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

Business development

Collaboration agreement: Scribe & Sanofi

Scribe Therapeutics (CA, USA; www.scribetx.com), a genetic medicines company unlocking the potential of CRISPR to transform human health, has expanded collaboration with Sanofi (France; www.sanofi.com) [1]. Under the agreement, Sanofi receives an exclusive license to use Scribe's CRISPR X-Editing (XE) genome editing technologies for the development of in vivo therapies, including sickle cell disease. The agreement follows the launch of the companies' existing collaboration focused on ex vivo editing of natural killer (NK) cell therapies for the treatment of cancer. Scribe to receive $40 million upfront, with the potential for more than US$1.2 billion in milestones across all programs, and royalties tiered into the double digits with an option to co-promote and profit share on one program coming out of the collaboration.

Achievements, launches…

bit.bio

bit.bio (UK; www.bit.bio), the company coding human cells for novel cures, has launched its first set of muscle cell disease model products designed to advance the discovery and development of treatments for Duchenne muscular dystrophy (DMD) [2]. The disease models, ioSkeletal Myocytes DMD Exon 44 Deletion™ and ioSkeletal Myocytes DMD Exon 52 Deletion™, are human skeletal myocytes that carry a genetically engineered deletion of exon 44 or exon 52 in the gene that encodes for the dystrophin protein. Cells have been precision reprogrammed from induced pluripotent stem cells (iPSCs) with bit.bio's opti-ox™ technology.

Gamida cell

Gamida Cell (Israel; www.gamida-cell.com), a cell therapy pioneer working to turn cells into powerful therapeutics, has announced the publication in press of a prospective sub-study of the phase 3 clinical trial for Omisirge^® (omidubicel-onlv), the company's allogeneic stem cell transplant therapy, characterizing immune reconstitution kinetics following hematopoietic stem cell transplantation (HCT) with Omisirge compared with umbilical cord blood (UCB) [3–5].

37 patients (Omisirge: n = 17, UCB: n = 20) from 14 global sites were included in the sub-study and blood samples were collected from seven to 365 days post-transplantation. The findings suggest that omidubicel efficiently promotes immune reconstitution across multiple immune cells, including CD4⁺ T cells, B cells, NK cells, and dendritic cell subtypes as early as 7 days post-transplantation, potentially endowing recipients with early protective immunity. The early reconstitution may account for the reduced rate of viral infections observed after transplantation with Omisirge versus UCB.

Clinical trials

Immune cells

Caribou

Caribou Biosciences (CA, USA; www.cariboubio.com), a clinical-stage CRISPR genome-editing biopharmaceutical company, has reported long-term follow-up data from the dose escalation portion of the ongoing ANTLER phase 1 trial [6,7]. The dataset includes all 16 patients treated in dose escalation with CB-010, an allogeneic anti-CD19 CAR-T cell therapy being evaluated in patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL). In ANTLER dose escalation, three dose levels of CB-010 were evaluated (40 × 10⁶, 80 × 10⁶, and 120 × 10⁶ CAR-T cells) in patients with multiple subtypes of aggressive r/r B-NHL. As of the data cut-off date, results demonstrated:

• CB-010 was generally well tolerated with adverse events consistent with autologous or allogeneic anti-CD19 CAR-T cell therapies; as previously reported, no dose-limiting toxicities (DLTs) were observed at dose levels 2 or 3 following a single DLT at dose level 1;

• 94% overall response rate (ORR; 15 of 16 patients) was observed following a single dose of CB-010;

• 69% of patients (11 of 16) achieved a complete response (CR);

• 44% of patients (7 of 16) had a CR at ≥6 months; 24 months is the longest CR maintained to date;

• For the subset of patients with large B cell lymphoma (LBCL) (n = 10):

  	○	A 90% ORR (9 of 10) was observed;
  	○	70% (7 of 10) achieved a CR;
  	○	50% (5 of 10) had a CR at ≥6 months; 18 months is the longest CR maintained to date.

Each of the 16 patients had aggressive r/r B-NHL and had received two or more prior lines of chemoimmunotherapy or were primary refractory patients.

