‘That’s $425,000 right there’ — the anxious launch of a gene therapy with a record sticker price

BOSTON — The trouble had started over a decade ago, when the Hogans noticed something wasn’t right with their son Jack. As a baby, he would spend hours staring into the lights in his nursery. Later, he sometimes walked into walls or fell down the stairs. When they asked him to pick up his toys, he wouldn’t — not because he didn’t want to, it turned out, but because he didn’t have the peripheral vision with which to see them strewn across the floor. They soon found out he was night-blind, too.

This past Sunday, his parents drove him five hours from New Jersey to Boston in the hope that he might regain some of his vision. On Tuesday, he was to be the first person in the U.S. to receive a gene therapy for a rare inherited disease since the treatment had hit the market.

Jack is 13 now — a smiley kid with blond hair and taped-together, blue-rimmed glasses — and his family had been anticipating this moment for years. They’d monitored the painstaking progression of the clinical trial. They’d recorded the evening news on the day last December when the drug got approved. And they’d watched as the price was announced at $850,000 for both eyes — a record price so high that Spark Therapeutics worked out a way for insurers to pay in installments, as if the medication were a fancy car.

Late last week, everything seemed set. The surgery to inject the treatment was one of several scheduled across the country on Tuesday and soon after. For both the doctors and the families involved, the week had brought a mix of stress and relief.

But for Dr. Jason Comander, Jack’s surgeon at Mass. Eye and Ear, there was one final hitch, even before he stepped into the operating room.

On the day the vials were supposed to be shipped from Philadelphia to Boston, he got a call about the family’s insurance: The company needed evidence showing that the specific genetic mutation in each of Jack’s eyes was the cause of his visual impairment.

Comander started to panic. He’s usually pretty unflappable, accustomed to carefully maneuvering instruments in through the whites of people’s eyes. While there is plenty of research on mutations in the RPE65 gene generally, not much of it had focused on the specific genetic error Jack had in one of his two copies of that gene. Without that kind of proof, the caller seemed to imply, the vials wouldn’t be shipped.

The surgery was a few days away. “I left a message for our genetic counselor and said, ‘This is as close to a genetic testing emergency as you’re going to get, please help,’” Comander told STAT.

It was a high-profile procedure, and families around the country were already nervous enough. The clinical trial results had been good — and in some cases, almost miraculous, with patients able to see the stars for the first time. Still parents couldn’t be absolutely sure that the one-time treatment would work. And no matter how dazzling the possibilities, any parent would be anxious about a surgery that involved digging into the depths of their child’s eye.

Their kids are part of a relatively small number born with defective versions of the RPE65 gene, which means they aren’t able to properly produce a protein that helps the eyes process light. Some can see during the day, with vision shrinking to nothing after dusk; others are legally blind.

The treatment, developed after decades of research, is called Luxturna, and it is sometimes referred to as the first “true” gene therapy to be approved by the Food and Drug Administration. Cancer treatments such as Kymriah and Yescarta are also sometimes described as a kind of gene therapy, but they involve removing a patient’s cells, genetically modifying them, and sending them back into the body to fight the disease. With Luxturna, a doctor injects a virus underneath the retina, where it delivers a healthy, lab-grown copy of the RPE65 gene into the cells. If the therapy works for these patients, it could help restore some of the images they have been missing.

Comander knew how long some of these families had been waiting, by choice or by necessity, so he was glad that he was able to reach a genetic variant analyst, who dug up a paper on Hogan’s particular mutation. A copy was sent to the insurer. The drug was soon packed into a cryo-container that could keep it at minus-80 degrees Fahrenheit and was on its way to Boston.

On the night before his surgery, Jack sat in the hotel lobby, sitting on his hands, playing with his fidget spinner, smiling at the thought of the school he would miss. “I don’t like that there’s a needle for my IV,” he said. “That’s the only thing I’m worried about. I don’t like needles.”

His parents had first heard about Luxturna in 2010, at a Foundation Fighting Blindness dinner at the Marriott Marquis in New York City. One of the organizers had seated them next to Dr. Eric Pierce, a specialist in inherited retinal disorders at Mass. Eye and Ear, and not long after that, Jack became his patient, coming up to Boston once a year.

But Jeanette and Shawn Hogan weren’t so sure about enrolling their kid in a clinical trial. His visual impairment meant he couldn’t do anything outside at night, had trouble seeing his teacher’s writing on the white board, and couldn’t play on a baseball team. “A six o’clock game, it would get dark by seven o’clock, and they could hit a fly ball, or a ground ball right to him, he wouldn’t see it,” his mom said. Still, he’d grown up with many of the pleasures Fair Haven, N.J., had to offer: boogie boarding, basketball, biking around with his friends before it got dark. His parents didn’t want him to risk going completely blind for the sake of a drug that might not work.

So they’d waited, and waited some more. “Do you want to know how many times we called Dr. Pierce’s office? ‘When is it going to be approved, when is it going to be approved, put us on the list, put us on the list,’” said his father.

