The unanimous “yes” among the 16 voters at the end of the meeting of the Cellular, Tissue and Gene Therapies Advisory Committee of the FDA on October 12 took mere seconds, catapulting the first gene therapy to treat a genetic disease — an inherited form of blindness — the final giant step toward approval.
It had been an emotional and data-packed day as the committee evaluated the biologics license application for voretigene neparvovec (Luxturna), submitted by Spark Therapeutics Inc, to treat vision loss due to biallelic RPE65 mutation–associated retinal dystrophy.
“Nearly all patients progress to complete blindness that can’t be corrected. Other than voretigene neparvovec, there is no available treatment to stop the insidious loss of vision,” said Albert Maguire, MD, principal investigator at Children’s Hospital of Philadelphia, Pennsylvania, and professor of ophthalmology at the Perelman School of Medicine. He and Jean Bennett, MD, PhD, pioneered the gene therapy.
“These patients experience serious manifestations starting in early childhood. I see people who are tentative, who cling to family and friends, and are never without their canes. They can only see during bright light and avoid going out at night,” he added.
The Path to Approval
Results of the phase 3 clinical trial were published in August in the Lancet.
Until genetic testing became available, affected individuals were typically diagnosed with Leber congenital amaurosis (LCA; early onset) or retinitis pigmentosa (RP; later onset). “Some 250 different genes cause a clinically overlapping spectrum of disease. Mutations in RPE65 are responsible for 7% to 9% of LCA cases and 1% to 2% of RP cases. The hallmark is rod dysfunction resulting in night blindness. Cones are secondarily affected,” Mark Pennesi, MD, PhD, chief of the ophthalmic genetics division at Oregon Health and Science University, Portland, told the panel. One to two thousand individuals in the United States have the condition.
Katherine High, MD, PhD, president and head of research and development at Spark, explained the mechanism. “Voretigene neparvovec supplies a functional copy of RPE65 within the retinal pigment epithelium cells, restoring the visual cycle. These cells serve as nurse cells to the rods and cones.” The vector is AAV2.
The treatment received orphan drug designation in 2008, when the first patients in phase 1 were treated. A 2011 FDA advisory meeting addressed the need for novel endpoints tailored to the disease. Phase 3 began in 2012 based on high unmet need and promising early results, and the treatment received breakthrough designation in September 2014. “RPE65” was added to the indication in 2016. The clinical trial will follow up for 15 years.
The phase 1/2 clinical trial delivered 1.5 ´ 1011 vector genomes subretinally in 0.53 mL of fluid per eye, which was minimized to 0.3 mL for phase 3. Participants’ second eyes were treated 6 to 18 days later, with the closeness in time reducing the risk for an immune response. Clinical evaluation and imaging were used to determine the injection site, which covers about one fifth of the retina, Dr Maguire explained.
A novel primary endpoint, the multiluminance mobility test (MLMT), assessed functional vision; participants call it “the maze.” Patients navigate an obstacle course under a range of lighting conditions within 3 minutes, mimicking real-life situations, such as following hallways at school. Twelve variations of the MLMT course had the same number of turns, obstacles, and total distance.
Kathleen Reape, MD, head of clinical research and development at Spark, explained that the MLMT “evaluates input from the visual field and light sensitivity. The seven light levels span a wide range of everyday lighting conditions, from 1 lux corresponding to an indoor nightlight, to 50 lux corresponding to an outdoor train station at night, to a 100 lux office or food court.”
Results reflect the lowest light level at which a participant achieves a passing score for each eye alone and for both eyes. Two trained graders scored participants using videotaped sessions that were masked and evaluated in random order. Three errors or fewer earned a passing grade, and the graders derived a final score.
The primary outcome was bilateral MLMT score change at year 1. Several ophthalmologists who spoke at the meeting agreed that the test is valid, with the limitation that children under age 4 years and developmentally delayed children are unable to follow the directions.
(In preclinical experiments, the assay for success was spinning dogs. After Briard sheepdogs had their first eyes treated and suddenly saw half of a visual field, they whirled around to see more.)
Patients and their physicians related their own versions of success, one more spellbinding than the next. Said Stephen R. Russell, MD, principal investigator at the University of Iowa, Iowa City, where he is a professor of ophthalmology and visual sciences, “A 6-year-old shortly after the intervention went trick-or-treating for the first time. And the second oldest patient in the trial, 38 years old, shortly after the intervention got her first job and maintained it, and was finally able to go out in the evening with her friends.”
