TP-3654 Showcases Early Signs of Tolerability, Clinical Activity in Myelofibrosis

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By Chris Ryan

The PIM1 kinase inhibitor TP-3654 was well tolerated and showcased preliminary signs of activity, including spleen volume reduction, symptom improvement, and broad cytokine reduction, in patients with myelofibrosis who were previously treated with or were ineligible for a JAK inhibitor.

The PIM1 kinase inhibitor TP-3654 was well tolerated and showcased preliminary signs of activity, including spleen volume reduction (SVR), symptom improvement, and broad cytokine reduction, in patients with myelofibrosis who were previously treated with or were ineligible for a JAK inhibitor, according to results from the dose-escalation portion of a phase 1/2 trial (NCT04176198).

Data presented at the 2022 ASH Annual Meeting showed that among 8 evaluable patients who were on treatment for at least 12 weeks, 6 experienced SVR. The median SVR was 11%; 5 patients had a SVR of at least 10% and 2 had a SVR of at least 35%. Additionally, 7 of the 8 patients experienced an improvement in total symptom score (TSS). The median TSS improvement was 66%, and 5 patients experienced a TSS improvement of at least 50%.

“Dose escalation is ongoing and TP-3654 appears to be well tolerated, [with] no dose-limiting toxicities [DLTs] to date,” said Firas El Chaer, MD, the lead study author and an assistant professor of medicine in the Department of Hematology/Oncology at University of Virginia Health System in Charlottesville, Virginia, in a presentation of the data. “The most common adverse effects are grade 1 gastrointestinal toxicities that resolved in 1 to 2 weeks.”

PIM1 is a proto-oncogene regulated in part through the JAK/STAT pathway, and PIM1 kinase plays a vital role in cytokine-induced signal transduction by controlling transcription factors. The upregulation of PIM1 kinase results in increased cytokines relevant to immune activation and fibrosis. In bone marrow and peripheral blood mononuclear cell samples collected from patients with myelofibrosis, a significant increase of PIM1 expression has been observed. Investigators have hypothesized that novel therapies that selectively inhibit PIM1 may provide disease-modifying effects and avoid instances of cytopenia.

“In an aggressive murine MLP myelofibrosis mouse model, PIM1 inhibition led to reduced bone marrow fibrosis, [reduced] splenomegaly, and increased [overall] survival [OS],” El Chaer added.

The phase 1/2 trial is evaluating the TP-3654 in patients with primary, post–polycythemia vera (PV), or post–essential thrombocythemia (ET) myelofibrosis who are relapsed, refractory, intolerant, or ineligible to receive treatment with JAK inhibitors.

To participate on the trial, patients are required to have a Dynamic International Prognostic Scoring System (DIPSS) score of intermediate-1, intermediate-2, or high risk; a platelet count of at least 25 x 109 cells/L; an ECOG performance status of 0 to 2; splenomegaly with a volume of at least 450 cm3; and at least 2 symptoms per the Myelofibrosis Symptom Assessment Form v. 4.0.

Thus far in the dose-escalation portion of the trial, patients were treated with single-agent TP-3654 across 5 dose levels, including 480 mg per day, 720 mg per day, 360 mg twice per day, 480 mg twice per day, and 720 mg twice per day. Dose escalation is ongoing, and investigators plan to examine doses up to 1440 mg twice per day. The trial will then determine the maximum tolerated dose (MTD) and the recommended phase 2 dose of the agent before advancing to dose expansion in phase 2.

The primary end points of the trial are safety and tolerability. Secondary end points consist of SVR, TSS reduction, OS, bone marrow fibrosis change, and pharmacokinetics.

Among 9 patients enrolled in the dose-escalation portion of the research, the median age was 71 years (range, 61-77). The median spleen length was 12 cm (range, 0-25), the median spleen volume was 2231 cm3 (range, 857-4407), and the median TSS was 18 (range, 4-62). Additionally, the median platelet count was 120 x 109cells/L (range, 68-237), and 6 patients had a platelet count of at least 100 x 109 cells/L. The median hemoglobin was 10.1 g/dL (range, 5.9-13.7), and 5 patients had a hemoglobin level of at least 10 g/dL. Notably, 2 patients were transfusion dependent.

Patients enrolled to the trial had the following myelofibrosis subtypes: primary (n = 4), post-PV (n = 4), and post-ET (n = 1). They had a DIPSS score of intermediate-1 (n = 3), intermediate-2 (n = 4), or high risk (n = 2). Additionally, 7 patients had tumors that harbored JAK2 V617F mutations, and 2 patients had a CALR mutation.

All 9 patients received prior treatment with ruxolitinib (Jakafi) for a median of 33 weeks (range, 10-268), and 2 patients received prior fedratinib (Inrebic) for a median of 36 weeks (range, 36-49). Three patients were primary refractory to JAK inhibitors, 4 experienced a loss of response, and 2 were intolerant to these agents.

