On May 18, 2023 Be Biopharma, Inc. ("Be Bio"), a company pioneering the discovery and development of Engineered B Cell Medicines (BeCMs), reported that it will present preclinical research showing the precise genome engineering of human B cells to express diverse therapeutic proteins using the company’s proprietary platform (Press release, Be Biopharma, MAY 18, 2023, View Source [SID1234631839]). The findings will be presented during an oral session at the American Society of Gene & Cell Therapy (ASGCT) (Free ASGCT Whitepaper) 26th Annual Meeting at 2:15-2:30 p.m. PST with additional data in poster presentation 1453 on Friday, May 19th from 12:00-2:00 p.m. PST.

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Plasma cells are terminally differentiated B cells, which can live for decades1 and have the capacity to secrete extremely high levels of protein2 making them attractive for the sustained delivery of biologics to treat a wide range of diseases. However, it has historically been challenging to genetically engineer B cells efficiently, precisely, and in a manner that could produce proteins at therapeutic levels over long durations. Leveraging the convergence of advanced gene editing, deep insights into B cell biology and cell therapy technologies, Be Bio has designed a versatile CRISPR/Cas9 engineering platform capable of delivering a gene of interest via homology-directed repair (HDR) to produce stable BeCMs.

"In a short two years, Be Bio has validated key concepts of our B cell medicine platform including editing precision and efficiency, reproducible engraftment, and durable functional protein expression with the goal of creating a new class of cellular medicines with broad therapeutic utility," said Dr. Rick Morgan, Chief Scientific Officer, Be Bio. "B cell medicines have the potential to transform the lives of patients – they can be redosed when required, delivered autologously and allogeneically, and can be administered without preconditioning – offering distinct advantages over other advanced therapies."

Be Bio Platform Attributes

Engineering Precision and Efficiency:
Depending on the desired therapeutic protein expression level, the platform can target gene insertions to safe harbor sites as well as sites transcriptionally active in B cells. Across transgenes, targeting a transcriptionally active B cell site can enable up to a tenfold increase in protein secretion compared to insertion at the CCR5 safe harbor site. In addition, precisely targeted integration significantly reduces the risk of random gene insertion.

Using optimized cell culture and engineering conditions, the platform achieves gene knockouts with greater than 90% efficiency, stable gene insertion via precise HDR with up to 60% efficiency as measured by digital droplet PCR, and multiplexed expression of two genes with efficiencies above 20% as measured by flow cytometry.

Durable and Functional Protein Expression:
We observed the robustness of the platform through the expression of multiple therapeutic proteins such as Factor IX (FIX) for hemophilia B, acid sphingomyelinase (ASM) for Niemann-Pick Diseases (NPD) and an anti-CD19/CD3 bispecific T cell engager for acute lymphoblastic leukemia (ALL).

In each of two donors, FIX was detected in mouse plasma and lasted for greater than 18 weeks post BeCM transfer demonstrating persistence. In a separate experiment, BeCM-secreted ASM corrected the disease phenotype in NPD (SMPD1) gene knock-out cells.

In addition, in vitro and in vivo anti-tumor activity was observed. Potent in vitro anti-tumor activity was shown when supernatant from bispecific T cell engager-producing BeCMs directed primary human T cells to kill Raji tumor cells (CD19+). In a study conducted by Be Bio’s scientific co-founders and collaborators from the Seattle Children’s Research Institute, engineered B cells produced bispecific T cell engagers in vivo that mediated T cell activation and showed anti-tumor efficacy in a patient-derived xenograft mouse model3.

Rapid Screening:
To supplement adeno-associated virus (AAV) vector-mediated HDR, a rapid plasmid-based screening protocol was developed. The plasmid-based platform efficiently identifies the appropriate parameters for the secretion of a given protein of interest in primary B cells enabling rapid development from idea to prototype. The screening protocol assesses gene and protein design parameters for optimal transgene expression levels.

