Industry updates from the field of stem cell research and regenerative medicine in November 2023

Business development

Collaboration agreement: arcellx & kite

Arcellx (MD, USA; www.arcellx.com) and Kite (CA; www.kitepharma.com), a Gilead Company (CA, USA; www.gilead.com), have expanded their existing collaboration, which was originally announced in December 2022 [1].

Kite has exercised its option to negotiate a license for Arcellx's ARC-SparX program, ACLX-001, in multiple myeloma, which is comprised of ARC-T cells and SparX proteins that target BCMA. The companies have also expanded the scope of the collaboration for Arcellx's CART-ddBCMA to include lymphomas.

Upon closing, Arcellx will receive a US$200 million equity investment to purchase 3,242,542 shares of its common stock, which is expected to extend the company's cash runway into 2027. Following this investment, Gilead's estimated ownership will be 13%. Arcellx will also receive an upfront non-dilutive cash payment of US$85 million at closing and will be eligible for potential milestone payments, including the advancement of lymphoma and the license for ARC-SparX, as well as additional milestones, to offset prespecified development costs over a limited period of time. The transaction is expected to close around year-end 2023. Closing of the transaction is subject to expiration or termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvement Act and other customary conditions.

Collaboration agreement: bit.bio & king's college

bit.bio (UK; www.bit.bio), the company coding human cells for novel cures, and the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King's College London (UK; www.kcl.ac.uk) have announced a collaboration to build multi-cell models of the human brain using bit.bio's ioCells™ [2]. The collaboration will run for 3 years, initially developing models using the three ioWild Type products, glutamatergic and GABAergic neurons, and microglia. bit.bio and the team at King's College London also intend to incorporate ioDisease Model Cells™ – with gene edits that mimic what happens in a particular disease – into further multi-cell models of the human brain.

Collaboration & funding agreement: kyverna & charité

Kyverna Therapeutics (CA, https://kyvernatx.com), a clinical-stage cell therapy company with the mission of engineering a new class of therapies for serious autoimmune diseases, have signed a multi-year research funding agreement with Charité – Universitätsmedizin Berlin (Germany; www.charite.de/en/), to investigate the impact of B- and plasma cell-targeting therapies – including chimeric antigen receptor (CAR) T cells – on the immunologic profile and clinical outcomes of patients with systemic autoimmune diseases treated at Charité with current and novel treatment approaches, including KYV-101 [3]. Circulating and tissue resident B cell and plasma cell subsets as well as T cells and other immune cells will be profiled before and after the respective therapies in peripheral blood.

KYV-101 is an autologous version of a novel, fully human clinical-stage anti-CD19 CAR T cell construct with properties well suited for use in B cell-driven autoimmune diseases such as lupus nephritis, scleroderma, and other B cell-driven autoimmune diseases.

The two entities will share ownership of any results stemming from the research efforts subject to the agreement.

Collaboration & investment agreement: AstraZeneca & cellectis

AstraZeneca (UK; www.astrazeneca.com) has announced a collaboration and investment agreement with Cellectis (France; www.cellectis.com), a clinical-stage biotechnology company, to accelerate the development of next generation therapeutics in areas of high unmet need, including oncology, immunology and rare diseases [4].

Under the terms of the collaboration agreement, AstraZeneca will leverage the Cellectis proprietary gene editing technologies and manufacturing capabilities, to design novel cell and gene therapy products, strengthening AstraZeneca's growing offering in this space. As part of the agreement, 25 genetic targets have been exclusively reserved for AstraZeneca, from which up to ten candidate products could be explored for development.

Licensing agreement: legend & novartis

Legend Biotech Corporation (NJ, USA; https://legendbiotech.com), a biotechnology company developing, manufacturing and commercializing novel therapies to treat life-threatening diseases, has announced that Legend Biotech Ireland Limited, a wholly owned subsidiary of Legend Biotech, has entered into an exclusive, global license agreement with Novartis Pharma (Switzerland; www.novartis.com) for certain Legend Biotech CAR T-cell therapies targeting DLL3, including its autologous CAR-T cell therapy candidate, LB2102 [5,6]. The License Agreement grants Novartis the exclusive worldwide rights to develop, manufacture and commercialize these cell therapies, and Novartis may apply its T-Charge™ platform to their manufacture.

Legend Biotech is initiating clinical development of LB2102 for the treatment of extensive stage small cell lung cancer and large cell neuroendocrine carcinoma after the US FDA cleared its investigational new drug application in 2022. In 2023, the FDA granted the product candidate Orphan Drug Designation, a status conferred to drugs or biologics that are intended to treat, diagnose or prevent rare diseases and conditions.