As of the data cutoff date of October 11, 2022, 4 patients were still receiving treatment; this included 2 patients who received TP-3654 at 480 mg twice daily, 1 patient who was given the agent at 720 mg once daily, and 1 patient who received the drug at 720 mg twice daily. Reasons for discontinuation included physician withdrawal (n = 2), disease progression (n = 2), and patient withdrawal (n = 1). Notably, no patients discontinued due to adverse effects (AEs).

Additional data showed that cytokine reduction was observed as early as week 4 for the initial dose cohorts, and this reduction correlated with TSS reduction. Cytokines associated with myelofibrosis—including IL-6, IL-10, IL-12, IL-18, TGF-b, EGFR, ferritin, GRO-a, IL-1RA, MMP-9, PAI-1, RANTES, TIMP-1, TNFR-2, and VCAM-1—showed reduction after treatment.

Regarding safety, no DLTs or serious treatment-related AEs were reported. The most common treatment-emergent AEs (TEAEs) that were grade 1 or 2 included diarrhea (n = 7), nausea (n = 5), vomiting (n = 4), abdominal distention (n = 2), urinary tract infection (n = 2), muscle spasms (n = 2), insomnia (n = 2), fatigue (n = 2), dyspnea (n = 2), abdominal pain (n = 1), and increased bilirubin (n = 1). Grade 3 vomiting, abdominal pain, and increased bilirubin were experienced by 1 patient each.

Grade 1/2 hematological TEAEs included a decreased platelet count (n = 2), anemia (n = 1), and leukocytosis (n = 1). Grade 3 decreased platelet count, anemia, and leukocytosis were observed in 1 patient each. No patients required a dose reduction or discontinued treatment due to AEs.

“Enrollment continues as [TP-3654] monotherapy to identify the MTD, and [data] support the development of TP-3654 in combination with JAK inhibitors,” El Chaer concluded.

Reference

El Chaer F, McCloskey J, Rein LAM, et al. Preliminary data from the phase I/II study of TP-3654, a selective oral PIM1 kinase inhibitor, in patients with myelofibrosis previously treated with or ineligible for AK inhibitor therapy. Blood. 2022;140(suppl 1):594-595. doi:10.1182/blood-2022-159086

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Momelotinib Continues to Prove Itself as a Potential Treatment for Myelofibrosis

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In an interview with Targeted Oncology, Srdan Verstovsek, MD, discussed the potential use of momelotinib as a treatment for patients with myelofibrosis if approved by the FDA in June 2023.

As updated findings from the MOMENTUM trial (NCT04173494) continue to demonstrate positive results, momelotinib continues to prove its potential as a future treatment option for patients with anemic myelofibrosis.

Momelotinib is an investigational oral treatment for patients with myelofibrosis. The JAK1 and JAK2 inhibitor recently showed benefit in patients with myelofibrosis as momelotinib induced durable symptoms, transfusion independence, and splenic responses through 48 weeks of treatment.

The findings come from the phase 3 open-label, crossover phase of the MOMENTUM study (NCT04173494) which were presented at the American Society of Hematology (ASH) 2022 Annual Meeting.

In this trial, patients were either administered momelotinib or crossed over from danazol to receive momelotinib. Week 24 symptom responses continued through week 48 of treatment in 97% of patients on the momelotinib-to-momelotinib arm compared with 100% in the danazol-to-momelotinib arm.

Further, 29% of patients who crossed over to momelotinib at week 24 and did not have a Total Symptom Score (TSS) response to danazol and achieved TSS responses at week 48. Among patients, 20% who continued momelotinib in this phase of the trial were also new responders at week 48.

According to Srdan Verstovsek, MD, these findings from the MOMENTUM study confirm what have previously been reported in other phase 3 studies, including Simplify 1 study (NCT01969838) and SIMPLIFY 2 study (NCT02101268).

“Improvements in the spleen symptoms and anemia were seen significantly better than danazol. Now we know that these are long lasting benefits, the therapy does not need to be changed, the dose not need to be modified, it is very safe over a prolonged period, it works for a long period of time, and there is a strong suggestion that there may even be a survival benefit in some groups of patients in this setting where life is typically short. I would expect based on this blinded, randomized study that the momelotinib would be approved in United States next June,” stated Verstovsek, MD, associate professor of medicine in the Leukemia department at the University of Texas MD Anderson Cancer Center, in an interview with Targeted OncologyTM.

In the interview, Verstovsek discussed the potential use of momelotinib as a treatment for patients with myelofibrosis if approved by the FDA in June 2023.

Targeted Oncology: Can you discuss the mechanism of action of momelotinib?

