Category Archives: Uncategorized

Potential Therapeutic Target for Blood Cancers Discovered

Posted on by

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.

Read more

Momelotinib reduces symptom burden compared to danazol in patients with myelofibrosis

Posted on by
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

Posted on by

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.

Read more

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

Posted on by
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

Read more

Momelotinib Yields Clinically Significant Improvement in Myelofibrosis

Posted on by

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.

Read more

Dr. Mascarenhas on the Evolution of JAK Inhibitors in Myelofibrosis

Posted on by

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.

Read more

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

Posted on by

– 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.

Read more

Exploring Available and Anticipated Therapies for MPNs

Posted on by
Jordyn Sava

In an interview with Targeted Oncology, Andrew Kuykendall, MD, discussed the most recent approvals for MPNs, practice changing abstracts presented at ASH 2022, and what he expects to see in 2023.

In recent years, the field of myeloproliferative neoplasms (MPNs) has had several clinical developments, including the novel treatments ruxolitinib (Jakafi), fedratinib (Inrebic), and pacritinib (Vonjo).1-2

Ruxolitinib was the first JAK1/2 inhibitor to receive FDA approval and has made tremendous strides for patients with myelofibrosis (MF). Then, fedratinib, another JAK2 inhibitor, received regulatory approval in 2019. This option has shown promise in the second-line for patients who are ruxolitinib-resistant with intermediate-2 and high-risk MF.

However, there was an unmet need of severely thrombocytopenic patients with intermediate- or high-risk MF. This was addressed with the regulatory approval of the JAK2/IRAK1 inhibitor, pacritinib, in February 2022.

Now, clinical trials are ongoing to evaluate a new JAK1/2 option, momelotinib, for patients with JAK-inhibitor treated, symptomatic, and anemic patients with MF. Momelotinib is being evaluated in the ongoing phase 3 MOMENTUM trial (NCT04173494). Findings from the study have already shown there to be significant improvements in anemia measures, spleen size, and symptoms for this patient population.

According to Andrew Kuykendall, MD, if the FDA grants an approval for momelotinib in 2023, this will be practice changing for patients with MPNs.

“The main thing that will shake up treatment in 2023 is the anticipated approval of momelotinib. We’ve seen the positive data from the MOMENTUM study, and we are looking at an approval sometime during the summer of 2023. This is an agent that has been studied in the SIMPLIFY-1 and -2 trials [NCT01969838; NCT02101268] as well as the recently completed MOMENTUM study. This agent is another JAK inhibitor, but it has a little bit of a different niche. It seems to be a little more favorable, and its impact on anemia induces some transfusion independence, and it still has some good effect on spleen and symptoms,” Kuykendall, MD, an assistant member at the H. Lee Moffitt Cancer Center of University of South Florida in Tampa, FL, told Targeted OncologyTM, in an interview.

In the interview, Kuykendall discussed the most recent approvals for MPNs, practice changing abstracts presented at the 2022 American Society of Hematology Annual Meeting (ASH 2022), and what he expects to see in 2023.

What exciting changes have been seen in the MPN space over the past year?

Things with MPNs are changing relatively fast. Going back to November of [2021], we had the approval of ropeginterferon alfa-2b-nj for polycythemia vera, which was kind of the second approval we’ve had of a polycythemia vera medication, and certainly has transformed how we think about treating that disease with an idea of potential for disease modification. In February [2022], we had the accelerated approval of pacritinib for the treatment of myelofibrosis for patients that have severe thrombocytopenia. It was very exciting to get 2 drugs approved within the context of a year. Then, we have the continued enrollment of many phase 3 clinical trials that are potentially practice changing and may bring new therapeutic options to the table.

Can you discuss some of the new approvals?

