that Plek2 utilizes to mediate cell proliferation in JAK2-STAT mutated MPNs.

Using these techniques, they discovered that Plek2 is not only overexpressed by the JAK2-STAT pathway but also activates Akt — an essential protein kinase — and protects Akt from degradation, according to Ji.

“With the increase of Plek2, Akt will be hyperactivated, and Akt is important for cell proliferation. Therefore, this recruitment of Akt will drive cell proliferation in myeloproliferative diseases,” Ji said.

Based on this newly discovered mechanism, the investigators then used novel Plek2 small molecular inhibitors in mouse models of MPNs to block cellular signaling between Plek2 and Akt. The investigators administered either Plek2 inhibitors alone or in combination with an Akt inhibitor, discovering that both interventions demonstrated similar therapeutic efficacy to knocking out Plek2 in MPN cells in vivo.

The Plek2 inhibitors also reduced the proliferation of CD34 positive cells from MPN patients, which indicates similar efficacy in human cells.

“When Plek2 is overexpressed, it may induce cancer, but if you knock it out from the body, it doesn’t really matter since there are other compensatory mechanisms, so this really is an attractive target for the treatment of MPNs,” Ji said.

Xu Han, PhD, a postdoctoral fellow in the Ji laboratory, was lead author of the study. Co-authors include Rama Mishra, PhD, adjunct associate professor of Biochemistry and Molecular Genetics and Madina Sukhanova, PhD, assistant professor of Pathology in the Division of Cytogenetics and a member of the Lurie Cancer Center, Gary Schiltz, PhD, research professor of Pharmacology and a member of the Lurie Cancer Center, and Arabela Grigorescu, PhD, managing director of Northwestern University’s Keck Biophysics Facility.

Ji is also the founder of Aplexis, a startup that is developing novel therapies designed to treat MPNs and Plek2-overexpressing solid tumors.

This work was supported by National Institute of Diabetes and Digestive and Kidney Disease grant R01-DK124220, National Heart, Lung, and Blood Institute grant R01-HL148012, R01-HL150729, R01-HL148014, a Leukemia & Lymphoma Society Translational Research Grant and a Harrington Discovery Institute Scholar award.

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Momelotinib reduces symptom burden compared to danazol in patients with myelofibrosis

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byJessie WillisandTeddy Guo
 February 8, 2023

1. After a 24-week treatment period, a significantly greater proportion of patients randomized to momelotinib had symptom scores reduced by more than 50%.

2. Momelotinib was well tolerated overall with the most common adverse events being anemia and thrombocytopenia.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Myelofibrosis is a malignancy of the bone marrow that typically causes a low red blood cell count. Patients with myelofibrosis can be affected by debilitating symptoms such as weakness and fatigue. Momelotinib is an activin A receptor type 1 (ACVR1) inhibitor that has shown promise in previous phase 1-3 clinical trials in myelofibrosis. This study aimed to efficacy of momelotinib versus danazol in reducing the symptoms of myelofibrosis. Participants were enrolled to receive either momelotinib or danazol for a total of 24 weeks. In result, a significantly greater proportion of patients in the momelotinib group compared to the danazol group reported symptom reductions by more than 50%. Adverse events were similar between the two groups, with the most common being anemia and thrombocytopenia. Limitations of this study include the inability to assess long-term survival benefits between the two groups. Nonetheless, this study supports the use of momelotinib for treating myelofibrosis-associated symptoms.

Click to read the study in The Lancet

In-Depth [randomized controlled trial]: MOMENTUM was an international, randomized controlled phase 3 trial evaluating momelotinib versus danazol in patients with anemia and myelofibrosis. Participants were aged 18 years or older with confirmed primary myelofibrosis, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. A total of 195 patients were randomized 2:1 to either momelotinib 200 mg orally once per day plus danazol placebo (n=130) or danazol 300 mg orally twice per day plus momelotinib placebo (n=65). The treatment duration was 24 weeks. The primary endpoint was defined as the response rate at week 24 measured by a >50% reduction in the Myelofibrosis Symptom Assessment Form (MFSAF) TTS compared to baseline. The primary endpoint occurred in a significantly greater portion of the momelotinib group compared to the danazol group (25% vs. 9%, proportional difference 16% [95% CI 6-26], p=0.0095). The most frequent grade 3 adverse events associated with momelotinib and danazol were anemia (61% vs 75%) and thrombocytopenia (28% vs 26%). Other non-hematological adverse events include acute kidney injury (3% vs 9%) and pneumonia (2% vs 9%).

