Industry updates from the field of stem cell research and regenerative medicine in December 2021

Business development

Collaborations, partnerships & alliances

Collaboration agreement: AgeX & UC Irvine

AgeX Therapeutics (CA, USA; www.agexinc.com), a biotechnology company focused on developing therapeutics for human aging and regeneration, has announced a research collaboration with the University of California, Irvine (UCI; CA, USA; www.uci.edu) to explore the therapeutic potential of exosomes and other extracellular vesicles produced by neural stem cells derived from AgeX pluripotent stem cells, with the goal of developing therapies to treat adverse neurocognitive effects of cancer chemotherapy and radiation therapy on brain function [1]. The collaboration includes an opportunity for AgeX to license inventions that may arise from the research program, and to pursue clinical development and commercialization of therapies derived using those licensed inventions.

Collaboration agreement: BeThe Match & Vineti

Be The Match BioTherapies^® (MN, USA; https://bethematchbiotherapies.com), an organization offering solutions for companies developing and commercializing cell and gene therapies (CGTs) and Vineti (CA, USA; https://vineti.com), the provider of a digital enterprise platform for cell and gene therapy supply chains, have announced a collaboration to develop joint solutions that simplify and scale supply chain management of cell and gene therapies [2].

The nonexclusive collaboration will enable the Be The Match BioTherapies Cell Therapy Supply Chain Managers and Logistics Coordinators to utilize the Vineti’s Personalized Therapy Management^® (PTM^®) platform on behalf of shared biopharmaceutical clients with greater efficiency and simplicity.

The organizations leverage complementary strengths in starting material collection, cell therapy supply chain and managed logistics, chain of identity and chain of custody and enterprise-grade digital solutions for end-to-end value chain management. The collaboration will provide unique integrated solutions for these mission-critical components of CGT operations, and will simplify workflows, speed time to treatment and provide the flexibility that CGT development requires.

Collaboration agreement: Smart Immune & Memorial Sloan Kettering Cancer Center

Smart Immune (France; www.smart-immune.com), a clinical stage T-cell medicine company utilizing its proprietary ex-vivo biomimetic ‘thymus-in-a-dish’ technology to develop T-cell progenitors (ProTcell^™) to reset a rapid, safe and full immune reconstitution, has announced a research collaboration with Memorial Sloan Kettering Cancer Center ([MSKCC]; NY, USA; www.mskcc.org) [3]. The intent of this collaboration is to expand its ProTcell pipeline with next-generation CAR-ProTcell platform designed to address exhaustion of T-cell therapy and fulfil unmet medical needs in the treatment of hematological and solid cancers.

This collaboration has been setup to rapidly develop the next generation of chimeric antigen receptor (CAR) CAR-T cell therapies. Through its ex vivo thymus technology, Smart Immune aims to disrupt conventional approaches to CAR-T cell therapies by using its T-cell progenitors, in other words, ProTcell instead of mature T cell and generate a naïve long lasting, exhaustion-free CAR-T cell population. As part of this collaboration, MSKCC will contribute to the development of the CAR-ProTcell platform with a first proof-of-concept in a mouse-to-mouse model. Smart Immune will lead the humanized model proof-of-concept. This work has the potential to expedite the clinical development of next generation CAR-T cells combining long-term persistence, natural protection against infections and low risk of graft-versus-host disease in allogeneic setting.

The Smart Immune ProTcell platform generates allogenic T-cell progenitors that provide fully functional polyclonal T cells within 3 months following an allogeneic hematopoietic stem cell transplant (HSCT) while also reducing graft-versus-host disease, infections and relapses; thereby, reducing morbidity and mortality and improving the benefice risk ratio for allogeneic medicine. When infused, ProTcell progenitors migrate to the patient’s thymus where they expand, are selected, and then differentiate, resulting in fully functional T cells, tolerant to the patient’s own immune system and reactive to viral, fungal and malignant antigens. ProTcell has been accepted by the US FDA as an investigational new drug for acute lymphocytic leukemia (ALL) and acute myelocytic leukemia and has also been granted fast-track designation under its expedited program for serious conditions like severe combined immunodeficiency (SCID).