With ropeginterferon, for a long time, we’ve been using interferon formulations within polycythemia vera and essential thrombocythemia, maybe to a lesser extent within myelofibrosis. This is going back to the 90s. We know that it’s effective, it can help control counts, and we have seen in small numbers of patients that it may be able to decrease the JAK2 allele burden and potentially could correlate with delayed disease progression and potential disease modification. That’s something that has been exciting to patients.

Historically, interferon has been challenged by toxicity, especially the short acting forms. As we got pegylated interferon, we had longer acting, better tolerated, and lower doses, and patients stayed on for a longer period of time, did better, could appreciate some of those durable responses that you get when you’re on long term therapy. With ropeginterferon, we’ve now got an approved agent as opposed to using something off-label. It’s given less frequently, so every 2 weeks, and we have seen good long-term data with more robust datasets that have shown the ability to decrease allele fractions and JAK2 mutations. What that’s brought to the table is something not completely new, because we’ve been using interferons, but something that has stronger data to support it. It’s something that we can use as an approved on-label medication for many patients. I think it’s gotten patients very excited about potentially having something that can alter the natural history of disease.

Pacritinib on the other hand is something that was approved for an unmet need. It’s an accelerated approval for patients with thrombocytopenia with less than 50,000 platelets, and for those patients, we don’t have many great options. We have ruxolitinib and fedratinib that are approved, but typically, they’ve been given in patients with over 50,000 platelets. We have struggled to treat these patients with lower platelet counts. Pacritinib has great data in the PERSIST-1 trial and PERSIST-2 trials [NCT01773187; NCT02055781], and in the ongoing PACIFICA study [NCT03165734]. It shows that it can be safely leveraged in these patients with lower platelet counts. We were happy to get the accelerated approval because now, we have an option for those patients, and we’re not having to do things off-label or give modified doses. Now, we have something we can fully dose and bring an effective treatment for these patients that have an unmet need.

What abstracts presented at ASH 2022 do you think are practice changing or show potential for patients with MPNs?

There [were] 24 oral abstracts for MPNs this year [at ASH]. One [we saw was] the final dataset from the RUXOpeg study [​​NCT02742324]. It was a combination of ruxolitinib and peg-interferon. This could be immediately changed as both drugs are available to us right now. The question has always been, can we meaningfully combine these 2 agents in MPNs and is there a benefit to doing that? Ruxolitinib is thought of as something that helps with symptoms of the disease, spleen symptoms, and has a survival benefit in myelofibrosis for more of the advanced stages.

Then we have interferon, which is thought of in earlier stages of MPNs and something that has this potential for disease modification that maybe we don’t see with ruxolitinib. The idea of reusing them together is something we’ve talked about for a long time, we’ve seen early datasets, and we have the final results of the RUXOpeg study, which is an upfront combination of the 2 in intermediate-1 risk patients. We can get some support if we were to leverage this combination. Is that something that we get benefit out of? With the presentation [at ASH], we were able to see some of the impact that interferon has on stem cell populations and see if there is a rationale for leveraging this combination in early phase patients.

Looking ahead, what do anticipate the treatment landscape for MPNs to look like?

I think that we’re still going to be kind of gaining data from these phase 2 clinical trials. The main thing that will shake up treatment in 2023 is the anticipated approval of momelotinib. We’ve seen the positive data from the MOMENTUM study, and we are looking at an approval sometime during the summer of 2023. This is an agent that has been studied in the SIMPLIFY-1 and -2 trials as well as the recently completed MOMENTUM study. This agent is another JAK inhibitor, but it has a little bit of a different niche. It seems to be a little more favorable, and its impact on anemia induces some transfusion independence, and it still has some good effect on spleen and symptoms. We know that anemia is inherent to myelofibrosis, it’s going to be a part of everyone’s disease course over time. Unfortunately, with ruxolitinib and fedratinib, we’ve had to often punt that. Patients have had a worsening of their anemia, at least temporarily with those agents. We’ve said that we will accept that for the spleen and symptom benefits. With momelotinib, maybe we don’t have to do that, and this anemic patient population may have an alternative option that could treat multiple aspects of the disease and we won’t have to kind of ignore 1 aspect while treating the others. That will probably be the biggest thing that shakes things up.