Engraftment without Preconditioning:
Rapid homing (within one day) and engraftment without preconditioning were shown in two models. In immunodeficient (NOG-hIL6) mice, BeCMs engrafted and persisted for greater than 100 days. In non-human primates with intact immune systems, BeCMs administered by intravenous infusion homed to and engrafted in the bone marrow and spleen.

These fundamental platform attributes overcome historical challenges for scalable and effective B cell engineering. The platform has the potential to transform the power of B cells into the development of autologous and allogeneic B cell medicines and unlock a pipeline of product candidates for broad and meaningful therapeutic utility in rare disease, cancer and beyond.

About B Cells – 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 (BeCMs). BeCMs have the potential to be durable, allogeneic, redosable and administered without toxic conditioning. The promise of BeCMs could transform therapeutic biologics with broad application — across protein classes, patient populations and therapeutic areas.

On May 18, 2023 Athersys, Inc. (NASDAQ: ATHX), a regenerative medicine company developing MultiStem (invimestrocel) cell therapy for critical care indications, reported on Monday, May 15th financial results for the three months ended March 31, 2023 and provided a business update (Press release, Athersys, MAY 18, 2023, View Source [SID1234631837]).

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First Quarter 2023 and Recent Corporate and Operational Highlights:

•Continued reducing expenses to conserve cash and heightened focus on MASTERS-2 trial, thereby making Athersys more attractive to potential financial and strategic partners
•Maintained operating expenses below $2.5 million per month
•Raised $3.7 million through a registered direct offering with institutional investors
•Appointed biotechnology and pharmaceutical executive Joseph Nolan to the Board of Directors
•Participated in Request for Proposal (RFP) process with the Biomedical Advanced Research and Development Authority (BARDA) for a proposed clinical trial with MultiStem for acute respiratory distress syndrome (ARDS) and other COVID-19 co-morbidities
•Completed DSMB review of cohort 1 & 2 of MATRICS trauma trial using both cell factory and bioreactor manufactured clinical product
•Awarded a U.S. patent for the novel SIFU cryogenic storage system, the Company’s user-friendly system to improve storage and handling of cryogenic products in hospital settings

MASTERS-2

•Amended the clinical trial protocol reflecting modifications proposed during a Type B meeting with the U.S. FDA that best reflect the potential benefits of MultiStem in treating acute, moderate-to-severe ischemic stroke; protocol modifications include:
◦Primary endpoint assessed by shift analysis in modified Rankin Scale (mRS) score was changed to Day 365, from Day 90 previously
◦Shift analysis in mRS score at Day 90 is retained as a key secondary endpoint
◦Eligibility caps on concomitant reperfusion therapy (e.g., tPA, MR or tPA+MR) were removed to ensure the study population reflects the population eligible for this therapy
◦Added the option to conduct an interim analysis for powering to confirm 300 patient sample size is adequate to achieve statistical significance with new primary endpoint
Medical Affairs
•Athersys executives participated in several industry conferences to build awareness of Athersys and share clinical and manufacturing progress achieved with MultiStem , including:
◦Advanced Therapies Week presented by Phacilitate
◦2nd Allogeneic Cell Therapies Summit Europe
◦International Stroke Conference 2023
◦BioProcess International US West
◦The American Society for Neural Therapy and Repair Annual Conference
◦Cellular Therapies and Transfusion Medicine in Trauma and Critical Care Conference

Management Commentary

"We entered 2023 with greater clarity and confidence on our path forward with MultiStem having largely completed a significant restructuring in the second half of last year that reduced our operating expenses below $2.5 million per month. In addition, achieving a successful Type B meeting with the FDA on proposed MASTERS-2 trial modifications will now more appropriately represent the regenerative benefits of MultiStem over a longer period and reflect changes we’ve observed in ischemic stroke standard of care. We’ve also made meaningful progress with trial enrollment and advanced conversations with multiple parties exploring business development opportunities with MultiStem as well as our animal health franchise and SIFU," said Dan Camardo, Chief Executive Officer of Athersys. "We have more work to do, but I’m encouraged by the progress we’ve made."

