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Gene therapy at the crossroads

2022; Nature Portfolio; Volume: 40; Issue: 5 Linguagem: Inglês

10.1038/s41587-022-01346-7

1546-1696

Biotechnology and Related Fields

Gene therapy at the crossroadsTwo upcoming regulatory decisions represent a tipping point for commercial gene therapy, with implications for work on existing viral vectors and the pursuit of new ones. Next month, the US Food and Drug Administration (FDA) will convene an advisory panel meeting to review two lentiviral gene therapies: Zynteglo (betibeglogene autotemcel) for β-thalassemia in patients requiring regular blood transfusions and Lenti-D (elivaldogene autotemcel) for patients with cerebral adrenoleukodystrophy.Much rests on the outcome.If these treatments fail, bluebird bio, a gene therapy flagship, will likely fail.Following a recent raft of problems for both lentiviral and adeno-associated viral (AAV) gene therapies, the sector needs a winone that can provide continued industry momentum to invest in optimizing existing vector platforms and also spur research into new viruses that fill therapeutic niches currently out of reach.For several years, gene therapy has been flying high, with 11 FDA approvals, including February's for Carvykti (ciltacabtagene autoleucel).After decades of research and thousands of human trials, the field finally attained commercial recognition, with a succession of stratospheric acquisitions by big pharma: Bamboo Therapeutics, AveXis, Spark Therapeutics, Nightstar Therapeutics, Audentes Therapeutics, Asklepios BioPharmaceutical, Juno Therapeutics and Kite Pharma brought asking prices that together totaled $41 billion.Recently, however, a litany of setbacks has brought the field back to earth.An analysis from last year reported that, on average, 35% of 149 AAV gene therapy clinical trials were associated with treatment-emergent serious adverse events.This February, analysts at Jeffries attributed 40% of all clinical holds in 2021 to cell and gene therapies (although a portion of these related to manufacturing or quality issues rather than toxicity).Last September, adverse events associated with AAV treatments were frequent enough to warrant a special FDA panel.The year before, the agency suspended a phase 1/2 trial of Audentes Therapeutics' AAV-8 encoding MTM1 after two of three pediatric patients receiving a high dose experienced severe hepatotoxicity and died.Dose-limiting liver toxicities have also been observed in AAV trials carried out by Solid Biosciences, Sarepta Therapeutics, Pfizer and Homology Medicines.The problems don't stop there.