Based on these positive data, Caribou is enrolling second-line patients with LBCL in the ongoing dose expansion portion of the ANTLER clinical trial. In expansion, the mid dose, and the high dose from escalation (80 × 10⁶ and 120 × 10⁶ CAR-T cells) are being evaluated in approximately 30 second-line patients (~15 patients per dose level) to determine the recommended phase 2 dose (RP2D). Once the RP2D is determined, Caribou may enroll additional patients in ANTLER. Caribou plans to report initial dose expansion data from the ongoing ANTLER trial in H1 2024.

Other

Calidi

Calidi Biotherapeutics (CA, USA; www.calidibio.com), a clinical-stage biotechnology company that is pioneering the development of allogeneic cell-based delivery of oncolytic viruses, and City of Hope (CA, USA; www.cityofhope.org) jointly announced that the first brain tumor patient was treated at City of Hope in a multicenter, phase 1 clinical trial evaluating CLD-101, a leading-edge therapeutic candidate in Calidi's NeuroNova program, comprising tumor-tropic neural stem cells (NSCs) HB1.F3.CD.C21 that deliver an oncolytic adenovirus – CRAd-S-pk7 – selectively to tumor sites [8]. The trial seeks to determine the safety, immunogenicity and preliminary clinical efficacy of treatment with multiple intracerebral doses of CLD-101 in patients with recurrent high-grade glioma. An earlier open-label, phase 1, dose escalation trial has shown promissing results.

The CLD-101 platform, which includes NSC.CRAd-S-pk7, is an allogeneic, “off-the-shelf” therapy comprised of an immortalized NSC line loaded with an engineered oncolytic adenovirus [9–11]. Upon surgical resection of tumor, NSC-CRAd-S-pk7 is injected into the walls of the resection cavity. The anti-cancer virus it releases is expected to infect and kill any remaining tumor cells. A second mechanism of cytoxicity is that the oncolytic virus can elicit a tumor-specific immune response from the patient. Calidi holds an exclusive worldwide licensing agreement covering the NSC-CRAd-S-pk7 technology.

Tetrous

Tetrous (CA, USA; https://tetrous.com, a regenerative medicine company, has completed the first surgical cases in Australia using EnFix RC, a procedure-specific implant for rotator cuff repair that is specifically designed to address Enthesis Failure Syndrome [12]. The EnFix RC rotator cuff implant is made from proprietary demineralized cortical bone fibers. Using Bone Textile™ technology to produce the implant yields long and strong bone fibers that promote cell wicking, cell adhesion and cell proliferation, while our FormLok™technology imparts shape retention to the device, even when immersed in liquid, as is regularly required for use in arthroscopic surgery.

Regulations, approvals, acquisitions…

Mergers & acquisitions

Coloplast & Kerecis

Coloplast (Denmark; www.coloplast.com) has signed an agreement to acquire Kerecis (Iceland; www.kerecis.com), an innovative, fast-growing company in the biologics wound care segment, for up to US$1.3 billion (around DKK 8.9 billion), of which US$1.2 billion (around DKK 8.2 billion) is an upfront cash payment [13]. With a mission to improve wound care treatment, Kerecis has developed and patented a clinically differentiated, sustainable, and scalable technology platform based on intact fish skin.

Produced with minimal processing, the fish skin retains its similarity to human skin, resulting in improved wound healing. The technology is backed by compelling evidence from multiple clinical trials and has already been used to treat tens of thousands of patients.

Since the launch of its product offering in 2016 Kerecis has become the fastest growing company in the biologics wound care segment, with DKK 510 million in revenues and reaching break-even in FY 2021/221). Due to a highly cost-efficient production setup, Kerecis has an attractive gross margin level, accretive to Coloplast's gross margin. Kerecis has strong potential to expand its profitability driven by continued growth and scalability’ Revenue growth assumptions: Kerecis is expected to grow around 50% in FY 2022/23. The company is expected to continue its strong growth trajectory with an estimated three-year CAGR of around 30% until FY 2025/26.

