There have been a number of recent developments in cell and gene therapy, as detailed in our bimonthly newsletter, Cell and Gene Therapy Business Outlook.

1. The U.S. FDA has lifted clinical holds on two Phase III clinical studies evaluating gene therapies being developed by Pfizer, based in New York, NY. On April 28^th, Pfizer announced the reactivation of its Phase III study CIFFREO evaluating fordadistrogene movaparvovec (PF-06939926) for the treatment of Duchenne muscular dystrophy (DMD). The clinical hold was placed in response to a patient death in a Phase I trial for the therapy, and was lifted after Pfizer responded to the FDA’s requests for a potency assay and a protocol amendment. (See Cell and Gene Therapy Business Outlook 1, issue 8, p. 31 for more on Pfizer’s gene therapy for DMD.)  Then on May 3^rd, Pfizer announced that the FDA had lifted a hold on the Phase III study AFFINE evaluating giroctocogene fitelparvovec (PF-07055480) for the treatment of hemophilia A, which Pfizer is developing in collaboration with Richmond, CA-based Sangamo Therapeutics.  Hemophilia A is an X-linked inherited disorder resulting in a deficiency of coagulation factor VIII, and giroctocogene fitelparvovec uses an adeno-associated virus to deliver a functional factor VIII transgene.  The therapy was so effective that some participants in the trial were observed with factor VIII levels greater than 150%, levels which are high enough to carry an increased risk of blood clots.  The clinical hold was initiated to amend the protocol with guidelines to safely manage those elevated factor VIII levels.  Pfizer announced that the clinical hold had actually been lifted back in March, but that the trial would not resume immediately; Pfizer and Sangamo are continuing with a voluntary hold as they finalize study protocols and ensure all necessary study conditions have been met.
2. Matica Biotechnology, a gene therapy contract development and manufacturing organization (CDMO) based in College Station, TX, has announced the opening of a new 45,000 square-foot production facility for viral vectors and cell-based products for use in cell and gene therapies, vaccines, oncolytic therapies, and other genetic medicines. Two collaborations at the new facility have also been announced:  Matica Bio is working with Germany-based Sartorius to develop large-scale viral vector manufacturing technologies, and the company has also partnered with Texas A&M University’s Center for Innovation in Advanced Development and Manufacturing to speed up biotech R&D and commercial manufacturing.
3. Gilead Sciences, based in Foster City, CA, and Dragonfly Therapeutics, based in Waltham, MA, have announced a collaboration to develop a number of Dragonfly’s novel natural killer (NK) cell engagers for indications in oncology and inflammatory disease. Dragonfly’s proprietary TriNKETs (Tri-specific, NK cell Engager Therapies) are molecules which bind to proteins expressed on both cancer cells and NK cells, activating the NK cells to both kill the cancer cells directly and signal other immune cells to establish a coordinated immune response against the cancer cells. As part of the agreement, Gilead will receive an exclusive, worldwide license for DF7001, Dragonfly’s TriNKET targeting 5T4, an oncofetal antigen expressed on tumor cells and tumor-supporting stromal cells in several types of cancer including pancreatic, colorectal, breast, ovarian, gastric, lung, and head and neck cancers.  IND application for DF7001 is anticipated in the first half of 2023.  Gilead will also have the option to license additional NK cell engagers from Dragonfly’s TriNKET platform after completing certain preclinical activities.
4. Scribe Therapeutics, based in Alameda, CA, has announced an expansion of its ongoing collaboration with Cambridge, MA-based Biogen. Scribe was co-founded by Nobel Laureate Jennifer Doudna, PhD, and specializes in developing genome editing technologies adapted from CRISPR (clustered regularly interspaced short palindromic repeats) sequences found in bacterial genomes.  (Doudna and Emmanuelle Charpentier, PhD, were awarded the Nobel Prize in Chemistry in 2020 for their pioneering work adapting and streamlining the system into a powerful, programable gene editing tool.)  Back in 2020, Scribe announced a research collaboration with Biogen to develop and commercialize CRISPR-based therapies for the treatment for one of the underlying genetic causes of amyotrophic lateral sclerosis (ALS), which has been associated with genetic defects in more than 20 genes.  Scribe netted $15 million upfront for that deal, along with the potential for more than $400 million in milestone payments down the road.  With this announcement, Biogen has exercised an option in that agreement to pursue CRISPR-based gene therapies for an additional, undisclosed neurological disease target.
