On September 21, 2022 Coeptis Therapeutics, Inc. (OTC PINK: COEP) ("Coeptis" or "the Company"), a biopharmaceutical company developing innovative cell therapy platforms for cancer, reported entry into an exclusive license agreement with the University of Pittsburgh for the rights to a chimeric antigen receptor T cell (CAR T) technology – SNAP-CAR – designed to target multiple antigens simultaneously and potentially address a range of hematologic and solid tumors, including breast and ovarian cancer (Press release, Coeptis Pharmaceuticals, SEP 21, 2022, View Source [SID1234621329]). Completion of the exclusive license agreement for SNAP-CAR follows Coeptis’ entry into an option agreement with the University of Pittsburgh announced in May 2022.

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Current CAR T therapies are designed to target specific tumor antigens that correspond to a specific cancer indication. This approach has proven effective in certain cancer types but limits the applicability of those CAR T therapies. SNAP-CAR is designed to be a "universal" CAR T cell therapy platform that can be adapted to different cancer indications. Instead of directly binding to a target on the tumor cell, CAR T cells are co-administered with one or more antibody adaptors that bind to the tumor cells and are fitted with a chemical group that irreversibly connects them to the SNAP-CAR on the therapeutic cells via a covalent bond. Pre-clinical studies in mice have demonstrated that by targeting tumors via antibody adaptor molecules, the SNAP-CAR therapy provides a highly programmable therapeutic platform.

"SNAP-CAR T cells can be engineered to address numerous cancers, including solid tumors, while providing researchers with the ability to rapidly screen multiple antibody candidates without the need to generate individual receptors," said Jason Lohmueller, Ph.D., Assistant Professor of Surgery and Immunology in the Division of Surgical Oncology Research at the University of Pittsburgh. "Additionally, SNAP-CAR may offer the potential to mitigate the toxicity of CAR T therapy by allowing clinicians to control the adaptor dose. Further, the ability to combine SNAP-CAR T cells with antibodies targeting multiple antigens offers the potential to reduce the likelihood of cancer relapse," said Alex Deiters, Ph.D., Professor of Chemistry at the University of Pittsburgh.

"SNAP-CAR represents a potential breakthrough in CAR T approaches and a significant addition to Coeptis’ expanding cell therapy product portfolio," said Dave Mehalick, President and CEO of Coeptis Therapeutics. "Research at the University of Pittsburgh suggests that SNAP-CAR offers an opportunity to direct the power of CAR T to an array of cancers that have, until now, been inaccessible via current cell therapy technologies by providing a highly programmable antigen targeting platform. It is believed that SNAP-CAR could enable the development of CAR T therapies for many hematologic cancers as well as several types of solid tumors, including breast and ovarian cancer."

Mr. Mehalick concluded: "Our vision at Coeptis is to be at the forefront of developing the next-generation cell therapy technologies, and we believe the advancements at the University of Pittsburgh, as well as those at VyGen-Bio, are potentially groundbreaking."

On September 21, 2022 Immunitas Therapeutics ("Immunitas"), a precision immunotherapy company committed to discovering and developing novel, differentiated therapeutics for patients with cancer, reported that the U.S. Food and Drug Administration (FDA) has cleared the Investigational New Drug (IND) application for IMT-009, a fully human monoclonal antibody against a novel immuno-oncology target CD161 (Press release, Immunitas Therapeutics, SEP 21, 2022, View Source [SID1234621328]). The Phase 1 study is designed to evaluate the safety, tolerability, pharmacodynamic biomarkers, and preliminary efficacy of IMT-009 as well as identify the Recommended Phase 2 Dose (RP2D). The trial will then transition into Phase 2 with multiple expansion cohorts to assess the safety and efficacy of IMT-009 alone or in combination with another antineoplastic agent.

