June 5, 2023

Key points:

• New research links Agent Orange to an increased risk of blood cancers in veterans.
• Specifically, exposure could result in myeloproliferative neoplasms (MPNs), which are acquired stem cell disorders that can lead to overproduction of mature blood cells.
• Agent Orange has previously been associated with sarcomas and B-cell lymphomas, but not MPNs or leukemias.

Research conducted using a database of veterans exposed to Agent Orange found an association for an increased risk of developing myeloproliferative neoplasms (MPNs), which are acquired stem cell disorders that can lead to overproduction of mature blood cells complicated by an increased risk of blood clots in arteries and veins. When MPNs progress, they can become deadly leukemias.

The Agent Orange chemical has previously been associated with sarcomas and B-cell lymphomas, but not MPNs or leukemias.

For this study, researchers utilized the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database and examined records of 93,269 MPN patients among 12,352,664 veterans over 17 years. The team used veterans from the state of Illinois as a control population since Illinois is highly representative of the United States, according to the U.S. Census Bureau.

According to the findings, the odds of Agent Orange exposure among MPNs are 1.63 times greater than the odds of exposure among controls. When comparing people with MPNs vs. age-, gender-, and race-matched controls, there was more clotting in the arteries (37% vs. 18.5%), more clotting in the veins (14.8% vs. 5.2%) and more bleeding events (39.1% vs. 13.5%), respectively.

Additionally, people with MPNs had more hypertension (75.5% vs. 43.2%), diabetes (31.2% vs. 19%), and more heart failure (26.1% vs. 11%) than age-, gender, and race-matched controls, respectively.

The odds of Agent Orange exposure among matched controls with arterial clots are 1.38 times greater than the odds of exposure among controls without arterial clots. The odds of Agent Orange exposure among MPNs with arterial clots are 1.49 times greater than the odds of exposure among MPNs without arterial clots.

Because the findings only point to possible associations and not causes, lead author Andrew Tiu said the researchers will need to dive more deeply into the biology of the disease. Specifically, they want to look at JAK2 mutations, which are one of the three driver mutations of MPNs that can cause uncontrolled proliferation of stem cells. JAK2 has also been associated with an increased risk of clotting.

“There are several associations between Agent Orange and health disorders that are not well understood and we hope our work helps uncover a few of these,” said Tiu.

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By Rob Dillard

June 3, 2o23

Pelabresib used as a monotherapy appears clinically beneficial in patients who have high-risk essential thrombocythemia (HR ET) and are intolerant to hydroxyurea (HU), according to a study presented at the 2023 American Society of Clinical Oncology Annual Meeting.

In this analysis of arm 4 of the MANIFEST study, lead investigator Francesco Passamonti and colleagues evaluated 20 patients with HR ET who received pelabresib monotherapy 225 mg QD. Their key end point of interest was complete hematologic response (CHR), which was defined as normalization of platelet count (≤400 x 10⁹/L) and WBC count (≤10 x 10⁹/L), confirmed after 1 cycle (3 weeks), and normal spleen size. Secondary end points included partial hematologic response (PHR; platelet count, 400-600 x 10⁹/L and WBC, ≤10 x 10⁹/L), symptom improvement (≥50% thrombosis with thrombocytopenia [TSS] reduction), and safety.

The investigators found that the majority of patients had a hematologic response (90% [18/20] unconfirmed CHR or PHR); confirmed CHR was observed in 40% of patients, and TTS reduction was observed in 86% of patients, with Hgb levels remaining stable through week 24. The investigators went on to note that the most common nonhematologic adverse events (AEs) were nausea (60%; 10% grade 3), diarrhea (35%; 5% grade 3), and dysgeusia (35%; no grade 3). No events of thrombocytopenia and no AEs of grade 4 or higher were reported.

“Preliminary results from arm 4 of the MANIFEST study suggest potential clinical benefit with [pelabresib] monotherapy in [patients] with HR ET refractory or intolerant to HU as supported by hematologic responses and symptom improvement. Safety results are consistent with the known safety profile of [pelabresib] and as expected in the underlying study population,” the researchers concluded.

Source: Passamonti F, Patriarca A, Knapper S, et al. Pelabresib (CPI-0610) monotherapy in high-risk essential thrombocythemia refractory or intolerant to hydroxyurea: preliminary results from MANIFEST study. Abstract #7019. Published for the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, Illinois.

