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Recipients of certain adeno-associated virus (AAV) vector-based gene therapies should be monitored closely for signs of thrombotic microangiopathy (TMA), FDA advisors agreed.

"Frequent laboratory assessments are necessary," said Barry Byrne, MD, PhD, of the University of Florida in Gainesville, based on his observations that patients on onasemnogene abeparvovec (Zolgensma) tend to first show IgM presence in sera -- IgM being an activator of the immune system's classical complement pathway -- and a positive D-dimer test before progressing to clinical TMA findings.

Byrne spoke before the FDA as a temporary voting member of the Cellular, Tissue, and Gene Therapy Advisory Committee (CTGTAC).

TMA is a rare condition, either genetic or acquired, involving endothelial injury in small vessels and blood clots. Initial presentation of TMA can include fever, vomiting, hypertension, decreased urine output, and acute kidney injury. Although activation of the classical complement pathway plays a role, the pathogenesis of TMA following AAV9 vector administration remains unclear and there are no known preventative measures.

"Hence, early clinical detection of TMA is really key, and that should be based on the recognition of signs and symptoms of TMA," said Deepa Chand, MD, executive director of patient safety for Novartis Gene Therapies in Bannockburn, Illinois, during the virtual CTGTAC meeting.

Chand shared that nine cases of TMA have been identified from more than 1,400 patients with spinal muscular atrophy who were dosed with Novartis's AAV9-based Zolgensma. TMA typically occurred within 7 to 9 days from dosing in these nine children, all girls, varying in age from 4 months to 4 years.

Separately, four out of 15 patients developed TMA during clinical development of two AAV9-based candidate therapies for Duchenne muscular dystrophy (DMD), Chand reported. TMA onset occurred within 2 weeks in these four patients, who were boys ages 7 to 12 years.

During the open public hearing of the CTGTAC session, Dan Levy, MD, PhD, the DMD gene therapy team lead for Pfizer in Collegeville, Pennsylvania, reported that three out of 21 people developed TMA in a phase Ib study of another AAV9-based candidate gene therapy for DMD.

Chand and Levy both noted that TMA cases were often treated with supportive management and the anti-complement drug eculizumab (Soliris). Most patients are now recovered or improving following treatment.

"Therapy must be individualized based on the clinical presentation and course," Chand said. "As with any therapy, individual patient benefit-risk should be considered."

Notably, B-cell depleting therapy can be used to prevent complement activation, but should be paired with rapamycin therapy to dampen the immune system when the B cells eventually recover, suggested CTGTAC panelist Roland Herzog, PhD, of Indiana University School of Medicine in Indianapolis.

Gene therapy-associated TMA had emerged as a risk during postmarketing surveillance of Zolgensma, the only FDA-approved systemically administered AAV9-based gene therapy. The product's package insert currently warns of TMA in the safety information, but monitoring and mitigation strategies should be detailed in product labeling, Chand urged.

Research considerations also call for a need for biomarker evaluation to probe the specific ways that endothelial injury and complement pathway aberrancies contribute to TMA, she said.

Byrne acknowledged the limited experience with TMA outside AAV9-based products, contrasting them with the AAV5- and AAV8-based hemophilia therapies that are given at much lower doses because they are targeted to the liver.

Additionally, although the frequency of TMA is related to capsid exposure, it's not currently possible to reduce the ratio of empty capsids versus vector-carrying capsids and maintain the amount of gene therapy delivered in a product like Zolgensma, he noted.

"Yes, less is better," but "that's the challenge we face in the field," he said.

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