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"We are thrilled to advance IMT-009 to the clinic as we believe it represents a new wave of immuno-oncology agents with transformative potential in both hematological malignancies and solid tumors," said Seng-Lai "Thomas" Tan, Ph.D., Chief Scientific Officer of Immunitas Therapeutics. "Based on compelling preclinical data demonstrating its dual-action mechanism and non-overlapping biology with other immune checkpoint pathways, IMT-009 will be investigated as a monotherapy and in combination with other cancer therapies."

IMT-009 is an Fc-attenuated monoclonal antibody that binds with high affinity and selectivity to CD161, a receptor that is broadly expressed on NK and a subset of memory T cells, blocking interactions between the receptor and its cognate ligand, CLEC2D, which is expressed on the surface of both cancer cells and immune cells. Preclinical data confirm that CD161 blockade with IMT-009 results in enhanced anti-tumor activity.

"IMT-009 is a first-in-class therapeutic with exciting potential for efficacy in a broad range of tumor types. I applaud the team at Immunitas that has driven it forward, and our academic founders who originally identified CD161 as an inhibitory T-cell target. IMT-009 will be progressed into the clinic using a biomarker-driven development plan designed to assess biological response and inform future patient selection," said Amanda Wagner, M.B.A., Chief Executive Officer of Immunitas Therapeutics. "This development plan illustrates our commitment to the advancement of precision immunotherapies. In addition to IMT-009, we continue to discover and progress a pipeline of next-generation differentiated immunotherapies using our cross-functional discovery engine, which pairs advanced computational biology approaches with deep immunology expertise and in-house antibody capabilities."

The IMT-009 Phase 1/2 clinical trial is anticipated to begin enrollment in Q4 2022.

On September 21, 2022 Medtronic plc (the "Company") ( NYSE: MDT) reported that its wholly-owned subsidiary Medtronic Global Holdings S.C.A. ( "Medtronic Luxco") has closed a registered public offering (the "Offering") of €500,000,000 principal amount of 2.625% Senior Notes due 2025, €1,000,000,000 principal amount of 3.000% Senior Notes due 2028, €1,000,000,000 principal amount of 3.125% Senior Notes due 2031 and €1,000,000,000 principal amount of 3.375% Senior Notes due 2034 (collectively, the "Notes") (Press release, Medtronic, SEP 21, 2022, View Source [SID1234621326]). All of Medtronic Luxco’s obligations under the Notes are fully and unconditionally guaranteed by the Company and Medtronic, Inc., a wholly-owned indirect subsidiary of Medtronic Luxco, on a senior unsecured basis.

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The net proceeds from the Offering are approximately €3.47 billion, after deducting underwriting discounts and commissions and estimated expenses related to the Offering payable by Medtronic Luxco. The net proceeds of the Offering are expected to be used to repay at maturity Medtronic Luxco’s outstanding 0.00% Senior Notes due 2022, 0.375% Senior Notes due 2023 and 0.00% Senior Notes due 2023 and for general corporate purposes. While Medtronic Luxco may elect at a later date to repay, redeem or repurchase such notes prior to maturity, it currently has no intention to repay, redeem or repurchase such notes prior to maturity.

Information Relating to the Offering
Barclays Bank PLC, BofA Securities Europe SA, Citigroup Global Markets Limited and HSBC Continental Europe were the joint book-running managers for the Offering and Academy Securities, Inc., R. Seelaus & Co., LLC, Samuel A. Ramirez & Company, Inc. and Siebert Williams Shank & Co., LLC were the co-managers for the Offering. The Offering was made by means of a prospectus and prospectus supplement, copies of which may be obtained for free by visiting EDGAR on the U.S. Securities and Exchange Commission website at www.sec.gov. Alternatively, copies of the prospectus and prospectus supplement for the Offering may be obtained by contacting Barclays Bank PLC, toll-free at +1-888-603-5847, BofA Securities Europe SA, at +33(0) 1 8770 0000, Citigroup Global Markets Limited, toll-free at +1-800-831-9146 and HSBC Continental Europe, at +1-866-811-8049.