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By Rob Dillard

June 3, 2o23

The up-regulation of the enzyme glutaminase (GLS), which plays a critical role in cancer cell metabolism, is a common feature in Philadelphia-negative (Ph-) and JAK2-V617F-driven myeloproliferative neoplasms (MPNs), according to a study presented at the 2023 American Society of Clinical Oncology Annual Meeting.

Almost all MPNs are driven by somatic mutations in either JAK2, CALR, or MPL. While these mutations lead to activation of JAK/STAT signaling, lead researcher Michele Ciboddo and colleagues noted that “JAK inhibitors are not curative and fail to alter disease progression and display unwanted side effects. Allogeneic stem cell transplantation remains the only curative therapy for MPNs but is associated with substantial morbidity and mortality.”

Recent data have shown that glutaminolysis plays a chief role in cancer cell metabolism. In this 2-step reaction process, GLS acts as a catalyst, helping to turn glutamine into glutamate. Subsequently, glutamate fuels energy production in the tricarboxylic acid cycle. “As many cancers have proven to be dependent on this pathway, targeting GLS has become an attractive therapeutic avenue,” the researchers wrote.

In this analysis, Dr. Ciboddo and colleagues assessed mRNA levels of GLS in peripheral blood mononuclear cells from 30 patients with MPN and 5 healthy donors. They tested GLS by stably overexpressing either JAK2-, CALR-, or MPL-mutated proteins. CALR overexpression was treated with the JAK inhibitor ruxolitinib. Subsequently, the sensitivity of MPN cells to GLS inhibition was assessed with a GLS inhibitor, CB-839, which is currently in advanced-phase clinical trials for other cancers, including myelodysplastic syndrome.

According to the findings, GLS mRNA expression increased in all patients with MPNs regardless of the driver mutation. The researchers observed that GLS expression in JAK2-V617F patients was higher in those patients with myelofibrosis than in those with essential thrombocythemia. Moreover, GLS protein expression and activity were increased in TF-1 cells expressing JAK2, MPL, and CALR mutations. “We also found that GLS mRNA and protein expression was up-regulated in a JAK/STAT-dependent manner,” the researchers wrote. “Interestingly, despite increased expression of GLS across all MPN driver mutations, only JAK2-V617F cells demonstrated significant sensitivity to GLS inhibition with CB-839 in vitro and with preliminary data in vivo. We found that combination treatment with [the] JAK inhibitor ruxolitinib further inhibited cell viability.” They concluded that “treatment with CB-839 may thus represent a novel therapeutic avenue for JAK2-V617F [positive] MPNs.”

Source: Ciboddo M, Yan G, Coen C, et al. GLS in Philadelphia-negative and JAK2 V617F-driven myeloproliferative neoplasms (MPNs). Abstract #e15092. Published for the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, Illinois.

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By Rob Dillard

June 2, 2023

Patients with myelofibrosis (MF) with a certain platelet (PLT) count who achieve spleen volume reduction (SVR) on pacritinib have notably better overall survival (OS), according to a study presented at the 2023 American Society of Clinical Oncology Annual Meeting. That association was not observed in patients taking best available therapy (BAT).

One of the characteristics of MF is splenomegaly, or spleen enlargement. JAK2 inhibitors have been known to reduce spleen volume, which is considered a surrogate for disease response. Investigators, led by Helen Ajufo, MD, noted that ≥10% SVR on ruxolitinib is associated with improved OS among patients with PLT counts ≥100×10⁹/L, and ruxolitinib cannot be administered at full dose in patients with a lower PLT count. Pacritinib is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that has shown SVR benefit versus BAT. This study analyzed SVR and OS in patients from the PERSIST-2 trial.

Researchers assessed PERSIST-2 patients on pacritinib who were alive and treated at the start of the 12-week SVR window (study week 10) on pacritinib 200 mg BID or BAT. Spleen volume was assessed radiographically, OS was analyzed using various SVR thresholds (≥35%, ≥20%, ≥10%, and >0%), and OS was compared using the log-rank test.

Results showed that among patients on pacritinib (n=89), any SVR at 12 weeks was notably linked with improved survival (hazard ratio [HR], 0.08; 95% CI, 0.01-0.51, P=.0007). Across all SVR response thresholds, SVR ≥10% showed the greatest separation in OS curves between responders and nonresponders on pacritinib, with no deaths among 65 responders versus 5 deaths among 24 nonresponders (HR, 0.0; 95% CI, 0.0-0.14; P<.0001). By contrast, the investigators noted, SVR did not predict OS benefit on BAT (n=84), including ruxolitinib (n=39).