Following the expected acquisition, Kerecis will operate as a stand-alone business unit under its own identity and brand, with integration focused on business support and other selected areas to support the company's strong growth outlook and continued expansion.

The total enterprise value for 100% ownership of Kerecis amounts to up to US$1.3 billion (around DKK 8.9 billion), consisting of US$1.2 billion (around DKK 8.2 billion) upfront cash payment and an earnout potential of maximum US$100 million (around DKK 680 million).

Green light

AvenCell

AvenCell Therapeutics (Germany; www.avencell.com), a clinical-stage cell therapy company focused on advancing both switchable and allogeneic engineered CAR-T cell therapies, has announced that the European Medicines Agency (EMA) has approved the company's Clinical Trial Application for AVC-201 for the treatment of relapsed/refractory Acute Myeloid Leukemia (AML) and other selected hematologic malignancies positive for CD123 [14].

The phase 1 study, which includes up to 35 patients, will be conducted at multiple sites in Germany [15]. The primary objective of the trial is to assess the safety profile of AVC-201 and to determine the maximum tolerated dose. Secondary measures will include efficacy, safety and CAR-T persistence.

AVC-201 is a CRISPR-edited CAR-T Cell therapy that embodies two discrete technology platforms. The first leverages AvenCell's ‘UniCAR’ universal/switchable technology which is comprised of a two-component system. Engineered T Cells are transduced with a ‘universal’ receptor that is completely biologically inert (expressing human La peptide) and are only activated when bound to a second biologic molecule which directs the T cells to a cancer antigen of interest (in this case, CD123). The presence or absence of the targeting module in circulation allows for exquisite ‘on’ and ‘off’ control, respectively, of the therapeutic activity. The second technology platform consists of an in-licensed allogeneic cell engineering technology developed by Intellia Therapeutics (MA, USA; www.intelliatx.com), which allows for unrelated donors to provide cells for patients. These cells are uniquely engineered via CRISPR/Cas9 to avoid GvHD and rejection via the host/patient immune system by either innate or adaptive mechanisms.

Fosun kite

Axicabtagene ciloleucel (trade name Yikaida^®), the product of Fosun Kite Biotechnology, jointly established by Shanghai Fosun Pharmaceutical (China; https://en.fosun.com) and Kite Pharma (CA, USA; www.kitepharma.com), a Gilead company (CA, USA; www.gilead.com), for the treatment of adult large B-cell lymphoma (r/r LBCL) who failed first-line immunochemotherapy or relapsed within 12 months is conditionally approved by the State Drug Administration (China, http://english.nmpa.gov.cn) [16]. This also marks the official launch of Yikaida for second-line indication. Yikaida has benefited more than 500 patients in the 2 years since its launch.

Innovent & IASO bio

Innovent Biologics (MD, USA; www.innoventbio.com), a biopharmaceutical company that develops, manufactures and commercializes medicines for the treatment of oncology, autoimmune, metabolic, ophthalmology and other major diseases, and IASO Biotechnology (China; www.iasobio.com), a clinical-stage biopharmaceutical company engaged in discovering, developing, and manufacturing innovative cell therapies and antibody products, have announced that China's National Medical Products Administration (China, http://english.nmpa.gov.cn) has approved the New Drug Application (NDA) for FUCASO^® (Equecabtagene Autoleucel, co-developed and co-commercialized by Innovent and IASO Bio, Innovent R&D code: IBI326, IASO Bio R&D code: CT103A), the first fully-human BCMA-directed chimeric antigen receptor (CAR) T cell therapy for adult patients with relapsed or refractory multiple myeloma (r/r MM) who have received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent [17].

FUCASO^® (Equecabtagene Autoleucel) is a BCMA-directed CAR T cell therapy, using lentivirus as a gene vector to transfect autologous T cells. The CAR contains a fully-human scFv, CD8a hinge and transmembrane, and 4-1BB-mediated co-stimulation and CD3ζ activation domains. Based on rigorous selection and screening of the molecular structures, and comprehensive in vivo and in vitro evaluation, FUCASO has demonstrated rapid and potent efficacy as well as prolonged persistency in r/r MM patients, providing higher and deeper responses and long-term clinical benefit. Innovent and IASO Bio are responsible for the joint development and commercialization of FUCASO for treatment of r/r MM in China.

