On December 10, 2023 Poseida Therapeutics, Inc. (Nasdaq: PSTX), a clinical-stage cell and gene therapy company advancing a new class of treatments for patients with cancer and rare diseases, reported early efficacy and safety results from its Phase 1 study of P-BCMA-ALLO1, its BCMA-targeted allogeneic, T stem cell memory (TSCM)-rich chimeric antigen receptor (CAR)-T therapy candidate (Press release, Poseida Therapeutics, DEC 10, 2023, View Source [SID1234638378]). The Company is investigating P-BCMA-ALLO1 in partnership with Roche for the treatment of relapsed/refractory multiple myeloma (RRMM). Detailed study findings, along with two additional Company poster presentations in cell and gene therapy, are being featured at the 65th ASH (Free ASH Whitepaper) Annual Meeting and Exposition being held in San Diego on December 9-12, 2023.

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"Today, far too many patients are unable to benefit from autologous CAR-T therapy due to its limited supply, lengthy timelines, complex logistics, and cost," said Kristin Yarema, Ph.D., President, Cell Therapy at Poseida. "We have long believed that readily produced, off-the-shelf allogeneic, TSCM-rich CAR-T products have the potential to offer a compelling efficacy and safety profile while also supporting patient access. TSCM-rich CAR-T products can be difficult to produce with older virus-based technology, but we are able to create a portfolio of such products using Poseida’s unique, non-viral set of technologies. We see these early P-BCMA-ALLO1 results in multiple myeloma, in which all enrolled patients received CAR-T therapy and most patients receiving adequate lymphodepletion achieved a stringent complete response (sCR) or very good partial response (VGPR), as validating our vision and eagerly await additional data yet to come from this study. This is also the first known publicly presented data set that provides clear clinical evidence supporting the hypothesis that TSCM cells are the ideal cell type for allogeneic CAR-T, extending our previous findings with autologous TSCM cells to the allogeneic setting. We hope that TSCM-rich allogeneic CAR-T therapies may potentially offer the optimal combination of clinical results, on-demand availability and high-volume production, while supporting broader access to CAR-T therapies. We are excited to have taken this first step with our early P-BCMA-ALLO1 clinical results. They inspire us to further develop P-BCMA-ALLO1 in partnership with Roche, and to continue advancing our entire allogeneic TSCM cell-based CAR-T portfolio."

P-BCMA-ALLO1 program data presentations

At the time of the October 23, 2023 data cut off, 39 patients were enrolled as an intent-to-treat (ITT) population in the ongoing Phase 1 multicenter, open-label dose-escalation study (NCT04960579). Enrolled patients had previously failed protease inhibitor, immunomodulatory drug (IMiD), and anti-CD38 antibody treatments or were otherwise triple-refractory. Previous treatment with B cell maturation antigen (BCMA)-targeted therapy was allowed including autologous BCMA CAR-T and bispecific T cell-engaging (TCE) antibodies. All enrolled patients completed lymphodepletion and went on to receive P-BCMA-ALLO1 a median of 7 days after enrollment for a 100% ITT treatment rate with no use of bridging therapy. Six patient cohorts varying in size (n=1 to n=6) received one of three fludarabine/cyclophosphamide (flu/cy) lymphodepleting conditioning regimens including 3 days of fludarabine at 30 mg/m2/day for all patients and, depending upon the patient cohort, 3 days of cyclophosphamide at 300, 500, or 1,000 mg/m2/day followed by infusion of P-BCMA-ALLO1 cells at cell doses varying by cohort up to 6×106 cells/kg to date.

Evaluable patients with at least 4 weeks of follow up (n=33) were heavily pretreated with a median of 7 prior lines of therapy. Additionally, 30% of these patients had high risk disease by cytogenetics and nearly 2 in 5 (39%) had received previous BCMA-targeted therapy. 11 of the 33 evaluable patients were in the two cohorts receiving 2×106 cells/kg of P-BCMA-ALLO1 and higher cyclophosphamide preconditioning doses at either 500 mg/m2 (‘P1 arm’; n=5) or 1,000 mg/m2 (‘P2 arm’; n=6).

An overall objective response rate (ORR) of 82% (9/11 total patients) was reached among patients in the pooled P1 and P2 arms. ORR in the P2 arm was 83% (5/6) with 100% (5/5) of the responding P2 patients achieving a VGPR or better and 40% (2/5) achieving sCR. 80% ORR was obtained in the P1 arm (4/5) with 50% of responding patients achieving VGPR. Both nonresponding patients, one in each of the P1 and P2 arms, had received and not achieved clinical response with the BCMAxCD3 bispecific TCE antibody therapy teclistamab prior to receiving P-BCMA-ALLO1.

A 100% ORR (9/9) was achieved among patients in P1 and P2 arms who had not received a prior BCMA-targeting bispecific TCE antibody as well as 100% ORR (2/2) in patients who had received prior autologous CAR-T BCMA targeted therapy.

P-BCMA-ALLO1 was very well tolerated, with no graft-vs-host disease (GvHD) at any dose and low rates of cytokine release syndrome (CRS) and neurotoxicity, all Grade 2 or less, found among all evaluable patients.

Expansion and persistence of the CAR-T cells in patients after infusion was found to be highly dependent upon the conditioning dose of cyclophosphamide, with P-BCMA-ALLO1 levels measured in the blood much higher in patient cohorts in the P1 and P2 arms receiving the 500 mg/m2 and 1,000 mg/m2 conditioning doses than in any of the 300 mg/m2 (arm ‘S’, n=20) cohorts. Clinical responses in patients receiving arm S conditioning treatment were inferior to those achieved by patients in P1 or P2.