On September 21, 2022 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported that the results from a Phase I and Phase II study of olverembatinib (HQP1351) for the treatment of chronic myeloid leukemia (CML) have recently been published in the renowned oncology journal, the Journal of Hematology & Oncology (JHO), further demonstrating the durable efficacy and safety of olverembatinib in patients with CML (Press release, Ascentage Pharma, SEP 21, 2022, View Source;oncology-further-validating-the-drugs-best-in-class-potential-301629866.html [SID1234621325]).

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As a journal highly regarded by global hematology and oncology communities, JHO publishes the most cutting-edge studies covering every aspect of the hematology and oncology research and is rated with an Impact Factor (IF) of 23.1681. It is the official journal of the Chinese American Hematologist and Oncologist Network (CAHON).

Results from these studies of olverembatinib were published in a paper titled "Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial" 2. The corresponding author of this paper is Prof. Xiaojun Huang, Director of the Institute of Hematology, Peking University, Director of the Hematology Department at Peking University People’s Hospital, and the principal investigator of olverembatinib in China; the first author is Prof. Qian Jiang, Deputy Director of the Hematology Department at Peking University People’s Hospital, and a co-principal investigator of olverembatinib in China.

The published results are based on 165 Chinese patients with CML heavily pretreated with multiple prior lines of treatment with tyrosine kinase inhibitors (TKIs). The patients also included those harboring the T315I mutation, and were followed up for a median of about 3 years.

In patients with CML in the chronic phase (CML-CP), the cumulative 3-year incidences of major cytogenetic response (MCyR) and major molecular response (MMR) were 79% and 56%, respectively; while in those with CML in the accelerated phase (CML-AP), the cumulative 3-year incidences of MCyR and MMR were 47% and 45%, respectively. Importantly, cytogenetic and molecular responses increased over time. In terms of safety, common non-hematologic AEs mainly included hyperpigmentation and hypertriglyceridemia, and most of these AEs were of Grade 1/2. Hematologic AEs were resolved after temporary treatment suspension or supportive care. Most AEs were controllable and tolerable, and the incidence of AEs such as thrombocytopenia fell steadily as the treatment went on.

Overall, olverembatinib demonstrated favorable tolerability and durable efficacy. Besides, olverembatinib was highly active against BCR-ABL1T315I mutants and had encouraging clinical activity against compound mutations for which no treatment option is available as of now.

CML is a hematologic malignancy of leukocytes, or white blood cells. The introduction of BCR-ABL1 TKIs significantly improved the clinical practice and management of CML. However, despite the clear clinical benefits brought by the first- and second-generation TKIs, resistance to TKIs remains a major challenge in the treatment of CML. BCR-ABL1 kinase domain mutations represent a key mechanism of drug resistance to TKIs. The T315I mutation is one of the most common mutations in drug-resistant CML, occurring in about 25% of all CML cases. Because patients with T315I-mutated CML are resistant to all first- and second-generation BCR-ABL1 inhibitors, there is an urgent unmet medical need for a safe and effective third-generation BCR-ABL1 inhibitor.

Olverembatinib, a potential best-in-class asset developed by Ascentage Pharma and a drug designated a National Major New Drug Development and Manufacturing Program, is the first and only approved third-generation BCR-ABL1 inhibitor in China, effectively ending the lack of treatment options for patients with T315I-mutated CML in the country. To date, olverembatinib has been included in the Chinese Society of Clinical Oncology (CSCO) Guidelines and the China Anti-Cancer Association’s (CACA) 2022 Guidelines for the Holistic Integrative Management of Cancers, for the treatment of patients with TKI-resistant CML harboring the T315I mutation. (The CACA Guidelines also recommended olverembatinib for the treatment of patients with TKI-resistant/intolerant CML who have received at least two prior treatments.)

