On December 10, 2023 InnoCare Pharma (HKEX: 09969; SSE: 688428), a leading biopharmaceutical company focusing on the treatment of cancer and autoimmune diseases, reported that the latest data from InnoCare’s oncology studies were presented at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, InnoCare Pharma, DEC 10, 2023, View Source [SID1234638392]). The study of orelabrutinib’s regimen in patients with untreated mantle cell lymphoma (MCL) was selected as an oral presentation.

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A Prospective Multicenter Phase II Study of Orelabrutinib-Lenalidomide-Rituximab (OLR) in Patients with Untreated Mantle Cell Lymphoma (MCL) in China (POLARIS Study): Preliminary Analysis on Efficacy, Safety, Mutation Spectrum and Impact of Mutation Profiling on Treatment Responses (Abstract Number: 736)

The POLARIS study is a single arm, multicenter, open-label phase II study that uses a combination regimen of orelabrutinib, lenalidomide and rituximab to treat untreated MCL patients, with a maximum duration of 24 cycles.

As of July 10, 2023, a total of 28 patients were enrolled. The overall response rate (ORR) was 100%, and the complete response rate (CRR) was 76.2%. The median time to response (TTR) was 3 months, with the estimated 12-month duration of response (DOR) rate and progression-free survival (PFS) rate of 90.9% and 92.3%, respectively.

The preliminary findings show that the Orelabrutinib-Lenalidomide-Rituximab exerted synergistic anti-tumor activity, with manageable toxicity in untreated MCL.

The first author and corresponding author of the abstract is Professor Huilai Zhang from the Tianjin Medical University Cancer Institute and Hospital.

Preliminary Safety, Pharmacological, and Efficacy Data from Patients with Relapsed or Refractory B-cell Malignancies Treated with the ICP-248, a Next Generation BCL2 Inhibitor (Abstract Number: 6149)

This is a phase I study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ICP-248 in patients with relapsed or refractory B-cell malignancies.

ICP-248 demonstrated a favorable PK profile, with approximate dose proportionality observed across the ramp-up stage. No dose-limiting toxicities (DLTs) were observed. All the AEs were grade 1 to 2 without dose interruption or modifications. No TLS including laboratory TLS was observed.

As of data cutoff date, three patients had been completed tumor assessment. Two patients were assessed as complete response (CR) at the end of cycle 2 with undetectable MRD, and another patient was assessed as stable disease (SD).

Preliminary results suggest that ICP-248 is safe and well tolerated in relapsed or refractory B-cell malignancies. Preliminary efficacy data demonstrated good response with deep remission. Further assessment of safety and efficacy with additional dose levels and dosing strategies will be pursued in expanded patient population and in the combination with orelabrutinib.

The first author and corresponding author of the abstract is Professor Shuhua Yi from the Chinese Academy of Medical Sciences and Peking Union Medical College.

Effectiveness and Safety of Orelabrutinib Combined with Rituximab As First-Line Treatment in Marginal Zone Lymphoma (Abstract Number: 6146)

The retrospective study evaluated the effectiveness and safety of orelabrutinib combined with rituximab as first-line treatment in marginal zone lymphoma (MZL). The primary endpoint was the overall response rate (ORR); secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety.

The ORR was 90%. After a median follow-up of 13.0 months, the median PFS was not reached and a 6-month PFS rate was 100%. Off-target related AEs such as atrial fibrillation, diarrhea, and major hemorrhage were not reported.

This retrospective data suggests that orelabrutinib in combination with rituximab has an encouraging anti-tumor activity in MZL, with a favorable safety profile. These results provide a potential first-line treatment strategy in MZL. Further verification in prospective clinical trials of orelabrutinib in first-line MZL is warranted.

The corresponding author of the abstract is Professor Peng Liu from the Zhongshan Hospital, Fudan University.

For more study results, please visit ASH (Free ASH Whitepaper) website.

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 Be Biopharma, Inc. ("Be Bio"), a company pioneering the discovery and development of Engineered B Cell Medicines (BCMs), reported results from a new preclinical study demonstrating that the company’s novel engineered BCM, BE-101, produces active and sustained levels of Factor IX (FIX) for the treatment of hemophilia B (Press release, Be Biopharma, DEC 10, 2023, View Source [SID1234638393]).​ These data were shared during an oral presentation at the 65th annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) taking place in San Diego, California. Also today, Be Bio announced plans to advance BE-101 as its lead program for the treatment of people with severe or moderately severe hemophilia B.​

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In addition, the company announced the appointment of Glenn Pierce, M.D., Ph.D., globally renowned hemophilia physician-researcher, as a member of the Be Bio Scientific Advisory Board.

