Industry Updates from the Field of Stem Cell Research and Regenerative Medicine in January 2020: Industry News

Abstract

Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from nonacademic institutions in January 2020.

Keywords::

• industry
• regenerative medicine
• stem cells

Business development

Collaborations, partnerships & alliances

Co-development agreement: Astellas & AdaptImmune

Astellas Pharma (Japan; www.astellas.com), through its wholly owned subsidiary Universal Cells (WA, USA; www.universalcells.com) and Adaptimmune Therapeutics (UK; www.adaptimmune.com) have announced that they have entered into a co-development and co-commercialization agreement to bring new stem-cell derived allogeneic T-cell therapies to people with cancer [1]. Astellas and Adaptimmune will agree on up to three targets and co-develop T-cell therapy candidates directed to those targets. These targets will exclude target specific T-cell products in preclinical or clinical trials or those developed for other partners at Adaptimmune. The collaboration will leverage Adaptimmune’s target identification and validation capabilities for generating target-specific T-cell receptors (TCRs), chimeric antigen receptors and human leukocyte antigen (HLA)-independent TCRs that recognize surface epitopes independently of the HLA profile of the tumor cell. The collaboration will also utilize Astellas’ Universal Donor Cell and Gene Editing Platform it obtained through the acquisition of Seattle-based Universal Cells. Adaptimmune has been collaborating with Universal Cells since 2015 on development of gene-edited induced pluripotent stem cell (iPSC) lines, for which Adaptimmune has rights to develop and commercialize resulting T-cell therapy products using its proprietary process for generating T cells from stem cells without the use of feeder cell lines. Astellas will fund research up until completion of a Phase I trial for each candidate. Upon completion of the Phase I trial for each candidate, Astellas and Adaptimmune will elect whether to progress with co-development and co-commercialization of the candidate, or to allow the other party to pursue the candidate independently through a milestone and royalty-bearing license, with the agreement allowing for either company to opt out. The companies will each have a co-exclusive license covering the co-development and co-commercialization of the product candidates within the field of T-cell therapy. If a candidate is developed by one company only, the appropriate licenses will become exclusive to the continuing party. Astellas will also have the right to select two targets and develop allogeneic cell therapy candidates independently. Astellas will have sole rights to develop and commercialize these products, subject to necessary licenses and the payment of milestones and royalties. Under the terms of the agreement, Adaptimmune may receive up to $US 897.5 million in payments, including:

• an upfront payment of $US 50 million.

• development milestones totaling up to $US 73.75 million for each product if the collaboration product discovered in this partnership is co-developed and commercialized by both companies.

• Up to $US 147.5 million in milestone payments per product and up to $US 110 million in sales milestones for products developed unilaterally by Astellas.

In addition, Adaptimmune will receive research funding of up to $US 7.5 million per year. Finally, Adaptimmune would receive tiered royalties on net sales in the mid-single to mid-teen digits. Under the terms of the agreement, Astellas may receive up to $US 552.5 million, including:

• Up to $US 147.5 million in milestone payments per product and up to $US 110 million in sales milestones for products developed unilaterally by Adaptimmune.

In addition, Astellas would receive tiered royalties on net sales in the mid-single to mid-teen digits. To the extent that Astellas and Adaptimmune co-develop and co-commercialize any T-cell therapy, they will equally share the costs of such co-development and co-commercialization, with the resulting profits from co-commercialization also shared equally.

Collaboration & licensing agreement: Ncardia & BlueRock

Ncardia (the Netherlands; www.ncardia.com) and BlueRock Therapeutics (MA, USA; https://bluerocktx.com), a wholly owned and independently operated subsidiary of Bayer (Germany; www.bayer.com), have announced an agreement covering process development technologies for the manufacture of iPSC-derived cardiomyocytes [2]. Under the terms of the agreement, Bluerock gains access to Ncardia’s large-scale production processes and intellectual property for the production of iPSC-derived cardiomyocytes for therapeutic use.