Analysis of P-BCMA-ALLO1 cellular kinetics in two patients with high CAR-T expansion showed CAR-T cells persisted and were measurable in the peripheral blood of one patient for at least 4 weeks and engrafted and persisted at a high level in the bone marrow of the other for at least 6 weeks. Moreover, in both cases cells in the TSCM-rich CAR-T infused drug product underwent differentiation after infusion to generate a much more effector T cell-rich population, particularly among the important CD8+ ‘killer T cell’ subpopulation. These findings are the first known direct clinical evidence supporting the theory that allogeneic TSCM-based CAR-T cells can act as effective prodrugs because they can expand, traffic to the relevant tissues, differentiate into effector cells and persist, all of which may contribute to driving deep clinical responses in patients while also being well-tolerated.

"Despite the emergence of autologous BCMA-targeted therapies, multiple myeloma remains an incurable malignancy. Autologous CAR-T therapies may be associated with numerous challenges for patients and physicians, including prolonged manufacturing times, inconsistent drug quality and serious safety issues," said Bhagirathbhai Dholaria, M.D., Associate Professor of Medicine (Hematology/Oncology) at the Vanderbilt-Ingram Cancer Center. "Allogeneic CAR-T therapies have the potential to overcome many of these challenges. Today’s data demonstrate that P-BCMA-ALLO1 is a well-tolerated off-the-shelf therapy with a favorable emerging safety profile and encouraging evidence of early clinical activity. In addition, the data show that P-BCMA-ALLO1 can achieve deep clinical responses in patients with high-risk disease and those who have previously received BCMA targeting therapies. Importantly, P-BCMA-ALLO1 was delivered to all patients in the ITT population with all drug product meeting all quality specifications. We look forward to continuing to enroll patients in this study."

Enrollment is ongoing including additional exploration of dose regimens and lymphodepleting conditioning regimens. While still early to assess durability, at the time of the data cut off 8 of the 9 responding patients in P1 and P2 arms remained in response. The Company, together with Roche, plans to present additional clinical data updates for P-BCMA-ALLO1 at scientific meetings in 2024, subject to coordination with Roche.

A second Poseida-sponsored poster highlights the development of an in vivo bioassay for assessing BCMA CAR-T final product potency and presents data suggesting P-BCMA-ALLO1 drug product may have greater potency than drug products produced in the Company’s earlier, autologous P-BCMA-101 CAR-T program.

P-FVIII-101 program data presentation

The Company has also presented a third poster describing P-FVIII-101, a fully non-viral liver-directed gene therapy combining Poseida’s proprietary piggyBac DNA Delivery System with nanoparticle delivery for the treatment of Hemophilia A. This poster demonstrates the capabilities of the piggyBac DNA insertion system and non-viral approach in providing stable Factor VIII (FVIII) transgene expression through genomic integration, along with the potential for redosing. The poster highlights 52-week durability in an adult Hemophilia A model along with a favorable tolerability profile of Poseida’s liver-targeted non-viral delivery platform providing further proof-of-principle toward developing an effective and durable treatment for Hemophilia A.

Company-Hosted Webcast and Conference Call Information:

Poseida will host a webcast and conference call today, December 10th at 11:00 AM PST / 2:00 PM EST. The conference call can be accessed by dialing 800-225-9448 (United States) or 203-518-9708 (International) with the conference ID PSTX23. A live webcast may be accessed using the link here, or by visiting the Events and Presentations section of the Poseida website at investors.poseida.com. After the live webcast, the event will remain archived on the Poseida site for 90 days.

Poster Presentation Details:

Title: Early Safety Results of P-BCMA-ALLO1, a Fully Allogeneic Chimeric Antigen Receptor T-Cell (CAR-T), in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Presenting Author: Bhagirathbhai Dholaria, M.D., Associate Professor of Medicine (Hematology/Oncology) at the Vanderbilt-Ingram Cancer Center
Session Date & Time: Sunday, December 10, 2023, at 6:00 – 8:00 PM PT
Publication Number: 3479
Session Title: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster II
Location: Halls G-H
Title: A Tumor-Bearing Murine Xenograft Model as a Bioassay for Assessing CAR-T Product Potency Shows Positive Predictive Value for Clinical Performance

Presenting Author: Stacey Cranert, Ph.D., Poseida Therapeutics
Session Date & Time: Saturday, December 9, 2023, at 5:30 – 7:30 PM PT
Publication Number: 2293
Session Title: 803. Emerging Tools, Techniques and Artificial Intelligence in Hematology: Poster I
Location: Halls G-H
Title: Effective Gene Therapy for Hemophilia A: Novel Re-Dosable Non-Viral Formulation That Provides Stable, and Durable FVIII Expression with Improved Tolerability

Presenting Author: Brian Truong, Ph.D., Poseida Therapeutics
Session Date & Time: Saturday, December 9, 2023, at 5:30 – 7:30 PM PT
Publication Number: 1232
Session Title: 321. Coagulation and Fibrinolysis: Basic and Translational: Poster I
Location: Halls G-H
About P-BCMA-ALLO1

P-BCMA-ALLO1 is an allogeneic CAR-T product candidate licensed to Roche targeting B-cell maturation antigen (BCMA) for the treatment of relapsed/refractory multiple myeloma in Phase 1 development. This allogeneic program includes a VH-based binder that targets BCMA and has shown early evidence of encouraging safety and efficacy. Additional information about the Phase 1 study is available at www.clinicaltrials.gov using identifier: NCT04960579.