Verstovsek: Momelotinib is an interesting medication that inhibits JAK1 and JAK2, which is something that we would expect to benefit patients with the myeloproliferative neoplasms, particularly myelofibrosis, in inhibiting proliferation and inflammation and leading to some clinical benefits like improving quality-of-life, and the reduction in the spleen. It also uniquely improves anemia and that is because it’s an ACVR1 inhibitor. ACVR1 is also called ALK-2, [which is] a receptor on the liver where inhibition of that receptor would alter the iron metabolism. It decreases hepcidin, a master regulator of iron metabolism, and allows more iron to be available for erythropoiesis, the blood making process. Therefore, this medication would inhibit more than what you would expect with the JAK inhibitor and lead to clinical benefits on all 3 fronts: The spleen, the symptoms, and the anemia benefits.

Can you discuss the MOMENTUM study of momelotinib in patients with symptomatic and anemic myelofibrosis?

At this age, we have learned a lot from the MOMENTUM study. This is the 1 that finally confirmed what we have seen earlier on in 2 other phase 3 studies. The study is the phase 3 randomized study, blinded, between 2 therapies, momelotinib and danazol in the second-line setting. The standard practice frontline therapy is ruxolitinib [Jakafi], a JAK inhibitor that improves the spleen and symptoms but can worsen anemia. Anemia is the leading cause of why you stop ruxolitinib. Many patients, most of them are anemic when they get to the second-line, so that would be the setting for the development of a new drug like momelotinib. This is where the phase 3 study was done.

Improvements in the spleen symptoms and anemia were seen significantly better than danazol. Now we know that these are long lasting benefits, the therapy does not need to be changed, the dose not need to be modified, it is very safe over a prolonged period, it works for a long period of time, and there is a strong suggestion that there may even be a survival benefit in some groups of patients in this setting where life is typically short. I would expect based on this blinded, randomized study that the momelotinib would be approved in the United States next June.

What studies complement the MOMENTUM trial?

There is a study called the Simplify 1 study which was a frontline study comparing momelotinib with ruxolitinib where momelotinib was as effective as ruxolitinib in controlling the spleen. It was also better than ruxolitinib in the control of anemia, so anemia benefit was already seen in the past. The Simplify 2 study is a phase 3, randomized study in people who had the hematological toxicities from ruxolitinib. They were randomized between momelotinib or best radiotherapy. In that setting as well, there were anemia benefits and symptomatic improvements. There are multiple sources, several phase 3 studies, when you put them together to tell us that this drug is unique [and has the] ability to help a good proportion of patients on anemia, on the spleen, and on the symptoms.

What are some of the data from the studies? What sets them apart from one another?

Transfusion independence is a hallmark of a drug that we seek, in a good way, because anemia may be of a different degree. We talk of anemia, loosely described, as a hemoglobin less than 10. There are patients that have hemoglobin less than 10 but are not symptomatic and don’t need intervention. When you start transfusions, you become transfusion-requiring or even transfusion-dependent [where you need] 2 transfusions monthly for a few months, and that is the different ballgame. Here, we talk about the therapy that would prevent transfusions to happen or eliminate the need for transfusions in about a third of the patients in a second-line setting. Similar happened earlier in studies of momelotinib, the Simplify 1 or Simplify 2 studies, in frontline or intolerant patients. Therefore, we have plenty of evidence of the uniqueness of this medication. We will account for its use in a wider group of patients when it comes, and hopefully it will become available for us in community settings.

What are the next steps for this research?

[The next step is looking at] how to optimize the therapy amount further. If we have on 1 hand the ruxolitinib medication as a frontline choice to control the spleen symptoms and for the second setting, we have momelotinib in addition to pacritinib and fedratinib [Inrebic], where else can we see improvements? Well, combination studies with the novel agents may complement what the JAK inhibitors do further. Further improvement in anemia, further improvement in spleen, and the symptoms. Finally, [looking at] potential combinations with the non-JAK inhibitors. Clinical studies of combinations are underway [and evaluating] what would set them apart, not only enhancement of these 3 benefits, but your ability of a control the disease signs and symptoms to say hey, with this combination, maybe with a momelotinib-based combination with another agent, we are going to enhance the control of anemia, spleen, and symptoms, but it will last much longer where overall survival is prolonged. This is where we are heading.

What other ongoing research in the MPN space seems exciting to you?

Momelotinb is the 1 that will be practice changing as it comes available next summer. In a plenary session [at ASH], there was a clinical presentation of something that may have a significant impact on the subgroup of patients with myelofibrosis or MPN in general. I’m talking about the development of the antibody that would target mutated calreticulin. Now, what is muted calreticulin? We know that everybody has hyperactivity over the JAK/STAT pathway, an intracellular signaling pathway, that drives this process. We also know that about a third of the patients have a mutation in a gene called calreticulin, it makes muted calreticulin that comes outside the cell and binds to the receptors from outside the cells in the bone marrow and makes the cells grow without control. That is the case in about a third of the patients. Developing the antibody that would attach itself to the mutated calreticulin and destroy that malignant cell is a desirable next step in the development of our medications. Targeting a genetically identifiable group of people with the marker that you can then utilize for the elimination of malignant cells.

