With the 2022 Cell & Gene Meeting on the Mesa (#CGMesa22) underway, here’s a look at some notable recent developments in cell and gene therapy featured in the bimonthly newsletter, Cell and Gene Therapy Business Outlook.

• Myrtelle, a clinical-stage gene therapy company based in Wakefield, MA, and Forge Biologics, a gene therapy contract development and manu-facturing organization (CDMO) based in based in Grove City, OH, have announced a manufacturing partnership to bring Myr-201, Myrtelle’s gene therapy for monogenic hearing loss, into Phase I/II clinical trials for the treatment of autosomal recessive nonsyndromic deafness 8 (DFNB8).  DFNB8 is caused by mutations in the TMPRSS3 gene encoding trans-membrane protease, serine 3, and Myr-201 uses a low-dose, locally administered adeno-associated virus (AAV) vector to deliver a functional copy of that gene.  Under the agreement, Forge will provide manufacturing services for research-grade and GMP-pathway plasmids as well as cGMP AAV process development and scale-up for Myr-201.  Development and cGMP manufacturing will take place in Columbus, OH, at The Hearth, Forge’s 200,000-square-foot gene therapy cGMP production facility, where Forge will use its platform process, including its proprietary Ingition HEK 293 suspension cell line and its pEMBR adenovirus helper plasmid.  Financial details were not disclosed.
• Oncternal Therapeutics, a clinical-stage oncology company based in San Diego, CA, has announced that it has received IND clearance from the U.S. FDA for a Phase I/II dose escalation study of ONCT-808, an autologous chimeric antigen receptor (CAR) T cell therapy targeting ROR1 for the treatment of aggressive B cell non-Hodgkin’s lymphoma (B NHL).  ROR1 is a receptor tyrosine kinase that is highly expressed in many types of cancer (including both hematologic and solid tumors), but rarely expressed on healthy adult cells, and its expression has been associated with a survival advantage in tumor cells. Oncternal plans to begin the study in the next few months and present interim results in 2023.
• MaxCyte, a cell engineering company based in Gaithersburg, MD, has announced the signing of a strategic platform license (SPL) with Vertex Pharmaceuticals, a biopharmaceutical company based in Boston, MA, to allow Vertex to use MaxCyte’s Flow Electroporation technology and ExPERT platform to develop exagamglogene autotemcel (exa-cel, formerly CTX001), its ex vivo gene therapy for the treatment of beta thalassemia and sickle cell disease. Under the agreement, Vertex obtains non-exclusive rights to use MaxCyte’s technologies in exchange for platform licensing fees and program related revenue.  Both beta thalassemia and sickle cell disease are genetic blood diseases caused by mutations in the HBB gene encoding β-globin, a major component of hemoglobin A (HbA), the most common form of hemoglobin in human adults.  Exa-cel is an autologous gene therapy in which a patient’s hematopoietic stem cells (HSCs) are harvested and edited to produce red blood cells expressing high levels of fetal hemoglobin (HbF) to complete with the defective HbA. Vertex is developing exa-cel in collaboration with Swiss gene editing company CRISPR Therapeutics, which used the same MaxCyte technology to develop the therapy under an agreement with MaxCyte. Vertex recently announced that the company had concluded discussions with the U.S. FDA and will submit exa-cel’s biologics licensing application (BLA) for the treatment of sickle cell disease and transfusion-dependent beta thalassemia for rolling review beginning in November 2022, and anticipates completing the submission in early 2023.  Vertex also plans to submit marketing applications for exa-cel to the European Medicines Agency (EMA) and the U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA) by the end of 2022.