About P-FVIII-101

P-FVIII-101 is a liver-directed gene therapy combining Poseida’s non-viral piggyBac platform and nanoparticle delivery technologies for the in vivo treatment of Hemophilia A. Hemophilia A is a bleeding disorder caused by a deficiency in Factor VIII production with a high unmet need. P-FVIII-101 utilizes the piggyBac gene integration system delivered via lipid nanoparticle, which has demonstrated stable and sustained Factor VIII expression in juvenile and adult animal models.

On December 10, 2023 Vincerx Pharma, Inc. (Nasdaq: VINC)("Vincerx"), a biopharmaceutical company aspiring to address the unmet medical needs of patients with cancer through paradigm-shifting therapeutics, reported the presentation of two preclinical posters at the 65th Annual Meeting of the American Society for Hematology (ASH 2023) for VIP943, for leukemias and myelodysplastic syndrome, and VIP924, for B-cell malignancies (Press release, Vincerx Pharma, DEC 10, 2023, View Source [SID1234638377]).

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"We are excited to share new preclinical data for VIP943 and VIP94 with our stakeholders," said Ahmed Hamdy, M.D., Chief Executive Officer of Vincerx. "The compelling data from these studies underscore the differentiation of our next-generation ADCs and the power of VersAptx, our versatile and adaptable bioconjugation platform used to develop these ADCs."

"The preclinical data from the VIP943 poster highlight the on-target selectivity and activity of VIP943 in acute myeloid leukemia (AML) cell lines, including those with common AML mutations such as TP53. We also show that repeat dosing of VIP943 in cynomolgus monkeys has good overall tolerability without the myelosuppression and hepatotoxicity typically associated with ADCs, which is consistent with the favorable safety profile seen to date in our VIP943 Phase 1 dose-escalation trial. The first dosing cohort enrolled rapidly and completed the 28-day safety evaluation without evidence of drug-related adverse events. One of the three patients from this cohort continues treatment, and the second cohort is enrolling."

"The preclinical data from the VIP924 poster highlight the superior efficacy of VIP924 when compared with two commercially available ADCs, Polivy and Zynlonta, in a mouse model of mantle cell lymphoma. In this study, VIP924 shows significant efficacy (i.e., significant tumor growth inhibition and increased survival) with no substantial change in body weight, an indication of safety, while Polivy and Zynlonta show no improvement in tumor growth inhibition or survival. Based on the side-effect profile of current ADC and CAR-T therapies for B-cell malignancies, we believe VIP924 may have the potential to be used in earlier lines of therapy, either as a monotherapy or in combination with other targeted drugs (e.g., BTK or BCL2 inhibitors), to improve efficacy and safety," concluded Dr. Hamdy.

Poster Highlights

VIP943: CD123-KSPi ADC for leukemias and myelodysplastic syndrome

Poster #1435: Selectivity and Safety of VIP943: A novel CD123 Targeting Antibody-Drug Conjugate (ADC) Using a Proprietary Linker and Payload Class.

Objective: The poster outlines a series of assays used to characterize the preclinical properties of VIP943, including biochemistry, pharmacology, on-target selectivity and activity, safety, and toxicokinetics.

Results:

On-target selectivity and activity show that VIP943 is highly selective for the kinesin spindle protein (KSP) target, aka EG5, versus other members of the related KIF super family. This on-target activity translates to cell cycle arrest at the G2/M phase of mitosis, resulting in apoptosis in AML cell lines.
In vitro cytotoxicity assays show that most hematologic cell lines (n=56) are sensitive to VIP943’s payload and that DNA alterations (including common AML mutations such as TP53) did not reduce its cytotoxicity.
Nonhuman primate safety and toxicokinetic studies show that repeat dosing of VIP943 in cynomolgus monkeys has good overall tolerability without the myelosuppression and hepatotoxicity seen with other ADCs. This is consistent with the favorable safety profile seen to date in the VIP943 Phase 1 dose-escalation trial.
VIP924: CXCR5-KSPi ADC for B-cell malignancies

Poster #2809: Comparison of the CXCR5-Antibody Drug Conjugate (ADC; VIP924) to a CD19-ADC and a CD79b-ADC in a Humanized REC-1 Mantle Cell Lymphoma (MCL) Mouse Model.

Objective: To evaluate target expression (CXCR5, CD19, and CD79b) in human patient samples and to compare the activity of VIP924 to two commercially available, B-cell targeted ADCs, Polivy (a CD19-ADC, polatuzumab vedotin) and Zynlonta (CD79b-ADC, loncastuximab tesirine), in a humanized mouse model of MCL by evaluating in vivo activity, immunophenotyping of key tissues, and complete blood counts. VIP924 data are based on a dose level of 10 mg/kg compared with 3 mg/kg for Polivy and 0.66 mg/kg for Zynlonta. Doses were selected based on the literature as effective doses in mouse xenograft experiments and higher doses lead to toxicity in these models. Tumor growth was measured at day 25; blood work was assessed at days 0, 5, and 18.