The approval was based on the results from the FUMANBA-1 clinical study, a multi-center phase 1/2 registrational clinical trial conducted in China to evaluate the efficacy of Equecabtagene Autoleucel in patients with r/r MM [18].

Kyverna

Kyverna Therapeutics (CA, USA; https://kyvernatx.com), a cell therapy company with the mission of engineering a new class of therapies for serious autoimmune diseases, has announced the approval of its first Clinical Trial Application (CTA) by the Paul-Ehrlich-Institut in Germany for Kyverna's anti-CD19 CAR T-cell therapy, KYV–101, specifically targets CD19, a protein expressed on the surface of B cells, which are involved in various types of autoimmune diseases [19]. KYV–101 represents an innovative approach to fighting autoimmune diseases by harnessing the power of the body's immune system.

MyoPax

MyoPax (Germany; https://myopax.com) has been granted Rare Pediatric Disease Designation and Orphan Drug Designation by the US FDA for its regenerative cell therapy in Exstrophy-Epispadias Complex (EEC) [20,21]. EEC is a severe newborn condition within the urorectal congenital malformation spectrum impacting continence, sexual and renal function. MyoPax's cell therapy uses patient-specific muscle stem cells, harnessing their regenerative potential through a proprietary and patented stem cell technology to repair the patient's urinary sphincter muscle defect. The first-in-human trial with the lead candidate (Satori-01) targets this orphan disease and current unmet need [22]. The phase 1/2a trial is aimed at repairing the EEC sphincter defect and will investigate both safety and efficacy.

Poseida

Poseida Therapeutics (CA, USA; https://poseida.com), a clinical-stage cell and gene therapy company advancing a new class of treatments for patients with cancer and rare diseases, has announced that the US FDA has cleared its Investigational New Drug (IND) application for P-CD19CD20-ALLO1, the Company's first allogeneic dual CAR-T cell product candidate, which targets both CD19 and CD20 antigens for the treatment of relapsed or refractory B-cell malignancies and is being developed in partnership with Roche (Switzerland; www.rochwe.com) [23]. In addition to the dual targeting, P-CD19CD20-ALLO1 uses a novel CD19 binder that showed greater potency in in vivo preclinical models when compared with the canonical FMC63 Single-chain variable fragment (scFv) binder. P-CD19CD20-ALLO1 is an off-the-shelf CAR-T therapy for which patients do not have to undergo apheresis and wait for the cells to be manufactured, which can potentially overcome the limitation of autologous CAR-T therapies associated with significant manufacturing times. P-CD19CD20-ALLO1 will be evaluated in a phase 1 multicenter, open-label, dose-escalation study that will enroll up to 70 adult patients with relapsed or refractory B-cell malignancies. The study will evaluate the safety, tolerability, and preliminary efficacy of P-CD19CD20-ALLO1. After enrollment, patients will receive a chemotherapy-based lymphodepletion regimen followed by administration of P-CD19CD20-ALLO1 allogeneic CAR-T cells. With the P-CD19CD20-ALLO1 IND now cleared, the Company is actively focused on opening clinical sites.

Qihan

Hangzhou Qihan Biotech (China; www.qihanbio.com), a company applying multiplexable genome editing technology to cell therapies and organ transplantation, has announced that the National Medical Products Administration (China, http://english.nmpa.gov.cn) approved its clinical trial application for the product QN-019a either as monotherapy or in combination with other therapeutics [24]. It is the first IND approved in China for a gene-edited iPSC-derived cell therapy product.

Qihan Biotech utilizes multiplexable genome editing technology to modify iPSCs and differentiate them into natural killer (NK) cell therapy product QN-019a, targeting CD19-positive B-cell lymphoma. The clinical indication for QN-019a is CD19-positive relapsed/refractory aggressive B-cell non-Hodgkin lymphoma.