“In MF patients with PLTs ≤100×10⁹/L, achieving SVR on full-dose [pacritinib] was associated with significant OS benefit. By contrast, this association was not found with BAT, even though most responders were on [ruxolitinib], albeit at low doses,” the researchers concluded. “As [pacritinib] can be given at full dose regardless of PLT count, it is possible that [pacritinib] may offer a unique survival advantage for MF patients with moderate or severe thrombocytopenia who achieve spleen reduction.”

Source: Ajufo H, Bewersdorf JP, Harrison C, et al. Spleen volume reduction (SVR) predicts overall survival (OS) in myelofibrosis (MF) patients on pacritinib (PAC) but not best available therapy (BAT): PERSIST-2 landmark OS analysis. Abstract #7018. Published for the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, Illinois.

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By Georgetown University Medical Center

Research conducted at Georgetown University’s Lombardi Comprehensive Cancer Center and the Washington DC VA Medical Center on a database of veterans exposed to Agent Orange found an association for an increased risk of developing myeloproliferative neoplasms (MPNs), which are acquired stem cell disorders that can lead to overproduction of mature blood cells complicated by an increased risk of blood clots in arteries and veins. When MPNs progress, they can become deadly leukemias.

Agent Orange is an herbicide that was utilized by the United States military in Korea and Vietnam to clear foliage during combat. It has been associated with sarcomas and B-cell lymphomas, but not MPNs or leukemias to date.

“MPNs are associated with serious cardiovascular events and people with this disease have decreased overall survival chances,” says Andrew Tiu, MD, a second-year hematology/oncology fellow with Medstar Georgetown University Hospital who conducts research at Georgetown Lombardi Comprehensive Cancer Center and is the lead author of this finding.

“But until now, we haven’t been able to fully ascertain whether Agent Orange exposure truly leads to the development of myeloproliferative neoplasms, which is why we’ve undertaken what is the biggest population-based study to date to try to answer this question.”

To explore associations between Agent Orange and MPNs in addition to blood clots, bleeding, and a number of cardiovascular factors, the researchers utilized the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database and examined records of 93,269 MPN patients among 12,352,664 veterans over 17 years. The researchers used veterans from the state of Illinois as a control population since Illinois is highly representative of the United States according to the US Census Bureau.

Significant findings from the study include:

• The odds of Agent Orange exposure among MPNs are 1.63 times greater than the odds of exposure among controls.
• When comparing people with MPNs vs. age-, gender-, and race-matched controls, there was more clotting in the arteries (37% vs. 18.5%), more clotting in the veins (14.8% vs. 5.2%) and more bleeding events (39.1% vs. 13.5%), respectively.
• People with MPNs had more hypertension (75.5% vs. 43.2%), diabetes (31.2% vs. 19%), and more heart failure (26.1% vs. 11%) than age-, gender, and race-matched controls, respectively.
• The odds of Agent Orange exposure among matched controls with arterial clots are 1.38 times greater than the odds of exposure among controls without arterial clots.
• The odds of Agent Orange exposure among MPNs with arterial clots are 1.49 times greater than the odds of exposure among MPNs without arterial clots.

Because their findings only point to possible associations and not causes, Tiu notes that the researchers will need to dive more deeply into the biology of the disease. Specifically, they want to look at JAK2 mutations, which are one of the three driver mutations of MPNs (the other two being MPL and CALR mutations) that can cause uncontrolled proliferation of stem cells. JAK2 has also been associated with an increased risk of clotting.

“There are several associations between Agent Orange and health disorders that are not well understood and we hope our work helps uncover a few of these,” says Tiu. “We are proud of the fact that our work was selected for a 2023 Conquer Cancer Merit Award and we’ll be using those funds to further our research efforts.”

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By Rob Dillard

June 2, 2023

A proof-of-concept study indicates the combined use of ruxolitinib and magrolimab is effective in the treatment of myelofibrosis (MF). The results were presented at the 2023 American Society of Clinical Oncology Annual Meeting.

“In solid tumors, calreticulin (CALR) overexpression produces a prophagocytic signal and is counteracted by concomitant expression of antiphagocytic CD47, reflecting an apoptosis versus survival mechanism. We have previously found that CD47, not CALR, is overexpressed on the membrane of patients with [myeloproliferative neoplasms]. Anti-CD47 magrolimab is currently being evaluated in clinical trials in [acute myelogenous leukemia and myelodysplastic syndromes] but has yet to be tested, either in monotherapy or in combination, in MF,” the researchers noted.