Although another third-generation BCR-ABL1 inhibitor had been approved in other countries, substantial unmet medical needs remain in patients with drug-resistant CML because of limited accessibility and treatment-related adverse events, including cardiovascular disorders. Consequently, clinical progress with olverembatinib has garnered widespread interest from the global hemato-oncology research community in recent years. Since 2018, clinical results of olverembatinib have been selected for oral presentations at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meetings for four consecutive years and was nominated for "Best of ASH (Free ASH Whitepaper)" in 2019. To date, olverembatinib has been granted one Fast-Track designation and three Orphan Drug designations by the US Food and Drug Administration (FDA), and an Orphan designation by the European Medicines Agency (EMA) of the EU.

Prof. Xiaojun Huang, commented, "As a Chinese clinician with over 30 years of experience in hematologic research and a principal investigator of olverembatinib, I am pleased that clinical results on this innovative treatment have been published in the JHO, once again showing that olverembatinib brings a novel China-developed therapy to patients with CML around the world. I hope to see more domestically developed novel drugs that allow Chinese physicians the opportunity to lead more clinical trials. Our goal is to generate more China-based data and clinical experience and publish robust evidence-based prospective studies that can further elevate China’s status in the global research community."

Prof. Qian Jiang added that, "At present, approximately 20-30% of all CML cases are TKI-resistant/intolerant, thus resulting in disease progression in many patients. Many of these patients fail to achieve desired treatment outcomes because of drug resistance or complications even after switching to a second or third TKIs. This is why TKI-resistant CML remains a major clinical challenge globally. Results published in the JHO demonstrate that olverembatinib can effectively target CML including patients with T315I mutation and has encouraging clinical activity even in patients with drug-resistant compound mutations within the BCR-ABL1 kinase domain, signifying the drug candidate’s enormous potential as an effective treatment for CML."

Prof. Yifan Zhai, Chief Medical Officer of Ascentage Pharma said, "Olverembatinib is a novel drug candidate with best-in-class potential and is also a major component of Ascentage Pharma’s global innovation strategy. The publication of the Phase I/II results in the JHO signals olverembatinib’s therapeutic potential in drug-resistant CML as well as Ascentage Pharma’s robust R&D capabilities. We hope that olverembatinib will bring an effective and safe treatment to patients with CML globally. We remain committed to our dual mission of addressing unmet clinical needs in China and around the world. We are accelerating our global clinical development programs to benefit more patients and have also launched a Global Named Patients Program in collaboration with Tanner Pharma to make olverembatinib available to the needy patients in approximately 140 countries where the drug is not commercially available."

Highlights of the results published in the Journal of Hematology & Oncology are as follows:

Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial

Methods:

This was a multicenter, open-label Phase I/II study.
The Phase I study comprised a dose-escalation and expansion adopting a standard "3+3" design, with 11 successive cohorts of patients with TKI-resistant CML receiving orally-administered olverembatinib at increasing alternate-day (QOD) doses of 1–60 mg in 28-day cycles. The primary endpoint of the Phase I study was the recommended Phase II dose (RP2D).
The Phase II study evaluated the efficacy and safety of olverembatinib at RP2D in patients with T315I-mutated CML-CP and CML-AP. The primary endpoints of the Phase II study were major cytogenetic response (MCyR) in patients with CML-CP and major hematologic response (MaHR) in those with CML-AP.
Patient characteristics:

Between October 26, 2016, and October 8, 2019, 165 patients were enrolled: 127 with CML-CP and 38 with CML-AP. 66.7% (110) of those patients were men. The median age was 42 (range, 20–74) years, and the median interval from CML diagnosis to first olverembatinib dose was 5.7 (range, 0.3–23.2) years.
More than 80% of patients had received two prior TKIs: 90 (54.5%) with two and 45 (27.3%) with three or more.
Sanger sequencing identified 61.8% patients with a single T315I mutation, 15.2% with T315I and additional mutations, and 8.5% with other mutations.
Phase I study

