On December 11, 2022 Sana Biotechnology, Inc. (NASDAQ: SANA), a company focused on creating and delivering engineered cells as medicines, reported data in six presentations at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, taking place from Saturday, December 10 to Tuesday, December 13, 2022 in New Orleans, LA, which highlighted further progress with key technologies supporting Sana’s ex vivo allogeneic CAR T cell programs and in vivo platform (Press release, Sana Biotechnology, DEC 11, 2022, View Source [SID1234625030]).

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"Our HIP platform has the potential to transform the CAR T space, and with it, the treatment of hematologic malignancies, and we are pleased to share data from several drug candidates before our planned entry into the clinic in 2023," said Terry Fry, M.D., Sana’s Senior Vice President and Head of T Cell Therapeutics. "Separate oral presentations show that our HIP-modified allogeneic CD19-targeted CAR T cells can evade immune detection and kill tumor cells in a fully immunocompetent preclinical model, including with serial in vivo tumor stimulation, and that our manufacturing process is able to produce HIP-modified allogeneic CAR T cells reproducibly at scale with high gene editing efficiency and yield. We intend to develop this platform broadly to treat patients with lymphoma, leukemia, and multiple myeloma with a goal of three INDs over the next several years, including one this year for SC291 targeting CD19 positive cancers and one next year for SC263 for patients who have failed a CD19-directed CAR T therapy."

Transplanting cells or tissues from a donor to a different recipient currently requires intense immunosuppression to prevent rejection of the transplant. The goal of Sana’s hypoimmune (HIP) platform is to eliminate the need for immunosuppression by cloaking cells from immune recognition while at the same time generating the manufacturing scale and reproducibility of allogeneic cells. The challenge for the field to date in generating immune cloaked cells has been turning off both the adaptive and innate immune system concurrently. Sana’s platform includes disruption of major histocompatibility (MHC) class I and MHC class II expression to hide cells from the adaptive immune system, which includes antibody and T cell responses, as well as overexpression of CD47 to inhibit activation of the innate immune cell system, in particular macrophages and natural killer (NK) cells. The company has presented data across multiple preclinical models highlighting the potential of this platform to cloak cells from immune recognition. Sana’s goal is to use these HIP-modified cells to replace damaged or missing cells in the body in a number of different diseases, including, among others, cancer and type 1 diabetes.

On Sunday, December 11, Sonja Schrepfer, M.D., Ph.D., Sana’s Senior Vice President and Head of Hypoimmune Platform, gave an oral presentation (Abstract 485) titled "Engineered Hypoimmune CAR T Cells Provide Lasting Tumor Control in Fully Immunocompetent Allogeneic Humanized Mice." This presentation demonstrated that CD47 is an important mechanism to avoid innate immune rejection. CD47 overexpression comprehensively inhibits macrophage and NK cell killing after the disruption of MHC class I and MHC class II expression, making it a more complete approach against innate immune cell killing compared to other strategies. A single dose of HIP-modified CD19-targeted CAR T cells was able to eliminate CD19+ tumors in immune competent animals, including after tumor rechallenge, indicating that these cells may be able to persist and maintain anti-tumor efficacy without immunosuppression.

On Sunday, December 11, Christina Chaivorapol, Ph.D., Sana’s Vice President, Translational Technologies, gave an oral presentation (Abstract 663) titled "Efficient and Specific Multi-Locus Editing of Allogeneic CAR T Cells for Hypoimmunity during Large Scale Manufacture Using Cas12b." The presentation outlined the use of a novel of CRISPR enzyme, Cas12b, to engineer allogeneic hypoimmune CAR T cells at large scale in order to prevent recognition and clearance by the host immune system while maintaining anti-tumor efficacy. Cas12b has been highlighted in prior studies as exhibiting a high level of on-target editing specificity. Assessment of genome integrity of T cells manufactured using Cas12b demonstrated highly specific editing with no significant off-target editing and no evidence for editing-associated structural modifications beyond those expected from on-target cleavage. These data indicate that this scaled manufacturing process can produce fully engineered HIP-modified CD19-targeted allogeneic CAR T cells with high editing efficiency and specificity.