Licensing agreement: Astellas & Allele

Allele Biotechnology and Pharmaceuticals (CA, USA; www.allelebiotech.com), a San Diego-based private company, and Astellas Pharma (Japan; www.astellas.com), through its subsidiary Astellas Institute for Regenerative Medicine (MA USA; www.astellas.com/us/innovation/r-and-d), have entered into a licensing agreement to expand Astellas’ access to Allele’s iPSC technologies for various cell therapy programs [3]. Allele Biotechnology and Pharmaceuticals was founded in 1999. In 2015, the company completed an 18,000 square foot state-of-the-art facility in San Diego for the production of good manufacturing practice (GMP)-grade human iPSC lines. The facility also supports the production of tissue-specific cells differentiated from these iPSCs, including pancreatic β cells, neural progenitor cells and cardiomyocytes.

Partnership agreement: Cytovia & NYSCF

CYTOVIA Therapeutics (NY, USA; www.cytoviatx.com) and the New York Stem Cell Foundation Research Institute (NY, USA; https://nyscf.org/research-institute) have entered into a partnership to develop iPSC-derived chimeric antigen receptor natural killer (NK) therapeutics [4]. Cytovia focuses on NK cell biology and applies precision medicine tools to develop the right therapy for the right patient at the right stage of the disease. The NYSCF Research Institute is has developed the NYSCF Global Stem Cell Array^®, the premier automated robotic platform for reprogramming adult cells into iPSCs.

Launching new products, services…

bluebird

bluebird bio (MA, USA; www.bluebirdbio.com) has been launched in Germany ZYNTEGLO™ (autologous CD34⁺ cells encoding β^A-T87Q-globin gene), a one-time gene therapy for patients 12 years and older with transfusion-dependent β-thalassemia (TDT) who do not have a β⁰/β⁰ genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate but a HLA-matched related HSC donor is not available [5]. This is the first time ZYNTEGLO is commercially available. TDT is a severe genetic disease caused by mutations in the β-globin gene that result in significantly reduced or absent adult hemoglobin. In order to survive, people with TDT maintain hemoglobin levels through lifelong chronic blood transfusions. These transfusions carry the risk of progressive multi-organ damage due to unavoidable iron overload. ZYNTEGLO is a one-time gene therapy that addresses the underlying genetic cause of TDT and offers patients the potential to become transfusion independent, which, once achieved, is expected to be lifelong. Due to the highly technical and specialized nature of administering gene therapy in rare diseases, bluebird bio is working with institutions that have expertise in stem cell transplant as well as in treating patients with TDT to create qualified treatment centers that will administer ZYNTEGLO. bluebird bio has established a collaboration with University Hospital of Heidelberg as the first qualified treatment center in Germany. In addition, bluebird has entered into value-based payment agreements with multiple statutory health insurances in Germany to help ensure patients and their healthcare providers have access to ZYNTEGLO and that payers only pay if the therapy delivers on its promise. bluebird’s proposed innovative model is limited to five payments made in equal installments. An initial payment is made at the time of infusion. The four additional annual payments are only made if no transfusions for TDT are required for the patient.

Achievements

Emulate

Emulate (MA, USA; www.emulatebio.com) has announced a publication of a study in collaboration with Johns Hopkins University School of Medicine, that demonstrated superior functionality of the Duodenum Intestine-Chip populated with organoids, compared with organoids alone [6,7]. The study showed that the Intestine-Chip produced a nearly identical global transcriptomic profile compared with human intestine duodenum tissue, whereas the signature from the organoids alone had significant differences from the human intestine tissue. The authors further showed that the similarities at the transcriptomic level also resulted in significantly more accurate physiological function of the Intestine-Chip compared with organoids alone. These results demonstrate the potential of the Intestine-Chip to provide a robust system to accurately recreate human intestine tissues for highly predictive and human-relevant preclinical drug assessment, including drug transport, metabolism and drug–drug interactions. Emulate continues to develop a wide range of Organ-Chips and disease models through collaborations with industry partners and internal R&D programs.

