Inherited Retinal Diseases

On December 19, 2017, the FDA approved Voretigene Neparvovec (Luxturna, Spark Therapeutics), a one-time gene therapy treatment used to improve vision in patients with established genetic vision loss due to Leber congenital amaurosis or retinitis pigmentosa, both inherited retinal diseases (IRD).


ASGCT's full statement on the historic FDA approval of Luxturna for inherited retinal diseases, including media contact information, is available online.

A Brief History of Luxturna

In a historic first Luxturna (voretigene neparvovec, Spark Therapeutics), a gene therapy treatment for inherited retinal diseases Leber congenital amaurosis or retinitis pigmentosa cause by confirmed biallelic RPE65 mutations, became the first gene therapy for an inherited disease approved for clinical commercial use in the United States on December 19, 2017. While many may not have been familiar with the drug before its approval, the history of Luxturna dates back to the mid-1980s and the Human Genome Project.

“One of the long term questions around the Human Genome Project was whether we would be able to turn genes into medicines,” Dr. Katherine A. High, co-founder, president, head of research and development at Spark Therapeutics and president of ASGCT from 2004-05, says. “This is a simple idea that has taken a long time to reduce to practice, but if we are successful, it means that many diseases that have heretofore had no treatment, may now have the possibility of treatment.”

Development of Luxturna proper began in 2005, when High was at Philadelphia Children’s Hospital, in collaboration with Dr. Jean Bennett and her team at the University of Pennsylvania. The first clinical trial began in 2007 and the phase III trial began in 2012.

“We didn’t lose any time getting started,” Bennett, the F.M. Kirby Professor of Ophthalmology at the University of Pennsylvania’s Perelman School of Medicine, says. “We spent the next 8 months generating and optimizing the plasmid that was used to generate the vector. That required a huge amount of laboratory work.”

When Bennett and High were finally satisfied with their ability to efficiently deliver the RPE65 protein, there were still hurdles the team had to overcome—though these were institutional.

Even with the utmost support, there are always challenges when institutions come together in collaboration. Beyond the regulatory concerns of groundbreaking gene therapy, the team developing Luxturna had to navigate the institutional review boards of both organizations.

“They ended up uniting both boards because of this study. The other thing was equipment, we didn’t have the equipment we needed so I either brought equipment over from Penn or bought my own. We also didn’t have a dog model, so I bought affected dogs from a colleague at the University of Missouri and bred them myself so we could verify rescue in a canine model.”

Following the study, Bennett officially adopted the dogs used in the canine model.

In 2007, the first Phase I trial of Luxturna began and was competing with two other gene therapy trials for the inherited retinal diseases. When the Phase I trial wrapped up two years later, the results raised eyebrows in the scientific community.

“I was on the RAC [Recombinant DNA Advisory Council] when the first clinical trial to test this strategy was presented and I remember everyone being very impressed with the preclinical data from their dog model,” Dr. Helen E. Heslop, ASGCT President and Director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children’s Hospital and Houston Methodist Hospital says. “They showed how the dogs were unable to navigate through an obstacle course, but after receiving this gene therapy they could readily traverse it.”

Ultimately, following extensive conversations with industry regulators, High, Bennett and their research team would have to design a study to treat both eyes rather than treating one eye and using the patient’s other eye as the control.

“After we established the safety of [injecting the second eye], and observed signs of efficacy, we started the Phase III trial,” High says. “The Phase III trial for voretigene was the first randomized controlled Phase III study for gene therapy for a genetic disease.”

Inherited retinal diseases are such rare conditions that there wasn’t enough historical data to establish a control group, so a randomized control study was developed for Phase III testing—a group of patients wouldn’t receive the treatment. Internally, High says there were concerns that participants in the control group would leave for other, competing studies. As part of the study design, members of the control group were able to cross over and receive Luxturna after one year. Not one person left the study. Every participant in the control group crossed over into the treatment pool following the one-year study.

The groundbreaking results of the 2012 phase III trial were published in the July 2017 edition of The Lancet. In October 2017, Luxturna headed to the FDA Advisory Committee for possible recommendation for approval—the committee unanimously recommended Luxturna, the first gene therapy delivered directly to a person, for approval in the United States.

Luxturna Approval and Future

The development team had to hurry-up-and-wait in between the unanimous recommendation for approval from the Food and Drug Administration Advisory Committee and Luxturna’s groundbreaking approval. There were facility and laboratory tours, questionnaires, and interviews while the administration deliberated, but it was mostly a waiting game up against the January 12, 2018 Prescription Drug User Fee Act (PDUFA) date assigned following the Priority Review designation that came with the recommendation.

“There was a lot of huddling and anticipating in the lead up to the advisory council meeting, and a lot of relief when the unanimous recommendation came down,” Bennett says.

While the true impact of Luxturna is yet to be seen, the field of gene therapy is hopeful that the historic approval opens the door for durable, potentially curative treatments for inherited blindness diseases.

“This is a class of diseases for which there have been no pharmacological treatments,” High says. “There are over 250 genes involved in vision and we hope that this may pave the way for the development of treatment for other inherited retinal diseases and causes of congenital blindness.”

In addition to opening the door for further research into inherited retinal disease and associated blindness, Luxturna opens the door for an entire field of potential treatments currently in development as the first AAV vector gene therapy delivered directly to a person.

“This is what you might consider classic gene therapy when you have a patient who has an inherited disease and you administer a corrected gene delivered by AAV,” Heslop says. “It’s exciting to have the first gene therapy product for an inherited disease that uses a viral vector. That’s a major milestone for the field.”

Regardless of what comes next, High and Bennett are exceedingly proud of what their team has been able to accomplish as part of this project, now a decade in the making between inception and commercial application.

“For me, it’s just an unbelievable scientific and translational medical experience. To see something go all the way from the laboratory bench to approval is something that very few people have the opportunity to experience,” Bennett says. “Our team has worked so well together to generate something that can actually help people—help them see better and change their lives.

“A lot of the thanks for the success of this project goes all the way back to Gordon Gund, who has retinitis pigmentosa and started a foundation to research ways to cure blinding diseases like his.

It’s thanks to the patients who volunteered to be a part of this and offered so much of their time. We learned a ton from them and truly used that in the development of Luxturna.

And finally, it’s very hard to find a retinal surgeon who is willing to spend the time injecting thousands of mice and other animals and then to be the first person to inject a child with a non-lethal disease with a gene therapy. All of those people have been a part of this and all of those people should be acknowledged.”

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