Distribution agreement: Essent & Amnion Foundation

Essent Biologics, (CO, USA; https://essentbiologics.org/), a supplier of adult human-derived cell and scaffold materials, has entered into a global distribution partnership agreement with the Amnion Foundation (NC, USA; www.amnionfoundation.org), a non profit cell bank specializing in birth-tissue related cells and services [4].

This distribution agreement marks the first time that several unique cell types – cytotrophoblasts, Hofbauer cells (placental macrophages), placental microvascular endothelial cells and placental stem/stromal cells have been made commercially available worldwide for use in regenerative medicine, toxicology and drug development. The partnership furthers the companies’ shared mission to democratize global access to non controversial, full-term placental tissue-derived cell types.

License, codevelopment & commercialization agreement: Bristol Myers Squib & Immatics

Immatics (Germany; https://immatics.com/), a clinical-stage biopharmaceutical company active in the discovery and development of T cell-redirecting cancer immunotherapies, and Bristol Myers Squibb (NY, USA; www.bms.com), have entered into a license, development and commercialization agreement for Immatics’ T-cell receptor Bispecific candidate, IMA401 [5].

Under the terms of the agreement, Immatics will receive an upfront payment of US$150 million as well as up to US$770 million in development, regulatory and commercial milestone payments, in addition to tiered double-digit royalty payments on net sales of IMA401. Immatics retains the options to cofund US development in exchange for enhanced US royalty payments and/or to copromote IMA401 in the USA.

IMA401 is the most advanced product candidate in Immatics’ T-cell receptor Bispecifics pipeline, called T Cell Engaging Receptors (TCER)^®, in which one binding region targets MAGEA4/8, a highly prevalent antigen in multiple solid tumors and the other region engages and activates T cells. In preclinical proof-of-concept studies, IMA401 has shown antitumor activity with complete remissions in various in vivo tumor models including patient-derived xenograft models. The agreement outlines a development plan under which both companies will collaborate to advance the program through clinical development.

Manufacturing agreement: BrainStorm & Catalent

BrainStorm Cell Therapeutics (NY, USA; www.brainstorm-cell.com), a developer of cellular therapies for neurodegenerative diseases and Catalent (NJ, USA; www.catelent.com), a manufacturer and supplier of health care products, have announced that the technology transfer for NurOwn^® manufacturing at Catalent’s facility has been finalized [6]. NurOwn is BrainStorm’s autologous cellular therapy being developed for the treatment of amyotrophic lateral sclerosis (ALS), progressive multiple sclerosis and other neurodegenerative diseases.

Catalent entered into a partnership with Brainstorm in 2020 to provide CGMP clinical supply of NurOwn, in anticipation of the product candidate’s potential regulatory approval. NurOwn will be manufactured at Catalent’s world-class 32,000 square-foot cell therapy manufacturing facility in TX, USA.

he NurOwn technology platform (autologous MSC-neurotrophic factors [NTF] cells) represents a promising investigational therapeutic approach to targeting disease pathways important in neurodegenerative disorders. MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo. MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of NTFs. Autologous MSC-NTF cells are designed to effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression.

Purchase agreement: Bio-Techne & Wilson Wolf

Bio-Techne Corporation (MN, USA; www.bio-techne.com), a global life sciences company, has entered into an option agreement with Wilson Wolf Corporation (MN, USA; www.wilsonwolf.com) [7]. The agreement includes a potential 20% ownership investment in Wilson Wolf upon its achievement of approximately US$100 million in revenue or US$50 million in earnings before interest, taxes, depreciation and amortization as well as the opportunity to fully acquire the company upon its achievement of approximately US$225 million in revenue or US$135 million in earnings before interest, taxes, depreciation and amortization.

Founded in 1998, Wilson Wolf is focused on the development, manufacture and commercialization of cell culture technologies, including its Gas Permeable Rapid Expansion (G-Rex^®) product line. G-Rex devices are a critical component of the cell therapy workflow, serving as a vessel to create high quality cells that can reconstitute the immune system’s capacity to fight disease. G-Rex was created specifically to produce immune cells such as T cells, natural killer cells and hematopoietic stem cells. With a revolutionary design, G-Rex provides an easy, fast and cost-effective method for scaling cell therapies in the least amount of space.