5. Orchard Therapeutics, based in London, UK has announced an agreement with Gesetzliche Krankenversicherung Spitzenverband (GKV-SV), Germany’s national association of statutory health insurance funds, which grants access to Libmeldy (atidarsagene autotemcel) to all metachromatic leukodystrophy (MLD) patients in Germany within the scope of the European marketing authorization. MLD is rare genetic disorder caused by a mutation in the ARSA gene encoding the enzyme arylsulfatase A (ARSA).  Classified as a lysosomal storage disease, the enzyme deficiency results in the accumulation of fats called sulfatides which eventually destroy the myelin sheath surrounding nerve fibers in both the central and peripheral nervous systems.  Libmeldy is an autologous (patient-derived) CD34⁺ cell enriched population containing hematopoietic stem and progenitor cells (HSPCs) which have been transduced ex vivo with a lentiviral vector to express a functional copy of the ARSA gene encoding the human ARSA  The agreement follows close upon similar agreements with the England’s National Health Service (NHS) and Italy’s Agenzia Italiana del Farmaco (AIFA) in February and April of this year.
6. Eli Lilly and Company, based Indianapolis, IN, and Bachem, based in Bubendorf, Switzerland, have announced a strategic collaboration to develop and streamline the manufacture of oligonucleotide-based therapeutics. The agreement concerns the manufacture of active pharmaceutical ingredients (APIs) for the therapeutics, which will implement Lilly’s novel oligonucleotide manufacturing technology.  Bachem will supply R&D and production personnel at its facilities in Bubendorf, Switzerland, along engineering infrastructure and expertise in the manufacture of GMP-grade materials.  The agreement provides for a 7-year commitment from Lilly following successful implementation of its oligonucleotide manufacturing technology, with an annual order volume of up to 100 million Swiss francs ($101 million), depending on certain milestones being met.
7. Caladrius Biosciences, based in Bernards, NJ, and Cend Therapeutics, based in San Diego, CA, have announced that Cend will merge with a wholly-owned subsidiary of Caladrius, with the newly-merged company to be renamed Lisata Therapeutics. Caladrius also plans to immediately invest $10 million in Cend to advance its development pipeline.  The merger is anticipated to close in the third quarter of 2022, and Lisata will combine development pipelines from both companies, with an emphasis on Cend’s CendR  The new company’s lead candidate is expected to be CEND-1, a proprietary cyclic peptide that selectively facilitates anticancer drug delivery across the stroma of solid tumors to target tumor cells.  CEND-1 is currently being evaluated in Phase I and Phase II clinical studies for the treatment of pancreatic ductal adenocarcinoma (PDAC).
8. Ray Therapeutics, based in San Diego, CA, has announced that the California Institute for Regenerative Medicine (CIRM) has awarded the company a $4 million grant to support development of Ray-001, its lead optogenetic therapy for the treatment of retinitis pigmentosa (RP) and other inherited retinal diseases. Over 100 mutations in more than 70 different genes can lead to RP, and no effective treatment is available.  Rather than attempting to repair the specific genetic defect responsible for RP, Ray-001 is a mutation-independent optogenetic therapy that bypasses the defective photoreceptors entirely by targeting other retinal cells along the vision circuit pathway. The therapy is administered via intravitreal injection, where it diffuses from the vitreous into the retina to transduces the retinal ganglion cells (RGCs).  Preclinical studies indicate that Ray-001 could be a one-time treatment that is sustainable for a lifetime.
9. ViGeneron, an ophthalmic gene therapy company based in Munich, Germany, has announced a follow-on collaboration with Daiichi Sankyo Company, based in Tokyo, Japan. The initial collaboration began in January of 2021, when the two companies agreed to the first-stage research to develop therapies using ViGeneron’s novel engineered adeno-associated virus (vgAAV) vectors to deliver a novel therapeutic protein for the treatment of a highly prevalent, undisclosed ophthalmic disease target.  This follow-on collaboration allows the research collaboration to move into in vivo animal studies for the validation of potential vgAAV-based therapeutic candidates.  ViGeneron has identified and characterized two novel vgAAV vectors, termed GL and vgAAV.NN, using an in vivo directed-evolution approach with an AAV2-based peptide-display library.  The two vectors have demonstrated widespread, high-level transduction in retinal tissue over a wide range of preclinical models, and have also been shown to efficiently transduce human photoreceptor cells in human retinal explant cultures.  In addition to its vgAAV platform, ViGeneron’s REVeRT (Reconstitution via mRNA trans-splicing) technology platform overcomes the packaging size limitations of AAV vectors by taking advantage of cellular splicing machinery.   Two different mRNA molecules, each encompassing a portion of a large transgene mRNA molecule, are simultaneously co-delivered with separate vgAAV vectors, then spliced together inside the cell into to reconstruct the original large transgene mRNA.