Dr. Mascarenhas on the Evolution of JAK Inhibitors in Myelofibrosis

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John O. Mascarenhas, MD

John O. Mascarenhas, MD, professor of medicine, hematology, and medical oncology, Icahn School of Medicine at Mount Sinai, director, the Center of Excellence for Blood Cancers and Myeloid Disorders, member, the Tisch Cancer Institute, discusses evolution of JAK inhibitors in the treatment landscape of myelofibrosis.

For nearly a decade, ruxolitinib (Jakafi) was the only JAK inhibitor approved for the treatment of patients with myelofibrosis after the FDA approved ruxolitinib as the first drug to specifically treat patients with myelofibrosis in November 2011. However, fedratinib (Inrebic) and pacritinib (Vono) joined the treatment paradigm in recent years. In 2019, the FDA approved fedratinib for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis and, most recently, in 2022, the FDA granted an accelerated approval to pacritinib for the treatment of adult patients with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L. It is anticipated that momelotinib will be approved at some point in 2023, Mascarenhas notes.

Due to the expanding options for JAK inhibitors in the treatment of myelofibrosis, it is critical that practitioners be aware of the different niches that a JAK inhibitor may be applicable, Mascarenhas says.

Because ruxolitinib has been a part of the treatment landscape for nearly a decade and has an established role in the treatment of myelofibrosis, clinicians may be more comfortable with the drug due to a wealth of experience with that particular JAK inhibitor, and it will likely remain the mainstay of JAK inhibitor therapy for patients with myelofibrosis, Mascarenhas continues.

The other JAK inhibitor options can fill needs in specific subsets of patients. Pacritinib represents a treatment option for patients with platelet count of less than 50 x 109/L, and, notably, it can be utilized, irrespective of platelet count, as a second-line JAK inhibitor, Mascarenhas says. Moreover, fedratinib has broader label and can be utilized in the up-front or second-line settings, Mascarenhas says. As a second-line treatment, fedratinib represents a potential option specifically in patients who experience progression or a lack of spleen response with ruxolitinib, Mascarenhas adds. However, neither ruxolitinib nor fedratinib are good drugs for improving anemia and can be associated with myelosuppression, Mascarenhas concludes.

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Momelotinib May Be ‘No. 1 Choice’ for Second-Line Myelofibrosis, Anemia

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Nicholas Wrigley

Momelotinib, an inhibitor of ACVR1 and JAK1/JAK2, resulted in better total symptom scores (TSS), improved anemia measures, and better spleen responses than danazol (Danocrine) in patients with myelofibrosis and intermediate- or high-risk anemia previously treated with JAK inhibitors, according to data from the phase 3 MOMENTUM study (NCT04173494) published in Lancet.

“A combination of quality-of-life improvement, anemia response, and transfusion independence is the key to my excitement about momelotinib [for myelofibrosis.] [It] will probably become a number-one choice in the second-line setting,” according to an expert from the University of Texas MD Anderson Cancer Center.

Roughly one quarter (n = 32/130) of patients treated with momelotinib reported a 50% or greater reduction in TSS compared with 9% (n = 6/65) of those treated with danazol (P = .0095). At week 24, 40% of patients treated with momelotinib had a 25% or greater reduction in spleen volume vs 6% of patients in the danazol group (P < .0001). Moreover, reductions of 35% or more occurred in 23% vs 3% (P = .0006), respectively.

Additionally, anemia affected patients treated with danazol at a higher rate (75%) than those treated with momelotinib (61%).