On Saturday, December 10, Sana scientist Darin Salloum, Ph.D., presented a poster (Abstract 1974) titled "Functional T Cell Assays Are Predictive of Pre-Clinical Potency to Generate Allogeneic, Hypoimmune CD19 CAR T Cells." The presentation highlighted the use of several in vitro and in vivo assays to categorize T cells derived from healthy, allogeneic donors into excellent-, good-, or poor-performing T cells. These "stress test" assays may be used to identify T cell quality differences which may be used to select donors and reduce batch variability for allogeneic, HIP-modified CAR T manufacturing. Sana’s manufacturing process appears to create, in a replicable fashion, high quality T cells at a scale with the potential for hundreds of doses per batch.

On Saturday, December 10, Sana scientist Adam Johnson, Ph.D., presented a poster (Abstract 1988) titled "A Dual-Antigen Targeting, Hypoimmune Allogeneic CAR T to Evade Innate and Adaptive Immune Rejection and Overcome Antigen Escape." The presentation showed that a dual-transduction method using lentivirus encoding CD47-CD19CAR and CD47-CD22CAR could reproducibly generate dual-targeted hypoimmune CAR T cells, maintain CD47 overexpression for HIP function, and eliminate both CD19 and CD22 knockout tumor cell lines. Sana is developing SC263, a HIP-modified, CD22-directed CAR T with a clinically-validated CAR with the potential to treat patients with B cell malignancies who have not responded, relapsed, or are refractory to previous CD19-targeted CAR T therapies. The company expects to file an IND in 2023.

On Sunday, December 11, Sana scientist Jeremy Kinder, Ph.D., presented a poster (Abstract 3168) titled "BCMA-Targeted, Hypoimmune Allogeneic CAR T Cells Exhibit Potent Anti-Tumor Activity Together with the Ability to Evade Innate and Adaptive Immune Rejection in Pre-Clinical Tumor Models." The presentation showed that, in pre-clinical tumor models, HIP-modified BCMA-directed CAR T cells with the clinically-validated CT103A CAR construct licensed by Sana in January 2022 controlled myeloma tumor cells equivalently to HIP-modified CAR T cells with approved BCMA CAR constructs. In addition, HIP-modified BCMA CAR T cells showed equal in vitro efficacy and cytokine production against BCMA+ target cells compared to non-HIP BCMA CAR T cells. These data support advancing an allogeneic, HIP-modified BCMA-directed CAR T product to treat myeloma. Sana expects to file an IND for product candidate SC255 as early as 2024 to treat multiple myeloma.

On Sunday, December 11, Sana scientist Jesse Green, Ph.D., presented a poster (Abstract 3457) titled "CD8-Targeted, Integrating Viral Vectors Transduce Resting T Cells and Enable Extracorporeal Delivery (ECD) for Rapid CAR T Cell Therapies." The presentation highlighted that CD8-targeted CD19 CAR fusosomes are able to specifically transduce primary, non-activated CD8+ T cells to generate highly functional CAR T cells capable of eliminating CD19+ tumor cells in animal models. This result was accomplished by both a short-term ex vivo incubation with T cells followed by infusion, termed extracorporeal delivery (ECD), or by direct IV injection of fusosomes into animals engrafted with peripheral blood mononuclear cells. Data generated demonstrate ECD and direct IV are potential dosing options for patients with this fusosome for the in vivo production of CAR T cells. The company expects to study SG295, an in vivo CAR T with CD8-targeted fusosome delivery of a CD19-targeted CAR, in patients with B cell malignancies. With increased potency from a second-generation manufacturing process, SG295 has the potential to generate a comparable number of CAR T cells to current ex vivo manufacturing processes. The company remains on track to file an IND in 2023.