The other question that we have in polycythemia that was supported with abstracts presented at [ASH 2022] is, where do we leverage interferon vs hydroxyurea vs ruxolitinib. All 3 are approved and utilized within the realm of MPNs, especially polycythemia vera. We have used ropeginterferon more so for this allele fraction, this disease modification aspect, but more data presented on ruxolitinib suggests patients on long-term ruxolitinib who have [polycythemia vera] or [essential thrombocytopenia] may be able to get similar VAF or allele fraction reductions. That may shake things up a bit because we haven’t thought of that or seen that. Seeing that this occurs over the long-term is what we think about with ropeginterferon. These allele fractions, this disease burden, and reductions typically take a long time to happen. If we can see that and if we do believe this data coming out with ruxolitinib, that may shake things up as far as how we talk to patients and how we leverage these agents in clinical practice.

REFERENCES:
Masarova L, Bose P, Pemmaraju N, et al. Improved survival of patients with myelofibrosis in the last decade: single-center experience. Cancer. 2022;128(8):1658-1665. doi:10.1002/cncr.34103
Verstovsek S, Parasuraman S, Yu J, et al. Real-world survival of US patients with intermediate- to high-risk myelofibrosis: impact of ruxolitinib approval. Ann Hematol. 2022;101(1):131-137. doi:10.1007/s00277-021-04682-x

Read more

Clinical Review of ropeginterferon alfa-2b Suggests Amended Dosing Schedule May Support Improved Clinical Outcomes in Polycythemia Vera

Posted on by

Review of studies published in Frontiers in Oncology highlights dosing considerations that may help more patients achieve earlier complete hematological response

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 the publication of a review of clinical literature in the journal, Frontiers in Oncology. The research indicates that an amended dosing schedule, with higher initial dose and faster dose titration of ropeginterferon alfa-2b (marketed as BESREMi®), may correlate to earlier complete hematological response (CHR) in polycythemia vera (PV) in adults. The analysis titled, “An alternative dosing strategy for ropeginterferon alfa-2b may help improve outcomes in myeloproliferative neoplasms: An overview of previous and ongoing studies with perspectives on the future,” was co-authored by PharmaEssentia researchers.

“This latest research will help support more informed dialogue among physicians regarding their patients with PV.”

“This publication delves into the critical connection between an accelerated dosing regimen for ropeginterferon alfa-2b and the key efficacy, safety and tolerability outcomes we aim to achieve for our patients,” said John Mascarenhas, M.D., Director of the Adult Leukemia Program and Leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai and study author. “The data from these clinical and investigational studies suggest that a higher starting dose and faster titration could be an appropriate approach to attain clinical outcomes earlier while minimizing the risk of thrombosis and hemorrhage in patients with PV.”

PV is the most common myeloproliferative neoplasm (MPN) and a long-term, potentially life-threatening disease with limited treatment options. Recent clinical investigations suggest the potential for rapid titration and higher starting doses to benefit those with PV.1

The publication highlights the findings from multiple studies supporting the efficacy, safety and tolerability of a 250-350-500 mcg titration dosing regimen of ropeginterferon alfa-2b:

  • A compassionate use program (CUP) study in Taiwan (n=14; hydroxyurea and/or anagrelide resistance or intolerance patients) resulted in a CHR rate of 73% at 52 weeks vs 51% observed in a study with a slower titration method. No new safety signals were detected.
  • Interim results from an ongoing, Phase 2, single-arm study in Chinese PV patients (n=49; resistant or intolerant to hydroxyurea) showed that amended dosing achieved a CHR rate of 52% at Week 24 compared to 43% at Week 52 observed in PROUD-PV. Treatment-related Grade >3 adverse events (AEs) were reported in five patients (10.2%).
  • Data from an investigator-initiated trial in Korea (n=45; hydroxyurea naïve or pre-treated PV patients) indicated higher hematologic and molecular responses at 6 months. Dose reductions were required in 4.4% of patients and the majority of AEs were Grade 1 or 2 with no treatment-related serious AEs reported.