At week 24, transfusion independence occurred in 31% (95% CI, 23%-39%) of patients in the momelotinib group vs 20% (95% CI, 11%-32%) of those in the danazol group (one-sided P = .0064). Transfusion independence rates from baseline increased by 18% vs 5% in the momelotinib and danazol groups, respectively.

“The anemia benefit is what excites me the most as a clinician taking care of patients [with] myelofibrosis,” lead author Srdan Verstovsek, MD, PhD, said in an interview with CancerNetwork.

“[They] can maintain transfusion independence or…become transfusion independent. It’s a big deal not having blood transfusions. A combination of quality-of-life improvement, anemia response, and transfusion independence is the key to my excitement about momelotinib. [It] will probably become a number-one choice in the second-line setting.”

Verstovsek is a hematologist-oncologist, professor of medicine, director of the Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms, and chief of the section for myeloproliferative neoplasms in the department of leukemia at the University of Texas MD Anderson Cancer Center.

The international, double-blind, randomized, controlled MOMENTUM trial examined 195 patients at 107 sites across 21 countries between April 24, 2020, and December 3, 2021. The most common diagnosis was primary myelofibrosis (64%). Additionally, most patients had intermediate-2 risk disease (57%) and presented with a JAK2 mutation (76%). The mean duration of prior JAK inhibitor therapy was 2.6 years for the overall population.

The median age in the enrolled population was 71 years (interquartile range [IQR], 66-76) at baseline. Most patients were men (63%) and White (81%).

Patients were randomly assigned 2:1 to either the experimental (n = 130) or control (n = 65) group. Those in the experimental group received oral momelotinib at 200 mg daily plus danazol placebo during the 24-week treatment period, and those in the control group received danazol at 300 mg daily plus momelotinib placebo for the same duration.

Dose reductions of both drugs occurred in a stepwise manner. Momelotinib was reduced in 50 mg increments and danazol was reduced by 200 mg in the first step and then in 100 mg increments, thereafter. The lowest permitted doses of momelotinib and danazol were 50 mg and 200 mg, respectively.

The most common any-grade non-hematological treatment-emergent adverse effects (TEAEs) were diarrhea (22%), nausea (16%), and asthenia (13%) among those treated with momelotinib. The most common TEAEs following treatment with danazol were increased blood creatinine (15%), dyspnea (14%), and peripheral edema (14%). The most frequent non-hematological AEs of grade 3 or higher in the momelotinib and danazol groups were acute kidney injury (3% vs 9%) and pneumonia (2% vs 9%).

“For myelofibrosis, we’re good at counteracting the symptoms and the splenomegaly, and now we can counteract the anemia to a degree, but there’s room for more,” Verstovsek concluded. “There are several other drugs, many [with different] mechanisms of action, that may become very useful in combination with the JAK inhibitors. We may even start thinking about doublets or triplets in the future to make myelofibrosis as chronic as clinically possible.”

 

Reference

Verstovsek S, Gerds AT, Vannucchi AM, et al; MOMENTUM Study Investigators. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0

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Momelotinib Yields Clinically Significant Improvement in Myelofibrosis

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Feb 7, 2023

MONDAY, Feb. 6, 2023 (HealthDay News) — Treatment with momelotinib versus danazol yields clinically significant improvements for patients with myelofibrosis, according to a study published online Jan. 28 in The Lancet.

Srdan Verstovsek, M.D., from the University of Texas MD Anderson Cancer Center in Houston, and colleagues conducted a randomized phase 3 study at 107 sites across 21 countries involving adults with a confirmed diagnosis of primary myelofibrosis or post-polycythemia vera or post-essential thrombocythemia myelofibrosis. Patients were randomly assigned to receive momelotinib plus danazol placebo or danazol plus momelotinib placebo (130 and 65 patients, respectively).

