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Speakers at AAO 2019 event describe journey leading to approval of the first gene therapy for a genetic disease.
There is no question that retinal gene therapy has definitely arrived. Not only is it alive and well today, but looking at the current state of research, it will hopefully have a very bright future.
These were some of the messages contained in the 2019 Charles L Schepens MD Lecture Award given by Jean Bennett, MD, PhD, and Albert M. Maguire, MD, at the American Academy of Ophthalmology 2019 annual meeting in San Francisco.
In an informative and entertaining talk titled “Retinal Gene Therapy: From Theory to Practice,” they shared their experiences developing voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics), the first gene therapy approved in the United States to treat an inherited disease.
“When we began this research, there was no such thing as gene therapy. There were no clinical trials, no companies, not even laboratory techniques to do retinal gene transfer. Our original Leber’s congenital amaurosis (LCA) team numbered just six people,” said Dr. Maguire, professor of Ophthalmology, University of Pennsylvania, Philadelphia. “Now gene therapy is a multibillion dollar business involving countless investigators, dozens of startups, and several large pharmaceutical companies, all employing thousands of people.”
Dr. Bennett provided a clinical status update.
“There are now more than 1,150 patients enrolled in retina gene therapy clinical trials that are being conducted at more than 30 sites, and at least 13 Centers of Excellence are administering Luxturna,” she said. “Importantly, there are many more gene therapy clinical trials being planned, and we hope that Luxturna is just the first of many successful gene therapies.”
How it all began
Dr. Bennett, professor of Ophthalmology; Cell & Developmental Biology, University of Pennsylvania, took to the podium first. She recounted that Dr. Maguire first asked her in 1985, when they were both still in medical school, if she thought it would be possible to transfer genes to the retina.
Although Dr. Bennett said yes, she recognized the path forward would be difficult because there were no foundations to build on.
“There were no genes to work with, no animal models, no delivery vectors, no surgical methods, no outcome measures, and no funding,” she said.
After developing an effective vector for gene delivery to the retina, the proof of concept study was carried out in a canine model of RPE65 LCA. Treatment benefit was demonstrated through assessments of electroretinography, nystagmus, pupillary light reflex, and ability to function outdoors as well as in a mobility test, which led to early interest in developing a mobility test for patients.
Dr. Bennett credited the success of the preclinical development program to a number of steps that were taken early on to ensure the efficiency of gene delivery and success of the surgical procedure, and she described those measures.
Turning science into medicine
Dr. Maguire described the many challenges and surprises encountered as the research moved towards and through the clinical development pathway. First, the researchers faced a negative environment.
“Gene therapy was a novel concept that was widely viewed with skepticism and suspicion," Dr. Maguire said. "The death of Jesse Gelsinger had cast a pall over the field, and the fallout was paralyzing."
Then it was necessary to become educated about the complex regulatory requirements of drug development and navigate the problematic ethics of performing a clinical trial in the vulnerable pediatric population.
After positive results were achieved in the phase I study, problems were encountered in planning the phase II trial. The researchers were faced with the need to design and validate a new primary endpoint that the FDA would accept as clinically meaningful – thus the creation of the multi-luminance mobility test.
Choosing the control group for the phase III trial was also not straightforward.
The early success achieved with the retinal gene therapy was generating high patient interest among potential candidates, but everyone wanted to be in the treatment arm, Dr. Maguire explained.
“FDA regulations, however, stipulated the need for an untreated control population. A design in which the control group received delayed treatment after one year was acceptable to patients and satisfied the FDA,” he said.
Dr. Maguire concluded by describing a final surprise, noting that the enthusiasm of the advisory board that reviewed voretigene was another thing that was not anticipated.
“Our application asked for approval to treat children 3 years and older, but the FDA Advisory Committee recommended approval for children as young as 1 year of age, and that is where it stands today,” said Dr. Maguire. “It is a peculiar position to be told to do more, not less surgery."
In December, 2017, voretigene was approved by the FDA for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. In November 2018, it received marketing authorization from the European Commission.