Warning of TMA, Rare Blood Disorder, Added to Zolgensma’s Safety Label

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by Marta Figueiredo PhD |

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Novartis Gene Therapies has added thrombotic microangiopathy (TMA) — a rare condition characterized by blood abnormalities — to the list of safety concerns with use of Zolgensma in children with spinal muscular atrophy (SMA).

This decision was driven by reports of six confirmed cases of TMA within one to two weeks of the gene therapy’s single dose being given to children, 4 months to 4.5 years old, between October 2019 and February 2021, a company community announcement stated. Three of these cases were described in a case report study published in November 2020.

All children with this serious complication were given supportive or specific treatment, and all these cases were resolved.

“We continue to monitor product safety, including long-term safety follow-up studies in patients treated with [Zolgensma],” Novartis Gene Therapies, formerly known as AveXis, stated. The therapy’s benefit-risk profile “remains favorable and reported adverse events are monitorable and manageable.”

Administered directly into the bloodstream at a dose proportional to a patient’s body weight, Zolgensma is available to SMA patients up to age 2 in the U.S., and to babies and young children up to 21 kg (about 46 lbs) in the European Union and Canada.

It uses a modified and harmless virus to deliver a working copy of SMN1, the mutated gene in SMA, to cells. Due to the body’s natural immune reaction against the carrier virus, the therapy can only be given once.

Notably, the single dose may still promote an immune response, which can increase the levels of liver enzymes — an indicator of liver damage — and drop those of platelets, tiny blood cells responsible for blood clotting.

For that reason, an immunosuppressive regimen should be started on the day before treatment, with liver health and platelet counts monitored prior to treatment, and at regular periods thereafter.

TMA, a rare disorder, is characterized by the destruction of red blood cells (hemolytic anemia), low platelet counts (thrombocytopenia), and the formation of blood clots in small blood vessels that can injure the kidneys.

While its cause can be genetic, TMA is also associated with the use of some medications, including vaccines, immunosuppressive treatments, and antibiotics, as well as some herbal supplements. Treatment-induced TMA is thought to result from immune-mediated reactions, or a dose- or duration-dependent direct toxic effect.

As such, Novartis Gene Therapies noted that immune activators, such as vaccines and infections, should be avoided or minimized close to Zolgensma’s use.

The condition can resolve with timely and proper treatment, and early detection is key.

Parents and caregivers are recommended to seek urgent medical care if a child shows any signs or symptoms of TMA, such as unexpected bruising or bleeding, high blood pressure, seizures, or a drop in urination after receiving Zolgensma. Symptoms of illness, such as fever or vomiting, should also prompt medical attention.

If thrombocytopenia is found in regular platelet lab tests, which are recommended, further tests for hemolytic anemia and kidney health should be undertaken.

The company noted that the frequency of TMA in children with SMA, as well as the existence of predisposing factors, is not currently known.

Novartis Gene Therapies proposed adding TMA to the therapy’s prescribing information in all countries where it has been approved. Updated warning labels are in place in several of them, including the U.S. and those of the European Union.

The company is also directly informing healthcare professionals of this update and the need to be aware of TMA risk.

More than 1,000 children have been treated with Zolgensma worldwide across clinical trials, managed access programs — through which patients can access a therapy before its approval — and in commercial settings since January 2021, Novartis Gene Therapies reported.