A total of 101 patients with TKI-resistant CML were enrolled in the Phase I study between October 26, 2016, and December 12, 2018. Among them, 86 had CML-CP and 15 had CML-AP.
Across 11 dose cohorts (1 to 60 mg QOD) in 28-day cycles, dose-limiting toxicity (DLT) was observed at 60 mg, and the maximum tolerated dose (MTD) was 50 mg. Based on preliminary safety and efficacy results, 40 mg QOD was identified as the RP2D.
Phase II study

After determining the RP2D, two pivotal studies were initiated across 10 sites in China that enrolled 41 patients with T315I-mutated CML-CP and 23 with T315I-mutated
CML-AP, of whom more than 60% had received second-line therapies.
As of September 30, 2021, the median follow-up was 34.3 (range, 4.8–58.6) months, and a total of 69.0% (114) of patients remained on the treatment with olverembatinib.
– Safety

The median treatment duration was 30.7 (range, 1.2–58.6) months. Frequent nonhematologic treatment-related adverse events (TRAEs) included skin hyperpigmentation in 139 (84.2%) patients, followed by hypertriglyceridemia (57.6%), proteinuria (50.9%), hyperbilirubinemia (41.8%), hypocalcemia (38.8%), and elevated liver transaminases (35.8%).
Grade 3/4 hematologic TRAEs included thrombocytopenia (51.5%), anemia (23.0%), leukopenia (20.6%), and neutropenia (11.5%). Myelosuppression tended to occur early, and most TRAEs resolved after temporary treatment suspension or supportive care (including platelet or erythrocyte transfusion or dose adjustment).
Cardiovascular events (CVEs) possibly related to olverembatinib, such as hypertension (13.3%), pericardial effusion (8.5%), were observed in 53 (32.1%) patients. 11.5% of these CVEs were Grade 3/4, including a 5% incidence of arterial occlusive and venous thrombotic events, a value that is far lower than the 31% reported with the world’s first approved third-generation BCR-ABL1 inhibitor.
Except for skin hyperpigmentation and proteinuria, incidences of TRAEs decreased over time during the follow-up period. Decreased renal function was not observed in patients with persistent proteinuria. Serious AEs (SAEs; in ≥ 1% of patients) included thrombocytopenia (9.0%), anemia (6.0%), and pneumonia (3.0%), as well as pyrexia or atrial fibrillation (in 2.0% each) followed by acute myocardial infarction, cholelithiasis, pericardial effusion, upper-respiratory-tract infection, and urinary-tract infection (in 1% each). Most SAEs resolved after temporary treatment suspension or dose reduction.
– Efficacy

The median follow-up period of 126 evaluable patients with CML-CP since the start of an effective dose (≥30 mg QOD) was 37 (range, 7–58) months. 100% of patients achieved a complete hematologic response (CHR [not present at baseline]). MCyR and CCyR rates were 79.3% and 69.4%, respectively. 55.6% of patients experienced a major molecular response (MMR), 44.4% had MR4.0, and 38.9% showed MR4.5. Cytogenetic and molecular response rates increased over time. The cumulative 3-year incidences of MCyR, CCyR, MMR, MR4.0, and MR4.5 were 78.6%, 69.0%, 55.9%, 43.5%, and 38.6%, respectively. Probabilities of progression-free survival (PFS) and overall survival (OS) at 3 years were 92.0% and 94.0%, respectively.
In 38 evaluable patients with CML-AP, the median duration follow-up was 27 (range, 5–56) months since the onset of an effective dose. 78.4% patients had a MaHR and 73% experienced a CHR. MCyR and CCyR rates were both 47.4%; 44.7% and 36.8% of patients achieved MMR and MR4.0, respectively, and 34.2% had MR4.5. Cytogenetic and molecular response rates increased over time. The 3-year cumulative incidences of achieving MCyR, CCyR, MMR, MR4.0, and MR4.5 were 47.4%, 47.4%, 44.7%, 39.3%, and 32.1%, respectively. Probabilities of PFS and OS at 3 years were 60.0% and 71.0%, respectively.
Conclusions

Olverembatinib was well tolerated and exhibited robust and durable activity in patients with TKI-resistantCML-CP and CML-AP. In particular, olverembatinib was highly active against BCR-ABL1T315I mutants and demonstrated encouraging clinical activity against compound mutations.
*This is a study of an investigational drug that has not been approved in the US.