On December 11, 2022 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported positive new and updated data from a Phase 1 and pivotal Phase 2 trial (ELM-1 and ELM-2) evaluating investigational odronextamab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (Press release, Regeneron, DEC 11, 2022, View Source [SID1234625029]). These included first data from a Phase 2 cohort of patients naïve to prior CAR-T therapy (CAR-T naïve), as well as updated data from a dose expansion cohort of a Phase 1 trial in patients who had progressed on CAR-T therapy (post-CAR-T). The results were presented in an oral session at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in New Orleans, LA, and will form the basis of planned submissions to regulatory authorities in 2023, including to the U.S. Food and Drug Administration (FDA). Odronextamab is an investigational bispecific antibody designed to bridge CD20 on cancer cells with CD3-expressing T cells to facilitate local T-cell activation and cancer-cell killing.

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"People with diffuse large B-cell lymphoma face a disease that often relapses and becomes more aggressive each time it returns, leaving doctors with a shrinking set of treatment options," said Won Seog Kim, M.D., Ph.D., Samsung Medical Center and Division of Hematology-Oncology at Sungkyunkwan University, in Seoul, South Korea, and trial investigator. "The Phase 1 and pivotal Phase 2 odronextamab data demonstrated deep and durable responses that were consistent in patients who progress after CAR-T therapy, which is important as they have particularly difficult-to-treat disease and no effective treatment options. Coupled with its overall safety profile, these clinically important results reinforce the potential of odronextamab to treat this aggressive blood cancer."

At ASH (Free ASH Whitepaper), efficacy in R/R DLBCL was presented from 130 CAR-T naïve patients in a Phase 2 cohort (includes those with an opportunity for assessment at 12 weeks; median follow-up: 21 months, range: 3 to 30 months) and 31 CAR-T experienced patients in a dose expansion cohort of a Phase 1 trial (median follow-up: 24 months, range: 3 to 38.5 months). All patients had received at least two prior therapies, including a CD20 antibody and alkylating agent. Patients were treated with a step-up regimen of odronextamab in the first cycle to help mitigate the risk of cytokine release syndrome (CRS) before receiving the full dose of 160 mg. The step-up regimen was modified part way through the trial to further mitigate CRS. Results as assessed by independent central review were as follows:

Among CAR-T naïve patients, a 49% objective response rate (ORR), with 31% achieving a complete response (CR). The median duration of complete response (mDOCR) was 18 months (95% confidence interval [CI]: 10 months to not evaluable [NE]).
Among post-CAR-T patients, a 48% ORR, with 32% achieving a CR. The mDOCR was not reached (95% CI: 2 months to NE).
Among 140 patients in the Phase 2 cohort assessed for safety, adverse events (AE) occurred in 99% of patients, with 79% being ≥Grade 3. The most common AEs occurring in ≥20% of patients were CRS (55%), anemia (42%), pyrexia (39%), neutropenia (28%) and hypokalemia (20%). Discontinuations due to an AE occurred in 10% of patients, and there were 5 deaths due to pneumonia (n=3), COVID-19 (n=1) and pseudomonal sepsis (n=1) where the relationship to odronextamab treatment could not be excluded.

CRS was the most common AE, of which 64% of cases were mild (Grade 1) and all resolved within a median time of 2 days (range: 1-133 days). There were no Grade 4 or 5 CRS cases, and the incidence of Grade 2 or higher cases was reduced with the modified step-up regimen when compared to the original (original regimen n=67 vs. step-up regimen n=73; Grade 2: 18% vs. 14%, Grade 3: 7.5% vs. 1%).

Based on these data, the OLYMPIA Phase 3 development program investigating odronextamab in earlier stages of the disease is in the process of being initiated. In the U.S., odronextamab has been granted Fast Track Designation for DLBCL by the FDA. In the European Union, Orphan Drug Designation was granted for DLBCL by the European Medicines Agency. Odronextamab is currently under clinical development and its safety and efficacy have not been fully evaluated by any regulatory authority.

