An FDA advisory committee has proposed lower vector doses, stricter exclusion criteria, and long-term animal studies to address liver toxicities associated with adeno-associated virus (AAV) vector gene therapies .
During the second of four AAV safety sessions, the Advisory Committee on Cell, Tissue and Gene Therapies (CTGTAC) assessed the evidence of hepatotoxicity – ranging from elevated liver enzymes to liver failure and death – seen with the products in clinical trials for hemophilia, spinal muscular atrophy (SMA) and X-linked myotubular myopathy (XLMTM).
“Most of the hepatotoxicity seen at this point in hemophilia trials is fortunately more of a limitation in effectiveness than a real safety concern,” said Lindsey George, MD, Children’s Hospital. of Philadelphia at an Open Data Security Presentation.
However, she noted, there have been reports of acute liver failure in SMA and death in a trial involving XLMTM.
In the ASPIRO trial testing AT132 gene therapy in XLMTM, three deaths were presumed to be related to complications of hepatic failure in 17 patients included in the highest dose cohort (3.5E14 vg / kg), despite the fact that the The trial excluded patients with a history of clinically significant liver disease.
“As for the doses in this trial, they’re essentially the highest I’ve seen in any AAV trial,” said George.
The trial was then suspended and then lifted by the FDA late last year to a lower dose (1.3E14 yd / kg), but the liver problems continued. Earlier this week, the sponsor of the Astellas trial voluntarily announced a suspension of screening and testing after a patient has developed abnormal liver function within one month of administration.
“I think it is important to recognize that hepatotoxicity-related morbidity and mortality has only been observed with administration of systemic doses of AAV greater than 1E14 vg / kg, and indeed only in pediatric patients, ”said George. “So maybe one of the big things is to keep fighting for lower doses of vectors as part of the clinical development of these programs.”
To determine the appropriate dosage, committee member Raymond Roos, MD, University of Medicine of Chicago, noted that “there are different serotypes of AAV vectors and different transgenes, so it is difficult to generalize about a dose of particular vector “.
“I think it’s important to do some animal work to get a feel for this,” he said. “But, ultimately in clinical trials, it would be important to look at the dose response – starting at a low dose and challenging this patient population with increasing amounts of the AAV vector.”
CTGTAC President Lisa Butterfield, PhD, University of California, San Francisco, said that an upper limit does not appear to be the best approach, and that the total dose of the vector genome per kg or taking into account of a certain measure of body mass index for patients might be preferable. . Additionally, she said, it remains to be seen what role the vector dose and capsids played in the deaths seen in the XLMTM study.
Discussing mitigating the risk of liver injury, Theo Heller, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases, suggested that relying on liver enzyme measurements or ultrasound exams is not adequate. , and that strict exclusion criteria in trials and careful evaluation of patients “is essential”.
“The concept of hemophilia of not enrolling people with bypass fibrosis or greater is something that could be emulated in other diseases,” he said.
Learn from animal testing
Committee member James M. Wilson, MD, PhD, director of the gene therapy program at Perelman School of Medicine in Philadelphia, said that primates as a model offer several areas of agreement with human studies: “It It is important to note that the threshold for severe toxicity requiring minimal euthanasia with primates is almost perfect with the threshold for human studies, which is 2E14 vg / kg, ”he said.
But, there are important differences, he noted. “The severe liver toxicity seen in humans is often delayed compared to what we see in primates, which is a bit earlier.”
There are also several key limitations to the use of non-human primates – that is, macaques – in these studies, Wilson said. For example, it is difficult to assess the impact of disease factors in these animals because they do not have co-morbidities. Additionally, when macaques get sick at the start of a study, researchers are required to euthanize them; Wilson suggested that if animals received the same type of supportive care as humans, it could allow for a more in-depth assessment of these toxicities.
Regarding the acute toxicity seen in primates, however, Caroline Zeiss, DACVP, DACLAM, of the Department of Comparative Medicine at Yale University in New Haven, Connecticut, said, “We don’t see quite the same in people. But being able to follow these animals longer, and later, could be an opportunity to learn more about the mechanism of both acute and long-term effects, she added.