Clinical trials

Embryonic stem cells

Kadimastem

Kadimastem (Israel; www.kadimastem.com) has announced promising results of cohort A of its Phase I/IIa clinical trial for the treatment of patients with amyotrophic lateral sclerosis (https://clinicaltrials.gov; ID: NCT03482050) [8]. The primary objective of the trial is to evaluate the safety of AstroRx^®, an ‘off-the-shelf’ clinical-grade astrocyte cell product, developed and manufactured by the company. A secondary objective of the trial includes preliminary efficacy assessments. The company’s technology enables the injection of AstroRx cells into the cerebrospinal cord fluid using standard lumbar puncture procedure, with the goal of supporting the malfunctioning cells in the brain and spinal cord, in order to slow the progression of the disease and improve patients’ quality of life and life expectancy. AstroRx contains functional healthy astrocytes derived from human embryonic stem cells. All five patients included in cohort A were treated with a dose of 100 × 10⁶ AstroRx cells and completed the 6 months post-treatment follow-up period. No treatment related serious adverse events nor dose-limiting toxicities were reported during the 6 months post-treatment follow-up period of cohort A, suggesting a positive safety profile of the AstroRx dose provided. The findings indicated that for a period of 3–4 months following treatment the progression of the disease was reduced, providing a potentially meaningful clinical benefit to the patients. However, in the 5- and 6-month post-treatment periods, a statistically significant difference was not observed between the rate of disease deterioration during these periods and the rate during the pretreatment period. These data suggest a higher dose and/or repeated administrations may achieve prolonged efficacy as it was planned for cohort B, C and D. In cohort B the effect of a higher dose is assessed, and the treatment has been already completed with a higher dose of 250 × 10⁶ AstroRx cells. First patient has been enrolled to cohort C, which is intended to further assess safety and prolonged efficacy, with two consecutive injections of 100 × 10⁶ AstroRx cells separated by an interval of 2–3 months. Cohort D will include a repeated dose of (250 × 10⁶) AstroRx cells. Performance of cohort D will be discretionary, based on the results of previous cohorts.

Others

Exopharm

Exopharm (Australia; http://exopharm.com) has dosed the first patient in the PLEXOVAL Phase I study using exosomes isolated from human platelets for wound healing [9]. Exopharm was granted Human Research Ethics Committee approval to commence the PLEXOVAL wound healing study with its Plexaris™ (exosomes from platelets) autologous product under the Australian Clinical Trials Notification scheme in 2019. Exopharm owns a purification technology called Ligand-based Exosome Affinity Purification.

Promethera

Promethera Biosciences has announced the initiation of a Phase IIb clinical trial to evaluate the efficacy and safety of HepaStem™, the company’s liver-derived stem cell therapy candidate, in patients with acute-on-chronic liver failure [10]. The DHELIVER study (or HEP102) is a randomized, placebo-controlled, double-blinded, multicenter trial designed to assess the efficacy of HepaStem™ treatment on the overall survival proportion 90 days post-first infusion. Among the secondary trial objectives are additional efficacy assessments such as transplantation-free survival as well as continued evaluation of the treatment’s safety. Patients with Grade 1 or 2 acute-on-chronic liver failure will be eligible to screen for participation in the trial. The study will target enrollment of approximately 363 patients across two treatment arms: patients receiving two weekly intravenous infusions of HepaStem™ and patients receiving placebo at 110 study sites across 22 countries in Europe. Top line results are expected to be released at a medical conference at the end of 2023. HepaStem™ consists of liver-derived stem cells that are obtained from ethically donated healthy human organs and expanded in GMP culture conditions.