Investor Webcast Information
Regeneron will host a conference call and simultaneous webcast to share updates on the company’s hematology portfolio on Wednesday, December 14 at 8:30 AM ET. A link to the webcast may be accessed from the ‘Investors and Media’ page of Regeneron’s website at View Source To participate via telephone, please register in advance at this link. Upon registration, all telephone participants will receive a confirmation email detailing how to join the conference call, including the dial-in number along with a unique passcode and registrant ID that can be used to access the call. A replay of the conference call and webcast will be archived on the company’s website for at least 30 days.

About the Trials
ELM-2 is an ongoing, open-label, multicenter Phase 2 trial investigating odronextamab in more than 500 patients across five independent disease-specific cohorts, including DLBCL, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma and other subtypes of B-cell non-Hodgkin lymphoma (B-NHL). The primary endpoint is ORR according to the Lugano Classification, and secondary endpoints include CR, progression free survival, overall survival, duration of response, disease control rate, safety and quality of life.

ELM-1 is an ongoing, open-label, multicenter Phase 1 trial to investigate the safety and tolerability of odronextamab in patients with CD20+ B-cell malignancies previously treated with CD20-directed antibody therapy. Subcutaneous administration is being evaluated in two disease specific cohorts.

About Diffuse Large B-cell Lymphoma (DLBCL)
One of the most common subtypes of B-NHL, DLBCL is an aggressive form of B-NHL with up to 50% of patients with advanced stage disease progressing after first-line treatment (e.g., relapsing or becoming refractory to treatment). For patients with relapsed/refractory DLBCL, treatment options are limited and prognosis is poor.

On December 11, 2022 MaaT Pharma (EURONEXT: MAAT – the "Company"), a French clinical-stage biotech and a pioneer in the development of Microbiome Ecosystem TherapiesTM (MET) dedicated to improving survival outcomes for patients with cancer, reported detailed results from the completed Phase 1b CIMON trial with MaaT033 at the Annual Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in New Orleans, U.S.
To access the abstract, please click here (Press release, MaaT Pharma, DEC 11, 2022, View Source [SID1234625026]).

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"MaaT Pharma’s mission is to improve cancer patients’ lives by driving innovation in the microbiome therapeutics field," said Hervé Affagard, CEO and co-founder of MaaT Pharma. "These positive Phase 1b results reinforces the strong potential for our MET oral formulation, MaaT033, and we plan to investigate it as an adjunctive and maintenance treatment in patients with hematological malignancies."

Prof. Mohamad Mohty added, "Allo-HSCT is often the only curative approach for patients with hematological malignancies such as acute leukemia. Evidence of a significant reduction in the risk of infection and GvHD-related mortality following stem cell transplantation has been associated with a higher gut microbiome diversity. Our ability to maintain or induce a high richness, and a high diversity gut microbiome would be key to prevent or minimize these adverse effects and contribute to a better overall prognosis for these patients."

Key clinical findings with MaaT033 in Phase 1b study CIMON

In the dose-finding Phase 1b CIMON trial, 21 patients with acute myeloid leukemia (AML) were treated with MaaT033 and evaluated for safety, tolerability, and initial signs of microbial species engraftment.