References

1. 2-Year Impact Factor (2021) as released by ClarivateTM

2. Jiang Q, Li Z, Qin Y, et al. Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial. J Hematol Oncol. Aug 18 2022;15(1):113. doi:10.1186/s13045-022-01334-z

On September 21, 2022 CTI BioPharma Corp. (NASDAQ: CTIC) reported two poster presentations from the Company’s pacritinib program at the Society of Hematologic Oncology (SOHO) Tenth Annual Meeting, to be held in Houston, Texas and virtually September 28 – October 1, 2022 (Press release, CTI BioPharma, SEP 21, 2022, View Source [SID1234621323]).

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A new data analysis from the Phase 3 PERSIST-2 trial and an in vitro analysis of pacritinib, a novel JAK2/IRAK1 inhibitor approved by the U.S. FDA for patients with myelofibrosis and a platelet count below 50 x 109/L, will highlight pacritinib’s impact on anemia and inhibition of Activin A receptor type 1 (ACVR1).

"Treatment with pacritinb at the approved dose of 200 mg twice daily (BID) led to improvements in transfusion independence and anemia when compared to best available therapy (BAT) in patients treated on the PERSIST-2 Phase 3 study," said Dr. Stephen Oh, MD, PhD, Associate Professor of Medicine, Hematology Division at Washington University School of Medicine in St. Louis. "I am encouraged by these data, given the limited options to address anemia in myelofibrosis, especially high-risk patients with cytopenias who frequently require blood transfusions. I look forward to further investigation of pacritinib’s potential to alleviate anemia and related symptoms in this patient population."

"We are pleased to report that pacritinib is a highly potent inhibitor of ACVR1. This inhibition is thought to lead to improvements in blood transfusion requirements and anemia in patients with cytopenic myelofibrosis," said Adam Craig, MD, PhD, President and Chief Executive Officer of CTI BioPharma. "The data presented at SOHO 2022 support our belief that pacritinib is a simple, safe and effective JAK2 inhibitor. We plan to present additional data on pacritinib’s anemia benefit at a medical meeting later this year."

Presentation materials will be available at ctibiopharma.com.

Retrospective Analysis of Anemia Benefit of Pacritinib from the PERSIST-2 Trial

Abstract Number: MPN-145
Session Name: Poster Session
Session Date: Wednesday, September 28
Presentation Time: 5:05-6:30 p.m. CDT (06:05-7:30 p.m. EDT)
Presenter: Dr. Stephen Oh

Pacritinib is a novel JAK2/IRAK1 inhibitor approved by the U.S. Food and Drug Administration (FDA) for patients with myelofibrosis and severe thrombocytopenia (platelet count <50 x 109/L). Previous clinical trials have noted improvements in spleen volume and symptom scores, as well as improvement in anemia and a decline in transfusion burden. A retrospective analysis of the Phase 3 PERSIST-2 trial was conducted to further assess pacritinib’s impact on anemia, and an in vitro analysis was performed to explore pacritinib’s inhibition of Activin A receptor type 1 (ACVR1; also known as activin receptor-like kinase 2 [ALK2]).

On duplicate assays, pacritinib was shown to be a more potent inhibitor of ACVR1 compared to momelotinib, with a half maximal inhibitory concentration (IC50) of 10.8 and 22.6 nM versus34.9 and 70.2 nM, respectively. The percentage of patients who achieved transfusion independence over any 12-week intervals through week 24 was greater on pacritinib 200 mg twice daily than best available therapy (27% vs 7%), among evaluable non-transfusion independent patients (defined as any red blood cell transfusions in 90 days prior to the first dose or a baseline hemoglobin <8 g/dL). These data suggest an important role for pacritinib in addressing anemia in patients with myelofibrosis.