In this study, lead researcher Ciro Roberto Rinaldi and colleagues collated mononuclear cells from the bone marrow of 6 patients with MF and 2 controls. Cell expression of CALR and CD47 was measured by flow cytometry before and after incubation with ruxolitinib alone and in combination with magrolimab.

According to the results, CD47 membrane expression was 57% in untreated MF cells versus 12% in the control samples, while CALR membrane expression was observed at almost 52% in untreated MF cells compared with 12.5% in the control samples. Following incubation with ruxolitinib, MF CD34+ cell survival decreased to 98.2%, and after incubation with magrolimab alone, MF CD34+ cells showed no changes in survival. Notably, the analysis showed a significant membrane overexpression of CALR was observed in MF CD34+ cells when incubated with ruxolitinib and magrolimab (74.1%) versus ruxolitinib alone (52.6%), magrolimab alone (53.4%), and in untreated (51.8%).

“In vitro, treatment with ruxolitinib or ruxolitinib plus magrolimab slightly reduces the overall cell survival rate in CD34+ MF samples compared with no significant changes in single-agent magrolimab. However, the combination of ruxolitinib and magrolimab significantly increases CALR membrane expression compared with [ruxolitinib] or magrolimab alone, signaling a much stronger prophagocytic message in MF cells compared with controls,” the researchers concluded. They added that these findings “support the rationale of combining ruxolitinib with magrolimab in the next clinical trial stage in myelofibrosis.”

Source: Rinaldi C, Boasman K, Simmonds M. Effects of ruxolitinib and magrolimab on calreticulin in myelofibrosis CD34+ cells in vitro: proof of concept for combination therapy. Abstract #7064. Published for the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, Illinois.

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June 2, 2023

TAIPEI–(BUSINESS WIRE)–PharmaEssentia Corporation (TPEx:6446), a leading fully integrated biopharmaceutical company in Taiwan, today announced that it has entered into an exclusive license agreement with Pint-Pharma GmbH for the registration and promotion of BESREMi^® (ropeginterferon alfa-2b-njft) for the treatment of polycythemia vera (PV), a rare blood cancer, in Brazil, Argentina, Colombia, Chile, Peru, Ecuador, and Mexico.

“Expanding our geographic reach is critical to our mission to address clear gaps in therapeutic options for people with myeloproliferative neoplasms (MPNs). With its track record of successfully commercializing therapeutics for rare diseases and oncology, and its strong regional network, we’re confident that Pint-Pharma is the right partner to bring BESREMi to PV patients in Latin America,” said Ko-Chung Lin, Ph.D., Founder and Chief Executive Officer, PharmaEssentia. “This regional expansion is a logical extension of our growing leadership in the Americas, led by Meredith Manning. With strong momentum in the U.S., we know Meredith and her team will effectively champion the PharmaEssentia mission into Latin and South America.”

Under the terms of the agreement, PharmaEssentia may be eligible for certain milestone payments and royalties based on sales. Pint-Pharma will be responsible for obtaining and maintaining all marketing authorizations and for commercializing BESREMi in the region. PharmaEssentia will continue to be responsible for the supply of BESREMi. Pint-Pharma is an Austria-based pharmaceutical company with extensive experience in registering and commercializing rare disease, oncology and specialty treatments throughout Latin America. With this new partnership, Pint-Pharma further cements its position amongst the leaders in the field of haemato-oncology in Latin America.

“Our partnership with PharmaEssentia gives us the opportunity to provide another new treatment option to people living with MPNs in the region who are in need of effective therapies,” said David Munoz, Chief Executive Officer, Pint-Pharma. “We look forward to the potential to add BESREMi to our established haemato-oncology portfolio.”

About Polycythemia Vera
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 JAK2.¹

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 treatment of polycythemia vera (PV) in the United States. The product was approved by the European Medicines Agency (EMA) in 2019, in the United States in 2021, and has also received approval in Taiwan, South Korea and most recently, Japan. The product 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. The company retains full global intellectual property rights for the product in all indications.

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

Please see accompanying full Prescribing Information, including Boxed Warning.

About PharmaEssentia

PharmaEssentia (TPEx: 6446), headquartered in Taipei, Taiwan, is a leading fully integrated biopharmaceutical company in Taiwan. Leveraging deep expertise and proven scientific principles, PharmaEssentia aims to deliver effective new biologics for challenging diseases in the areas of hematology and oncology, with one approved product and a diversifying pipeline. Founded in 2000 by a team of Taiwanese-American executives and renowned scientists from U.S. biotechnology and pharmaceutical companies, today PharmaEssentia is expanding its global presence with operations in the U.S., Japan, China, and Korea, along with a world-class biologics production facility in Taichung, Taiwan.