MaaT033 was shown to be safe and tolerable in 21 patients. 4 severe adverse events (SAEs) were reported in 4 patients, only one considered as possibly related by the investigator.
Treatment with MaaT033 induced increased microbiota richness as well as strong and persistent engraftment in cohorts 3 and 4 of the dose escalation study, which consisted in the intake of 3 capsules of the drug candidate per day.
Engraftment following MaaT033 treatment correlated with increased anti-inflammatory marker levels and reduced inflammatory marker levels.
Detailed results from the Phase 1b CIMON trial were presented in a poster on December 11 at the ASH (Free ASH Whitepaper) Annual Meeting by Prof. Mohamad Mohty, Head of the Clinical Hematology and Cellular Department at the Saint-Antoine Hospital and Sorbonne University. As previously announced, MaaT Pharma is currently preparing a pivotal Phase IIb randomized, double-blind, placebo-controlled to evaluate MaaT033’s safety, engraftment, and efficacy in improving overall survival at 12 months and preventing complications in patients with blood cancers receiving hematopoietic stem cell transplantation. Initiation should take place shortly and the Company will provide a detailed status update in January 2023.

About MaaT033

MaaT033 is an oral, full-ecosystem, off-the-shelf, standardized, pooled-donor, high-richness Microbiome Ecosystem TherapyTM. MaaT033 is designed to restore the gut ecosystem to full functionality to improve clinical outcomes as well as to control adverse events related to conventional treatments for liquid tumors. The capsule formulation facilitates administration while maintaining the high and consistent richness and diversity of microbial species, including anti-inflammatory ButycoreTM species.

On December 11, 2022 IGM Biosciences, Inc. (Nasdaq: IGMS), a clinical-stage biotechnology company focused on creating and developing IgM antibodies, reported that the presentation of data from IGM’s expanding portfolio of T cell engagers for hematologic malignancies, including IGM-2644, IGM-2537 and imvotamab, at the 2022 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition being held virtually and in-person in New Orleans, Louisiana, December 10-13, 2022 (Press release, IGM Biosciences, DEC 11, 2022, View Source [SID1234625020]).

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"As shown today, the preclinical profiles of IGM-2644, our CD38 x CD3 bispecific IgM antibody, and IGM-2537, our CD123 x CD3 bispecific IgM antibody, demonstrate the potential for encouraging antitumor activity coupled with favorable safety profiles," said Chris Takimoto, M.D., Ph.D., F.A.C.P., Chief Medical Officer of IGM Biosciences. "We are also presenting today biomarker data from the Phase 1 trial of imvotamab, our CD20 x CD3 bispecific IgM antibody, showing its encouraging activity in patients with low CD20 expressing tumors."

The poster titled "IGM-2644, a Novel CD38 x CD3 Bispecific IgM T Cell Engager Demonstrates Potent Efficacy on Myeloma Cells with an Improved Preclinical Safety Profile" highlights IGM-2644’s greater complement dependent cytotoxicity (CDC) activity as compared to conventional IgG anti-CD38 antibodies. Additionally, IGM-2644 achieved potent T cell dependent cellular cytotoxicity (TDCC) killing of daratumumab-resistant cell lines with minimal cytokine release as well as potent TDCC killing of myeloma patient samples. IGM-2644 was also shown to inhibit CD38+ tumor growth in humanized xenograft models, but it avoids killing immune effector cells as compared to an IgG bispecific T cell engager. IGM plans to initiate a Phase 1 trial of IGM-2644 in multiple myeloma in the first quarter of 2023, subject to Investigational New Drug (IND) application clearance.

The poster titled "CD123 Directed IgM T-cell Engager, IGM-2537, Demonstrates Potent in vitro and in vivo Activity with Minimal Cytokine Release" highlights potent in vitro and in vivo activity with limited cytokine induction consistent with the potential for providing a favorable safety profile for a CD123-directed IgM-based T cell engager. IGM-2537 was shown to bind to human CD123 with high affinity, avidity, and specificity. IGM-2537 co-engaged with both CD123 and CD3 antigens, leading to T cell redirected killing of acute myeloid leukemia (AML) cell lines with concomitant T cell activation, and eliminated AML blast cells at physiologically relevant effector/target ratios in an ex vivo assay. IGM-2537 also showed significantly reduced cytokine release, exemplified by IFN-γ, TNF-α and IL-6, as compared to an IgG T cell engager molecule. IGM expects to file an IND application for IGM-2537 in AML in 2023.