This is where we all aspire to go. To start to talk about the molecular response. Not only control the signs and symptoms, but elimination of the disease and molecular response. So it was very exciting for a plenary session and hopefully within a few years, we will have a study with the calreticulin antibody.

In this past year, what would you say has been the most impactful research in the MPN space?

Understanding the preclinical complexity of the disease over the last 5-10 years led to the development of many different drugs that have nothing to do with the hyperactivity of the JAK/STAT pathway which is present in every case. We now potentially have 4 different JAK inhibitors. But understanding the 4 as I mentioned, the ACVR1 contribution to anemia, contribution of the epigenetic modifications or BCL-xl enhancement, or telomerase role in the disease process, these types of discoveries led to clinical studies with these specific medications for the different molecular or biological abnormalities in myelofibrosis cells. Understanding the biology better leads to clinical development of new drugs and that on its own is exciting. We have about 7 or 8 phase 3 randomized studies underway in myelofibrosis for the development of new drugs with medications that are not JAK2 inhibitors.

How do you foresee this research on momelotinib potentially impacting clinical practice?

As June of [this] year comes, we are expected to get the decision by FDA to approve or not approve momelotinib. I hope it will because the study was well done and clearly shows the benefit of the anemia symptoms and spleen. Right away we would find its place in the management of our patients with myelofibrosis, particularly where the phase 3 randomized study was done in the second-line setting where we struggle. We don’t have any therapies for anemia, people may have low platelets, and this drug can be given to people with lower platelets. Of course, it can control the spleen. The spleen has major problems, so I would say that these drugs may become the number 1 choice as a therapy in a secondary setting in myelofibrosis in the near future.

REFERENCE:
Gerds AT, Mesa RA, Vannucchi AM, et al. Updated results from the Momentum phase 3 study of momelotinib (MMB) versus danazol (DAN) in sympatomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. Presented at: 2022 ASH Annual Meeting; December 10-13, 2022; New Orleans, LA. Abstract 627

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Cellenkos Announces First Patient Dosed with CK0804 Cell Therapy in LIMBER-TREG108 Clinical Trial

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Category: DNA RNA and Cells

Published on Saturday, 07 January 2023 18:23

  • First patient dosed with CK0804 Treg cells as an add on therapy to ruxolitinib in patients with myelofibrosis who experience a suboptimal response to ruxolitinib.
  • On-going Phase 1b study evaluating safety of CK0804

HOUSTON, TX, USA I January 06, 2023 I Cellenkos Inc, a clinical stage biotechnology company focused on the development of allogeneic, off-the-shelf, T regulatory cell therapies targeting inflammatory disorders and autoimmune diseases, today announced that the first patient was dosed in the Phase 1b LIMBER-TREG108 study evaluating CK0804 as an add on therapy to ruxolitinib in patients with myelofibrosis who experience a suboptimal response to ruxolitinib. CK0804 is a novel allogeneic, CXCR4 enriched, T regulatory cell therapy product that utilizes Cellenkos’ proprietary CRANE™ technology to generate disease specific products.

The LIMBER-TREG108 trial (NCT05423691) is part of a development collaboration between Cellenkos and Incyte.

“This is an exciting milestone for our company. The initiation of this study of CK0804 as on add on therapy to ruxolitinib is an important achievement that brings us closer to delivering a potential new treatment which may have a life-changing impact for myelofibrosis patients who have less than optimal response to treatment with ruxolitinib,” said Tara Sadeghi, Chief Operating Officer of Cellenkos Inc., “Myelofibrosis patients who do not respond to ruxolitinib have limited treatment options and can progress to leukemia. This experimental immunotherapy treatment in combination with the standard of care may represent a new hope for the patients with myelofibrosis potentially enhancing the efficacy of current JAK inhibitor therapy while also offering possible immune modulation and restoration of impacted hematopoiesis.”

LIMBER-TREG108 is a multicenter study at The University of Texas MD Anderson Cancer Center, The University of Columbia Hospital and University of California, Davis. The study is led by principal investigator Lucia Masarova, M.D., Assistant Professor of Leukemia at MD Anderson. This Phase 1b study will evaluate the safety, pharmacodynamics and immunogenicity of intravenous CK0804, administered monthly for up to 6 doses. The study will consist of 2 phases: an open-label safety run-in of 9 patients (Stage 1) and an expansion cohort of 15 additional patients (Stage 2).

