- Two children with a rare neuromuscular disease have died after receiving a high dose of a gene therapy in a clinical trial run by Audentes Therapeutics, according to two letters sent by the company to patient groups.
- Both of the children suffered liver problems that ultimately led to sepsis. The most recent death occurred this month, though the letters revealed Audentes halted dosing of new patients before either occurred. The Food and Drug Administration subsequently placed the study on a formal clinical hold.
- The gene therapy, called AT132, is designed to treat X-linked myotubular myopathy, a deadly disease caused by mutations in a single gene. Audentes, which was bought by Japan's Astellas Pharma for $3 billion in December, aimed to submit the treatment for approval this year, but those plans are now on hold, according to the letter.
Gene therapy has emerged rapidly in recent years because the field overcame safety concerns — most notably, the tragic death of teenager Jesse Gelsinger in a clinical trial in 1999 — that cooled initial optimism and slowed research.
Newer methods to deliver genetic medicine have been proven out in clinical testing and two therapies are now approved in the U.S., both for rare inherited diseases. Others, for diseases like hemophilia and Duchenne muscular dystrophy, could soon follow.
So far, this current wave of therapies have generally appeared safe. Encouraged, developers have tested higher and higher doses of gene therapies, aiming to expand their potential effectiveness. Higher doses are particularly important for neuromuscular diseases, since the treatment must travel through the bloodstream to reach the right tissue.
Two years ago, gene therapy pioneer Jim Wilson — who led the Gelsinger trial at the University of Pennsylvania two decades ago — expressed concern about the strategy, fearing that pushing doses too high might lead to safety problems. Wilson and UPenn colleagues published a paper in the journal Human Gene Therapy noting liver and nerve damage in animal experiments with a certain type of gene therapy, and called for researchers to do more monitoring.
While other gene therapy studies have been stopped in recent years, the deaths observed in Audentes' trial are particularly worrisome.
Audentes' therapy has shown promise in early tests, enough for Astellas to pay $3 billion for the company in December. The pivotal study of AT132 began in 2017 and Audentes aimed to submit an application with the Food and Drug Administration this year.
According to a letter Audentes sent to patient groups, however, that will no longer happen.
On May 6, Audentes told the groups that a patient treated with a high dose of AT132 had died from sepsis. Two others also given the high dose had then experienced serious side effects.
Six weeks later, on June 23, Audentes CEO Natalie Holles and chief medical officer Edward Conner sent a second letter explaining that one of those two had also died. That patient experienced progressive liver dysfunction, which didn't respond to standard treatment. His condition worsened and he ultimately died from a bacterial infection and sepsis.
"There have been some incredible outcome measures with some of the children but the science needs to continue to evolve," said Alison Rockett Frase, president of the Joshua Frase Foundation, one of the patient groups Audentes wrote. "Our community is devastated by the loss of these two children," she added in an interview.
Audentes is still collecting information, monitoring all of the study's other patients and is in touch with regulators. A total of 17 patients have been treated with the high dose of AT132 — 300 trillion vector genomes per kilogram of body weight.
"We are taking all necessary steps to understand these events and incorporate what we learn into our development plan going forward," Holles and Conner wrote in their letter. "We are currently assessing the impact on potential regulatory filing timelines, however we will not be filing in mid-2020 as previously communicated."
They added, however, that none of these issues have been seen in the six patients treated with a lower dose, and all of those patients are "years out from treatment." Four of those patients had a history of liver or biliary system problems.
Both of the patients who died also had evidence of pre-existing liver problems, Audentes said. All three patients with liver problems were of older age and heavier weight.
An Astellas spokesperson confirmed the contents of the letters in an email to BioPharma Dive.
Audentes uses a type of adeno-associated virus, called AAV8, to deliver its gene therapy. Other companies, including Ultragenyx, RegenxBio and Biogen are developing gene therapies that also rely on AAV8.
The high dose Audentes uses is among the largest being tested in gene therapy.
Ned Pagliarulo contributed reporting.