Results:

Target expression analysis in a panel of 20 human MCL samples shows that CXCR5 and CD19 expression was medium to high in all samples, while CD79b showed slightly lower expression.
In vivo activity in a humanized mouse model shows that VIP924 demonstrates significant efficacy (i.e., tumor growth inhibition and increased survival) with no substantial change in body weight (an indication of safety). In comparison, the commercially available ADCs, Polivy and Zynlonta, show no improvement in tumor growth inhibition or survival in this setting.
Immunophenotyping of key immune tissues show that:
VIP924 treatment yielded no difference in the percent of CD45+ cells versus the control, while the other two ADCs showed a clear reduction in CD45+ cells.
VIP924 treatment reduced T-follicular helper cells (Tfhs) in the blood, tumor and spleen; significantly increased T-regs; and had no meaningful impact on myeloid-derived suppressor cells (MDSCs) compared with controls. Zynlonta also reduced peripheral blood Tfhs and significantly increased MDSCs compared with control.
Complete blood counts (CBCs) show that VIP924 had minimal impact on the six elements of the CBC reported in these studies. Zynlonta reduced the levels of all cell populations in the CBC, except for platelets.
About VIP943

VIP943, the first ADC from our VersAptx platform, consists of an anti-CD123 antibody, a unique linker cleaved intracellularly by legumain, and a novel kinesin spindle protein inhibitor (KSPi) payload enhanced with our CellTrapper technology. Our proprietary effector chemistry (linker + payload) was designed to reduce non-specific release of the payload and ensure payload accumulation in cancer cells versus healthy cells. The increased therapeutic index has the potential to address challenges associated with many ADCs by improving efficacy and reducing severe toxicities. VIP943 is in a Phase 1 dose-escalation trial evaluating patients with relapsed/refractory acute myeloid leukemia, myelodysplastic syndrome, and B-cell acute lymphoblastic leukemia who have exhausted standard therapeutic options (NCT06034275). We expect to expand into these CD123-positive indications, including TP53 mutated AML both as monotherapy and in combination, as safety and efficacy data are generated. Preliminary Phase 1 data are expected in mid-2024.

About VIP924

VIP924, the second ADC from our VersAptx Platform, consists of an anti-CXCR5 antibody, a unique linker cleaved intracellularly by legumain, and a novel KSPi payload enhanced with our CellTrapper technology. Our proprietary effector chemistry (linker + payload) was designed to reduce non-specific release of the payload and ensure payload accumulation in cancer cells versus healthy cells. The increased therapeutic index has the potential to address challenges associated with many ADCs by improving efficacy and reducing severe toxicities. VIP924 has the potential to be evaluated in B-cell malignancies, such as mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia, both as monotherapy and in combination. We continue to judiciously pace our investment in VIP924 to focus resources on VIP236 and VIP943.

About VersAptx Platform

VersAptx is our versatile and adaptable, next-generation bioconjugation platform. The modular nature of this innovative platform allows us to combine different targeting, linker, and payload technologies to develop bespoke bioconjugates to address different cancer biologies. With this platform (i) antibodies and small molecules can be used to target different tumor antigens (ii) linkers can be designed to reduce non-specific release of the payload, cleave intracellularly or extracellularly, and conjugate to single or multiple payloads, and (iii) payloads can be designed with reduced permeability using our CellTrapper technology to ensure accumulation in cancer cells or to be permeable for release in the tumor microenvironment. The VersAptx platform allows us to optimize these technologies to a specific target and develop bioconjugates designed to address the safety and efficacy challenges of many ADCs and the needs of cancer patients.

About Enitociclib

Enitociclib is a highly selective CDK9 inhibitor that prevents activation of RNA polymerase II, resulting in reduction of known oncogenes MYC and MCL1. It is currently in a dose-escalation Phase 1 trial (NTC05371054) in collaboration with the National Institutes of Health evaluating the combination of enitociclib, venetoclax, and prednisone in DLBCL and peripheral T-cell lymphoma (PTCL). The first dose level completed enrollment with no drug-related safety signal (n=3; 1=DLBCL, 2=PTCL). The first patient on the second dose level (n=1; 1=PTCL) remains on study with a partial response due to an 80% reduction in the pulmonary lesion on computerized tomography (CT) scan and resolved skin lesions. Investigators are pleased with the safety profile of this novel combination and continue with enrollment. Early-stage clinical studies in patients with hematologic malignancies and solid tumors provided monotherapy proof-of-concept. Additional combination studies will be determined based on financing/partnering support.

On December 10, 2023 Incyte (Nasdaq:INCY) and Syndax Pharmaceuticals (Nasdaq:SNDX) reported the full results from the pivotal Phase 2 AGAVE-201 trial of axatilimab, an anti-CSF-1R antibody, in adult and pediatric patients with refractory chronic graft-versus-host disease (GVHD) who had received at least two prior lines of systemic therapy (Press release, Syndax, DEC 10, 2023, View Source [SID1234638376]). These data are featured today in the Plenary Scientific Session (Abstract #1) at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting 2023 (ASH 2023), held December 9-12, 2023, in San Diego and virtually.

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This press release features multimedia. View the full release here: View Source

The results, which build on previously announced topline data, show that the trial met the primary endpoint across all cohorts receiving axatilimab, at doses of 0.3 mg/kg every two weeks, 1.0 mg/kg every two weeks and 3.0 mg/kg every four weeks. Patients who received axatilimab at 0.3 mg/kg every two weeks achieved the highest overall response rate (ORR) of 74% within the first six months of treatment (95% CI; 63-83). Patients in this cohort experienced a median time to response to axatilimab of 1.7 months (0.9-8.1), and 60% of patients maintained a response at 12 months (measured from first response to new systemic therapy or death, based on the Kaplan Meier estimate). The recommended dose of axatilimab for future trials in chronic GVHD is 0.3 mg/kg every two weeks.

