Gene therapy is part of a new wave of medicine that approaches disease treatment by addressing the root causes rather than focusing on treating or reducing symptoms. Currently, gene therapies are being developed for treatment of inherited diseases, autoimmune diseases, cancer, and infectious diseases. In July 2023, we posted about a series of FDA approvals in the first half of 2023 of several first-in-class gene- and cell-therapies for various rare inherited diseases. These therapies included a topical gene therapy for treatment of wounds in patients with dystrophic epidermolysis bullosa (DEB), VyjuvekTM, granted to Pittsburgh, Pennsylvania-based Krystal Biotech, Inc; a gene therapy treatment for Duchenne Muscular Dystrophy (DMD), ElevidysTM (delandistrogene moxeparvovec-rokl), developed by Cambridge, Massachusetts-based Sarepta Therapeutics (“Sarepta”); a therapy treatment for adults with severe hemophilia A, RoctavianTM, developed by San Rafael, California-based BioMarin; and upcoming CRISPR-based ex vivo cell therapy exagamglogene autotemcel (exa-cel) being co-developed by Vertex Pharmaceuticals and CRISPR Therapeutics, with target action dates on December 8, 2023 and March 30, 2024. In this post, we provide updates on new advances in gene therapies in Q3 and early Q4 of 2023.

On October 18, 2023, the FDA cleared the Investigational New Drug (IND) application for NTLA-2001, the first in vivo CRISPR-based genetherapy treatment for transthyretin (ATTR) amyloidosis with cardiomyopathy. NTLA-2001 was developed by Intellia Therapeutics, Inc. (“Intellia”) in collaboration with Regeneron Pharmaceuticals (“Regeneron”). ATTR amyloidosis is a rare inherited disease caused by mutations in the TTR gene, which causes the liver to produce misfolded transthyretin (TTR) proteins. The structurally abnormal TTR proteins build up in the body and damages multiple tissues, including the heart, nerves, and digestive system, progressively leading to nerve damage or heart failure. NTLA-2001 is a single-dose treatment for ATTR amyloidosis that uses lipid nanoparticles (LNPs) to deliver a guide RNA to target the DNA editing Cas9 enzyme to the disease-causing gene and a mRNA encoding the Cas9 enzyme. The treatment involves producing the Cas9 enzyme using the patient’s cells’ own machinery, followed by precision editing by inactivating the target disease causing gene. Intellia plans to initiate a pivotal Phase 3 trial in the United States for NTLA-2001 by year-end 2023.

This clearance comes on the heels of another regulatory success for Intellia as another one of its CRISPR-based gene therapy candidates, NTLA-2002 for hereditary angioedema (HAE), received Priority Medicines (PRIME) Designation from the European Medicines Agency (EMA). PRIME Designation is granted for drug candidates that either offer therapeutic advantage over existing treatments or offer therapies to patients without treatment options. In 2022, NTLA-2002 also received Orphan Drug Designation, which is granted by the FDA to drugs intended for the treatment, diagnosis, or prevention of rare diseases that affect fewer than 200,000 people in the U.S.

On October 31, 2013, an advisory committee provided independent expert advice to the FDA regarding potential off-target effects from Vertex Pharmaceuticals and CRISPR Therapeutics’ CRISPR-based gene therapy exa-cel, which we previously discussed. Exa-cel is poised to become the first FDA approved CRISPR-based gene therapy and has been co-developed by Vertex Pharmaceuticals and CRISPR Therapeutics for the treatment of sickle cell disease (SCD) and beta thalassemia. The meeting focused on safety concerns due to potential off-target edits. Vertex Pharmaceuticals and CRISPR Therapeutics used in silico and cellular analysis methods to identify likely off-target sites in human genomic DNA. The in silico testing used algorithms and sequence homology to nominate potential off-target loci and perform confirmatory testing using hybrid capture sequencing. Cellular analysis was performed by treating human donor cells with exa-cel and using GUIDE-seq and hybrid capture sequencing to identify off-target editing in healthy donor cells. The FDA concluded that the analysis was sufficiently detailed and demonstrated the safety of exa-cel, but required Vertex Pharmaceuticals and CRISPR Therapeutics to continue monitoring long-term safety. The FDA is set to release its decision on exa-cel for SCD by December 8, 2023.

Also in the SCD space, Editas Medicine, Inc. (“Editas”) received Regenerative Medicine Advanced Therapy (RMAT) designation from the FDA for its gene editing medicine, EDIT-301, on October 16, 2023. The RMAT designation is granted to promising regenerative medicine therapies to expedite development and review of treatments or cures for serious or life-threatening diseases or conditions. The FDA previously granted Orphan Drug Designation and Rare Pediatric Disease designation to EDIT-301 for both SCD and beta thalassemia.

On October 30, 2023, Sarepta Therapeutics, Inc. (Sarepta) announced results from EMBARK, a phase 3 study designed as a confirmatory study for its existing indication and to support an expansion of the approval of ELEVIDYS. As discussed in our previous article, ELEVIDYS was granted accelerated approval in June 2023 for pediatric patients from four through five years of age suffering from Duchenne Muscular Dystrophy (DMD). The results failed to meet the study’s primary endpoint as the primary measure of motor function used in the study did not show statistically significant results compared to patients treated with a placebo. However, some secondary measures, including the quantity of shortened dystrophin produced by ELEVIDYS, timed function tests, stride velocity, and validated patient reported outcome measures, did show statistically significant benefit for patients treated with ELEVIDYS compared to patients treated using a placebo in patients ages 4 to 5 and ages 6 to 7. Sarepta is also conducting another phase 3 study, testing ELEVIDYS in older patients with DMD.

On October 20, 2023, the FDA approved the BioMarin Pharmaceutical Inc. (“Biomarin”) supplemental New Drug Application (sNDA) for VOXZOGO® (vosoritide) to expand its indication, which was originally approved in 2021, for children of all ages with achondroplasia. This approval was based on a phase 2 clinical trial in children at or under 5 years of age, which showed positive results and a consistent safety profile as in older patients. Additionally, VOXZOGO® has also received Orphan Drug Designation in the U.S. for the treatment of hypochondroplasia. Hypochondroplasia is a genetic disorder caused by a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene that causes a form of short-limbed dwarfism, which presents a milder form of impaired bone growth compared to achondroplasia.

BioMarin also has several other first-in-class gene therapy candidates in its pipeline, including BMN 365 for treatment of plakophilin-2 mutations and arrhythmogenic right ventricular dysplasia/cardiomyopathy; and BMN 293 for treatment of myosin binding protein C3 hypertrophic cardiomyopathy.

Due to advances in the genetic engineering field and a number of recent successes, an increasing number of gene therapies have received approvals or passed significant regulatory milestones in 2023. Gene therapies, particularly for treatment of rare inherited diseases, are poised to continue its strong year of regulatory approvals with the FDA decision for exa-cel scheduled for December 8. Furthermore, 2024 is also set to be a strong year for first-in-class gene therapies as the FDA is scheduled to review exa-cel’s second indication for beta thalassemia and Orchard Therapeutics’ Biologics License Application (BLA) for OTL-200 in the Spring. There are already several key players developing multiple gene therapies in this space, and additionally, several large pharmaceutical companies are entering the gene therapy space by collaborating with, or acquiring rights to, promising gene therapy projects. For example, Eli Lilly and Company (“Lilly”) recently announced that it will acquire Beam Therapeutics Inc.’s opt-in rights to Verve Therapeutics’ gene therapies for certain cardiovascular diseases, including for PCSK9, ANGPTL3, and an undisclosed cardiovascular target. We will continue to monitor updates in this area and provide updates as they become available.