In 2020, Wilson Wolf, Bio-Techne and Fresenius Kabi (Germany; www.fresenius.com), a global healthcare company, have announced the formation of the ScaleReady^™ joint venture (MN, USA; www.scaleready.com), bringing together tools and technologies for cell culture, cell activation, gene editing and cell processing. ScaleReady is empowering the field of cell and gene therapy by delivering a simple, scalable and versatile manufacturing platform for cell and gene therapies.

Achievements

ViaCyte

ViaCyte (CA, USA; www.viacyte.com), a clinical-stage regenerative medicine company focused on developing novel cell replacement therapies to address diseases with significant unmet needs, has announced publication of promising preliminary results of an ongoing, first-in-human phase I/II study demonstrating that its stem cell-derived therapy can produce insulin in people with severe Type 1 diabetes [8–10].

The first paper reports on 17 patients who were implanted with ViaCyte’s PEC-Direct devices, comprising pancreatic cells (PEC-01) contained within pouches designed for subcutaneous placement [9]. Results indicate positive C-peptide levels (a biomarker for insulin) as early as 6 months post-implant in some patients. Initial data suggest that pancreatic endoderm cells can be differentiated into, and offer a potential scalable, renewable source of insulin-producing, pancreatic islet cells.

The second paper reports on findings from 15 patients at the trial’s largest participating site, the University of British Columbia (UBC) and Vancouver Coastal Health (VCH) in Canada [10]. About 6 months after implantation, researchers observed that the cells had matured into insulin-producing islet cells. They also detected a rise in C-peptide levels after patients ate a meal, indicating functional insulin production. Furthermore, patients spent 13% more time in target glucose range, with some able to reduce the amount of their injected insulin.

The international phase I/II clinical trial is focused on evaluating safety, tolerability and efficacy of PEC-Direct (VC-02) in patients with hypoglycemia unawareness or extreme glycemic lability. PEC-Direct devices are comprised of millions of pancreatic endoderm cells designed to mature into insulin-producing islet cells. The devices are configured to enable direct vascularization of the engrafted cells; therefore, requiring concurrent immunosuppression. ViaCyte is advancing PEC-Direct and its portfolio of stem cell-derived therapies with the goal of enabling patients with diabetes to regulate their blood glucose levels, improve health outcomes and one day achieve independence from the burden of daily insulin injections.

Clinical trials

Mesenchymal stromal/stem cells

BrainStorm

BrainStorm Cell Therapeutics (NY, USA; www.brainstorm-cell.com), a developer of cellular therapies for neurodegenerative diseases, has published the results of NurOwn phase III study for ALS [11–13]. Data from the paper are from a randomized, double-blind, placebo-controlled, phase III trial evaluating the safety and efficacy of repeat doses of NurOwn in study participants. Although, previously announced results showed the trial did not reach statistical significance on the primary or secondary end points, prespecified and post hoc analyses show a NurOwn-induced treatment effect across both primary and secondary efficacy outcomes in those with less advanced disease.

Potential participants with ALS were screened during an 18 week run-in period and those who were rapid progressors (defined as patients with at least a 3-point decrease in ALSFRS-R score during the run-in period) were randomized 1:1 to receive three intrathecal injections (8 weeks between each injection) of NurOwn or placebo. Participants were followed for 28 weeks after treatment. The primary end points of the trial were safety assessments and a responder analysis of the rate of decline in ALSFRS-R score over 28 weeks, where response was defined as participants with a 1.25 points/month improvement in the post-treatment versus pretreatment slope in ALSFRS-R at 28 weeks following the first treatment. Secondary end points included the percentage of patients with disease progression halted or improved, ALSFRS-R change from baseline, combined analysis of function and survival, slow vital capacity, tracheostomy-free survival, overall survival (OS) and cerebrospinal fluid biomarker measurement.