The Novartis T-Charge platform is a next-generation CAR-T cell therapy manufacturing platform designed to preserve T cell stemness and facilitate CAR-T cell expansion primarily in vivo. The T-Charge platform is designed to reduce the need for extensive culture time outside the body and results in T cells with greater proliferative potential, as well as fewer exhausted T cells. LB2102 would be the first application of T-Charge by Novartis to a cell therapy candidate targeting solid tumors.

Achievements, launches…

Heartseed & I peace

I Peace (CA, USA; www.ipeace.com), GMP cell CDMO specializing in induced pluripotent stem cells (iPSCs) and iPSC-derived cell therapies, and Heartseed (Japan; https://heartseed.jp), a biotechnology company developing iPSC-derived cardiomyocytes for heart failure, have collaborated to generate cardiomyocytes using multiple donor-derived GMP grade iPS cell lines by I Peace, and Heartseed's proprietary cardiomyocytes differentiation and purification methods [7]. Heartseed has successfully produced high-purity cardiomyocytes consistently from all I Peace manufactured iPS cell lines used in this study. This achievement marks a significant step forward in the realization of autologous cardiac regenerative medicine with I Peace's personal iPS cell banking service (My Peace), to manufacture and store iPS cells, and induce them into cardiomyocytes for use in autologous cell therapy.

Kyverna

Kyverna Therapeutics (CA, https://kyvernatx.com), a patient-centered clinical-stage biopharmaceutical company focused on developing cell therapies for patients suffering from autoimmune diseases, has announced the publication by a group of German investigators describing the first case of treatment using KYV-101 in a 33 year-old patient with severe, treatment-refractory, anti-acetylcholine receptor auto-antibody positive, generalized myasthenia gravis (MG), who was treated on a named patient basis outside of a clinical trial setting [8,9].

Within the 2-month post-treatment follow-up period, the patient was not observed to experience any adverse events related to chimeric antigen receptor (CAR) T-cell therapy, such as cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). In this period, the patient experienced improved muscle strength and reduced fatigue, along with elimination of B cells and a 70% reduction in pathogenic anti-acetylcholine receptor autoantibodies.

KYV-101 is an autologous, fully human CD19 CAR T-cell product candidate for use in B cell-driven autoimmune diseases such as MG. KYV-101, specifically targets CD19, a protein expressed on the surface of B cells, which is involved in various types of autoimmune diseases. Kyverna plans to continue to explore additional indications for KYV-101 and develop a robust pipeline of promising product candidate immunotherapies aimed at addressing unmet medical needs in autoimmune diseases.

Clinical trials

Immune cells

Atara bio

Atara Biotherapeutics (CA, USA; www.atarabio.com), a in T-cell immunotherapy company leveraging its novel allogeneic Epstein-Barr virus (EBV) T-cell platform to develop transformative therapies for patients with cancer and autoimmune diseases, has announced primary analysis data from its phase II EMBOLD study of ATA188 in non-active progressive multiple sclerosis (PMS) [10,11]. The study did not meet the primary end point of confirmed disability improvement (CDI) by expanded disability status scale (EDSS) at 12 months compared with placebo. In addition, fluid and imaging biomarkers did not provide further supportive evidence.

Multiple sclerosis (MS) is a debilitating disease affecting millions, with limited treatment options and high unmet medical need in progressive forms. Evidence shows that Epstein-Barr virus is the leading cause of MS, which is why Atara is investigating the potential of their EBV T-cell platform ATA188 to treat progressive forms of the disease.

EMBOLD is a multi-national, randomized, double-blind, placebo-controlled study with an open-label extension to evaluate the safety and efficacy of ATA188 in participants with non-active progressive MS. The study primary analysis at 12 months included 103 adult participants with PMS (non-active PPMS and non-active SPMS).

In year one, study participants received two cycles of treatment (ATA188 or placebo) at the recommended part two dose, which was identified in part one, and were followed for 12 months, which is the timepoint for the primary end point. In year two, all patients received two cycles of therapy to maintain the blinding – those initially receiving placebo received ATA188 (two cycles) and those initially receiving ATA188 received one cycle of ATA188 followed by one cycle of placebo. After year two, all participants can continue into a three-year open-label extension during which they will receive annual treatment with ATA188.

Going forward, the Company plans to significantly reduce its expenses on ATA188 and further focus resources on advancing its differentiated allogeneic CAR-T pipeline, in addition to executing the expanded tab-cel partnership with Pierre Fabre through the Biologics License Application (BLA) transfer.