Retrospective Comparison of Patient Outcomes on Pacritinib Versus Ruxolitinib in Patients with Myelofibrosis (MF) and Thrombocytopenia (encore)

Abstract Number: MPN-141
Session Name: Poster Session
Session Date: Wednesday, September 28
Presentation Time: 5:05-6:30 p.m. CDT (06:05-7:30 p.m. EDT)
Presenter: Dr. Prithviraj Bose

Pacritinib is a novel JAK2/IRAK1 inhibitor approved by the U.S. FDA for patients with myelofibrosis and severe thrombocytopenia (platelet count <50 x 109/L). Unlike the JAK 1/2 inhibitor ruxolitinib, which must be dose-reduced or held in patients with thrombocytopenia, pacritinib has been studied at full dose regardless of platelet count. This retrospective analysis reported on the outcomes in patients treated with pacritinib versus ruxolitinib in the Phase 3 PERSIST-2 study. Patients were randomized 1:1:1 to pacritinib 200 mg BID, pacritinib 400 mg once daily (QD) or BAT, with 45 percent of patients on BAT receiving ruxolitinib.

Results show that pacritinib, administered at the full dose of 200 mg BID, yielded higher response rates and a similar safety profile compared to lower-dose ruxolitinib in patients with myelofibrosis who have moderate or severe thrombocytopenia.

About VONJO (pacritinib)
Pacritinib is an oral kinase inhibitor with activity against wild type Janus Associated Kinase 2 (JAK2), mutant JAK2V617F form and FMS-like tyrosine kinase 3 (FLT3), which contribute to signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. Myelofibrosis is often associated with dysregulated JAK2 signaling. Pacritinib has higher inhibitory activity for JAK2 over other family members, JAK3 and TYK2. At clinically relevant concentrations, pacritinib does not inhibit JAK1. Pacritinib exhibits inhibitory activity against additional cellular kinases (such as CSF1R and IRAK1), the clinical relevance of which is unknown.

VONJO is indicated for the treatment of adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L. This indication is approved under accelerated approval based on spleen volume reduction. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Important VONJO Safety Information
Hemorrhage:
Serious (11%) and fatal (2%) hemorrhages have occurred in VONJO-treated patients with platelet counts <100 × 109/L. Serious (13%) and fatal (2%) hemorrhages have occurred in VONJO-treated patients with platelet counts <50 × 109/L. Grade ≥3 bleeding events (defined as requiring transfusion or invasive intervention) occurred in 15% of patients treated with VONJO compared to 7% of patients treated on the control arm. Due to hemorrhage, VONJO dose reductions, dose interruptions, or permanent discontinuations occurred in 3%, 3%, and 5% of patients, respectively.

Avoid use of VONJO in patients with active bleeding and hold VONJO seven days prior to any planned surgical or invasive procedures. Assess platelet counts periodically, as clinically indicated. Manage hemorrhage using treatment interruption and medical intervention.

Diarrhea:
VONJO causes diarrhea in approximately 48% of patients compared to 15% of patients treated on the control arm. The median time to resolution in VONJO-treated patients was two weeks. The incidence of reported diarrhea decreased over time, with 41% of patients reporting diarrhea in the first eight weeks of treatment, 15% in weeks 8 through 16, and 8% in weeks 16 through 24. Diarrhea resulted in treatment interruption in 3% of VONJO-treated patients. None of the VONJO-treated patients reported diarrhea that resulted in treatment discontinuation. Serious diarrhea adverse reactions occurred in 2% of patients treated with VONJO compared to no such adverse reactions in patients in the control arm.

Control pre-existing diarrhea before starting VONJO treatment. Manage diarrhea with antidiarrheal medications, fluid replacement, and dose modification. Treat diarrhea with antidiarrheal medications promptly at the first onset of symptoms. Interrupt or reduce VONJO dose in patients with significant diarrhea despite optimal supportive care.

