An FDA advisory committee made history Thursday with its unconditional support for Spark Therapeutics Inc.’s Luxturna, which is on track to become the first gene therapy to be approved in the U.S. to treat an inherited disease.

The Cellular, Tissue and Gene Therapies Advisory Committee voted 16-0 that Luxturna (voretigene neparvovec) demonstrated an overall favorable benefit-risk profile in treating biallelic RPE65 mutation-associated retinal dystrophy, an ultra rare progressive disease that leads to blindness. The next step is up to the FDA, as it considers approval and labeling by the Jan. 12 PDUFA date.

At the outset of the meeting, Wilson Bryan, director of the Office of Tissues and Advanced Therapies at the FDA, set the tone for the adcom. “This is exactly the type of disease that we hoped that gene therapy would someday be able to treat,” he said in his opening comments. However, he reminded the committee members that the enthusiasm for the promise of gene therapy must be balanced by the data.

The data Spark presented – along with the testimony of patients, parents and retinal specialists during the public hearing – supported Luxturna’s promise so much that statisticians on the committee applauded the Philadelphia-based company on its strong data and the fact that everything made sense statistically.

That included the novel multi-luminance mobility test (MLMT) Spark used as a primary endpoint to measure improvement in its pivotal trial. While a few committee members suggested a different way of expressing the results of the test, they all agreed that the MLMT results were clinically meaningful.

The test consisted of a large white mat laid out like a maze with black arrows that patients had to follow within three minutes in decreasing levels of light. Steps and black obstacles added to the challenge of the test and stood in for real-life obstacles like curbs, dogs and debris that could trip up someone with impaired vision. Different patterns were used throughout the test.

As part of its presentation, Spark showed side-by-side videos of patients maneuvering the maze before and after injections of Luxturna. The results were undeniable. Using the first treated eye, two-thirds of the patients were able to walk through the maze at 1 lux, the lowest level possible, which is comparable with the light of a moonless summer night.

Spark reported a median MLMT score change of two light levels occurring in the treatment group at day 30. According to the FDA’s briefing document, that level was sustained through one year, but data on the duration of the effect beyond a year was limited. At the meeting, Spark presented four-year data for a handful of patients and anecdotal evidence of sustained results in a patient who received the injection nine years ago. All the patients in the phase I and III trials are being followed for 15 years.

Clinical significance

While the FDA had acknowledged the statistical significance in meeting the MLMT endpoint, it had questioned the clinical value of the endpoint itself, pointing out that Luxturna didn’t meet a secondary endpoint of visual acuity. (See BioWorld, Oct. 11, 2017.)

Noting that the MLMT results were supported by the scores from a Full-Field Light Sensitivity Threshold test and a patient-reported outcomes questionnaire, committee members agreed that the novel test was clinically meaningful as it was representative of the obstacles patients face every day.

Those results were further backed up by testimony from patients and their parents. Children and young adults who had faced a life of blindness spoke of the wonder of seeing the stars for the first time, getting to stay out late with their friends, eating in candlelight and achieving their dreams.

The MLMT did have a drawback in including young children in the trial. Although the phase III trial was open to kids as young as 3, the youngest child enrolled was 4 because younger children had difficulty understanding the instructions for the maze.

Since biallelic RPE65 mutation-associated retinal dystrophy can begin at a young age, Spark has recommended that Luxturna be labeled for use in children as young as 3. While some of the committee members suggested it might be useful in younger children, panelist Geoffrey Emerson, chief of staff at Phillips Eye Institute and an assistant adjunct professor at the University of Minnesota, noted that while early treatment would be desirable, the eye is anatomically almost the size of an adult eye at the age of 3. Cellular changes in the eye in infancy also could affect the efficacy of a gene therapy.

Although Spark is looking at Luxturna as a one-time injection in each eye, the FDA wanted the panel’s thoughts on repeat administration and the data that would be needed to support it. Part of the reasoning is that only one-fifth of the retina is treated. For some members of the committee, that raised the potential that vision might be improved even more if more of the retina were treated.

“There is an upper limit,” said Katherine High, Spark’s president and chief scientific officer. When developing the adeno-associated viral (AAV) vector gene therapy, researchers began to see focal necrosis in the retina with higher doses even in the initial injection. High also reminded the committee that a person getting a second administration of a gene therapy is not the same person who got the first administration.

Limited experiments in animal studies suggest a second administration does not carry toxicity, High said, but she has found that human cellular immune responses to AAV are poorly predicted by animal studies. Thus, human studies would be needed to determine the safety and efficacy of a second administration.

Moving forward

While the committee’s support was not unexpected, it was welcomed. “Today’s recognition of this technology’s impressive capabilities moves the entire field forward, to the benefit of patients and their families worldwide,” the Alliance for Regenerative Medicine said.

Albert Maguire, a professor at the Scheie Eye Institute at the University of Pennsylvania’s Perelman School of Medicine and a principal investigator in the Spark trials, said, “As a practicing physician who often speaks with patients and families living with IRDs [inherited retinal diseases], these conversations have been, up to now, frustrating in that there has been nothing to offer. Today’s advisory committee vote is an important step closer to the day that discussion can include potentially treating the blindness caused by their IRD.”

Spark has been preparing for a possible launch of its lead product for more than a year. Its team has been educating doctors on the potential use of the therapy, and it expects an immediate demand from young patients who have already been genotyped for the mutation, said Jefferies LLC analyst Michael Yee. The bigger market of older patients likely will need to be genotyped and identified.

If Luxturna is approved, Yee expects Spark to start treatment at three to five centers and then double that number over time. As a result, he said he anticipates a “fairly modest but steady uptake” of the gene therapy.

Since it is for an ultra rare disease, Luxturna has been touted as the first potential $1 million drug. Yee added some context to that number, saying Spark is considering a price of $350,000 to $500,000 per eye. Given the rareness of the disease, payers may be willing to pay a lump sum payment for the therapy, which was supported in part by the Foundation Fighting Blindness.