“We are pleased that the first patient first dose milestone in the LIMBER-TREG108 study – one of several studies in our LIMBER clinical program evaluating multiple monotherapy and combination strategies to improve and expand treatments for patients with MPNs – has been achieved. We look forward to the results of the study, and to continuing our partnership toward important scientific advances for these patients,” said Ekaterine Asatiani, M.D., Division Vice President and Head of Early Development at Incyte.

About Myelofibrosis

Myelofibrosis is a rare, chronic and progressive blood cancer that is part of a group of diseases known as myeloproliferative neoplasms. In myelofibrosis, scar tissue forms in the bone marrow and impairs its ability to produce normal blood cells. This can result in an enlarged spleen, as well as symptoms such as fatigue, itching and night sweats, which can severely impact a patient’s quality of life. About 16,000 to 18,500 people in the U.S. are living with myelofibrosis1. Patients who have had a suboptimal response to the standard of care treatment have limited options and a poor prognosis.

About CK0804

CK0804 is a novel allogenic cell therapy product consisting of T-regulatory cells that exploit the CXCR4/CXCL12 axis and are derived from clinical-grade umbilical cord blood units and manufactured using Cellenkos’ proprietary CRANE™ process. Multiple doses of CK0804 can be manufactured from a single umbilical cord blood unit, where the final cryopreserved product is readily available for use. No requirement for HLA matching to the patients makes CK0804 an ideal therapy that can be infused intravenously, in the outpatient setting.

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Global Myeloproliferative Disorders Drugs Market to Reach $11.2 Billion by 2027

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ReportLinker
ReportLinker
·24 min read
In the changed post COVID-19 business landscape, the global market for Myeloproliferative Disorders Drugs estimated at US$8. 5 Billion in the year 2020, is projected to reach a revised size of US$11.

New York, Dec. 28, 2022 (GLOBE NEWSWIRE) — Reportlinker.com announces the release of the report “Global Myeloproliferative Disorders Drugs Industry” – https://www.reportlinker.com/p06032290/?utm_source=GNW
2 Billion by 2027, growing at aCAGR of 3.9% over the period 2020-2027. Ph+ Chronic myelogenous leukemia (CML), one of the segments analyzed in the report, is projected to record 3.4% CAGR and reach US$8.1 Billion by the end of the analysis period. Taking into account the ongoing post pandemic recovery, growth in the Ph- Myeloproliferative Neoplasms (MPNs) segment is readjusted to a revised 5.5% CAGR for the next 7-year period.

The U.S. Market is Estimated at $2.3 Billion, While China is Forecast to Grow at 6.4% CAGR

The Myeloproliferative Disorders Drugs market in the U.S. is estimated at US$2.3 Billion in the year 2020. China, the world`s second largest economy, is forecast to reach a projected market size of US$2.2 Billion by the year 2027 trailing a CAGR of 6.4% over the analysis period 2020 to 2027. Among the other noteworthy geographic markets are Japan and Canada, each forecast to grow at 2.3% and 3.1% respectively over the 2020-2027 period. Within Europe, Germany is forecast to grow at approximately 2.8% CAGR.

Select Competitors (Total 34 Featured) –
Bristol-Myers Squibb
Inctye
Novartis
Pfizer
Takeda
Teva

Read the full report: https://www.reportlinker.com/p06032290/?utm_source=GNW

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Overview of Treatment Options for Myelofibrosis

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Rami S. Komrokji, M.D., Ruben Mesa, M.D.

Transcript:

Rami Komrokji, M.D.: I think ET (essential thrombocythemia) and PV (polycythemia vera) are similar but myelofibrosis probably is a little bit different, so the spectrum of symptoms and the goals of treatment may be different. I’ll ask you to walk us through how you think of managing myelofibrosis patients.

 

