10 Recent Developments in Cell and Gene Therapy

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. Intellia Therapeutics, based in Cambridge, MA, has acquired Berkeley, CA-based Rewrite Therapeutics, a private biotech company specializing in developing novel genome editing technologies. Rewrite’s Rewriter platform utilizes CRISPR-guided DNA polymerases capable of making targeted corrections, insertions, deletions, and the full range of single-nucleotide changes in the genomes of both dividing and non-dividing cells, without making double-stranded breaks.  The technology can be administered with adeno-associated viral (AAV) vector and lipid nanoparticle (LNP) delivery systems.  As part of the acquisition deal, Intellia will pay Rewrite shareholders $45 million up front, with an additional $155 million in milestone payments as a mix of Intellia common stock and cash.
2. Orchard Therapeutics, based in London, UK, has announced an agreement with the National Health Service (NHS) that enables access to Libmeldy (atidarsagene autotemcel) for all children with metachromatic leukodystrophy (MLD) in England and Wales who fall within the scope of the European marketing authorization. MLD is rare genetic disorder caused by defective copies of the ARSA gene encoding the enzyme arylsulfatase A.  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 consists of 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 the ARSA gene encoding the human arylsulfatase-A enzyme.  The therapy is the first lentiviral hematopoietic stem cell treatment to be approved for reimbursement by England’s NHS.
3. CRISPR Therapeutics, based in Zug, Switzerland, and ViaCyte, based in San Diego, CA, have announced the first patient has been dosed in their Phase I clinical trial of VCTX210 for the treatment of type 1 diabetes (T1D). VCTX210 is an allogeneic, gene-edited, stem cell-derived product designed as a functional replacement for insulin-producing beta cells and other blood glucose-regulating islet cells of the pancreas. Immune-modulatory genes within the cell line have been specifically engineered to avoid destruction by the host’s immune system using CRISPR’s CRISPR/Cas9 ex vivo editing platform.  (See Cell and Gene Therapy Business Outlook 1, issue 11, p. 18 for more on CRISPR Therapeutics and ViaCyte’s clinical trial for the treatment of T1D.)
4. LogicBio Therapeutics, based in Lexington, MA, has announced that the FDA has placed a clinical hold on its Phase I/II clinical trial of LB-001, its single-dose, adeno-associated virus (AAV) genome editing therapy for the treatment of pediatric patients with methylmalonic acidemia (MMA). Four patients have been dosed so far, and the first two patients, both in the 3 to 12 years old group, are doing well and have not experienced serious adverse events (SAEs) related to the therapy.  The third patient, who was in the 6 months to 2 years old age group, experienced a drug-related SAE in the form a blood clotting disorder, thrombotic microangiopathy (TMA), which has been previously associated with AAV therapies.  That patient responded well to treatment and the SAE eventually resolved.  LogicBio implemented additional safety measures in the trial, however in January the fourth patient dosed, also in the younger age group, experienced an SAE in the form of TMA.  That patient has been steadily improving, and for the present the trial remains on clinical hold.
5. NexImmune, a clinical-stage biotech company based in Gaithersburg, MD, has announced a collaboration with Rutgers University, The State University of New Jersey. NexImmune’s proprietary Artificial Immune Modulation (AIM) platform uses engineered nanoparticles that function as “synthetic dendritic cells” and are able to direct specific immune responses by delivering signaling proteins to T cells, much like natural dendritic cells do in a healthy immune system. The collaboration with Rutgers will focus on targeting immune checkpoint proteins for indications in neuroendocrine tumors and other cancers.
6. Oxford Biomedica, based in Oxford, UK, has announced that Sio Gene Therapies, based in New York, NY, intends to cease work on AXO-Lenti-PD (formerly OXB-102) and return the therapy’s global rights to Oxford. AXO-Lenti-PD is an investigational gene therapy for the Parkinson’s disease that utilizes a lentiviral vector to deliver three genes required for dopamine synthesis:  TH, encoding tyrosine hydroxylase; GCH1, encoding GTP cyclohydrolase 1; and DDC, encoding aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase.  The therapy is currently being evaluated in a Phase II clinical study with six patients already dosed, and strong improvement observed in two evaluable patients at a six-month followup.  Oxford plans to out-license AXO-Lenti-PD again rather than to invest in its further development.