"The data presented today at ASH (Free ASH Whitepaper) represent a significant step forward in expanding the treatment options for patients with refractory chronic GVHD," said Pablo J. Cagnoni, M.D., President and Head of Research and Development, Incyte. "An unmet need remains for treatments that are well tolerated and efficacious for patients with refractory chronic GVHD, and the data presented today show that axatilimab could provide a valuable option. We look forward to working with our partners at Syndax as we move axatilimab towards regulatory filing."

The AGAVE-201 trial also met key secondary endpoints in the 0.3 mg/kg dose, with 55% of patients achieving a ≥7-point improvement in the modified Lee Symptom Scale (mLSS) score. Organ-specific responses, including complete responses (CRs), were seen across all organs involved at baseline, including lower gastrointestinal (GI), upper GI, esophagus, joints/fascia, mouth, lungs, liver, eyes and skin. Additionally, responses were notable in fibrosis-dominated organs, including the esophagus (78%), joints and fascia (76%), lungs (47%) and skin (27%).

"The additional positive data from AGAVE-201 further strengthen axatilimab’s strong safety and efficacy profile as a well-differentiated treatment option for patients with refractory chronic GVHD," said Michael A. Metzger, Chief Executive Officer of Syndax. "As a potentially first-in-class anti-CSF-1R antibody targeting inflammation and fibrosis through the inhibition of disease associated macrophages, we have more conviction than ever that axatilimab is poised to transform the treatment paradigm for chronic GVHD. Axatilimab has the potential to positively impact patients with this devastating disease and we are working diligently with Incyte to bring this agent to market."

The AGAVE-201 pivotal trial enrolled 241 patients with relapsed and refractory cGVHD who had received two or more prior systemic therapies, with 74% having previously received ruxolitinib, 31% having previously received ibrutinib and 23% having previously received belumosudil. Patients were enrolled across 121 sites in 16 countries.

The most common treatment-emergent adverse events (TEAEs) were consistent with the on-target effects of CSF-1R inhibition and with what was previously observed with axatilimab treatment. TEAEs in greater than 20% of patients in the overall population (n=239) include increases in aspartate aminotransferase, blood creatine phosphokinase, lipase, lactate dehydrogenase, and alanine aminotransferase.

In the overall trial population, 33% of patients experienced at least one grade ≥3 TEAE, with 15.5% experiencing adverse events leading to discontinuation of treatment. For patients who received axatilimab at 0.3 mg/kg (n=79), grade ≥3 TEAEs occurred in 17.7% of patients, with 6.3% experiencing TEAEs leading to discontinuation of treatment.

"Approximately 50% of chronic GVHD patients are refractory to first-line treatment and 25% of patients require at least four lines of treatment, representing a great need for additional effective treatment options," said Daniel Wolff, M.D., Ph.D., Head, Senior Physician, and Professor at University Hospital Regensburg. "Full results from the AGAVE-201 trial show rapid durable responses documented in all organs and patient subgroups, with significant symptom burden reduction reported by most of these heavily-pretreated patients. I am pleased that the results of the AGAVE-201 trial showed potential advances for patients who had not responded to previous lines of treatments and look forward to further research to underscore the efficacy of axatilimab patients with chronic GVHD."

Based on these results and pending agreement from the U.S. Food and Drug Administration (FDA), Syndax and Incyte expect to submit a Biologics License Application (BLA) to the FDA by year-end 2023.

About Chronic Graft-Versus Host Disease

Chronic graft-versus-host disease (GVHD), an immune response of the donor-derived hematopoietic cells against recipient tissues, is a serious, potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation which can last for years. Chronic GVHD is estimated to develop in approximately 40% of transplant recipients, and affects approximately 14,000 patients in the U.S.1,2. Chronic GVHD typically manifests across multiple organ systems, with skin and mucosa being commonly involved, and is characterized by the development of fibrotic tissue3.

About Axatilimab

Axatilimab is an investigational monoclonal antibody that targets colony stimulating factor-1 receptor, or CSF-1R, a cell surface protein thought to control the survival and function of monocytes and macrophages. In pre-clinical models, inhibition of signaling through the CSF-1 receptor has been shown to reduce the number of disease-mediating macrophages along with their monocyte precursors, which has been shown to play a key role in the fibrotic disease process underlying diseases such as chronic graft-versus-host disease (GVHD) and idiopathic pulmonary fibrosis (IPF). Phase 1/2 data of axatilimab in chronic GVHD demonstrating its broad activity and tolerability were last presented at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and data were published in the Journal of Clinical Oncology. Additionally, positive topline results from the Phase 2 AGAVE-201 trial showing the trial met its primary endpoint were recently announced. Axatilimab was granted Orphan Drug Designation by the U.S. Food and Drug Administration for the treatment of patients with chronic GVHD and IPF. In September 2021, Syndax and Incyte entered into an exclusive worldwide co-development and co-commercialization license agreement for axatilimab. Axatilimab is being developed under an exclusive worldwide license from UCB entered into between Syndax and UCB in 2016.

