After decades of intense scientific research into developing gene editing technologies, and more than a few setbacks, the field has produced a number of success stories in recent years, demonstrating that regulatory agencies are increasingly likely to accept safety, efficacy, and durability data to approve such therapies. These advances have culminated in a series of FDA approvals in 2023, each a first gene therapy for various rare diseases.

On May 19, 2023, the FDA approved the first topical gene therapy for treatment of wounds in patients with dystrophic epidermolysis bullosa (DEB), VyjuvekTM, granted to Pittsburgh, Pennsylvania-based Krystal Biotech, Inc. DEB is a rare and serious disease that affects the skin and mucosal tissues caused by one or more mutations in the COL7A1 gene. The COL7A1 gene is responsible for the production of functional COL7 protein that forms anchoring fibrils necessary to bind the dermis (inner layer of the skin) to the epidermis (outer layer of the skin). The lack of functional anchoring fibrils in DEB patients leads to extremely fragile skin that blisters and tears with minor friction or trauma. DEB patients suffer from open wounds, which lead to recurrent skin infections and fibrosis that can cause fusion of fingers and toes, and ultimately increase the risk of developing an aggressive form of skin cancer. VyjuvekTM is a genetically modified (engineered in a laboratory) herpes-simplex virus used to deliver normal copies of the COL7A1 gene to the wounds. COL7 molecules arrange themselves into long, thin bundles that form anchoring fibrils that hold the epidermis (skin) and dermis together, which is essential for maintaining the integrity of the skin. VyjuvekTM has also been modified to eliminate its ability to replicate in normal cells. This application received Orphan Drug and Fast Track designations. VyjuvekTM also received Regenerative Medicine Advanced Therapy and Priority Review designations and a Rare Pediatric Disease Priority Review Voucher. VyjuvekTM is the first-ever redosable gene therapy and the first and only medicine approved by the FDA for the treatment of DEB, both recessive and dominant, that can be administered by a healthcare professional in either a healthcare professional setting or in the home. VyjuvekTM is expected to be available in the United States in the third quarter of 2023.  Outside of the U.S., the European Medicines Agency (EMA) has granted VyjuvekTM orphan drug designation and PRIME (PRIority MEdicines) eligibility for the treatment of DEB. VyjuvekTM is estimated to cost $631,000 per patient per year.

On June 22, 2023, the FDA approved the first gene therapy treatment for Duchenne Muscular Dystrophy (DMD), ElevidysTM (delandistrogene moxeparvovec-rokl), developed by Cambridge, Massachusetts-based Sarepta Therapeutics (“Sarepta”). ElevidysTM is a one-time treatment for pediatric patients four through five years of age with a confirmed mutation in the DMD gene. Loss of function of the DMD gene means that the patient’s body cannot make properly functioning dystrophin, which leads to progressive loss of muscle. The therapy works by directly delivering a gene that codes for ElevidysTM micro-dystrophin, a functional shortened dystrophin protein compared to the dystrophin protein of normal muscle cells. The ElevidysTM micro-dystrophin contains selected domains of the dystrophin protein present in normal muscle cells that is predicted to benefit patients with DMD within the approved age range who do not have pre-existing antibody titers against the AAV rh74 vector or other contraindications by slowing or stopping progression of the disease.

ElevidysTM was granted accelerated approval, which means that the company still has to complete a confirmatory trial to evaluate the clinical benefits and safety issues associated with this therapy. Sarepta has fully enrolled a global phase 3 trial and expects results in late 2023.