7. Bristol Myers Squibb, based in New York, NY, has announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approval of Breyanzi (lisocabtagene maraleucel) for the treatment of adults with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma grade 3B (FL3B) after two or more lines of systemic therapy. Breyanzi is a chimeric antigen receptor T cell (CAR-T) therapy targeting CD19, a protein ubiquitously expressed on the surface of human B cells.  The European Commission (EC) will review the CHMP recommendation and render a final approval decision within 67 days.  Breyanzi is approved by the U.S. FDA for the treatment of adults with R/R large B-cell lymphoma after two or more lines of systemic therapy, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, and has been approved in Japan for third-line plus R/R LBCL and follicular lymphoma.
8. Excision BioTherapeutics, a clinical-stage biotech company based in San Francisco, CA, has announced the initiation of a Phase I/II clinical trial of EBT-101 in individuals living with human immunodeficiency virus type 1 (HIV). Excision is developing CRISPR-based therapies to cure chronic viral infectious diseases, and EBT-101 is a potentially curative therapy for HIV.  The therapy utilizes an adeno-associated virus (AAV) to deliver CRISPR-Cas9 and dual guide RNAs targeting three sites within the HIV genome in order to excise large portions of HIV proviral DNA in vivo.  (See Cell and Gene Therapy Business Outlook 1, issue 7, p. 15 for more on EBT-101 and the rest of Excision BioTherapeutics’ pipeline.)
9. FUJIFILM Corporation, based in Tokyo, Japan, has announced that it will acquire a 90,000-square-foot cell therapy manufacturing facility in Thousand Oaks from Atara Biotherapeutics for $100 million. FUJIFILM Diosynth Biotechnologies, a contract development and manufacturing organization (CDMO) subsidiary of FUJIFILM, will run the new facility, and plans to offer approximately 140 current highly-skilled manufacturing positions and quality staff at the site. FUJIFILM says the site is readily expandable and will be able produce cell therapies at both clinical and commercial scale, including allogeneic T-cell and CAR T immunotherapies. FUJIFILM Diosynth and Atara will also sign a long-term manufacturing and services agreement to support the Atara’s clinical pipeline, including tabelecleucel for the treatment of Epstein-Barr virus positive post-transplant lymphoproliferative disease (EBV⁺PTLD).  FUJIFILM is strongly invested in expanding its cell therapy manufacturing capabilities. The West Coast campus will join FUJIFILM Diosynth’s existing facilities in College Station, TX, Research Triangle Park, NC, Billingham, UK, and Hillerød, Denmark, with new facilities under construction in Holly Springs, NC, and Watertown, MA, as well as plans to substantially expand the Denmark and UK facilities.
10. Nanoscope Therapeutics, a clinical-stage optogenetic biotech company based in Bedford, TX, has announced it has received IND clearance from the FDA to begin a Phase II study evaluating its Multi-Characteristic Opsin (MCO-010) ambient-light activatable optogenetic monotherapy for the treatment of Stargardt disease, an inherited form of macular degeneration. MCO-010 uses a proprietary adeno-associated virus, serotype 2 (AAV2) vector, delivered by a single intravitreal injection, to transduce retinal bipolar cells to express a gene encoding multi-characteristic opsin (MCO) on their surfaces, effectively transforming them into functional photoreceptor cells.  Since the therapy bypasses the diseased photoreceptor cells entirely, it is “gene-agnostic” and potentially capable of treating multiple vision indications, regardless of underlying gene mutations.  Nanoscope is currently evaluating MCO-010 in a Phase IIb study for the treatment of retinitis pigmentosa (RP), and expects to begin the Phase II Stargardt study in the first half of 2022.