Secondary endpoints were full-field light sensitivity threshold, visual field testing by Goldmann perimetry, Humphrey computerized testing for macular static fields with foveal sensitivity thresholds, contrast sensitivity testing, and pupillary light reflex. Participants completed a visual function questionnaire to assess activities of daily living.
For the phase 3 trial, an estimated minimal sample size of 24 with 16 interventional and 8 controls would yield power of greater than 90% to detect differences in one light level on the MLMT. Of 31 initially enrolled individuals, 1 was withdrawn by the referring physician because of preexisting retinal thinning and 1 left, leaving 20 in the interventional group and 9 in the control-intervention group, who crossed over to receive treatment after 1 year.
For phase 3, all procedures were performed on an outpatient basis and the average time was 1 hour — longer than it took to do the informed consent, Dr Maguire said.
“What We Saw in the Clinic Was Remarkable”
“The data from the phase 3 trial demonstrate that treatment resulted in clinically meaningful and highly satisfactory improvement in functional vision, light sensitivity, and visual function. These improvements were observed as early as 30 days after administration and were maintained up to 3 years with continual observation,” said Dr Reape.
But several participants related seeing lights, stars, sun and moon, food on plates, and faces of loved ones just a few days after treatment of the first eye. Kids could ride bikes, a high school student joined a varsity cheerleading squad, and a young woman saw her dream of becoming a statistician come true. “And then there was the sun. Man, that thing is bright! I could practically feel my pupils contracting,” the patient recalled.
In the phase 3 trial, 93% of patients showed improvement on the MLMT. “What we saw in the clinic was remarkable. Most patients pushed aside their guides and explored their environment with confidence. Rarely did I see a cane after treatment,” said Dr Maguire.
Full-field light sensitivity improved more than 100-fold. “Imagine how difficult it would be to see if I diminished the light in this room to 1/100th of what it is now,” said Dr Maguire as he did just that. He continued, “The increase of 300 degrees in visual field opens up a huge area of vision that had previously been choked off by the disease. The responses were prompt and durable.”
He’d just examined a 10-year-old who’d been treated at age 6. “She couldn’t remember how poor her vision had been. She now finds it hard to believe she ever failed the mobility test,” he said as the screen showed her stumbling through the maze.
By age 3 years eyes have reached 90% of their adult size and present no increased risk based on development, Dr Maguire said. Spark is designating that age as the youngest.
The safety profile was consistent with the risks of vitrectomy and subretinal injection, and most adverse events resolved, reported Deborah Kelly, MD, head of pharmacovigilance at Spark. For the two clinical trials, adverse events included four retinal tears, three cases of intraocular inflammation or infection, one instance of loss of foveal function 24 days after the intervention with loss of visual acuity by 1 year, eight cases of elevated intraocular pressure, and nine patients with cataracts.
The treatment taps skills that retinal specialists already have. “I believe the injection of 0.3 mL into a perimacular space is entirely within the skills of an adequately trained retinal surgeon. The complications were not unexpected. As with all surgical procedures this is likely to improve. If my child, my patient, or myself had this condition I would advocate strongly for it,” said Eugene de Juan, MD, from University of California San Francisco Medical Center.
Julia Haller, MD, ophthalmologist-in-chief at the Wills Eye Institute, Philadelphia, and retinal surgeon, agreed because she did it. “I backed up Al Maguire, scrubbing in for 2 days. Al did two patients the first day and the next day I did the surgery. These are standard maneuvers in retinal surgery. The only difference is that instead of injecting tPA [tissue plasminogen activator] underneath the retina, we were injecting voretigene.”
Spark has proposed a risk management plan to balance the need for collecting further safety data with the need to make the treatment available, said Dr Kelly. Rollout will be at “five to eight centers of excellence with experience in inherited retinal disease treatment. Providers will have to complete a surgical training program and in-person workshops with the principal investigators as well as wet lab training. There will be a detailed surgical manual and a pharmacy training program and manual,” she said.
The vision community hopes that voretigene will pave the way for many similar gene therapies. Summed up Joan M. O’Brien, MD, chair, Department of Ophthalmology at Penn Medicine and director, Scheie Eye Institute in Philadelphia, “More than 250 genes cause inherited retinal diseases. Not only will this work transform the lives of individuals with RPE65 mutations, but it will ultimately transform the lives of perhaps millions of individuals who are now facing a life of blindness.”
Spark Therapeutics provided travel funds for several of the speakers at the meeting.