Thrombocytopenia:
VONJO can cause worsening thrombocytopenia. VONJO dosing was reduced due to worsening thrombocytopenia in 2% of patients with pre-existing moderate to severe thrombocytopenia (platelet count <100 × 109/L). VONJO dosing was reduced due to worsening thrombocytopenia in 2% of patients with pre-existing severe thrombocytopenia (platelet count <50 × 109/L).

Monitor platelet count prior to VONJO treatment and as clinically indicated during treatment. Interrupt VONJO in patients with clinically significant worsening of thrombocytopenia that lasts for more than seven days. Restart VONJO at 50% of the last given dose once the toxicity has resolved. If toxicity recurs hold VONJO. Restart VONJO at 50% of the last given dose once the toxicity has resolved.

Prolonged QT interval:
VONJO can cause prolongation of the QTc interval. QTc prolongation of >500 msec was higher in VONJO-treated patients than in patients in the control arm (1.4% vs 1%). QTc increase from baseline by 60 msec or higher was greater in VONJO-treated patients than in control arm patients (1.9% vs 1%). Adverse reactions of QTc prolongation were reported for 3.8% of VONJO-treated patients and 2% of control arm patients. No cases of torsades de pointes were reported.

Avoid use of VONJO in patients with a baseline QTc of >480 msec. Avoid use of drugs with significant potential for QTc prolongation in combination with VONJO. Correct hypokalemia prior to and during VONJO treatment. Manage QTc prolongation using VONJO interruption and electrolyte management.

Major Adverse Cardiac Events (MACE):
Another JAK)-inhibitor has increased the risk of MACE, including cardiovascular death, myocardial infarction, and stroke (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which VONJO is not indicated.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with VONJO, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur.

Thrombosis:
Another JAK-inhibitor has increased the risk of thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which VONJO is not indicated.

Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately.

Secondary Malignancies:
Another JAK-inhibitor has increased the risk of lymphoma and other malignancies, excluding non-melanoma skin cancer (NMSC) (compared to those treated with TNF blockers), in patients with rheumatoid arthritis, a condition for which VONJO is not indicated. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with VONJO, particularly in patients with a known malignancy (other than a successfully-treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.

Risk of Infection:
Another JAK-inhibitor has increased the risk of serious infections compared to best available therapy (BAT) in patients with myeloproliferative neoplasms. Serious bacterial, mycobacterial, fungal and viral infections may occur in patients treated with VONJO. Delay starting therapy with VONJO until active serious infections have resolved. Observe patients receiving VONJO for signs and symptoms of infection and manage promptly. Use active surveillance and prophylactic antibiotics according to clinical guidelines.

Interactions with CYP3A4 Inhibitors or Inducers:
Co-administration of VONJO with strong CYP3A4 inhibitors or inducers is contraindicated. Avoid concomitant use of VONJO with moderate CYP3A4 inhibitors or inducers.

Drug interruptions due to an adverse reaction occurred in 27% patients who received VONJO 200 mg twice daily compared to 10% of patients treated with BAT. Dosage reductions due to an adverse reaction occurred in 12% of patients who received VONJO 200 mg twice daily compared to 7% of patients treated with BAT. Permanent discontinuation due to an adverse reaction occurred in 15% of patients receiving VONJO 200 mg twice daily compared to 12% of patients treated with BAT.

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About Myelofibrosis
Myelofibrosis is bone marrow cancer that results in formation of fibrous scar tissue and can lead to thrombocytopenia and anemia, weakness, fatigue and an enlarged spleen and liver. Within the United States, there are approximately 21,000 patients with myelofibrosis, 7,000 of which have severe thrombocytopenia (defined as blood platelet counts of less than 50 x109/L). Severe thrombocytopenia is associated with poor survival and high symptom burden and can occur as a result of disease progression or from drug toxicity with other JAK2 inhibitors, such as JAKAFI and INREBIC.