Ruben Mesa, M.D.: Well, I think that’s very helpful, Rami. I think that was a great description of how we treat ET and PV. Again, we’re trying to use a range of therapies, and we’ll discuss a little later some of the newer therapies. What I do is kind of early MPNs (myeloproliferative neoplasms), and not every patient leaves as an early MPN patient based on risk of blood clots, bleeding, potential symptoms, but they can progress to myelofibrosis. As we mentioned earlier, myelofibrosis in our spleen, difficult symptoms and sometimes lower blood counts has some variable risk of progression to acute leukemia. Now, MF (myelofibrosis) patients can have evolved from ET or PV. Again, as we’re monitoring those diseases, if they start to change, such as a bigger spleen, worsening symptoms, lower blood counts or scarring in the bone marrow, and we think they’ve progressed from MF or they’ve started it, we call it primary myelofibrosis. Now, when we consider treating MF, we do treat it differently than ET or PV, because it has the potential to be life-shortening. Now, it’s not life-shortening in everyone. Our therapies are helping to extend life. Individuals might be diagnosed (at older ages) and they may die of something else, but it does have that potential. Because of that, the first decision we (consider) as your physicians and you as a patient is “Should we pursue a bone marrow transplant?” Bone marrow transplant, it’s synonymous with stem cell transplant, can cure myelofibrosis. However, it’s a very complex therapy. It’s probably one of the most complex medical therapies an individual can undergo. Even in the best of circumstances, there is a real risk that the transplant could potentially be a life-threatening complication. Who do we transplant? We consider that in individuals, the younger you are, the more aggressive we think your myelofibrosis might be. The more fit you are, and the more aggressive you wish to be with your health care, the more we consider it. We will consider it (in ages up to) the late 70s, but as we get older, the risks become higher and the likelihood of it being a good option is lower. That’s a discussion and a thought process that occurs usually in parallel with us deciding on treatment. For treatment, we again consider the risks and benefits and stratify patients accordingly. First, there are low-risk patients who have no symptoms. There’s an occasion when we find someone who came in for a general physical and the spleen was enlarged, and we finally find myelofibrosis, but otherwise, they wouldn’t know they were sick. This is a minority. In these individuals, sometimes we will watch the disease. That is still a small minority of patients. People who have more risk than that and more symptoms, we typically will start on a medicine. Now we have three approved medicines. By far the one that has been used the greatest up to this point because it’s been approved now over 10 years is ruxolitinib. This is a medicine, a pill, that’s given twice a day, and it was approved because of the benefit it had for patients with MF, such as improving enlargement of the spleen. Sometimes the spleen can be under the rib cage on the left side, and sometimes it can be many times larger than it should be. It can cause discomfort, fullness and pain, and because of that, we like to reduce it. It can help with symptoms, and it can even impact the course of the disease; ruxolitinib clearly can have that benefit. It can improve symptoms, help you gain weight and help to improve the other symptoms such as fatigue, night sweats and so on. It likely helps patients with myelofibrosis live longer, and perhaps, in some individuals, even significantly longer than they would have lived otherwise. We know you can take it for a long time. I saw a patient yesterday in-clinic who first went on ruxolitinib in 2009 and has been on it ever since then. That’s dramatically longer than we might have expected that individual to live. It’s really made a big impact. Now, it has limitations. It sometimes can cause anemia, increase the risk of skin cancers and increase the risk of some infections, but it’s a good therapy. Second, we have fedratinib, which was approved much more recently in 2019. It can be helpful like ruxolitinib. It sometimes can be helpful to give if ruxolitinib initially didn’t help. It also can cause anemia, diarrhea or nausea. We usually give medicines for that. It rarely can lower vitamin B1 in the blood, which can cause something called encephalopathy, so we monitor for that. Usually, monitoring for that and giving vitamin B1 helps to nip that in the bud. The third medicine approved much more recently is for the subset of patients with myelofibrosis who have a very low platelet count that increases their risk of bleeding. Ruxolitinib and fedratinib can lower the platelet count, so the having pacritinib is a big plus. We can give it at full dose. We can have benefits for the spleen or for symptoms in individuals with a low platelet count. There are these three options, and some more are on the way. We’ll talk about some of the therapies on the way in a moment.

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Dr. Oh on the Anemia Benefit of Pacritinib in Myelofibrosis

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Dec 22, 2022

By Stephen Oh, MD, PhD

Stephen T. Oh, MD, PhD, co-chief, Division of Hematology, associate professor, Department of Medicine, Hematology Division, associate professor, Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, discusses the anemia benefit of pacritinib (Vonjo) in patients with myelofibrosis.

The phase 3 PERSIST-2 study (NCT02055781) evaluated the safety and efficacy of oral pacritinib compared with best available therapy in patients with thrombocytopenia and primary or secondary myelofibrosis. At the 2022 ASH Annual Meeting, investigators presented an analysis of pacritinib as a potent ACVR1 inhibitor and its clinical impact on transfusion independence in patients with myelofibrosis.

Although pacritinib is approved by the FDA 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, data from the analysis showed that the agent provides an anemia benefit for other patients with myelofibrosis, Oh says.

Pacritinib displayed activity as an inhibitor of ACVR1 and reduced hepcidin levels in vitro. Treatment with the agent can lead to transfusion independence for patients with myelofibrosis who require red blood cell transfusions. These data, along with the efficacy findings from PERSIST-2, should be taken into consideration for deciding considering pacritinib, Oh concludes.

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Top Researcher Mesa to Lead Atrium Health Cancer Program

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December 13, 2022

CHARLOTTE– Dr. Ruben A. Mesa has been named president and executive director of Atrium Health’s cancer service line – which includes Atrium Health Levine Cancer Institute and Atrium Health Wake Forest Baptist Comprehensive Cancer Center – and vice dean for cancer programs at Wake Forest University School of Medicine.