First Quarter Results

There was no revenue for the first quarter of 2023 compared with $2.9 million for the first quarter of 2022, which included the delivery of services under the arrangement with Healios. As of September 30, 2022, services under this arrangement were largely complete and were limited to close-out activities.
Research and development expenses were $4.5 million for the first quarter of 2023 compared with $20.9 million for the comparable period in 2022. The decrease reflects our restructuring plan which resulted in reduced clinical trial expenses which includes personnel, manufacturing and other costs.
General and administrative expenses were $2.8 million for the first quarter of 2023 compared with $4.1 million for the comparable period in 2022, with the decrease primarily due to the restructuring. The Company expects further decreases in general and administrative expenses.
Net loss for the first quarter of 2023 was $7.8 million, or $0.43 per share, compared with a net loss of $22.2 million, or $2.27 per share, for the comparable period in 2022.
Cash and cash equivalents were $3.1 million as of March 31, 2023 compared with $9.0 million as of December 31, 2022.

About MultiStem
MultiStem (invimestrocel) cell therapy is a patented regenerative medicine product in clinical development that has shown the ability to promote tissue repair and healing in a variety of ways, such as through the production of therapeutic factors in response to signals of inflammation and tissue damage. MultiStem therapy’s potential for multidimensional therapeutic impact distinguishes it from traditional biopharmaceutical therapies focused on a single mechanism of benefit. The therapy represents a unique "off-the-shelf" stem cell product that can be manufactured in a scalable manner, may be stored for years in frozen form, and is administered without tissue matching or the need for immune suppression. Based upon its efficacy profile, its novel mechanisms of action, and a favorable and consistent tolerability demonstrated in clinical studies, we believe that MultiStem therapy could provide a meaningful benefit to patients, including those suffering from serious diseases and conditions with unmet medical need.

On May 18, 2023 Alligator Bioscience (Nasdaq Stockholm: ATORX) reported that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to its lead asset mitazalimab for the treatment of pancreatic cancer (Press release, Alligator Bioscience, MAY 18, 2023, View Source [SID1234631836]).

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Mitazalimab is a monoclonal antibody targeting CD40 with the potential to sensitize tumors to chemotherapy and induce immune mediated tumor killing by activating dendritic cells, B cells, and macrophages. Mitazalimab is currently being evaluated in OPTIMIZE-1, a Phase 2 open-label, multi-center study to assess its safety and efficacy in combination with chemotherapy, mFOLFIRINOX, in previously untreated patients with metastatic pancreatic ductal adenocarcinoma (NCT04888312).

In January 2023, Alligator announced strong interim results from OPTIMIZE-1, in which mitazalimab combined with mFOLFIRINOX demonstrated an objective response rate (ORR) of 52% in 23 evaluable patients, as per the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). In comparison, a similar patient population treated only with FOLFIRINOX reported an ORR of around 32%[1]. Disease control rate, the proportion of patients with objective response or stabilization of disease, was more than 90%. In April 2023, Alligator announced that OPTIMIZE-1 had been fully enrolled.

"This designation is a key milestone for our lead asset mitazalimab, which is producing outstanding clinical results in its Phase 2 trial in pancreatic cancer," said Søren Bregenholt, CEO of Alligator Bioscience. "Orphan designation confers significant benefits in the form of cost savings during development and marketing exclusivity following approval, and we are very pleased to see the potential of mitazalimab being recognized with the award of this designation."

Orphan designation is granted by the FDA to a drug or biological product to prevent, diagnose or treat a rare disease or condition, and it qualifies sponsors for various incentives, including seven years of market exclusivity after approval, exemption from user fees and a tax credit of qualified clinical trials.

The orphan designation for mitazalimab and the positive interim results from OPTIMIZE-1 will be a key component of discussions with regulatory authorities regarding subsequent clinical development and approval pathway for mitazalimab in pancreatic cancer. Additional interim data from OPTIMIZE-1, including Progression Free Survival, are due in mid-2023 and full top-line data are expected in the beginning of Q1 2024.