Forward Looking Statement

This press release may contain forward-looking statements, including statements regarding the commercialization plans and expectations for commercializing BESREMi in Latin America, the registration and regulatory approval of BESREMi in the region, and the potential benefits of BESREMi. For those statements, we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995 and similar legislation and regulations under Taiwanese law. These forward-looking statements are based on management expectations and assumptions as of the date of this press release, and actual results may differ materially from those in these forward-looking statements as a result of various factors. These factors include PharmaEssentia’s dependence on the commercial success of BESREMi, the ability to receive regulatory approvals for BESREMi in the region, whether BESREMi is successfully adopted by physicians and patients in the region, and the extent to which reimbursement is available for BESREMi in the region. Any forward-looking statements set forth in this press release speak only as of the date of this press release. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof.

¹ Cerquozzi S, Tefferi A. Blast Transformation and Fibrotic Progression in Polycythemia Vera and Essential Thrombocythemia: A Literature Review of Incidence and Risk Factors. Blood Cancer J. 2015;5, e366; doi:10.1038/bcj.2015.95

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Jun 1, 2023

Dr. Rudolf Widmann, Founder and Board Member of the AOP Health Group/ Copyright: Studio Koekart: Natasche Unkart & Isabella Köhle

June 1, 2023

VIENNA–(BUSINESS WIRE)–With the publication of the final results from the LOW-PV study in the New England Journal of Medicine Evidence conducted by Fondazione per la Ricerca dell’Ospedale di Bergamo (FROM) under the leadership of Professor Tiziano Barbui, AOP Health announces an important advancement reinforcing its clinical development program for ropeginterferon alpha-2b (BESREMi®) in polycythaemia vera (PV), a rare blood cancer. The academic LOW-PV study supported and funded by AOP Health and public organizations in Italy complements a series of trials performed by AOP Health over more than 10 years to achieve marketing authorization in Europe and the Middle East. With these clinical studies, including PEGINVERA, PROUD-PV, and CONTINUATION-PV, AOP Health opened a new area of treatment options for patients suffering from PV. A further study (PEN-PV) was performed to develop a pen for self-injection allowing ease of self-administration, exact dosing and minimal waste of the medical product. AOP Health’s comprehensive development program in PV is considered by many key opinion leaders as the most significant development in the field of PV treatment in the past 30 years.

This series of studies has enabled marketing authorizations to be obtained in numerous countries in addition to the AOP Health territories EU, Switzerland, Liechtenstein and Israel and allows patients to have access to BESREMi® in countries including Taiwan, Korea, the US, and Japan. Further studies are ongoing to substantiate the long-term safety and efficacy of BESREMi®. A post-approval safety study (BESREMI-PASS) with a recruitment period of about three years has just completed patient recruitment.

“The global marketing authorizations of BESREMi®, all based on AOP Health´s clinical development program conducted in Europe, are proof of the integrated drug development and commercialization expertise of AOP Health. Our success and know-how allow us to further pursue our goal of making treatment options for rare diseases available to patients worldwide” says Dr. Rudolf Widman, Founder and Board Member of the AOP Health Group.

About BESREMi®

BESREMi® is the first and currently only interferon approved for polycythaemia vera, a myeloproliferative neoplasm (MPN), indicated in the European Union as monotherapy in adults for treatment of polycythaemia vera without symptomatic enlarged spleen. Its overall safety and efficacy were demonstrated in multiple clinical studies.

BESREMi® (ropeginterferon alfa-2b) is a long-acting, mono-pegylated proline interferon (ATC L03AB15). It is administered with a pen (250 and 500 ug) for self-injection once every 2 weeks initially, or up to every 4 weeks after stabilization of blood values. BESREMi® is designed to be self-administered subcutaneously with a pre-filled pen.

For the EMA Summary of Product Characteristics please visit: BESREMi®

Link: https://www.ema.europa.eu/en/documents/product-information/besremi-epar-product-information_en.pdf

The drug substance Ropeginterferon alfa-2b was discovered by PharmaEssentia, a long-term partner of AOP Health. In 2009, AOP Health in-licensed the exclusive rights for clinical development and commercialization of ropeginterferon alfa-2b in polycythaemia vera and other MPNs such as chronic myelogenous leukemia (CML) for European, Commonwealth of Independent States (CIS), and Middle Eastern markets.

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Some symptoms of myeloproliferative neoplasms are “pretty broad,” highlighting the importance of open communication with cancer teams to manage the symptoms and improve quality of life.