"The preclinical study findings presented today demonstrate that BE-101 can produce predictable, persistent FIX activity levels with the potential to prevent bleeding and joint damage in persons with hemophilia B," said Richard A. Morgan, Ph.D., chief scientific officer, Be Bio. "We are excited by these findings as we advance this novel BCM into clinical development to address enduring unmet medical needs for people living with hemophilia B. Our data demonstrate that a single dose of BE-101 allows for sustainable, steady-state FIX levels, making it a potentially transformative FIX replacement option for adults and children with hemophilia B."​

"Despite several major advances in treatment options for people with hemophilia B, including extended-release recombinant factor IX biologics and the availability of a new gene therapy, significant unmet needs remain for people living with hemophilia B. Many people living with hemophilia B still experience bleeding episodes, irreversible joint damage and pain with current extended-release factor IX biologic therapy. A redosable treatment that can provide sustained therapeutic levels of FIX has the potential to prevent irreversible joint damage before it occurs, which could be a major therapeutic advance for adults and importantly, children living with hemophilia B," Dr. Pierce said.

"Our goal is to create a new, potentially transformative treatment option that will provide people with hemophilia B the freedom to live a normal life, free of limitations from hemophilia B. We look forward to filing our Investigational New Drug application for BE-101 in mid-2024​," said Joanne Smith-Farrell, Ph.D., chief executive officer, Be Bio. ​"As we announce our lead program in hemophilia B, we are delighted to welcome Dr. Pierce to our Scientific Advisory Board," Smith-Farrell said. "Dr. Pierce is a tireless patient advocate, hemophilia survivor, biotechnology industry leader, and deeply respected hematology thought leader. All of us at Be Bio are inspired by the opportunity to advance BE-101 as the first program in a bold new class of cell therapies with the potential to transform care for people living with serious disease."

Dr. Pierce has more than 30 years of experience in biopharmaceutical research and development and has been involved in the development and approval of six hemophilia therapies. He currently serves on the World Federation of Hemophilia (WFH) Vice President Medical and WFH USA Board of Directors and the U.S. Medical and Scientific Advisory Council of the National Bleeding Disorders Foundation. The co-author of more than 200 scientific papers, Dr. Pierce also served on the Blood Products Advisory Committee of the U.S. Food and Drug Administration and the Committee on Blood Safety and Availability of the US Department of Health and Human Services.

BE-101 Oral Presentation at American Society of Hematology (ASH) (Free ASH Whitepaper)

Poster Title: "Development of an Ex Vivo Precision Gene Engineered B Cell Medicine That Produces Active and Sustained Levels of FIX for the Treatment of Hemophilia B"
Presentation #: 463
Oral Presentation Session: 703. Cellular Immunotherapies: Basic and Translational: Novel Approaches for Next Generation Cellular Immunotherapies
Date/Time: Sunday, December 10, 9:30am PT
Presenter: Richard A. Morgan, Ph.D., Chief Scientific Officer, Be Bio

Study Summary

In this study, primary human B cells were isolated and engineered by CRISPR/Cas9 genome editing followed by AAV-mediated homology directed repair (HDR) insertion of human FIX gene into the CCR5 safe harbor locus. The cells were then further expanded and differentiated toward the plasma cell lineage, resulting in FIX-producing BCMs. Approximately 50% targeted integration was achieved, as measured by droplet digital PCR (ddPCR). Engineered BCMs secreted up to 60 ng/1e6 cells/hour of FIX protein, approaching 40% of IgG secretion rate as measured by ELISA. Vitamin K-dependent activated partial thromboplastin time (aPTT), using the one stage clotting assay, demonstrated biological activity of BCM-produced FIX. Similarly, FIX-expressing BCMs exhibited vitamin K-dependent activity in vitro in the chromogenic assay. FIX-expressing BCMs were transferred into immunodeficient NOG-hIL6 mice, with stable FIX production demonstrated for >168 days in vivo. Redosability was demonstrated with increased engraftment (measured by human IgG levels) and a concomitant increase in plasma FIX. The safety of FIX-expressing BCMs has been characterized based on 28-day and 5-month in vivo studies in NOG-hIL6 mice (n=168 mice). Neither abnormal clinical observations nor mortality were observed in those studies. Biodistribution of the FIX-expressing BCMs was assessed using qPCR. The data confirmed the expected biodistribution of FIX-expressing BCMs in bone marrow tissue, where they engraft stably over time.

About Hemophilia B

Hemophilia B is an X-linked recessive bleeding disorder that affects approximately 1:20,000 males. It is caused by mutations in the gene that encodes for the FIX protein, an essential enzyme in the coagulation cascade. This can lead to spontaneous bleeding as well as bleeding following injuries or surgery.1 People with hemophilia B bleed longer than other people. Bleeds can occur internally, into joints and muscles, or externally, from minor cuts, dental procedures or trauma.2 While an adeno-associated virus (AAV) vector-based gene therapy has been approved for some adults as a potential new option, the current standard of care and only treatment for children remains prophylactic administration of exogenous FIX derived from recombinant protein. The short biological half-life of FIX requires frequent infusions to maintain therapeutic levels.