Across the studies, ropeginterferon alfa-2b was generally well-tolerated. No thromboembolic complications have been reported with the accelerated titration regimen in PV. Rather, the review authors indicate that it is reasonable to believe that the accelerated dosing regimen may potentially minimize the risk of thrombosis and hemorrhage associated with an under-dosing during dose titrations.

“As more clinicians gain familiarity with BESREMi®, we want to support treatment goals by ensuring patients can effectively achieve and maintain their target clinical and molecular responses, as this may help reduce the risk of disease progression over time,” said Raymond Urbanski, M.D., Ph.D., Senior Vice President and U.S. Head of Clinical Development and Medical Affairs. “This latest research will help support more informed dialogue among physicians regarding their patients with PV.”

PharmaEssentia is interested in the attributes of the amended dosing approach with ropeginterferon alfa-2b that may extend into related MPNs with unmet needs such as essential thrombocythemia (ET) and pre-fibrotic primary myelofibrosis (pMF). Several planned or ongoing Phase 3 clinical trials will further evaluate this regimen of ropeginterferon alfa-2b in ET (SURPASS and EXCEED trials) and PV (ECLIPSE trial). Plans for a Phase 3 clinical trial in pMF are also underway.

Follow PharmaEssentia USA on Twitter and LinkedIn for news and updates.

About Polycythemia Vera (PV)

Polycythemia vera (PV) is a cancer originating from a disease-initiating stem cell in the bone marrow resulting in a chronic increase of red blood cells, white blood cells, and platelets. PV may result in cardiovascular complications such as thrombosis and embolism, and often transforms to secondary myelofibrosis or leukemia. While the molecular mechanism underlying PV is still subject of intense research, current results point to a set of acquired mutations, the most important being a mutant form of JAK2.2

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.

Indication

BESREMi is indicated for the treatment of adults with polycythemia vera.

Important Safety Information

WARNING: RISK OF SERIOUS DISORDERS

Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping therapy.

CONTRAINDICATIONS

  • Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation, or suicide attempt
  • Hypersensitivity to interferons including interferon alfa-2b or any of the inactive ingredients of BESREMi.
  • Moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment
  • History or presence of active serious or untreated autoimmune disease
  • Immunosuppressed transplant recipients

Read more

Myeloproliferative Neoplasm Management: Future Directions in Care

Posted on by

Feb 2, 2023

Naveen Pemmaraju, MD
John Mascarenhas, MD

 

Closing out their discussion on myeloproliferative neoplasms, key opinion leaders share excitement for future evolutions in the treatment paradigm.

Transcript:

Naveen Pemmaraju, MD: So team, what I want to do is, I’m going to go to each of you and get some final comments, and ask you to give me 2 or 3 things. Maybe 1 is something that you learned, maybe at ASH [American Society of Hematology meeting] or in the last few months leading up to ASH, and then 2 and 3 is what’s your wish list? What do you want us as the field to think about and focus on in 2023, either in the setting of clinical trials, transplant symptom burden, to give folks out there a sense of what you are thinking about and what you’re excited about? Dr Palmer, we’ll start with you, and we’ll go down the panel.