Rubius

Rubius Therapeutics (MA, USA; www.rubiustx.com), a clinical-stage biopharmaceutical company that is genetically engineering red blood cells, has announced that the first patient has been dosed in its Phase Ib trial of RTX-134, an allogeneic, off-the-shelf cellular therapy for the potential treatment of patients with phenylketonuria (PKU) (https://clinicaltrials.gov; ID: NCT04110496) [11]. The trial is designed to evaluate the safety and pharmacokinetics of RTX-134 in adult patients with PKU. RTX-134 is a Red Cell Therapeutic product candidate that is genetically engineered to express the enzyme PAL inside the cell. RTX-134 is designed to circulate in the bloodstream and degrade toxic levels of phenylalanine (Phe) that accumulate due to a deficiency in the phenylalanine hydroxylase enzyme. Compared to current therapeutic interventions, RTX-134 may have a more sustained treatment effect given the 120-day circulating time of red blood cells and may have a lower incidence of immune-driven adverse events since PAL is inside RTX-134 and shielded from the immune system. As a result, RTX-134 may provide a well-tolerated, efficacious and convenient treatment option for patients. The Phase Ib clinical trial is an open-label, single-dose safety, tolerability and pharmacokinetics study of RTX-134 in up to 12 PKU patients whose Phe levels are above 600 μmol/l. The primary objectives of the study are to evaluate the safety and tolerability of RTX-134, correlate dose with percent reduction in serum Phe levels relative to baseline and determine a preliminary dose to achieve serum Phe levels less than 360 and 600 μmol/l, respectively. The study will also evaluate the pharmacodynamics of RTX-134, including measurement of trans-cinnamic acid (TCA) and cell circulation time. The Phase Ib clinical trial includes four dose cohorts with two patients treated per dose cohort. The design of the trial provides flexibility to enroll additional patients to planned cohorts or add additional cohorts.

SQZ

SQZ Biotechnologies (MA, USA; https://sqzbiotech.com), a clinical-stage company engineering innovative cell therapy candidates for patients with cancer and other serious diseases, has announced that the first patient in its Phase I clinical trial of SQZ-PBMC-HPV has received the first dose (https://clinicaltrials.gov; ID: NCT04084951) [12]. SQZ-PBMC-HPV is an autologous cell therapy candidate comprising SQZ-engineered antigen-presenting cells (APCs) designed to induce CD8 T-cell responses against HPV16. The doses for the patient were manufactured in under 24 h, leveraging SQZ’s novel technology and rapid manufacturing process. The first dose was administered to the patient while additional doses are cryopreserved and available on-demand. This marks the first patient dosed with a cell therapy candidate developed from SQZ’s proprietary Cell Squeeze^® cell engineering technology. It is the first product candidate stemming from the 2018 collaboration expansion between Roche and SQZ to develop SQZ-APCs for oncology indications. The SQZ APC platform is designed to present tumor antigens to the body’s endogenous CD8 T cells. By enabling presentation of the appropriate target, this approach can potentially induce powerful CD8 T-cell responses in patients to attack their tumors.

Regulations, approvals, acquisitions…

Green light

Acepodia

Acepodia (Taiwan; www.acedopodia.com), a biotechnology company developing cancer immunotherapy based on its novel ACC™ (Antibody–Cell Conjugation) technology platform, has announced that it has received clearance of its investigational new drug application from the US FDA to initiate a Phase I clinical study of its NK cell therapy and lead drug candidate ACE1702 in patients with HER2-expressing solid tumors [13]. Antibody–Cell Conjugation platform, which can link any antibody, including those that have already proven effective in targeting tumors, to proprietary off-the-shelf NK cell line without the need for genetic engineering.

Celularity

Celularity (NJ, USA; www.celularity.com) has announced the FDA has cleared the Company’s investigational new drug application for CYNK-001 in patients with glioblastoma multiforme (GBM) [14]. The clinical investigation of CYNK-001 in patients with GBM is expected to be the first clinical trial in the USA to investigate intratumoral administration of an allogeneic NK cell therapy. The company plans to initiate first-in-human clinical testing of CYNK-001 administered either intravenously or intratumorally. This study is expected to evaluate the safety, feasibility and tolerability of multiple doses of CYNK-001 in subjects with relapsed GBM. CYNK-001 is the only cryopreserved allogeneic, off-the-shelf NK cell therapy being developed from placental HSCs as a potential treatment option for various hematologic cancers and solid tumors. NK cells are a unique class of immune cells, innately capable of targeting cancer cells and interacting with adaptive immunity. NK cells derived from the placenta are intrinsically safe and versatile, allowing potential uses across a range of organs and tissues.