Capital market & finances

Caribou

Caribou Biosciences (CA, USA; www.cariboubio.com), a clinical-stage CRISPR genome-editing biopharmaceutical company, has commenced an underwritten public offering of US$100 million of shares of its common stock. All the shares in the proposed offering will be offered by Caribou [25].

Shortly after, the company upsized underwritten public offering of 19,230,769 shares of its common stock at a public offering price of US$6.50 per share [26]. The gross proceeds to Caribou from the offering, before deducting underwriting discounts and commissions and offering expenses, are expected to be approximately US$125 million, excluding any exercise of the underwriters' option. Caribou has granted the underwriters a 30-day option to purchase up to an additional 2,884,615 shares of its common stock at the public offering price per share, less underwriting discounts, and commissions.

Caribou & pfizer

Caribou Biosciences (CA, USA; www.cariboubio.com), a clinical-stage CRISPR genome-editing biopharmaceutical company, has announced that Pfizer (NY, USA; www.pfizer.com) has made a $25 million equity investment in the company. Pfizer purchased 4,690,431 of Caribou common shares at a price of $5.33 per share, pursuant to the terms of a Securities Purchase Agreement dated 29 June 2023 [27]. Caribou will use the proceeds of this investment to advance CB-011, an immune cloaked allogeneic CAR-T cell therapy currently being evaluated in the CaMMouflage phase 1 clinical trial in patients with r/r MM [28]. Caribou will maintain full ownership and control of its pipeline of allogeneic CAR-T and CAR-NK cell therapies.

NK:IO

NK:IO (UK, https://nk-io.com), a company developing off-the-shelf NK cell therapies targeting solid tumours, has raised US$ 1.5 M (£1.2 M) [29]. This brings total seed funding to US$6.4 M (£5.1 M) and will enable the company to reach key milestones in progressing its differentiated NK cell therapy candidates into development.

Ossium health

Ossium Health, a bioengineering company developing the world's first bank of on-demand bone marrow, has announced a US$52 M Series C funding round [30]. This round of funding will also support the launch of Ossigraft™, an orthopedic product for the repair, replacement, and reconstruction of musculoskeletal defects. This product is derived from the same vertebral bodies as Ossium's other products.

Ossium works with Organ Procurement Organizations (OPOs) that represent just over half of all organ donors in the USA to recover viable vertebral bodies for bone marrow and orthopedic donations. Ossium's recovery process ensures that the bone marrow is phenotypically and functionally equivalent to cells from living donors. The product is then cryopreserved and stored indefinitely until requested by a treating physician. This process has enabled Ossium to create the world's first bone marrow bank at industrial scale.

Verismo

Verismo Therapeutics (PA, USA; https://verismotherapeutics.com), a clinical-stage CAR T company, Penn spinout, and pioneer of the novel KIR-CAR platform technology, has raised US$17 M in a second pre-Series A financing round [31]. The financing will support continued advancement of the clinical trial for SynKIR™-110, a first-in-class KIR-CAR T cell immunotherapy candidate for solid tumors, and pre-clinical development of SynKIR-310, a KIR-CAR T cell immunotherapy therapeutic for blood cancers. With this US$17 M investment Verismo will have secured a total of US$50 M in financing since launching in 2020.

The KIR-CAR platform is a dual-chain CAR T cell therapy and has been shown in preclinical animal models to be capable of maintaining antitumor T cell activity even in challenging solid tumor environments. DAP12 acting as a novel costimulatory molecule for T cells, aids additional T cell stimulating pathways, further sustaining chimeric receptor expression, and improving KIR-CAR T cell persistence. This continued T cell function and persistence can lead to ongoing regression of solid tumors in preclinical models, including those refractory to traditional CAR T cell therapies. Furthermore, the KIR-CAR platform can be combined with many additional emerging technologies, such as in vivo gene engineering, advanced cell manufacturing and reprogramming, combinational therapies, and even allogeneic cellular therapies to provide the next-generation multimodal targeted immunotherapy for patients in need.