Mesenchymal stromal/stem cells

InGeneron

A phase II/III, 480-patient clinical trial, sponsored by Emory University (GA, USA; www.emory.edu), aimed to identify the safety and efficacy of cell injections from autologous bone marrow aspirate concentrate, autologous adipose stromal vascular fraction and allogeneic human umbilical cord tissue-derived mesenchymal stromal cells, in comparison to corticosteroid injection (CSI), revealed that at 1 year post injection, none of the three orthobiologic injections was superior to another, or to the CSI control for knee osteoarthritis [12,13].

InGeneron (TX, USA; https://ingeneron.com), a provider of the adipose tissue-derived MSCs for this study, found a positive twist in the report [14]. The study reported no serious treatment-related adverse events from any of the 109 patients treated with InGeneron's Transpose^® RT cell therapy system.

Other

MaaT pharma

MaaT Pharma (France; www.maatpharma.com), a clinical-stage biotech company and a leader in the development of Microbiome Ecosystem Therapies™ (MET) dedicated to improving survival outcomes for patients with cancer, has announced that the first patient has been treated as part of its phase IIb trial, called PHOEBUS, investigating the efficacy of MaaT033 in improving overall survival (OS) at 12 months for patients with blood cancer receiving allo-HSCT [15,16]. The trial is an international, multicenter, randomized, double-blind, placebo-controlled study, which will be conducted in up to 56 clinical investigation sites and is expected to enroll 387 patients. It is to date the largest randomized controlled trial assessing a microbiome therapy in oncology.

Regulations, approvals, acquisitions…

Green light

Carisma therapeutics

Carisma Therapeutics (PA, USA; www.carismatx.com), a clinical stage biopharmaceutical company focused on discovering and developing innovative immunotherapies, has announced the clearance of its Investigational New Drug application (IND) by the US FDA for CT-0525, an ex vivo gene-modified autologous chimeric antigen receptor-monocyte (CAR-Monocyte) cellular therapy intended to treat solid tumors that overexpress HER2 [17]. Having received a Study May Proceed notification from the FDA, Carisma expects to initiate a phase I study in the coming months and to treat the first patient in the first half of 2024.

Monocytes are the precursor cells to macrophages, and there are numerous potential benefits to a CAR-Monocyte approach to help overcome certain challenges of treating solid tumors. The CAR-Monocyte manufacturing platform enables the ability to manufacture up to 10 billion cells from a single apheresis and utilizes a rapid, single-day manufacturing process. This manufacturing process holds the potential to significantly reduce the future cost of goods and manufacturing turnaround time associated with this autologous cell therapy.

CT-0525 is the first CAR-Monocyte to be evaluated in the solid tumor setting. With a CAR-Monocyte's in vivo persistence, ability to differentiate into pro-inflammatory CAR macrophages, and multi-modal anti-tumor mechanism of action, along with its high cell yield, CT-0525 has the potential to improve the treatment paradigm for patients with HER2 overexpressing metastatic solid tumors.

Kyverna

Kyverna Therapeutics (CA, https://kyvernatx.com), a patient-centered clinical-stage biopharmaceutical company focused on developing cell therapies for patients suffering from autoimmune diseases, has announced the clearance of its fifth IND application for KYV-101 by the US FDA [18]. This will allow Kyverna to initiate a phase II open-label, multicenter study of KYV-101, an autologous, fully human CD19 CAR T cell product candidate for the treatment of myasthenia gravis (MG) [19].

The trial, named KYSA-6, expands Kyverna's current pipeline, which includes the ongoing phase I KYSA-1 trial in the USA and the ongoing phase I/II KYSA-3 trial in Germany, where KYV-101 is currently investigated in adults with active lupus nephritis, and the ongoing phase I/II KYSA-5 trial in adults with diffuse cutaneous systemic sclerosis in the USA. Kyverna also obtained clearance of two additional INDs for investigator-initiated trials of KYV-101 in the USA.

NeoImmuneTech

NeoImmuneTech (MD, USA; http://neoimmunetech.com), a clinical-stage T cell-focused biopharmaceutical company, today announced that the US FDA has granted Orphan Drug Designation (ODD) for their investigational drug NT-I7 (efineptakin alfa) (rhIL-7-hyFc) for the treatment of Acute Radiation Syndrome (ARS) [20].

ARS is an illness that occurs following a high dose of radiation exposure, leading to severe damage to the bone marrow and the immune system. Currently, there are no treatments available that effectively promote T cell recovery after such exposure. NT-I7, a novel long-acting IL-7, is expected to address this unmet medical need, with the potential to rapidly recover and improve the immune response. In the clinical setting, NT-I7 has demonstrated impressive results by effectively and consistently boosting T cell counts, all while maintaining a remarkable level of safety and tolerance.

