The gene therapy for Duchenne muscular dystrophy (DMD) from Roche in Switzerland, which was the first in the world to receive approval, has raised safety concerns again after it resulted in fatalities. The cause was identified as liver toxicity, similar to the gene therapy that Pfizer abandoned. Amidst the collapse of gene therapies from global corporations, a stem cell treatment from a domestic corporation that has entered Phase 2 of clinical trials has emerged as an alternative.
Roche and U.S.-based Sarepta Therapeutics announced on the 15th (local time) that two patients with walking difficulties died from acute liver failure in the ongoing confirmatory clinical trial of Elevidys, which involves over 900 patients worldwide.
The company has immediately suspended the clinical trial and plans to resubmit a clinical plan to the U.S. Food and Drug Administration (FDA) that includes the addition of immunosuppressants to reduce the risk of liver toxicity. Roche had previously received approval for the confirmatory clinical trial on the condition that it proves the efficacy of Elevidys in follow-up studies.
Duchenne muscular dystrophy (DMD) is a rare genetic disease where muscles throughout the body gradually degenerate, affecting the arms, legs, and torso. It occurs due to a mutation in the gene on the X chromosome, which produces the dystrophin protein that helps maintain muscle cells. Symptoms typically begin between the ages of 2 and 5, and most patients are unable to walk and must use wheelchairs by around 10 years old.
Muscle weakness affects the heart and respiratory system, leading to death for most by their 20s. There are an estimated 300,000 pediatric and adolescent patients worldwide. Existing treatments for DMD have only involved the use of steroids to reduce inflammation and slow the progression of the disease.
Elevidys, co-developed by Sarepta and Roche, delivers a normal dystrophin gene to the patient's muscle cells using a harmless adeno-associated virus (AAV). In Phase 2 results, expression of the dystrophin gene was observed in patients' skeletal muscles, making Elevidys a promising treatment that addresses the underlying genetic cause of DMD.
The FDA conditionally approved Elevidys in 2023 as a treatment for DMD in patients over 4 who can walk, based solely on Phase 2 results. Subsequently, in June of last year, it expanded approval for use in other ambulatory patients. However, it stipulated the need for confirmatory clinical trials to verify efficacy and safety before using it on urgent cases. A mortality incident occurred during this latest confirmatory trial.
Experts have identified the AAV virus used for gene delivery as the cause of death. AAV causes little to no immune response when entering the human body, making it commonly used as a gene delivery vector. However, there are safety concerns as the virus may induce an excessive immune response in liver cells.
When immune cells recognize the viral vector or therapeutic gene as an external invader and attack, it can cause inflammation in the liver, potentially leading to acute liver failure in severe cases. In fact, Pfizer also halted a clinical trial for its DMD gene therapy due to liver toxicity issues that arose during development and significantly reduced its research workforce in this area.
As global pharmaceutical companies face safety issues with gene therapies, alternative cell therapies being developed domestically are gaining attention. ENCell is developing a stem cell-based treatment called 'EN001' instead of a virus vector-based gene therapy. Stem cells are undifferentiated cells that have the potential to grow into any cell type in the body.
The ENCell treatment does not correct the genetic defect itself like Elevidys does. Instead, it works by allowing stem cells to grow into muscle cells, reducing muscle loss and promoting muscle tissue regeneration. In a clinical Phase 1 trial conducted domestically from January to December 2022, safety and tolerability were confirmed through intravenous injection in six DMD patients, and preparations for Phase 2 are currently underway. If efficacy is proven in Phase 2 without significant issues, conditional approval may also be pursued.
According to ENCell, the risk of liver toxicity for the stem cell treatment EN001 is lower compared to AAV gene therapy. Although there is a risk of immune rejection since the stem cells may come from another individual, the company explains that mesenchymal stem cells, in particular, exhibit relatively low rates of immune rejection.
A representative from ENCell stated, 'EN001 has already been validated for safety in Phase 1, and due to the characteristics of mesenchymal stem cell mechanisms, it is comparatively free from liver toxicity and immune rejection.' They added, 'We plan to focus on proving safety and therapeutic effects in Phase 2.'