About Engineered B Cell Medicines – A New Class of Cellular Medicines

Imagine what could "Be?" In nature, a single B cell engrafts in the bone marrow and can produce thousands of proteins per second at constant levels over decades. B cells are nature’s exquisite medicine factories, manufacturing proteins to fight disease and maintain health. Unleashing the power of B cells is driving a new class of cellular medicines – Engineered B Cell Medicines (BCMs). BCMs have the potential to be durable, allogeneic, redosable and administered without toxic conditioning. The promise of BCMs could transform therapeutic biologics with broad application — across protein classes, patient populations and therapeutic areas.

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 Adicet Bio, Inc. (Nasdaq: ACET), a clinical stage biotechnology company discovering and developing allogeneic gamma delta T cell therapies for cancer, reported that an abstract outlining PK and PD profiling data from the Company’s ongoing Phase 1 study of ADI-001 for the potential treatment of relapsed or refractory aggressive B-cell NHL was made available as part of the 65th ASH (Free ASH Whitepaper) Annual Meeting, being held December 9-12, 2023 in San Diego, California (Press release, Adicet Bio, DEC 10, 2023, View Source [SID1234638394]). The data will be provided during a poster presentation at the ASH (Free ASH Whitepaper) Annual Meeting on Sunday, December 10, 2023.

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"We are pleased to share encouraging observations from the pharmacokinetic and pharmacodynamic analyses of ADI-001 at ASH (Free ASH Whitepaper), further characterizing its potential as a best-in-class allogeneic CAR T platform. The data presented today showed dose-dependent expansion and persistence that met or exceeded that in prescribing information of approved autologous CD19 CAR T therapies, supporting ADI-001’s potential as an effective therapeutic option for patients with advanced cancers," said Francesco Galimi, M.D., Ph.D., Chief Medical Officer. "Historically, expansion and persistence of cell therapy products and release of functional cytokines have correlated with patient outcomes. We remain on track to provide a clinical update from the Phase 1 study in NHL patients in the second half of 2024."

Data highlights included in the ASH (Free ASH Whitepaper) presentation were as follows:

Robust dose-dependent expansion and persistence of ADI-001 were observed using three different methodologies for measuring exposure.
ADI-001 displayed a strong exposure profile and was positively associated with both PD correlates and clinical response, as supported by the following:
At DL3 and DL4, ADI-001 Cmax and Tmax that met or exceeded that in prescribing information of approved autologous CD19 CAR T therapies.
Increasing dose levels showed higher Cmax and AUC and were associated with patient clinical responses.
ADI-001 stimulation and proliferation were associated with peak levels of CAR+ cells and higher production of polyfunctional cytokines, particularly in patients whose best overall response was complete response or partial response.
Elevating levels of endogenous cytokines, comprising stem cell factor and IL-15, may potentially contribute to increased ADI-001 expansion and clinical response.
ADI-001 exposure or clinical response showed no correlation with the degree of shared HLA alleles between patient and ADI-001.
Details of the poster presentation are as follows:

Title: Expansion, Persistence and Pharmacodynamic Profile of ADI-001, a First-in-Class Allogeneic CD20-Targeted CAR Gamma Delta T Cell Therapy, in Patients with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin’s Lymphoma
Poster Number: 3478
Session Name: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster II
Presenting Author: Monica Moreno, Ph.D.
Date/Time: Sunday, December 10, 2023, from 6:00 – 8:00 p.m. PST
About ADI-001

ADI-001 is an investigational allogeneic gamma delta CAR T cell therapy being developed as a potential treatment for relapsed or refractory B-cell NHL. ADI-001 targets malignant B-cells via an anti-CD20 CAR and via the gamma delta innate and T cell endogenous cytotoxicity receptors. Gamma delta T cells engineered with an anti-CD20 CAR have demonstrated potent antitumor activity in preclinical models, leading to long-term control of tumor growth. ADI-001 was granted Fast Track Designation by the U.S. Food and Drug Administration (FDA) for the potential treatment of relapsed or refractory B-cell NHL.

About the GLEAN Study

The Phase 1 study is an open-label, multi-center study of ADI-001 enrolling adults diagnosed with B-cell malignancies who have either relapsed, or are refractory to, at least two prior regimens. The primary objectives of the study are to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ADI-001, and to determine optimal dosing as a monotherapy. For more information about the clinical study design, please visit www.clinicaltrials.gov (NCT04735471).