TC BioPharm

TC BioPharm (UK; http://tcbiopharm.com) a clinical stage biotechnology company developing platform allogeneic gamma-delta T cell therapies for cancer, has announced that the US FDA provided clearance on the Company's IND application for a Phase 1B study in relapse/refractory acute myeloid leukemia (AML) [21].

Vertex

Vertex Pharmaceuticals (MA, USA; www.vrtx.com) and CRISPR Therapeutics (Switzerland; https://crisprtx.com/) have announced that the UK Medicines and Healthcare products Regulatory Agency (MHRA) has granted conditional marketing authorization for CASGEVY™ (exagamglogene autotemcel [exa-cel]), a CRISPR/Cas9 gene-edited therapy, for the treatment of sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT) [22].

CASGEVY has been authorized for the treatment of eligible patients 12 years of age and older with SCD with recurrent vaso-occlusive crises (VOCs) or TDT, for whom a human leukocyte antigen (HLA) matched related hematopoietic stem cell donor is not available. There are an estimated 2000 patients eligible for CASGEVY in the UK.

In the UK, exa-cel was granted an Innovation Passport under the Innovative Licensing and Access Pathway (ILAP) from the MHRA, and Vertex is already working closely with national health authorities to secure access for eligible patients as quickly as possible.

Red light

Brainstorm

A class action lawsuit has been filed against Brainstorm Cell Therapeutics (NY, USA; https://brainstorm-cell.com) in the US District Court for the Southern District of New York on behalf of all persons and entities who purchased or otherwise acquired Brainstorm Cell securities between 15 August 2022 and 27 September 2023, both dates inclusive (the “Class Period”) [23–27]. Investors have until 2 January 2024, to apply to the Court to be appointed as lead plaintiff in the lawsuit.

According to the lawsuit, throughout the Class Period, defendants made materially false and/or misleading statements and/or failed to disclose that: Brainstorm Cell downplayed the severity of the FDA refusal to file letter; Brainstorm Cell continued to conceal the risks associated with the submission of the biologics license application (BLA); and as a result, Defendants statements about its business, operations, and prospects, were materially false and misleading and/or lacked a reasonable basis at all relevant times.

Capital market & finances

Mytos

Mytos (UK; www.mytos.bio), an automated cell manufacturing company, has closed US$19 M in Series A financing [28]. The funding will accelerate the manufacturing and distribution of Mytos' automated cell production system to more biotech and pharma companies to meet growing demand. The company's platform is already in use by a number of life sciences companies globally. Mytos also has plans to expand its sales and development team.

Neuralink

Neuralink (CA, USA; https://neuralink.com), a company developing implantable chips that can read brain waves, has raised an additional $43 million in venture capital, according to a filing with the SEC on 22 November 2023 [29,30]. The filing shows the company increased its previous tranche, from US$280 million to US$323 million in early August. Thirty-two investors participated, according to the filing.

Neuralink hasn't disclosed its valuation recently. But in June, Reuters reported that the company was valued at about US$5 billion after privately executed stock trades.

Independently of the filing, US lawmakers ask to the SEC to investigate Neuralink for omitting details about the deaths of at least a dozen animals who were surgically fitted with its implants [31].

Vivodyne

Vivodyne (PA, USA; www.vivodyne.com), a biotech that discovers and develops more effective drugs by testing them on lab-grown human organs, has announced the close of US$38 million in total seed financing [32].

The funding will advance Vivodyne's discovery pipeline and clinically predictive AI stack, which identifies novel therapeutic targets and predicts patient responses to new drugs by testing directly on lab-grown human organ tissues. Vivodyne has bioengineered over 20 types of human organ tissues that mimic native human physiology and function to accurately capture the effects of new therapies and predict patient outcomes at the cellular, tissue, organ, and systemic scale.

One of the main bottlenecks in drug development is the inability to gather human-predictive data that is realistic, scalable, and reproducible. Vivodyne's transformative approach for drug discovery produces patient-level human results before a drug is ever tested in clinical trials. The company's platform can cultivate, dose, and analyze more than 10,000 individual human tissues at a time using robotic automation, allowing the production of vast human datasets that will power the next generation of human-trained AI for drug discovery.

Importantly, their platform's ability to create human data overcomes the key obstacle of AI-driven drug discovery: the unavailability of large, high-quality human datasets for AI training, and the overreliance on simple cell culture to fill this void.