[Updated, 1/31/18, see below] Gene therapy pioneer James Wilson and University of Pennsylvania colleagues sounded an alarm Tuesday morning about the use of gene therapy to treat severe diseases like spinal muscular atrophy and Duchenne muscular dystrophy, sending a chill across the sector.
Shares of several companies inched downward as word spread about the UPenn work on Tuesday. Reached this afternoon, Wilson called for close monitoring of patients receiving high doses of a certain type of gene therapy delivered into the bloodstream.
Outside experts acknowledge that the studies were small but important. “The paper is getting the attention it deserves,” says Aravind Asokan, an associate professor of genetics and part of the gene therapy center at UNC School of Medicine in Chapel Hill, NC.
The findings raise questions about several experimental gene therapies in or not far from human trials. The paper, published in the journal Human Gene Therapy, reported that nerve and liver damage occurred in two separate animal tests of a potential gene therapy for SMA.
Specifically, the researchers saw one case of acute liver failure and shock in a monkey test, and damage to sensory nerve cells in both monkeys and piglets. One monkey and three piglets had to be euthanized.
Wilson and his team could not say if the results were specific to these tests or an indication of a broader problem. They concluded that “careful monitoring” is needed in similar settings—that is, when infusing a high dose of adeno-associated viruses (AAV) directly into the bloodstream to deliver genetic instructions.
Wilson (pictured), whose work on AAV technology has been crucial to the field’s development, was measured about these findings in a conversation late Tuesday. “AAV still remains, from my experience over three decades, one of the safest delivery systems,” he told Xconomy. “We should expect with any biologic product that if you push the dose high enough, you’re going to encounter dose-limiting toxicities.”
But Wilson also says seeing these side effects in two different studies with two different gene therapy products gave him pause. These problems have occurred amidst the rapid advance of gene therapy, with one product finally approved in the U.S. and several more in human trials. They’ve spurred his lab to publish the results as quickly as possible.
“We are seeing some indications of what you may want to monitor if you are in that space,” he said, citing immediate bleeding or a rapid spike in liver enzymes, for example. “I would encourage those involved in these studies to monitor their research subjects.”
The problems reported in the paper have not yet occurred in human tests of AAV gene therapies. Many have shown promise and in some cases stunning results for several different diseases. The most common side effects have been delayed immune reactions that are easily contained with a short course of steroids.
It’s possible the side effects Wilson and colleagues saw “are not applicable to humans, are only related to the specific variants [in] Dr. Wilson’s lab, and/or are related to manufacturing impurities,” RBC Capital Markets analyst Brian Abrahams wrote in a research note Tuesday.
The UPenn team notes in the paper that its studies offer “provocative but incomplete evidence for a unifying mechanism of toxicity.”
Still, the paper is cause for concern. “I think dose-finding studies and very careful clinical design are going to be critical,” said UNC researcher Asokan.
[Updated with comments from Vandenberghe] Luk Vandenberghe, the director of the Grousbeck Gene Therapy Center at Massachusetts Eye and Ear, said that because the study showed the “first clear documentation of [high] toxic doses with AAV,” the results “cannot be ignored, and are important as they set a dose range for the field to be on the lookout for toxicity.”
Vandenberghe—a listed inventor on the patent for AAV9, one of the AAV variants being delivered in human clinical tests, systemically, at high doses—added that the study highlights the need to standardize how gene therapy products are characterized. Until that happens, researchers can’t compare one gene therapy program to another or, in this specific case, how UPenn’s findings “impact ongoing and pending clinical programs.”
Safety incidents, such as the death of teenager Jesse Gelsinger in 1999 in a trial co-led by Wilson, chilled investment in gene therapy work for years. But Wilson and many others plugged away on the underlying technology, and now there are several AAV therapies in development that put high doses directly into the bloodstream to reach skeletal muscle, the brain, and other tissues.
Among those fitting this description is a gene therapy from Chicago-based AveXis (NASDAQ: AVXS), for a deadly form of SMA affecting infants, that is in late-stage testing. Gene therapies from Sarepta Therapeutics (NASDAQ: SRPT), Solid Biosciences (NASDAQ: SLDB), and Pfizer (NYSE: PFE) for Duchenne muscular dystrophy have recently begun human trials or are about to start. There are others in development, like a treatment from Audentes Therapeutics (NASDAQ: BOLD) for the rare X-linked myotubular myopathy, or the Abeona Therapeutics (NASDAQ: ABEO) treatment for Mucopolysaccharidosis IIIB.
In a statement to Xconomy, AveXis chief medical officer Sukumar Nagendran distanced the company’s program from Wilson’s work. Nagendran said the UPenn studies used a different AAV virus than AveXis, and that the data are “inconsistent” with high-dose AAV studies from AveXis, Abeona, and Audentes. “The ‘process defines the product,’” Nagendran said in the statement. “Wilson’s manufacturing process is non-GMP”—a term that stands for industry-grade ‘good manufacturing practice’—“and is not the AveXis process.”
Terence Flotte, the dean of UMass School of Medicine and editor in chief of the journal Human Gene Therapy, was wary of drawing conclusions. He said that the small size of the UPenn studies and other variables could have affected the results.
“It’s important to get the information out there so that other groups can carefully study this,” Flotte said. But he doesn’t think testing of high-dose, systemic AAV therapy should stop—particularly when it comes to devastating afflictions like SMA or Duchenne, in which time lapsed can mean disease progression and death. In a commentary article published in the journal, Flotte called on the gene therapy community to “neither ignore, nor overreact to” UPenn’s findings.
Wilson’s concerns first emerged in Solid’s IPO prospectus. The company revealed on Jan. 16 that Wilson had resigned a few days earlier as the chair of its scientific advisory board over “emerging concerns about the possible risks” of the Duchenne gene therapy. In a separate filing last week, Solid disclosed that the FDA had partially suspended testing of the therapy, SGT-001, in November. Solid has not been able to administer a high dose to patients but is allowed to continue testing a lower dose.
Wilson declined to talk about Solid. But as Xconomy reported last week, other developers of Duchenne gene therapies say that preclinical tests haven’t produced any suggestions that human trials could have safety problems.
Jerry Mendell, the lead investigator in the early study of AVXS-101 at Nationwide Children’s Hospital in Columbus, Ohio, said the most significant issue was a spike in liver enzymes in four patients that was suppressed with steroids and didn’t lead to notable side effects. Meanwhile, he noted, the study featured children who survived beyond the age of two, instead of dying, and who were walking when they weren’t expected to.
“Does that mean that a patient will never have life threatening liver failure? No, I think this study definitely raises that concern,” says Charlotte Sumner, a Johns Hopkins Medicine professor who treats patients with SMA. While Sumner says there is “incredible excitement” about SMA gene therapy, at minimum she’d like to see more monitoring measures in future tests, such as peripheral and sensory nerve testing.
Beyond such monitoring, Wilson believes the gene therapy community must commit to “as much sharing and transparency of preclinical safety data” as possible.
“All of it is going to inform the field,” Wilson says.