The Cellular, Tissue, and Gene Therapies Advisory Committee (“the Committee”) voted 8 to 6 to approve ElevidysTM for accelerated approval. The FDA was concerned that Sarepta’s manufacturing of the drug changed between the second and third clinical trials with the new process using a lower percentage of full capsid. The FDA was concerned that this change will reduce efficacy. Furthermore, reviewing the results of the clinical study, the FDA decided that the data only supported approving this therapy for individuals between four to five years of age, as a change in underlying disease pathology occurs at approximately age six and the FDA did not believe that the clinical data supported approving this therapy for six to seven year-old patients. However, the FDA decided that the clinical data, compelling patient and family testimony citing clinical improvement following the administration of the drug during clinical trials, and positive safety data were sufficient to approve this therapy for four to six year-old patients.  ElevidysTM is estimated to cost $3.2 million per patient. On June 20, 2023, RegenxBio and University of Pennsylvania (“UPenn”) filed a second complaint for patent infringement against Sarepta based on U.S. Pat. No. 11,680,274 that covers adeno-associated virus (AAV) gene therapy technology. A separate patent infringement action previously brought by RegenxBio and UPenn against Sarepta is pending, arising from Sarepta’s manufacture and use of cultured host cell technology covered by another UPenn patent, U.S. Patent No. 10,526,617.

On June 29, 2023, the FDA approved the first gene therapy treatment for adults with severe hemophilia A, RoctavianTM, developed by San Rafael, California-based BioMarin. The one-time, single-dose infusion is the first approved gene therapy for severe hemophilia A in the U.S. ROCTAVIAN was first approved by the EMA in August 2022.  Hemophilia A is a lifelong, genetic condition caused by a mutation in the gene responsible for producing a protein called FVIII, which is necessary for blood clotting. When severely deficient in amount, the condition puts people with hemophilia A at risk for painful and potentially life-threatening bleeds, which can occur spontaneously. With the current standard of care, individuals undergo lifelong preventative therapy, receiving infusions or injections at burdensome routine intervals to maintain enough clotting factor in the bloodstream to prevent bleeds. ROCTAVIAN is designed to replace the function of the mutated gene, allowing people with severe hemophilia A to produce their own FVIII and thereby limit bleeding episodes.

“Today’s approval of ROCTAVIAN builds on BioMarin’s proven track record of advancing treatments that target the underlying cause of life-threatening genetic conditions, which has produced eight best- or first-in-class commercial therapies,” said Jean-Jacques Bienaimé, chairman and chief executive officer of BioMarin. “We are proud to now offer adults with severe hemophilia A, a one-time, single-dose treatment option. We are especially grateful to the bleeding disorders community for its support of this program, and to all the patients and healthcare providers who participated in our clinical trials.”

Of the 134 patients who received ROCTAVIAN in the study, 112 patients had baseline annualized bleeding rate (ABR) data prospectively collected during a period of at least six months on FVIII prophylaxis prior to receiving ROCTAVIAN. The remaining 22 patients had baseline ABR collected retrospectively. All patients were followed for at least three years. Results from the three-year analysis of the Phase 3 GENEr8-1 study showed that study participants had an 82.9% reduction in treated bleeds overall compared with baseline. ROCTAVIAN is estimated to cost $2.9 million per patient.

These approvals come on the heels of the highly anticipated first FDA approval of 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. Exa-cel is an investigational, autologous, ex vivo CRISPR/Cas9 gene-edited therapy that is being evaluated for patients with SCD or TDT, in which a patient’s own hematopoietic stem cells are edited to produce high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is the form of the oxygen-carrying hemoglobin that is naturally present during fetal development, which then switches to the adult form of hemoglobin after birth. The elevation of HbF by exa-cel has the potential to reduce or eliminate painful and debilitating VOCs for patients with SCD and alleviate transfusion requirements for patients with TDT. In the U.S., exa-cel has been granted Regenerative Medicine Advanced Therapy (RMAT), Fast Track, Orphan Drug, and Rare Pediatric Disease designations from the FDA for both TDT and SCD. In Europe, the Marketing Authorization Applications (MAAs) for exa-cel were submitted in December 2022 and validated by the EMA and the Medicines and Healthcare products Regulatory Agency (MHRA) in January 2023.

Gene therapy treatments are part of a new wave of therapies based on developments in the genetic engineering field, with the first gene therapy approved by the FDA as recently as 2018. They represent a radical shift in approaching disease treatment by addressing the root causes of diseases rather than focusing on treating the symptoms of the disease. Furthermore, they have the ability to transform the quality of life of patients with inherited diseases that previously had no hope of cure or even significant clinical improvement. Gene therapies are also being developed for treatment of autoimmune diseases, cancer, and infectious diseases. We will continue to monitor updates in this area and provide updates as they become available.