The researchers found that a significantly greater proportion of patients in the momelotinib group versus the danazol group reported a 50 percent or greater reduction in total symptom score (25 versus 9 percent, respectively). Hematologic abnormalities by laboratory values were the most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol, including anemia (61 and 75 percent, respectively) and thrombocytopenia (28 and 26 percent, respectively). Acute kidney injury and pneumonia were the most frequent nonhematologic grade 3 or higher treatment-emergent adverse events with momelotinib and danazol (3 versus 9 percent; 2 versus 9 percent, respectively).

“These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anemia,” the authors write.

Several authors disclosed ties to the pharmaceutical industry, including Sierra Oncology, which funded the study and sponsored momelotinib.

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Dr. Mascarenhas on the Evolution of JAK Inhibitors in Myelofibrosis

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John O. Mascarenhas, MD

John O. Mascarenhas, MD, professor of medicine, hematology, and medical oncology, Icahn School of Medicine at Mount Sinai, director, the Center of Excellence for Blood Cancers and Myeloid Disorders, member, the Tisch Cancer Institute, discusses evolution of JAK inhibitors in the treatment landscape of myelofibrosis.

For nearly a decade, ruxolitinib (Jakafi) was the only JAK inhibitor approved for the treatment of patients with myelofibrosis after the FDA approved ruxolitinib as the first drug to specifically treat patients with myelofibrosis in November 2011. However, fedratinib (Inrebic) and pacritinib (Vono) joined the treatment paradigm in recent years. In 2019, the FDA approved fedratinib for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis and, most recently, in 2022, the FDA granted an accelerated approval to pacritinib for the treatment of adult patients with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L. It is anticipated that momelotinib will be approved at some point in 2023, Mascarenhas notes.

Due to the expanding options for JAK inhibitors in the treatment of myelofibrosis, it is critical that practitioners be aware of the different niches that a JAK inhibitor may be applicable, Mascarenhas says.

Because ruxolitinib has been a part of the treatment landscape for nearly a decade and has an established role in the treatment of myelofibrosis, clinicians may be more comfortable with the drug due to a wealth of experience with that particular JAK inhibitor, and it will likely remain the mainstay of JAK inhibitor therapy for patients with myelofibrosis, Mascarenhas continues.

The other JAK inhibitor options can fill needs in specific subsets of patients. Pacritinib represents a treatment option for patients with platelet count of less than 50 x 109/L, and, notably, it can be utilized, irrespective of platelet count, as a second-line JAK inhibitor, Mascarenhas says. Moreover, fedratinib has broader label and can be utilized in the up-front or second-line settings, Mascarenhas says. As a second-line treatment, fedratinib represents a potential option specifically in patients who experience progression or a lack of spleen response with ruxolitinib, Mascarenhas adds. However, neither ruxolitinib nor fedratinib are good drugs for improving anemia and can be associated with myelosuppression, Mascarenhas concludes.

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Incyte Reports 2022 Fourth Quarter and Year-end Financial Results, Provides 2023 Financial Guidance and Updates on Key Clinical Programs

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– Total FY’22 net product revenues grew 18% to $2.75 billion; total FY’22 revenues of $3.4 billion (+14% Y/Y)

– Jakafi® (ruxolitinib) net revenues of $647 million (+9% Y/Y) in Q4’22 and $2.41 billion (+13%) in FY’22; Jakafi net revenues guidance range of $2.53 – $2.63 billion for FY 2023

– Opzelura™ (ruxolitinib) Cream net revenues of $61 million in Q4’22 and $129 million in FY’22, driven by strong demand in atopic dermatitis, a successful launch in vitiligo and broadening formulary access

Conference Call and Webcast Scheduled Today at 8:00 a.m. ET

WILMINGTON, Del.–(BUSINESS WIRE)–Incyte (Nasdaq:INCY) today reports 2022 fourth quarter financial results, provides 2023 financial guidance and provides a status update on the Company’s clinical development portfolio.

“We are well positioned for strong growth with our current product portfolio and we expect to deliver many important updates this year as we continue to execute on our growth and diversification strategy.”