The poster titled "Pharmacodynamics and Biomarker Correlates of Imvotamab (IGM-2323), the First-in-Class CD20xCD3 Bispecific IgM Antibody with Dual Mechanisms of Action, in Patients with Advanced B Cell Malignancies" features biomarker data from the Phase 1 trial evaluating imvotamab, the Company’s IgM T cell engaging bispecific antibody. The poster highlights that complete responses were observed even in patients with low CD20 expressing tumors. Biomarker data obtained from patients in dose escalation cohorts also demonstrated pharmacodynamic changes that support the TDCC and CDC mechanisms of action of imvotamab.

On December 11, 2022 CTI BioPharma Corp. (Nasdaq: CTIC) reported an oral presentation and two poster presentations from the Company’s pacritinib program at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, taking place in New Orleans, Louisiana and virtually December 10-13, 2022 (Press release, CTI BioPharma, DEC 11, 2022, View Source [SID1234625017]).

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A new post-hoc data analysis from the Phase 3 PERSIST-2 trial of pacritinib, a novel JAK2/IRAK1 inhibitor approved by the U.S. Food and Drug Administration (FDA) for patients with myelofibrosis and severe thrombocytopenia (platelet count below 50 x 109/L), highlights pacritinib’s potential anemia benefit in patients with myelofibrosis through its inhibition of Activin A receptor type 1 (ACVR1).

"The ACVR1/hepcidin pathway has a major role in the control of anemia in patients with myelofibrosis. Importantly, pacritinib has now been shown to be a potent ACVR1 inhibitor that reduces hepcidin levels in vitro. Furthermore, in the PERSIST-2 trial, at the approved dose of 200 mg twice daily (BID), treatment with pacritinib led to transfusion independence in patients with myelofibrosis who required red blood cell (RBC) transfusions," said Dr. Stephen Oh, MD, PhD, Associate Professor of Medicine, Hematology Division at Washington University School of Medicine in St. Louis. "As anemia poses a substantial burden for patients with myelofibrosis, the potential role of pacritinib in addressing anemia is highly encouraging."

"As our understanding of the mechanism of action of pacritinib expands, the full potential of pacritinib as a therapy for cytopenic myelofibrosis is emerging," said Adam Craig, MD, PhD, President and Chief Executive Officer of CTI BioPharma. "We continue in our commitment to meaningfully change the treatment paradigm for cytopenic myelofibrosis."

Presentation materials will be available at ctibiopharma.com.

The details of the oral presentation are as follows:

Pacritinib Is a Potent ACVR1 Inhibitor with Significant Anemia Benefit in Patients with Myelofibrosis

Abstract Number: 628
Session Name: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Towards Personalized Medicine in Myeloproliferative Neoplasms and Mastocytosis: New and Repurposed Drugs for Unmet Clinical Needs
Session Date: Sunday, December 11, 2022
Presentation Time: 5:15–5:30 p.m. CST/6:15–6:30 p.m. EST
Presenter: Dr. Stephen Oh

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) and can be administered at the full approved dose (200 mg BID) regardless of cytopenias. Pacritinib demonstrated hemoglobin improvement in the randomized Phase 3 PERSIST-2 study, though the mechanism behind and the extent of pacritinib’s anemia benefit has not been fully described. A retrospective analysis of the Phase 3 PERSIST-2 study was performed to assess pacritinib’s in vitro potency against ACVR1 and its ability to reduce hepcidin and to describe the impact of pacritinib 200 mg BID on RBC transfusion independence.

Results from in vitro testing suggest pacritinib is a potent ACVR1 inhibitor that reduces hepcidin expression. Analysis of the clinical data shows that pacritinib therapy results in transfusion independence in patients with myelofibrosis who require RBC transfusions. Given this unique mechanism of action, pacritinib may provide a therapeutic option that provides spleen, symptom and anemia benefits to patients with myelofibrosis.

