Novartis Reported Two Deaths Following Zolgensma Gene Therapy

Two patients who received Zolgensma, Novartis’s gene therapy to treat spinal muscular atrophy(SMA), reported death due to liver complications. The deaths occurred in Russia and Kazakhstan.

Both of the patients developed acute liver failure between five and six weeks after infusion with the gene therapy and one to 10 days after tapered doses of steroid. Although the acute liver injury is a known risk of Zolgensma, there have been no fatalities before. 

Related article: 10 Top Gene Therapy Companies in 2021

What is SMA and Could It be Cured?

SMA is a rare, inherited genetic defect that makes the muscle weaker and causes problems with movement. The most severe form of SMA usually occurs in babies and often causes death before the age of two.

A person with SMA inherits two copies of a missing or faulty (mutated) survival motor neuron 1 (SMN1) gene, while an adult who has a single copy of the defective gene is known as a carrier. Carriers do not develop SMA, however, there is a 1 in 4 chance that two carriers will have a child with SMA.

A healthy SMN1 gene produces SMN protein, which is essential for motor neurons to survive and function properly. People with SMA do not make enough SMN protein, and so the motor neurons shrink and die. As a result, the brain loses control of voluntary movements, especially motion in the head, neck, arms, and legs. 

There is no cure for SMA except for supportive therapy. The two currently available treatments including disease-modifying therapy and gene-replacement therapy, such as Zolgensma, target different age groups.

Zolgensma’s Mechanism and Risk of Liver Failure

Zolgensma is a one-time gene therapy that uses an adeno-associated viral (AAV) vector to deliver a copy of the functional SMN gene that replaces the missing or faulty SMN1 gene. 

Transduction and subsequent expression of the AAV vector in fixed tissue macrophages in the liver, known as Kupffer cells, can elicit an immune response and effectively eliminate the therapeutic effect by developing antibodies to the capsid through a cytotoxic T-cell-mediated mechanism. Once a certain threshold of capsid antigen load has been reached, activation of capsid-specific T cells may result in hepatotoxicity.

As in the case of Zolgensma, the risk of liver injury is mentioned on the FDA’s product labeling, which means liver function assessment is a must before infusing Zolgensma and regular steroids administration before and after to manage increases in liver enzyme counts.

Nevertheless, the two deaths reported by Novartis could further raise discussion of gene therapy safety, as well as the evaluation of the balance between benefits and risks of treatment.

Author

Nai Ye Yeat