About AGAVE-201

The global Phase 2 AGAVE-201 dose-ranging trial evaluated the efficacy, safety, and tolerability of axatilimab in 241 adult and pediatric patients with recurrent or refractory active chronic GVHD whose disease had progressed after two prior therapies. Patients were randomized to one of three treatment groups that investigated a distinct dose of axatilimab administered at 0.3 mg/kg every two weeks, 1.0 mg/kg every two weeks or 3.0 mg/kg every four weeks. The trial’s primary endpoint is the proportion of patients in each dose group who achieved an objective response as defined by 2014 NIH Consensus Criteria for chronic GVHD by cycle 7 day 1. Secondary endpoints include duration of response, percent reduction in daily steroids dose, organ specific response rates and validated quality-of-life assessments using the Modified Lee Symptom Scale.

For more information about AGAVE-201, visit View Source

On December 10, 2023 Seagen Inc. (NASDAQ: SGEN) reported that clinically meaningful progression-free survival (PFS), a secondary endpoint, was observed in a Phase 2 study evaluating the antibody-drug conjugate (ADC) ADCETRIS (brentuximab vedotin)in combination with the PD-1 inhibitor nivolumab and standard chemotherapy agents doxorubicin and dacarbazine (AN+AD) as first-line treatment for early and advanced stage classical Hodgkin lymphoma (cHL) (Press release, Seagen, DEC 10, 2023, View Source [SID1234638375]). This is the first time 12-month PFS results were presented for the treatment combination, which avoids use of vinblastine and bleomycin in patients with early stage cHL. Results from the trial, called SGN35-027, were presented in an oral session at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in San Diego.

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"Hodgkin lymphoma commonly strikes young adults, and our goal is to achieve the highest cure rate possible while reducing treatment and toxicity burden," said Jeremy Abramson, M.D., Director, Jon and Jo Ann Hagler Center for Lymphoma at Massachusetts General Hospital, and principal investigator of the part of the trial that evaluated patients with early stage cHL. "These data show encouraging activity and safety for combining an ADC and immunotherapy, two medicines that have distinct and complementary mechanisms of action, allowing reduced reliance on traditional cytotoxic chemotherapies."

"These data continue to demonstrate favorable clinical outcomes of an ADCETRIS plus nivolumab immunotherapy combination that reduces chemotherapy treatment burden and warrant further study," said Roger Dansey, M.D., President, Research and Development and Chief Medical Officer at Seagen.

Oral #611: Brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine (AN+AD) for early-stage classical Hodgkin lymphoma: Updated results reporting progression-free survival in an ongoing Phase 2 study (SGN35-027 Part C)

SGN35-027 Part C is investigating the novel ADCETRIS combination in 154 patients with early stage (non-bulky Stage I or II) cHL.

Among 150 efficacy-evaluable patients, 98% had an overall response (OR) (95% CI: 94.3, 99.6) and 93% had a complete response (CR) (95% CI:88.1, 96.8) at the end of treatment.
99% of patients who responded (95% CI: 95.0, 99.9) had a duration of response (DOR) beyond 12 months; 98% of patients who had a complete response (95% CI: 93.7, 99.6) had a duration of CR (DOCR) beyond 12 months.
The PFS rate was 100% (95% CI: 100, 100) at 12 months and 97% (95% CI: 90.3, 99.1) at 18 months.
The most frequently reported treatment-emergent adverse events (TEAEs) Grade 3 or higher were neutropenia (9%), increased alanine aminotransferase (7%), and increased aspartate aminotransferase (5%).
Peripheral sensory neuropathy was primarily low grade (3% Grade ≥3).
There were no cases of febrile neutropenia and no deaths.
Treatment-emergent immune-mediated adverse events (IMAEs) were primarily low-grade and consistent with the individual safety profile of nivolumab.
Oral #608: Brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine for advanced stage classical Hodgkin lymphoma: Updated efficacy and safety results from the single arm Phase 2 study (SGN35-027 Part B)

SGN35-027 Part B is investigating the novel ADCETRIS combination in 57 patients with advanced-stage cHL (Stage II with bulky disease, Stage III or IV).

Among 56 efficacy-evaluable patients, 95% had an OR (95% CI: 85.1, 98.9) and 89% had a CR (95% CI: 78.1, 96.0).
88% of patients who responded (95% CI: 75.7, 94.6) had a DOR beyond 24 months; 88% of patients who had a CR (95% CI: 76.0, 94.6) had a DOCR beyond 24 months.
The estimated PFS rate at 24 months was 88% (95% CI: 75.7, 94.6), with a median follow-up of 24.2 months (95% CI: 23.4, 26.9).
The most frequently reported TEAEs Grade 3 or higher were increased alanine aminotransferase (11%) and neutropenia (9%).
Peripheral sensory neuropathy was primarily low grade (4% Grade ≥3).
No febrile neutropenia and no deaths were reported.
IMAEs were primarily low-grade and consistent with the individual safety profile of nivolumab. No subsequent radiation therapy was given to patients.
ADCETRIS is a proven foundation of care for CD30-expressing lymphomas with more than 120,000 patients treated globally across seven indications. In combination with Adriamycin, vinblastine and dacarbazine (AVD) chemotherapy, ADCETRIS is the first medicine to include overall survival data in its Prescribing Information for previously untreated Stage III/IV cHL.1

Please see Important Safety Information, including a BOXED WARNING for progressive multifocal leukoencephalopathy (PML), for ADCETRIS below.