The details of the poster presentations are as follows:

Differential Impact of Thrombocytopenia and Anemia on Myelofibrosis (MF) Symptom Burden

Abstract Number: 1712
Session Name: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster I
Session Date: Saturday, December 10, 2022
Presentation Time: 5:30–7:30 p.m. CST/6:30–8:30 p.m. EST
Presenter: Dr. Jeanne Palmer

Patients with myelofibrosis and thrombocytopenia (platelet count <50 x 109/L) report worse fatigue, inactivity, early satiety and quality of life compared to patients with higher platelet counts. Because thrombocytopenia and anemia frequently co-occur in myelofibrosis, the relative impact of thrombocytopenia and anemia on myelofibrosis symptoms is unknown. A retrospective analysis of baseline data from the Phase 3 PERSIST-1 and Phase 2 PAC203 trials was performed to describe the differential impact of thrombocytopenia and anemia on symptom burden by analyzing symptom data from patients with myelofibrosis who have isolated thrombocytopenia (platelet count <100 x 109/L and hemoglobin ≥8 g/dL) versus isolated anemia (platelet count ≥100 x 109/L and hemoglobin <8 g/dL).

Results showed that patients with isolated thrombocytopenia had more severe symptom burden than those with isolated anemia, particularly with physical function- and spleen-related symptoms. While amelioration of anemia is an important therapeutic goal for patients with cytopenic myelofibrosis, these data suggest that additional efforts aimed at the control of platelet count and underlying disease should be implemented to achieve optimal symptom control.

PACIFICA: A Randomized, Controlled Phase 3 Study of Pacritinib Versus Physician’s Choice in Patients with Primary or Secondary Myelofibrosis and Severe Thrombocytopenia

Abstract Number: 4316
Session Name: 631. Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational: Poster III
Session Date: Monday, December 12, 2022
Presentation Time: 6:00–8:00 p.m. CST/7:00–9:00 p.m. EST
Presenter: Dr. John Mascarenhas

Pacritinib is a novel JAK2/IRAK1/ACVR1 inhibitor approved by the U.S. FDA for patients with myelofibrosis and severe thrombocytopenia (platelet count <50 x 109/L). So far, treatment options for patients with myelofibrosis and severe thrombocytopenia are limited due to the high incidence of treatment-related thrombocytopenia when other JAK inhibitors are used. Previously, pacritinib demonstrated clinical activity in myelofibrosis in two Phase 3 studies (PERSIST-1 and PERSIST-2) and a Phase 2 dose-finding study (PAC203), all of which included patients with severe thrombocytopenia. PACIFICA is a multinational, multicenter, 2:1 randomized, controlled Phase 3 trial (NCT03165734) designed to confirm the efficacy and safety of pacritinib 200 mg twice daily vs physician’s choice therapy in patients with myelofibrosis and severe thrombocytopenia.

About VONJO (pacritinib)
Pacritinib is an oral kinase inhibitor with activity against wild type Janus Associated Kinase 2 (JAK2), mutant JAK2V617F form, IRAK1, ACVR1 (ALK2) 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. At clinically relevant concentrations, pacritinib does not inhibit JAK1.

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 x 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). CTI is conducting the Phase 3 PACIFICA study of VONJO in patients with myelofibrosis and severe thrombocytopenia as a post-marketing requirement.

Important VONJO Safety Information
Hemorrhage:
Serious (11%) and fatal (2%) hemorrhages have occurred in VONJO-treated patients with platelet counts <100 x 109/L. Serious (13%) and fatal (2%) hemorrhages have occurred in VONJO-treated patients with platelet counts <50 x 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 x 109/L). VONJO dosing was reduced due to worsening thrombocytopenia in 2% of patients with pre-existing severe thrombocytopenia (platelet count <50 x 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 x 109/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.