There were others for whom waiting was not a choice. Creed Pettit is a 9-year-old who is legally blind, and he is set to have the first of his eyes treated in Miami on Wednesday, the day after Jack. Around six years ago, he flew with his mother from Florida to Iowa to try to get the therapy while it was still being tested. To qualify for the trial, patients had to navigate a maze in differing levels of light, so that the researchers could figure out if Luxturna had improved their vision enough to make everyday tasks easier. But the test was too complicated for Creed, even when he returned the following year.

“He was 3 1/2, and then 4 1/2,” said Sarah Pettit, his mother. “He tried very hard, he just couldn’t do it.”

Both families were excited about being among the first to get this treatment after its approval, but the feeling was also tempered with nerves. “It’s weird,” Sarah Pettit said by text message Tuesday. “I have been nervous for so long and today I am extremely calm … I know it’ll hit me hard tonight.”

“Once this is all said and done and Jack tells me he can see better, that’s when we’ll celebrate,” said Jeanette Hogan the night before the surgery. “There’s still so many unanswered questions. Is it going to work? Will there be a difference? That’s what I’m waiting to see.”

Jack Hogan was wheeled into the operating room a little after 8:45 in the morning Tuesday. His mom was allowed in, too, and she sat by his side in a yellow gown and green mask as the anesthesiologist started to put him under.

“He talks in his sleep,” she said, as his eyes began to close.

“We’ll take good care of him,” the nurse anesthetist said.

His mother kissed him, and then walked out, pulling off her mask and dabbing her eyes.

The team reviewed the details of the case aloud, and then the operation began. A resident daubed Betadine around his left eye, the lid opening and closing as she rubbed the brown liquid into his lashes. They covered his right eye — it’s going to get the same treatment next week — and inserted a wire retractor into the left to keep it open.

The vials of Luxturna had spent about an hour thawing out in the pharmacy earlier that morning, and had been diluted. The liquid sat in two syringes inside a plastic bag, and the team discussed how they would get them out. Tracy Condron, the nurse director, who was watching from the sidelines, chuckled. “Everybody’s nervous about taking out the medication, because it’s so expensive,” she said.

“Do you want me to open it, and you pull them out?” asked Deborah Aloise, a nurse who often works with Comander. That became the plan, and Comander reached in with forceps. He gingerly placed the syringes on a table, as if they might break at any second.

“That’s $425,000 right there,” he said, laughing.

By 9:15, Comander had slipped out of his loafers, left them in a corner, and sat down at Hogan’s head: The machines that would be doing much of the work were partially controlled by pedals, and he was able to use them more precisely if he was in stocking feet.

A microscope and camera were now over Hogan’s face, and screens around the room showed his eye, huge and unnerving, the pupil glowing salmon pink. Comander began to poke holes in the white sclera, inserting three green plastic ports, so that his instruments wouldn’t cause more damage then they had to. One port would be used to continually pump in a saline-like solution, to prevent the eye from collapsing. Comander would use the other two ports to maneuver a tiny light inside Hogan’s eye, as well as a number of hair-thin tools.

Now, the view on the screens changed, so everyone in the room was looking deep down inside Hogan’s eye, at the orange-red dome of his retina.

Before he could inject the gene therapy, Comander had to suck out the gel that filled the back of the eye so that he could reach the retina. He injected a white powder to help him see the gel, which is clear, and then turned on the suction with his left foot. Suddenly, the inside of Jack’s eye became a snow globe set on Mars, flakes swirling against a backdrop of red.

After fiddling with a spidery membrane on the surface of the retina, the surgeon was ready for the injection itself. Anyone who wasn’t needed in the operating room was sent away: Comander wanted no distractions. He knew this was the most challenging part. He’d carefully mapped his injection spot — away from blood vessels and close to the center of the eye, but not so close that it could cause damage — and planned his exact movement.

“If you don’t put just the right amount of pressure up against the retina, and if the assistant doesn’t put just enough pressure on the plunger, the fluid can be blocked and not go anywhere … or it can be wasted by being injected into the center of the eye, where it can cause inflammation,” he’d explained the night before.

He needed to avoid that waste at all costs. He’d performed this operation some 18 times before, during other clinical trials, but somehow, his plan wasn’t working now: He couldn’t quite inject the fluid where it was supposed to go. He knew he was at risk of running out of the medication, and he tried again, eventually turning to the backup syringe to squeeze those precious drops of liquid under Jack’s retina. Time slowed down. And then, after 10 nerve-wracking minutes, he saw a blister form — a sign that he’d gotten it right.

“It was a bit of a nail-biter,” he said afterward.

It was just the beginning. Just then, the same surgery was just getting started on another patient in Los Angeles, and the next day it would happen again in Miami. For Comander and the Hogans, there was still the other eye to do next week, and it was still up in the air as to whether the treatment would work at all. (Spark, to help win acceptance of the treatment’s high price, has set up a program to provide some kind of refund in case it doesn’t.)

But for now, the surgery was deemed a success, and Comander slipped the ports back out of Jack’s eyes and sutured the holes, the pupil jiggling every time he pulled the string taut. Then, once the drapes had been removed and the eye patched, Jack was wheeled out of the OR.