Mesa will assume the roles filled by Dr. Derek Raghavan, who had previously announced his mid-January 2023 retirement and by Dr. William Blackstock, professor and chair of radiation oncology at Wake Forest University School of Medicine, who has served as interim director of Wake Forest Baptist’s Comprehensive Cancer Center since February.

Mesa will advance the growth and development of the health system’s cancer center and the entire cancer service line. He will be responsible for all aspects of the cancer program, including clinical operations, research, education, community outreach and diversity, equity and inclusion.

“Dr. Mesa is a nationally renowned researcher, academic and oncology expert who has been at the forefront of cutting-edge advancement for cancer prevention, screening and treatment across the country,” said Eugene A. Woods, CEO of Advocate Health, of which Atrium Health is a part. “Most importantly, he has a patient-first philosophy and will be the chief advocate leading the charge in the battle against cancer.”

Mesa serves as executive director of the Mays Cancer Center at UT Health San Antonio MD Anderson and professor of medicine at UT Health Science Center San Antonio. He has dedicated his career to research and drug development for myeloproliferative neoplasms – a group of chronic leukemias that can cause bone marrow problems, acute leukemia and premature death.

Over the past 11 years, Mesa has led or co-led the development of six drugs that have been FDA-approved for chronic leukemias. He has been the principal investigator or co-principal investigator for more than 100 cancer clinical trials, including numerous global Phase III trials.

Mesa’s accomplishments during his tenure at UT Health San Antonio include leading the planning and design of a new research specialty hospital to focus on cancer, integrating cancer prevention and screening practice and research activities, and expanding oversight for Greehey Children’s Cancer Research Institute – one of only two institutes in the country dedicated solely to pediatric cancer research.

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MPN Research Foundation Awards Additional $1.8 Million for Blood Cancer Research Into Myeloproliferative Neoplasms

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CHICAGO, IL, UNITED STATES, December 14, 2022 /EINPresswire.com/ — MPN Research Foundation (MPNRF) announces its 2022 Thrive Initiative recipients for projects that fill research funding gaps, some of which surfaced due to the pandemic. This $1.8 million in awards is in addition to currently funded research projects supported for 2021-2023.

MPNRF has invested more than $18.4 million over the past 21 years toward better understanding and treatment of essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), rare blood cancers collectively known as myeloproliferative neoplasms (MPNs).

“The 2022 Thrive Initiative will fund 11 additional MPN research projects totaling $1.8 million over two years,” according to Kapila Viges, MPNRF chief executive officer. “These include an exciting mix of seasoned MPN researchers, awarded for follow-on support to continue their existing projects, in many cases stalled by the pandemic, as well as junior and established investigators with new ideas and perspectives to explore. Together, they bring new talent and energy to solve compelling MPN questions, pioneering the way for new research and treatments.”

“We are thrilled to fund so many new or incomplete projects that otherwise might be left on the research bench without support,” says Brandon Goetzman, MPNRF board member and chair of the Scientific Steering Committee. “Each project went through a rigorous peer review process, with final selections based on scientific merit, independent of research focus.“

 

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Incyte’s Novel Mutant CALR Antibody Unveiled at ASH 2022 Plenary Scientific Session

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– INCA033989, a new anti-mutant calreticulin (CALR)-targeted monoclonal antibody, represents important research milestone in myelofibrosis (MF) and essential thrombocythemia (ET)

– INCA033989 abstract selected as one of only six ASH plenary presentations

– INCA033989 clinical trials to begin in 2023

– Research highlights Incyte’s discovery capabilities and progress of its LIMBER program evaluating new targets and combinations for patients with myeloproliferative neoplasms (MPNs) and graft-versus-host disease (GVHD)

WILMINGTON, Del.–(BUSINESS WIRE)–Incyte (Nasdaq:INCY) today announced new research detailing the development and mechanism of action of INCA033989, an Incyte-discovered, investigational novel anti-mutant calreticulin (CALR)-targeted monoclonal antibody. Pre-clinical data indicate that INCA033989 can alter disease course by reducing mutant CALR allele burden and thus may be an efficacious and safe treatment in patients with myelofibrosis (MF) and essential thrombocythemia (ET). This research was featured in the Plenary Scientific Session (Abstract #6. Session: Hematology Disease Topics & Pathways: Research, Diseases, Therapies, Myeloid Malignancies) at the 64th American Society of Hematology (ASH) Annual Meeting, held December 10-13, 2022, in New Orleans and virtually1.

“As a leader in the field, Incyte is uniquely positioned to develop novel medicines for these rare blood cancers, and this research provides strong rationale for the continued investigation and clinical advancement of INCA033989 – a novel treatment approach that targets CALR mutations.”