10. Porton Advanced Solutions, a contract development and manufacturing organization (CDMO) based in Suzhou, China, and Guizhou Sinorda Biomedicine Co, a cancer immunotherapy biotech company based in Guiyang, China, have announced a long-term collaboration in cell and gene therapy development. Porton Advanced will provide its end-to-end gene and cell therapy CDMO service platform to accelerate the development, production, and registration of Sinorda Biomedicine’s current development pipeline. The first collaborated project will be Sinorda’s SND002 (Sentinel Lymph Node T cell), a T-cell immunotherapy for the treatment of colorectal cancer.  SND002 was designated as a Breakthrough New Drug by the Chinese National Science and Technology Major Project, and was recently approved to begin Phase II clinical trials in Europe.
11. The Ohio State University has launched a new Gene Therapy Institute to be led by Russell Lonser, MD, professor and chair of neurological surgery, and Krystof Bankiewicz, MD, PhD, professor of neurological surgery, both at the Ohio State College of Medicine. The university is currently conducting ten active human clinical trials, with a $14.6 million grant for a first-in-human nervous system gene therapy trial and a $4.8 million grant for translational CRISPR-gene therapy research from the National Institutes of Health.  Gene therapy-related research in being conducted by over 50 faculty across multiple colleges at Ohio State, with industry collaborations that include partnerships with Battelle, Medtronic, Biogen, and Bayer.
12. Ilya Pharma, based in Uppsala, Sweden, has acquired long-term partner Nordic Bioanalysis, based in Södertälje, Sweden. Ilya develops therapies using modified lactic acid bacteria to deliver therapeutic proteins, and its lead candidate is ILP100 (in both topical and oral formulations), which consists of the lactic acid bacterium Limosilactobacillus reuteri R2LC, genetically modified to express the human cytokine CXCL12 1a.  Nordic Bioanalysis specializes in bioanalytical development and validation for small molecule pharmaceuticals and biologics, including antibodies and Advanced Therapy Medicinal Products (ATMPs), and Ilya plans to use the acquisition to streamline its development pipeline. Under the terms of the acquisition, Nordic will continue to operate as an independent commercial entity.
13. Celogics, based in Seattle, WA, and NEXEL, a Seoul, Korea-based spinoff from Korea University specializing in induced pluripotent stem cell (IPSC) technologies, have announced the exclusive licensing of NEXEL’s Cardiosight-S, an iPSC-derived cardiomyocyte product line. Cardiosight-S will be the first product offered by Celogics, a joint venture between NEXEL and Curi Bio. Curi Bio is also based in Seattle, and specializes in developing in vitro tissues derived from IPSCs for disease modeling and drug discovery.  Celogics is a manufacturer of human iPSC-derived cell products, and has just announced the planned construction of a 20,000 square-foot biomanufacturing facility in the Seattle area.
14. TreeFrog Therapeutics, a cell therapy company based in Bordeaux, France, has announced the launch of The Stem Cell SpaceShot Grant, a $100,000 grant open to PhD-level scientists and PhD candidate students working in stem cell biology, biophysics, gene editing, cell therapy, and bioproduction engineering. The grant is intended to facilitate TreeFrog’s goal of advancing stem cell therapies while improving their safety, efficiency, and affordability.  TreeFrog was founded in 2018 and has so far raised $82 million to advance its cell therapy pipeline. The company’s proprietary C-Stem technology platform utilizes micro-capsules to protect induced pluripotent stem cells (iPSCs) from external stress and simulate in vivo growth conditions during culture, allowing the cells to be mass-produced and differentiated into ready-to-transplant microtissues.