BrainStorm has also announced that FDA recommended that BrainStorm submit an Expanded Access Protocol (EAP) amendment to provide additional dosing for the participants who had completed the phase III NurOwn trial for multiple sclerosis and who met specific eligibility criteria had the opportunity to receive three doses of NurOwn [14,15]. Under the amended EAP protocol, these eligible participants will receive up to three additional doses. Data collected from the original EAP treatments informed the decision to move forward with additional doses for participants who completed it.

Immune cells

Bristol Squib Myers

Bristol Myers Squibb (NY, USA; www.bms.com) has announced the first disclosure of results from a prespecified interim analysis of the pivotal TRANSFORM study, a global, randomized, multicenter, phase III study evaluating Breyanzi (lisocabtagene maraleucel; liso-cel), a CD19-directed CAR T-cell therapy, as a second-line treatment in adults with relapsed or refractory large B-cell lymphoma compared with the standard of care consisting of salvage chemotherapy followed by high-dose chemotherapy plus autologous HSCT [16,17]. In the TRANSFORM study, 184 patients with primary refractory large B-cell lymphoma or relapsed disease within ≤12 months after first-line therapy who were eligible for autologous HSCT were randomized to receive Breyanzi (n = 92) or salvage chemotherapy followed by high-dose chemotherapy and autologous HSCT (n = 92), which is considered the current standard of care for these patients. In the trial, which allowed for crossover, 50 patients switched from the standard of care arm to receive Breyanzi following failure to achieve a response by 9 weeks post randomization (after three cycles of salvage chemotherapy) or after disease progression at any time.

The majority of patients (86%) treated with Breyanzi achieved a complete or partial response, with 66% of patients achieving a complete response. In comparison, less than half (48%) of patients who received the standard of care achieved a response, and only 39% of these patients achieved a complete response (p < 0.0001). Median progression-free survival was significantly longer with Breyanzi compared to standard of care (14.8 vs 5.7 months [HR: 0.406; p = 0.0001]). Although OS data were not yet mature, the prespecified interim analysis showed a trend favoring Breyanzi compared with the standard of care (HR: 0.509; 95% CI: 0.258–1.004; p = 0.0257).

Breyanzi exhibited a manageable safety profile with very low rates of severe cytokine-release syndrome (CRS) and neurologic events, and no new safety signals were observed in this second-line setting. In the trial, no Grade 4/5 CRS or neurologic events were reported. Any-grade CRS was reported in 49% of patients, with Grade 3 CRS reported in only one patient. Any-grade neurologic events were reported in 12% of patients treated with Breyanzi, with Grade 3 neurologic events reported in four patients (4%).

Breyanzi is a CD-19 directed CAR T-cell therapy with a defined composition and 4-1BB costimulatory domain. Breyanzi is administered as a defined composition to reduce variability of the CD8 and CD4 component dose. The 4-1BB signaling domain enhances the expansion and persistence of the CAR T cells.

Poseida

Poseida Therapeutics (CA, USA; https://poseida.com), a clinical-stage biopharmaceutical company utilizing proprietary genetic engineering platform technologies to create cell and gene therapeutics, has reported interim results from its phase I/II PRIME clinical trial of P-BCMA-101 for the treatment of relapsed/refractory multiple myeloma [18,19]. The PRIME trial is a phase I/II, open-label 3 + 3 single-dose escalation of P-BCMA-101 CAR-T cells. The primary objective of the study is to determine the safety and maximum tolerated dose of P-BCMA-101 based on dose limiting toxicities, and the key secondary objective is to assess the antimyeloma effect of the product. The median patient age was 62, with a median time since diagnosis of approximately 5.8 years. Patients were heavily pretreated, with a median of seven prior lines of therapy (2–18). As of the data cut-off date of 15 October 2021, a total of 98 patients have been dosed with P-BCMA-101.

The best observed treatment regimen was a combination with rituximab (n = 14), with an overall response rate of 78%, a very good partial response/stringent complete response rate of 43 and 100% OS at the time of the data cutoff. Progression-free survival was also improved with rituximab, with median OS rates not yet reached in several cohorts including the rituximab combination cohorts. Response rates for other cohorts are consistent with results previously reported.