Jeanne M. Palmer, MD: This year at ASH, it was great to hear some of the updated information and to try to understand the new drugs that are coming out and have discussions with people about where we think they’re going to fall into the landscape of the therapy. I look forward to exploring that further. Although I recognize it’s certainly going to be a goal for the next 5 years, probably more than the next year, I’m hopeful that we’ll be able to do that. One of the things that’s on my wish list is I think we need to better understand the response criteria we’re looking at, so what is the meaningful response that we have for a patient? Right now, we’ve been using spleen size, reduction, and symptom burden, which are very important factors that contribute to it, but what are the markers that are going to predict survival? Because it takes a long time to see survival. We must figure that out. What are the markers that are most meaningful to patients? What can we anchor with something like the Global Impression of Change that tells us this makes the patient feel a lot better. It doesn’t just make me feel better to look at their numbers or look at different things, but it makes them feel better also, more importantly, associated with survival. That’s my wish list is to come up with the best way to figure out what works.

Naveen Pemmaraju, MD: Wonderful. Dr Oh, your final thoughts?

Stephen Oh, MD, PhD: We are at a very exciting time for this field with more new agents becoming available, and many are now in phase 3 that may soon become approved. It continues to be an extremely exciting time for the field. In terms of specific things that I will highlight, I’ll be the broken record and keep coming back to inflammation and anemia, and more recognition that this is something important in terms of the clinical features of patients with mild fibrosis, anemia related to inflammation, targeting these pathways, hepcidin. It’s also something as far as updates on the lab side that is increasingly being investigated. What I continue to say as far as that’s concerned is, we all ask, can we more potently target the abnormal inflammation? But I think there is an opportunity to leverage these abnormal inflammatory signaling pathways in a way that not just reduces symptoms and improves bone marrow function, but can turn it on its head to target the malignant cone as well in a more effective way. That’s what I would highlight. The last thing I would say, we talked about this new monoclonal antibody for mutant calreticulin. The other obvious approach, and along those lines, is something specific for mutant JAK2 [Janus kinase 2]. We still don’t have that. There are obvious reasons why that has not been the case over the years, but I think there is a growing hope, maybe it’s the best way to say it, that a truly mutant selective JAK2 inhibitor may be here in the coming years.

Naveen Pemmaraju, MD:Wow. That’s exciting. I’ll share my thoughts with the panel. At this year’s ASH, the exciting thing for me was mainly in our myelofibrosis sessions, the emphasis on what all of you discussed here, which was the elucidation and understanding of disease biology and biomarkers that you can hang your hat on, or at least have a sense of what’s going on. The one that really captured that for me was what Dr Oh presented, which was the ACVR1 [activin A receptor type I] story in pacritinib [Vonjo], our third approved JAK inhibitor. We now have several JAK inhibitors, momelotinib and pacritinib, which can be not only delivered in the setting of cytopenias, but actually improving the cytopenias, including the holy grail of anemia. I want to see how the combination therapies do, not only in terms of overall survival, spleen and symptoms, but how they do with the anemia, and how durable that is. I thought that was an exciting finding. For the future, as you all know in our own discussions, I hope you’ll allow me to say a unified theory of disease modification, what we’ve all talked about, and I still think it’s an aspirational goal. It can be something like overall survival as the top most important thing for our patients and for us, coupled with the traditional factors that Ruben and Serge pioneered of spleen size reduction symptoms, and then coupled with some of the newer markers that Steve, Dr Angela Fleischman [University of California, Irvine] and our colleagues are working on, including VAF, variant allele fraction, cytokine state, and maybe even bone marrow fibrosis. Can we couple all those into something meaningful for our patients? John, let me turn it to you, and then Ruben for your final thoughts.

John Mascarenhas, MD:It’s difficult to be the fourth person in a row to do this. I thought that’d be Ruben, because he set all the right things you said all the top line.

Naveen Pemmaraju, MD:It’s all supervised here, OK.