“We are entering 2023 with significant momentum, following a year of strong commercial performance and progress of several important mid-to-late stage programs across our pipeline. Opzelura has now become the market share leader among branded agents for new atopic dermatitis patients and the adoption in vitiligo has been strong,” said Hervé Hoppenot, Chief Executive Officer, Incyte. “We are well positioned for strong growth with our current product portfolio and we expect to deliver many important updates this year as we continue to execute on our growth and diversification strategy.”

Portfolio Updates

MPNs and GVHD – key highlights

LIMBER (Leadership In MPNs and GVHD BEyond Ruxolitinib) program: Important LIMBER updates were presented at the American Society of Hematology (ASH) Annual Meeting in December 2022:

  • Parsaclisib + ruxolitinib in myelofibrosis (MF): Final results from the Phase 2 trial in MF patients with a suboptimal response to ruxolitinib demonstrated additional spleen volume response and symptom improvement with the addition of parsaclisib. Add-on parsaclisib was generally well-tolerated. A Phase 3 trial evaluating parsaclisib as an add-on to ruxolitinib in suboptimal responders is ongoing with results expected at the end of 2023.
  • Zilurgisertib (ALK2) ± ruxolitinib in MF: Initial results from the Phase 1 study evaluating zilurgisertib as monotherapy or in combination with ruxolitinib in patients with anemia due to MF were presented, establishing proof of mechanism in improving anemia. Updated combination data with ruxolitinib are expected later this year.
  • INCA33989 (mCALR) in MF and essential thrombocythemia (ET): A novel anti-mutant calreticulin (mCALR) monoclonal antibody was unveiled during the ASH plenary session. These data highlight Incyte’s discovery capabilities and research progress in MF and ET; two patient populations where 25-35% of patients have a CALR mutation. INCA33989 is expected to enter the clinic later this year.

Ruxolitinib extended release (XR) formulation: The New Drug Application (NDA) was accepted by the U.S. Food and Drug Administration (FDA) with a Prescription Drug User Fee Act (PDUFA) target action date of March 23, 2023.

Axatilimab in chronic graft-versus-host disease (GVHD): In December, Syndax and Incyte announced that results from the Phase 1/2 trial of axatilimab in patients with recurrent or refractory chronic GVHD following two or more prior lines of therapy were published in the Journal of Clinical Oncology. The data demonstrate that treatment with axatilimab resulted in an overall response rate (ORR) by cycle 7, day 1 of 67% across all patients. AGAVE-201, a global pivotal Phase 2 trial of axatilimab in patients with cGVHD, is ongoing with results expected mid-2023. A Phase 1/2 combination trial of axatilimab with ruxolitinib in patients with newly-diagnosed cGVHD is expected to initiate later this year.

Jakafi patent extension: Incyte was granted pediatric exclusivity which adds six months to the expiration for all ruxolitinib patents, thereby extending the patent expiry for Jakafi through December 2028.

Indication and status

Ruxolitinib XR (QD)

(JAK1/JAK2)

Myelofibrosis, polycythemia vera and GVHD: NDA under review

Ruxolitinib + parsaclisib

(JAK1/JAK2 + PI3Kδ)

Myelofibrosis: Phase 3 (first-line therapy) (LIMBER-313)

Myelofibrosis: Phase 3 (suboptimal responders to ruxolitinib) (LIMBER-304)

Ruxolitinib + INCB57643

(JAK1/JAK2 + BET)

Myelofibrosis: Phase 2

Ruxolitinib + zilurgisertib

(JAK1/JAK2 + ALK2)

Myelofibrosis: Phase 2

Ruxolitinib + CK08041

(JAK1/JAK2 + CB-Tregs)

Myelofibrosis: Phase 1 (LIMBER-TREG108)

Axatilimab (anti-CSF-1R)2

Chronic GVHD: Pivotal Phase 2 (third-line plus therapy) (AGAVE-201)

Ruxolitinib + axatilimab2

(JAK1/JAK2 + anti-CSF-1R)

Chronic GVHD (newly diagnosed): Phase 1/2 in preparation

1

Development collaboration with Cellenkos, Inc.

2

Clinical development of axatilimab in GVHD conducted in collaboration with Syndax Pharmaceuticals.

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