On May 18, 2023 Imugene Limited (ASX: IMU), a clinical stage immuno- oncology company, reported that its onCARlytics technology, in combination with Eureka Therapeutics, Inc.’s ARTEMIS cell receptor platform, has presented preclinical data at the American Society of Gene and Cell Therapy’s Annual Meeting (ASGCT) (Free ASGCT Whitepaper) demonstrating enhanced anti-tumour activity in vivo against hepatocellular carcinoma (liver cancer) tumours (Press release, Imugene, MAY 18, 2023, View Source [SID1234631817]).

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The data, presented as a poster presentation at the ASGCT (Free ASGCT Whitepaper) conference held in Los Angeles, titled ‘Effective combination immunotherapy using onCARlytics and ARTEMIS CD19 T cells against hepatocellular carcinoma’, investigates the combination in the most common type of primary liver cancer and sixth most common cancer worldwide.

Hepatocellular carcinoma (HCC) occurs most often in people with chronic liver diseases, such as cirrhosis caused by hepatitis B or hepatitis C infection.

Currently, there are few systemic therapies available for patients with advanced disease in addition to the traditional treatments including ablation, surgical resection, and liver transplantation. CD19-targeting chimeric antigen receptor (CAR) T cell therapy has demonstrated impressive clinical outcomes in blood cancers, but translating this therapy to solid-tumour cancers has met various challenges, including the immunosuppressive microenvironment, on-target off-tumour toxicity, and antigen heterogeneity. To date, CAR T cell therapies against HCC have shown nominal efficacy in clinical trials. Therefore, development of novel and innovative therapeutic approaches against HCC is needed to overcome the challenges and improve clinical outcomes.

onCARlytics in combination with ARTEMIS T cells potentially provide a solution. ARTEMIS T cells differentiate from CAR T cells with lower CRS risks, better tumour infiltration, and higher T cell persistence in pre-clinical studies, making them ideal cell therapy candidates for solid tumours.

The ASGCT (Free ASGCT Whitepaper) event is now in its 26 th year and attracts a range of professionals in the area of gene and cell therapy, who observe new scientific research and technologies alongside peers in the industry. It is being held 16-20 May 2023 at the Los Angeles Convention Center, CA, USA.

The poster presentation can be viewed on the Imugene website.

On May 17, 2023 Modiblast GmbH, a preclinical-stage biopharmaceutical company developing novel immunomodulatory cancer therapies, reported that its lead development program MB101 has passed a recent scientific advice and pre-CTA meeting with the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) – Germany’s Federal Institute for Drugs and Medical Devices – without objections. Achieving this milestone significantly increases the chances to get final regulatory approval and expedites the transition of the Company’s lead development program into a planned Phase 1/2 clinical trial in acute myeloid leukemia (AML) and Myelodysplastic syndromes (MDS).

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"Today’s news is a significant step forward for Modiblast and paves the way for a swift transition into clinical-stage development once the necessary funding can be secured. The meeting outcome validates that Modiblast has addressed all safety aspects sufficiently to initiate a clinical study, that our preclinical data package is considered adequate, and that the study design is well substantiated. I want to thank all our collaborators and clinical partners that have contributed to achieving this milestone," commented Prof. Dr. rer. nat. Helga Schmetzer, Managing Director and Founder of Modiblast.

Modiblast’s therapeutic approach combines two crucial factors to turn ‘foe’ into ‘friend’. A myeloid differentiation factor fosters the creation of dendritic cell progenitor cells and hematological recovery. The patented combination with a danger signal and maturation factor drives the formation of dendritic cells (DCs). Both signals combined trigger the reprogramming of cancer blast into dendritic cells of leukemic origin, or DCleu, and boost the creation of healthy DC. Our first program, MB101, aims for a fixed-dose combination of granulocyte-macrophage colony stimulation factor (GM-CSF), and prostaglandin E1 (PGE1) as a ‘danger signal’.

(Press release, Modiblast, MAY 17, 2023, https://www.modiblast.com/modiblast-mb101-program-passes-bfarm-scientific-advice-and-pre-cta-meeting-without-objections/ [SID1234662144])