Cynata

Cynata Therapeutics (Australia; www.cynata.com) has received approval from the UK Medicines and Healthcare products Regulatory Agency to proceed with its Phase II clinical trial of the Cymerus™, iPSC-derived mesenchymal stem cell (MSC) product CYP-002 in patients with critical limb ischemia [15]. Cynata’s lead product candidate CYP-001 met all clinical end points and demonstrated positive safety and efficacy data for the treatment of steroid-resistant acute graft-versus-host disease in a Phase I trial. Cynata plans to advance its Cymerus MSCs into Phase II trials for graft-versus-host disease, critical limb ischemia and osteoarthritis. In addition, Cynata has demonstrated utility of its Cymerus MSC technology in preclinical models of asthma, diabetic wounds, heart attack and cytokine release syndrome, a life-threatening condition stemming from cancer immunotherapy.

Precigen

Precigen (MD, USA; www.precigen.com) has announced that the FDA has granted orphan drug designation to PRGN-3006, a first-in-class investigational therapy using Precigen’s nonviral UltraCAR-T™ therapeutic platform for patients with relapsed or refractory acute myeloid leukemia (https://clinicaltrials.gov; ID: NCT03927261) [16]. Precigen had completed enrollment for the first cohort of this clinical trial and expects an initial data readout in the second half of 2020.

Acquisitions

BioNTech & Neon

BioNTech (Germany; www.biontech.de) and Neon Therapeutics (MA, USA; www.neontherapeutics.com) have announced that they have entered into a definitive merger agreement under which BioNTech will acquire Neon in an all-stock transaction valued at approximately $US 67.0 million [17]. Neon is a biotechnology company developing novel neoantigen-based T-cell therapies. Upon closing, it will operate as a subsidiary of BioNTech, a global clinical-stage biotechnology company focused on patient-specific immunotherapies for the treatment of cancer and other serious diseases. The transaction will combine two organizations with a common culture of pioneering translational science and a shared vision for the future of cancer immunotherapy. Neon’s most advanced program is NEO-PTC-01, a personalized neoantigen-targeted T-cell therapy candidate consisting of multiple T-jhuy=-0987654321’cell populations targeting the most therapeutically relevant neoantigens from each patient’s tumor. Neon is also advancing a precision T-cell therapy program targeting shared neoantigens in genetically defined patient populations. The lead program from this approach, NEO-STC-01, is a T-cell therapy candidate targeting shared RAS neoantigens. In addition, Neon has assembled libraries of high-quality TCRs against various shared neoantigens across common HLAs. Neon’s pipeline is underpinned by its platform technologies including RECON^®, its machine-learning bioinformatics platform and NEO-STIM™, its proprietary process to directly prime, activate and expand neoantigen-targeting T cells ex vivo. Under the terms of the definitive agreement, Neon will, following consummation of the acquisition, merge with Endor Lights, Inc., a Delaware corporation and a direct, wholly owned subsidiary of BioNTech and become a wholly owned subsidiary of BioNTech. At closing, BioNTech will issue and Neon shareholders will receive 0.063 American Depositary Shares (ADS) (each ADS representing one ordinary share of BioNTech) in exchange for each of their shares of Neon. The exchange ratio implies a deal value of $US 67 million or $US 2.18 per share of Neon, based on the closing price of BioNTech’s ADSs of $US 34.55 on 15 January 2020. The transaction was unanimously approved by both BioNTech’s and Neon’s boards of directors.

Capital market & finances

Jasper

Jasper Therapeutics (CA, USA; https://jaspertherapeutics.com), a biotechnology company focused on hematopoietic cell transplant therapies, has announced the expansion of its Series A financing with an additional investment of $US 14.1 million, bringing the total company financing to more than $US 50 million to date [18]. Jasper plans to use the proceedings to advance and expand the study of its lead clinical asset, JSP191. A humanized antibody targeting CD117 on HSCs, JSP191 is designed to replace toxic chemotherapy and radiation therapy as conditioning regimens to prepare patients for curative stem cell and gene therapy. JSP191 is the only antibody of its kind in clinical development as a single conditioning agent for people undergoing curative hematopoietic cell transplantation. This investigational agent is currently being evaluated in a Phase I/II dose-escalation and expansion study as a conditioning agent to enable stem cell engraftment in patients with severe combined immunodeficiency who received a prior stem cell transplant that resulted in poor outcome (https://clinicaltrials.gov; ID: NCT02963064).

Financial & competing interests disclosure

The author Dusko Ilic has received an honorarium from Future Science Group for the contribution to this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.