About SGN35-027

SGN35-027 is an ongoing open-label, multiple part, multicenter, single-arm Phase 2 clinical trial evaluating brentuximab vedotin treatment combinations in patients with early- and advanced-stage cHL. Parts B and C of the trial are investigating brentuximab vedotin in combination with the PD-1 inhibitor nivolumab and chemotherapy agents doxorubicin and dacarbazine. Part B is evaluating the combination in patients with stage II bulky (mediastinal mass ≥10 cm), Stage III or IV cHL. Part C is evaluating the combination in patients with Stage I or II cHL without bulky mediastinal disease (<10 cm). The primary endpoint for Parts B and C is the proportion of participants with complete response at end of treatment according to the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC).

About Hodgkin Lymphoma

Lymphoma is a general term for a group of cancers that originate in the lymphatic system affecting a type of white blood cell called lymphocytes. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Hodgkin lymphoma is distinguished by the presence of Reed-Sternberg cells that usually have a protein called CD30 on their surface. Approximately 8,830 cases of classical Hodgkin lymphoma will be diagnosed in the United States during 2023 and 900 people will die from the disease.2 According to the International Agency for Research on Cancer in 2020, over 83,000 people worldwide were diagnosed with Hodgkin lymphoma and approximately 23,000 people died from this cancer.3

About ADCETRIS

ADCETRIS is an antibody-drug conjugate (ADC) comprised of a CD30-directed monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seagen’s proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-positive tumor cells.

ADCETRIS is approved for seven indications in the U.S.:

Pediatric patients 2 years and older with previously untreated high risk cHL in combination with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide (2022)
Adult patients with previously untreated Stage III/IV cHL in combination with doxorubicin, vinblastine, and dacarbazine (2018)
Adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone (2018)
Adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) after prior systemic therapy (2017) Adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation (2015)
Adult patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. (2011)
Adult patients with cHL after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates (2011)
ADCETRIS has marketing authorization in more than 70 countries for relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma.

Seagen and Takeda jointly develop ADCETRIS. Under the terms of the collaboration agreement, Seagen has U.S. and Canadian commercialization rights, and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seagen and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

ADCETRIS (brentuximab vedotin) for injection U.S. Important Safety Information

BOXED WARNING

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.

CONTRAINDICATION

Contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

WARNINGS AND PRECAUTIONS

Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay, change in dose, or discontinuation of ADCETRIS.

Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.

Hematologic toxicities: Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS.

Administer G-CSF primary prophylaxis beginning with Cycle 1 for adult patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL, and pediatric patients who receive ADCETRIS in combination with chemotherapy for previously untreated high risk cHL.

Monitor complete blood counts prior to each ADCETRIS dose. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.

Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in ADCETRIS-treated patients. Closely monitor patients during treatment for infections.

Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden may be at increased risk. Monitor closely and take appropriate measures.

Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment. Avoid use in patients with severe renal impairment.

Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment. Avoid use in patients with moderate or severe hepatic impairment.

Hepatotoxicity: Fatal and serious cases have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.

PML: Fatal cases of JC virus infection resulting in PML have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider PML diagnosis in patients with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.

Pulmonary toxicity: Fatal and serious events of noninfectious pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, have been reported. Monitor patients for signs and symptoms, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.

Serious dermatologic reactions: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.

Gastrointestinal (GI) complications: Fatal and serious cases of acute pancreatitis have been reported. Other fatal and serious GI complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately.

Hyperglycemia: Serious cases, such as new-onset hyperglycemia, exacerbation of preexisting diabetes mellitus, and ketoacidosis (including fatal outcomes) have been reported with ADCETRIS. Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Monitor serum glucose and if hyperglycemia develops, administer anti-hyperglycemic medications as clinically indicated.

Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of this potential risk, and to use effective contraception during ADCETRIS treatment and for 2 months after the last dose of ADCETRIS. Advise male patients with female partners of reproductive potential to use effective contraception during ADCETRIS treatment and for 4 months after the last dose of ADCETRIS.

ADVERSE REACTIONS

The most common adverse reactions (≥20% in any study) are peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, mucositis, thrombocytopenia, and febrile neutropenia.

DRUG INTERACTIONS

Concomitant use of strong CYP3A4 inhibitors has the potential to affect the exposure to monomethyl auristatin E (MMAE). Closely monitor adverse reactions.

USE IN SPECIAL POPULATIONS

Lactation: Breastfeeding is not recommended during ADCETRIS treatment.

Please see the full Prescribing Information, including BOXED WARNING, for ADCETRIS here.

On December 10, 2023 Sanofi reported that the Phase 3 trial investigating Sarclisa (isatuximab) in combination with carfilzomib, lenalidomide and dexamethasone (KRd) showed a statistically significant improvement in the rate of minimal residual disease (MRD) negativity, compared with KRd alone, after autologous stem cell transplant (ASCT) consolidation in transplant-eligible patients with newly diagnosed multiple myeloma (MM) (Press release, Sanofi, DEC 10, 2023, View Source [SID1234638374]). These results from the IsKia trial conducted by the European Myeloma Network (EMN) were presented during the oral plenary session (#4) at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting by Francesca Gay, Associate Professor at the University Division of Hematology, AOU Città della Salute e della Scienza di Torino, University of Torino and Department of Molecular Biotechnology and Health Sciences – member of the Young EMN board of directors.

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MRD negativity is defined as the absence of myeloma cells in the bone marrow after treatment, as measured by diagnostic techniques that must have a sensitivity of at least 1 in 100,000 cells. In this trial, MRD negativity was detected with a sensitivity of 10-5 (no cancer cells detected within 100,000 bone marrow cells) and 10-6 (no cancer cells detected within 1,000,000 bone marrow cells).