• Legend Biotech Corporation, a clinical-stage immune cell therapy company based in Somerset, NJ, has announced that that Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved CARVYKTI (ciltacabtagene autoleucel, or cilta-cel) as a fourth-line treatment for adults with relapsed/refractory (R/R) multiple myeloma (MM). CARVYKTI, developed in collaboration with Janssen Biotech, is a genetically modified, autologous T-cell immunotherapy with a CAR design featuring two single-domain antibodies targeting B-cell maturation antigen (BCMA), which is primarily expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B-cells and plasma cells.  CARVYKTI was approved by the U.S. FDA as a fifth-line treatment for adults with R/R MM in February 2022, and was granted conditional marketing authorization as a fourth-line treatment for adults with R/R MM by the European Commission (EC) in May 2022.  The therapy has received Breakthrough Therapy designation in the U.S. and China, and Orphan Drug designation in the U.S., EU, and Japan.
• Scribe Therapeutics, a molecular engineering company based in Alameda, CA, and Sanofi, a multinational healthcare company based in Paris, France, have announced a strategic collaboration to use Scribe’s CRISPR by Design platform technology in Sanofi’s engineered natural killer (NK) cell therapies.  The agreement grants Sanofi a non-exclusive license to Scribe’s CasX-Editor (XE) genome editing technology to create ex vivo NK cell therapies for multiple oncology targets.  In exchange, Scribe will receive $25 million up front, and will be eligible for more than $1 billion in development and commercial milestone payments, as well as tiered royalties on any future sales.
• ArsenalBio, a programmable immune cell therapy company based in South San Francisco, CA, has announced a multi-year collaboration with Genentech (a member of the Roche Group), also based in South San Francisco.  The two companies will combine their capabilities to evaluate effective T cell modifications and identify critical success circuits in T cell-based therapies, then apply those discoveries to the development of future therapeutic candidates. ArsenalBio’s proprietary technology platform combines non-viral genome editing, computational biology, and large-scale genetic screening to reprogram chimeric antigen receptor (CAR)-T cells to overcome cell exhaustion, improve memory, and enable persistence.  Under the agreement, ArsenalBio will receive $70 million up front in additions to research, development, and commercial milestone payments.
• Pfizer, a multinational biotech and pharmaceutical company based in New York, NY, and Sangamo Therapeutics, a cell and gene therapy company based in Brisbane, CA, have announced plans to resume their Phase III study AFFINE evaluating giroctocogene fitelparvovec (PF-07055480) for the treatment of hemophilia A.  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.  Based on that risk, the U.S. FDA initialed a clinical hold to amend the protocol with guidelines to safely manage those elevated factor VIII levels.  The FDA lifted that clinical hold in March, but Pfizer and Sangamo decided to continue with a voluntary hold until now as they finalized study protocols and ensured all necessary study conditions had been met.
• Emercell, an immunotherapy company based in Montpellier, France, and Cell-Easy, an analytics-driven contract development and manufacturing organization (CDMO) based in Toulouse, France, have announced a strategic agreement for the scale-up and manufacturing of NK-001, Emercell’s lead product. Emercell is developing a technology platform based on off-the-shelf natural killer (NK) cells, which can used alone as a monotherapy, in combination with therapeutic antibodies, or genetically engineered to create Chimeric Antigen Receptor (CAR)-NK cell therapies.  NK-001 consists of highly activated and alloreactive allogeneic NK cells derived from compatible pooled umbilical cord blood (UCB), to be used in combination with monoclonal antibodies (MAbs) for the treatment of refractory cancers such as lymphomas.  Emercell hopes to bring NK-001 to the clinic in 2023.
• Verve Therapeutics, a clinical-stage gene editing company based in Cambridge, MA, has announced that its Clinical Trial Authorisation (CTA) application for its lead therapeutic candidate, VERVE-101, has been cleared by the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of heterozygous familial hypercholesterolemia (HeFH).  VERVE-101 is an in vivo gene editing therapy engineered to knock out the PCSK9 gene encoding proprotein convertase subtilisin/kexin type 9, an enzyme involved the transport of cholesterol.  The therapy is comprised of a messenger RNA encoding an adenine base editor licensed from Beam Therapeutics and a guide RNA targeting the PCSK9 gene, packaged in a lipid nanoparticle (LNP) delivery system targeting the liver. A single A-to-G base change in the PCSK9 gene inactivates that gene, which has been shown to up-regulate low-density lipoprotein (LDL) receptor expression, leading to lower serum LDL cholesterol levels and a reduced risk for atherosclerotic cardiovascular disease (ASCVD).