“As a pioneer in the field of myeloproliferative neoplasms (MPNs), having brought the first FDA-approved treatment to patients, we are excited to have the opportunity to share details of our latest research,” said Dash Dhanak, Ph.D., Executive Vice President and Chief Scientific Officer, Incyte. “We continue to apply our deep understanding of the complex biology of MPNs to expand treatment options for patients and the work on INCA033989 presented today reflects our progress toward this goal. We look forward to continuing to advance the development of this potential new treatment and to initiating clinical trials for INCA033989 next year.”

CALR mutations are responsible for disease development in approximately 25-35%2,3 of patients with MF and ET – two common types of MPNs. INCA033989 binds with high affinity to mutant CALR and inhibits oncogenesis, the process of cells becoming cancerous, in cells expressing this oncoprotein. As described in our presentation, INCA033989 potently antagonizes CALR oncogenic function, resulting in selective inhibition of JAK/STAT signaling only in CALR-mutated cells with no effect on normal, non-oncogenic cells. This selectivity of action with INCA033989 results in the specific killing of tumor cells harboring the mutation and is suggestive of the potential to alter the course of disease in patients with CALR-mutant MF and ET.

“Diseases like myelofibrosis and essential thrombocythemia are often difficult to understand and treat, and unique approaches are necessary to develop effective and safe therapies,” said Srdan Verstovsek, M.D., Ph.D., Professor of Medicine, Department of Leukemia, University of Texas MD Anderson Cancer Center. “As a leader in the field, Incyte is uniquely positioned to develop novel medicines for these rare blood cancers, and this research provides strong rationale for the continued investigation and clinical advancement of INCA033989 – a novel treatment approach that targets CALR mutations.”

More information regarding the congress and the more than 50 abstracts from Incyte’s oncology portfolio being featured at the meeting is available on the ASH website: https://www.hematology.org/meetings/annual-meeting.

About Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPNs) are a closely related group of blood cancers in which the bone marrow functions abnormally. The bone marrow is where the body’s blood cells are made. MPNs are progressive blood cancers that can strike anyone at any age, but they are more common in older adults. Estimates of the prevalence of MPNs vary, but analysis of claims data suggests there may be as many as 200,000 people in the U.S. living with the most prevalent MPNs: myelofibrosis, polycythemia vera or essential thrombocythemia4.

About LIMBER

Incyte is a leader in the discovery and development of therapies for patients with myeloproliferative neoplasms (MPNs) and graft-versus-host disease (GVHD). The Leadership In MPNs and GVHD BEyond Ruxolitinib (LIMBER) program is designed to evaluate multiple monotherapy and combination strategies to improve and expand treatments for patients with MPNs and GVHD. The program currently has three key areas of focus: development of a new, once-daily formulation of ruxolitinib; ruxolitinib-based combinations with new targets such as PI3Kδ, BET and ALK2; and new therapeutic options such as mutant CALR.

About Incyte

Incyte is a Wilmington, Delaware-based, global biopharmaceutical company focused on finding solutions for serious unmet medical needs through the discovery, development and commercialization of proprietary therapeutics. For additional information on Incyte, please visit Incyte.com and follow @Incyte.

Forward-Looking Statements

Except for the historical information set forth herein, the matters set forth in this press release, including statements regarding the presentation of data from Incyte’s clinical development pipeline, whether or when any development compounds or combinations will be approved or commercially available for use in humans anywhere in the world outside of the already approved indications in specific regions and Incyte’s goal of improving the lives of patients, contain predictions, estimates and other forward-looking statements.

These forward-looking statements are based on Incyte’s current expectations and subject to risks and uncertainties that may cause actual results to differ materially, including unanticipated developments in and risks related to: unanticipated delays; further research and development and the results of clinical trials possibly being unsuccessful or insufficient to meet applicable regulatory standards or warrant continued development; the ability to enroll sufficient numbers of subjects in clinical trials; the effects of the COVID-19 pandemic and measures to address the pandemic on Incyte and its partners’ clinical trials, supply chain, other third-party providers and development and discovery operations; determinations made by the U.S. FDA and other regulatory authorities outside of the United States; the efficacy or safety of Incyte and its partners’ products; the acceptance of Incyte and its partners’ products in the marketplace; market competition; sales, marketing, manufacturing and distribution requirements; and other risks detailed from time to time in Incyte’s reports filed with the Securities and Exchange Commission, including its annual report and its quarterly report on Form 10-Q for the quarter ended September 30, 2022. Incyte disclaims any intent or obligation to update these forward-looking statements.

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1 Reis E, et al. Discovery of INCA033989, a Monoclonal Antibody That Selectively Antagonizes Mutant Calreticulin Oncogenic Function in Myeloproliferative Neoplasms. Presented at the 64 ASH Annual Meeting, December 10-13, 2022.
2 Nagalia et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013; 369:2391-2405.
3 Klampfl T et al. Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms. N Engl J Med 2013; 369:2379-2390.
4 Data on file.

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