In an intent-to-treat (ITT) analysis, the primary endpoint of rate of MRD negativity using next generation sequencing with a sensitivity of 10-5 after consolidation for patients receiving Sarclisa combination therapy (n=151) was 77% versus 67% for those who received KRd alone (n=151) (odds ratio [OR] 1.67; p=0.049). The respective rates of MRD negativity at sensitivity of 10-6 were 67% versus 48% (OR 1.93; p=0.006). The MRD negativity benefit, both at 10-5 and 10-6 sensitivities, was retained in all subgroups analyzed with similar benefit in both standard-risk and high-risk patients.

There was a statistically significant difference in MRD negativity rates after induction with Sarclisa in combination with KRd versus KRd (10-5: 45% versus 26%, p<0.001; 10-6: 27% versus 14%, p=0.004).

The safety and tolerability of Sarclisa observed in this trial were consistent with the observed safety profile of Sarclisa in other clinical trials, with no new safety signals observed. Rates of grade 3 or higher hematologic adverse events (AEs) were 40% versus 30% and rates of non-hematologic AEs were 41% versus 37% for the Sarclisa combination versus KRd, respectively. Discontinuation rates for AEs were similar in both study arms (7% and 5%, respectively). There were three treatment-related deaths in the Sarclisa combination arm and one in the KRd arm.

Peter C. Adamson
Global Development Head, Oncology, Sanofi

"The statistically significant rates of MRD negativity observed with Sarclisa combination therapy further support our belief in Sarclisa as a potential best-in-class therapy. Effective front-line treatment is critical for newly diagnosed patients, because achieving undetectable levels of disease early in the treatment journey may lead to better long-term outcomes. We look forward to our continued collaboration with the EMN to explore the potential of this novel combination regimen for those with transplant-eligible, newly diagnosed multiple myeloma."

The use of Sarclisa in combination with KRd in this patient population is investigational and has not been evaluated by any regulatory authority.

About the trial

The randomized, open-label Phase 3 IsKia trial enrolled 302 patients with newly diagnosed, transplant-eligible MM across eight countries and 42 sites in Europe. Patients were randomized into two arms. Patients in both arms received induction with four 28-day cycles of KRd followed by cyclophosphamide and stem cell collections, chemotherapy with Melphalan 200 mg/m2 followed by ASCT (Mel200-ASCT), four 28-day cycles of KRd post ASCT consolidation and 12 cycles of KRd light consolidation. Sarclisa was added to KRd in one trial arm only. During the trial, Sarclisa was administered through an intravenous infusion at a dose of 10 mg/kg once weekly for the first four weeks of cycle one, then every other week for the rest of the induction and full consolidation periods, then every four weeks during light consolidation period.

The primary endpoint was the rate of MRD negativity by next-generation sequencing (10-5) after consolidation in the ITT population. MRD was tested in all patients who achieved at least a very good partial response. Key secondary endpoints were the rate of next-generation sequencing MRD negativity (10-5) after induction and progression free survival. MRD rates were evaluated in an ITT analysis.

High-risk patient cytogenetics per the International Myeloma Working Group (IMWG) criteria were defined as the presence of t(4;14), t(14;16), or del(17p). High-risk cytogenetic abnormality (HRCA) was defined as the presence of one of the following abnormalities: del(17p13.1), t(4;14) (p16.3;q32.3), t(14;16) (q32.3;q23), gain(1q21), or amp(1q21). Two or more HRCAs was defined as the presence of at least two high-risk cytogenetic abnormalities.

About Sarclisa

Sarclisa is a monoclonal antibody that binds to a specific epitope on the CD38 receptor on multiple myeloma (MM) cells, inducing distinct antitumor activity. It is designed to work through multiple mechanisms of action including programmed tumor cell death (apoptosis) and immunomodulatory activities. CD38 is highly and uniformly expressed on the surface of MM cells, making it a potential target for antibody-based therapeutics such as Sarclisa.

Based on the Phase 3 ICARIA-MM study, Sarclisa is approved in >50 countries, including the U.S. and EU, in combination with pomalidomide and dexamethasone for the treatment of certain patients with relapsed refractory MM (RRMM) who have received ≥2 prior therapies, including lenalidomide and a proteasome inhibitor and who progressed on last therapy. Based on the Phase 3 IKEMA study, Sarclisa is also approved in 50 countries in combination with carfilzomib and dexamethasone, including in the U.S. for the treatment of patients with RRMM who have received 1–3 prior lines of therapy and in the European Union for patients with MM who have received at least 1 prior therapy. In the U.S., the generic name for Sarclisa is isatuximab-irfc, with irfc as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. Food and Drug Administration (FDA).

The IsKia trial marks the second positive Phase 3 trial of Sarclisa in transplant-eligible newly diagnosed multiple myeloma, and fifth positive Phase 3 readout for Sarclisa overall, demonstrating its best-in-class potential.

Sarclisa continues to be evaluated in multiple ongoing Phase 3 clinical trials in combination with current standard treatments across the MM treatment continuum. It is also under investigation for the treatment of other hematologic malignancies, and its safety and efficacy have not been evaluated by any regulatory authority outside of its approved indication.

For more information on Sarclisa clinical trials, please visit www.clinicaltrials.gov.

About multiple myeloma

MM is the second most common hematologic malignancy.1 Since MM does not have a cure, most patients will relapse. Relapsed MM is the term for when the cancer returns after treatment or a period of remission. Refractory MM refers to when the cancer does not respond or no longer responds to therapy.