• Cellenkos, a clinical-stage cell therapy company based in Houston, TX, has announced that it has received IND clearance from the U.S. FDA to initiate a Phase I safety study followed by a Phase Ib randomized, double-blind, placebo-controlled trial of CK0803 for the treatment amyotrophic lateral sclerosis (ALS), a fatal neurological disease.  Cellenkos is developing allogeneic T regulatory (Treg) cell therapies for the treatment of inflammatory diseases and autoimmune disorders, and CK0803 is an allogeneic cell therapy product consisting of robust, activated Treg cells that carry neurotropic detection signals which direct them to inflammatory pockets inside the central nervous system.  The therapy is derived from clinical-grade umbilical cord blood units using Cellenkos’ proprietary CRANE process and can be administered by a simple intravenous infusion, without requiring any HLA matching, immune suppression, or lymphodepletion prior to administration.
• Frontera Therapeutics, a clinical-stage gene therapy company based in Bedford, MA, has announced that it has received IND clearance from China’s Center for Drug Evaluation (CDE), National Medical Products Administration (NMPA), to evaluate FT-001, the company’s lead gene therapy candidate for the treatment of a rare genetic retinal disease.  Frontera is developing adeno-associated virus (AAV)-based gene therapies for indications in ophthalmology, hematology, neuromuscular diseases, and metabolic diseases.  FT-001 is an AAV-based gene therapy for the treatment of inherited retinal degenerations (IRDs) caused by a mutation in the RPE65 gene encoding retinoid isomerohydrolase.  The therapy is administered by a one-time injection into the subretinal space of the eye, where it delivers a functional copy of the RPE65 gene to the patient’s retinal cells.  FT-001 was previously granted IND approval from the U.S. FDA in April of this year.
• Avectas, an immune cell engineering company based in Dublin, Ireland, and GenScript Biotech Corporation, a life sciences research tools and services company based in Piscataway, NJ, have announced a partnership to improve non-viral based cell therapy manufacturing technologies.  Avectas is developing SOLUPORE, a patented, non-viral, cell permeabilization technology designed for use with mRNA, DNA, and proteins.  The technology can efficiently delivery cell engineering payloads, including gene editing tools such as CRISPR, to primary T cells and natural killer (NK) cells for immuno-oncology and gene editing applications.  The partnership will combine Avectas’ cell engineering technology platform with GenScript’s synthetic long oligo expertise, to co-deliver Avectas’ GenCRISPR synthetic sgRNA and Cas9 protein ribonucleoprotein (RNP) complexes with its GenExact ssDNA homology-directed repair (HDR) templates to the cell nucleus.
• The Center for Breakthrough Medicines (CBM), a cell and gene therapy contract development and manufacturing organization (CDMO) based in King of Prussia, PA, and jCyte, a clinical-stage cell therapy company based in Newport Beach, CA, have announced a multi-year manufacturing agreement that designates CBM as the primary manufacturer of jCyte’s intravitreal cell therapy, jCell.  Under the agreement, CBM will provide supplies for Phase III clinical studies of jCell, as well as commercial drug product following FDA approval the therapy. Administered by a minimally invasive intravitreal injection, jCell is designed to treat degenerative retinal disorders by providing sustained release of neurotrophic factors that have been shown to reduce photoreceptor cell death and improve the function of surviving photoreceptor cells. The therapy has received Regenerative Medicine Advanced Therapy (RMAT) designation from the U.S. FDA, and is currently in late-stage clinical development for the treatment of retinitis pigmentosa (RP).