Across the study, no dose-limiting toxicities were observed. About 28% of patients developed CRS and 7% of patients developed neurotoxicity. None of the patients developed Grade 3 or higher CRS, and 2% of patients developed Grade 3 neurotoxicity. There were no treatment-related deaths among the patient population and no patients needed ICU admission as a result of CAR-T related toxicities. A total of 28 patients were treated on a fully outpatient basis.

Regulations, approvals, acquisitions…

Green light

Longeveron

Longeveron (FL, USA; www.longeveron.com), a clinical stage biotechnology company developing cellular therapies for chronic aging-related and life-threatening conditions, has that the FDA has granted orphan drug designation for Lomecel-B^™ for the treatment of hypoplastic left heart syndrome, a rare and life-threatening congenital heart defect in infants. LomeceL-B cell-based therapy product is derived from culture-expanded medicinal signaling cells (MSCs) that are sourced from bone marrow of young, healthy adult donors [20]. Longeveron believes that by using the same cells that promote tissue repair, organ maintenance, and immune system function, it can develop safe and effective therapies for some of the most difficult disorders associated with the aging process and other medical disorders.

Poseida

Poseida Therapeutics (CA, USA; https://poseida.com), a clinical-stage biopharmaceutical company utilizing proprietary genetic engineering platform technologies to create cell and gene therapeutics, has announced that the US FDA has cleared its investigational new drug application for P-MUC1C-ALLO1, the Company's allogeneic CAR-T product candidate targeting multiple solid tumor indications [21]. P-MUC1C-ALLO1 has the potential to treat a wide range of solid tumors derived from epithelial cells, such as breast, colorectal, lung, ovarian, pancreatic and renal cancers, as well as other cancers expressing a cancer-specific form of the Mucin 1 protein, or MUC1C. P-MUC1C-ALLO1 is designed to be fully allogeneic, with genetic edits to eliminate or reduce both host-versus-graft and graft-versus-host alloreactivity. Poseida has demonstrated the elimination of tumor cells to undetectable levels in preclinical models of both triple-negative breast and ovarian cancer.

Name change

Evia Bio

BlueCube Bio officially announced a company name transition to Evia Bio™ (MN, USA; https://eviabio.com/), concurrent with the launch of a significant new cryopreservation technology for use in cell and gene therapies utilizing induced pluripotent stem cells (iPSCs) [22]. The osmolyte-based solution increases cell survival above that of commercially available DMSO-based options, which is critical for realizing the potential of these therapies [23]. This latest addition expands the company's portfolio of patented cryopreservation products that also include products for MSCs.

Capital market & finances

Kadimastem

Kadimastem (Israel; www.kadimastem.com), a clinical-stage cell therapy company developing a treatment for ALS and a potential cure for diabetes, has received a grant of NIS 1.6 million (US$500,000), 40% of the approved budget of NIS 4 million (US$1.29 million) from the Israel Innovation Authority ([IIA]; Israel; https://innovationisrael.org.il/en/) [24]. This brings the total amount of financing raised by Kadimastem in 2021 to NIS 51.6 million (US$16 million).

Longeveron

Longeveron (FL, USA; www.longeveron.com), a clinical-stage biotechnology company developing cellular therapies for chronic aging-related and life-threatening conditions, has closed previously announced private placement of common stock and warrants [25].

The Company sold approximately 1.17 million shares of its common stock and 1.17 million warrants to purchase 1.17 million shares of common stock. The warrants will be exercisable immediately upon the date of issuance and have an exercise price of US$17.50 per share. The warrants will expire 5 years from the date of issuance. The purchase price for one share of common stock and one corresponding warrant will be US$17.50. The gross proceeds to the Company from the private placement are estimated to be approximately US$20.5 million before deducting the placement agent’s fees and other estimated offering expenses.

Longeveron intends to use the net proceeds from the private placement to support the ongoing clinical development of Lomecel-B, the Company’s lead investigational product, which is currently being evaluated as a potential therapeutic for hypoplastic left heart syndrome, aging frailty Alzheimer’s disease and other diseases. In addition, the Company plans to use the proceeds to fund additional research and development, product development and for general and administrative purposes.