John Mascarenhas, MD:I agree with you all, and I know you share this enthusiasm. As a clinician investigator in this field, this is a great time to be in it because the science is driving the medicine and translating directly into the clinic. What we learned in the clinic feeds back and then helps us understand how to refine and go about it the right way. I’m most impressed with beyond the things I’ve been talking about, is how we sit down and listen carefully to a lot of the scientific sessions. You start to realize that there’s so much interconnectivity here between the pathways, seemingly redundancy here, and what we end up often doing is trying to target 1 pathway that we think is relevant, not understanding that there’s so many other pathways that are activated, and that compensate and sometimes overcompensate for shutting down 1 pathway. There’s a lot of examples of this, one clear example is if you shut down BET [bromodomain and extraterminal] regulated transcription, you have a consequence of down regulating NF-kappaB [nuclear factor-kappa B] activity, and down regulating BCL-2 [B-cell lymphoma 2] expression, c-MYC expression, all relevant nodes in the pathobiology of myelofibrosis. It begs the question, is there 1 specific target? Or is what we’re looking at such a complex interplay that we need to be approaching this from various angles at the same time? Which I think reinforces the theme that we’ve been discussing, which is rational combination, mechanism-based combination. I’m excited that a lot of the scientific abstracts that were presented today will in 2 years, 3 years, translate into the next wave of clinical trials. I think that’s fabulous. That’s why we’re here.

Naveen Pemmaraju, MD:That’s fantastic. Ruben, take us home and give us your final thoughts.

Ruben Mesa, MD:One thing I’ve learned this year is don’t let the perfect be the enemy of the good. Meaning, when ruxolitinib [Jakafi] was first approved, there were many detractors saying, “This is supportive care. I could just give patients 10 milligrams of prednisone, and they’d be the same.” That is just pure nonsense. The rate at which patients pass away from myelofibrosis is clearly decreased significantly over the years. Is it perfect? No. I think the expansion we’ve had now to hopefully have 4 JAK inhibitors is important. These drugs make an important difference. They each have their own role. I still agree with John, I want to look at novel combinations, but a combo that includes a JAK inhibitor probably is logical, based on several things that we have learned. Although these are not perfect, these are good drugs that make a real impact on patients both in terms of length of life and quality of life. Now my wish list is, I envisioned the situation where we’re 18 months from now, and we have 6 phase 3 clinical trials that have data that looks similar, we improve spleen and symptoms more than singulation ruxolitinib, and we have a toxicity profile that includes diarrhea, nausea, and vomiting. That’s what we’re going to be stuck with. So how do we sort through which patient goes on which drug because they’re going to be patients that have a fabulous response to rux [ruxolitinib] and pelabresib, rux [ruxolitinib] and parsaclisib, rux [ruxolitinib] and navitoclax, rux [ruxolitinib] and HDM2 inhibitor, on and on, but not everyone. How do we sort through that? I think the correlative studies are going to be important. How do we sort through so that we have any science behind I’m going to give which drug just comes to top of mind because they have very different mechanisms of action, and the patients are different? Those that develop these trials hope that the patients are going to be eligible, of course, but we realize that a drug has a 20% response rate. It means it has 100% response rate for 20% of the patients and has a 0% response rate for the other 80%. That’s my wish list. Our work is not done when we have the top line data on those phase 3 studies, but a tremendous sense of progress and hope. As Naveen and I were talking earlier at ASH, when you think about what ASH looked like in MF [myelofibrosis] in 2002. In 2002, I gave the oral presentation on thalidomide [Thalomid] and prednisone, and it was like the Super Bowl. There were so many people there because we showed some improvement in anemia, but that was it, no spleen, no symptoms, no disease modification. There was a bouncer outside keeping people out, so the progress we’ve made is unbelievable.

Naveen Pemmaraju, MD:Well, I must tell you, team, we have lovely discussions. This was one of the best yet. On behalf of my colleagues Ruben, John, Steve, and Jeanne, I want to thank you all for this very rich and informative discussion. I want to thank our audience for taking time to view this, and we hope that you found this OncLive Peer Exchange discussion to be useful and informative for your practices. With that, I’m Naveen Pemmaraju. We will sign off for now and see you next time. Thank you all so much.

Transcript edited for clarity.

 

Read more