Their parents thought they were afraid of the dark. Then these twins learned the truth — and the fight to save their sight began

Twins Nathan and Andre wouldn't leave their room at night, their parents recall.

They would call for us or move reluctantly toward our voices often bumping into things as if their eyes were closed," says their mother, Christina. We just thought they were afraid of the dark."

But that wasn't it.

When they were six, the family learned they had a rare and severe type of night blindness that was going to get worse.

We had problems with colours in kindergarten, we would mix them up," says Nathan, now 13, and when we would go in the dark we couldn't see," says Andre, After my mom took us to SickKids and we did some tests we found out we had this condition."

The Cordeiro twins were diagnosed by their doctors at the Hospital for Sick Children with a specific mutation in a gene called RPE65 that had resulted in their progressive condition.

It's a story that came to my attention as my colleagues, including my husband, worked long hours to find a way to help these boys, using the kind of gene-specific therapy that could be a game-changer for medicine in the years ahead. I'm an assistant professor in the department of ophthalmology and vision sciences at the University of Toronto.

Children with this mutation have profound night blindness and some restriction in their peripheral vision, but central vision for fine details like reading can vary.

Without treatment, vision declines in adolescence to legal blindness.

Five years after the diagnosis, the twins' parents, Christina and Kevin, learned that Health Canada had approved the first one-time gene therapy for an inherited retinal disease, and the twins were eligible for treatment.

Voretigene neparvovec-rzyl (Luxturna) is the first directly administered and targeted gene therapy to be approved by the U.S. Food and Drug Administration (FDA). It works by replacing the defective RPE65 gene with a normal one so that RPE cells can produce a protein necessary for light-detecting cells to regenerate.

The working copy of the RPE65 gene, attached to an inactivated virus to allow entry into the cell, is directly injected into the subretinal space to the RPE cells.

Doctors and the Cordeiros were under the impression that treatment was imminent, by the end of the school year for sure," says Christina.

Then came the hurdles.

While Health Canada had approved the treatment, the provinces had not agreed to pay for the costs of Luxturna, which is $515,750 (Canadian) per eye.

We as Canadians are always so proud of our universal health care, as we should be, but we are always among the last in the developed world to get access to new treatments, many of which can be life-changing and even life-saving," says Dr. Peter Kertes, professor of ophthalmology and a retina specialist at Sunnybrook hospital and the Hospital for Sick Children.

To date, 19 countries are publicly funding Luxturna or have a reimbursement pathway in place, including Croatia, Saudi Arabia, the U.A.E., Australia, Israel and several European countries.

The U.S. FDA approved Luxturna in December 2017, and the European Medicines Agency (EMA) in September 2018. Health Canada approved Luxturna in October 2020; some say this delay was in part due to the fact that the drug manufacturer, Novartis, chose to go to European markets first given the reimbursement hurdles in Canada.

New drugs in Canada are first assessed by Health Canada for their safety and efficacy. After approval, these drugs go through a health technology assessment, through either the Canadian Agency for Drugs and Technologies (CADTH) or the Quebec equivalent, which provides evidence on their clinical and cost effectiveness. Based on their recommendations, negotiations for reimbursement between the drug manufacturer and the pan-Canadian Pharmaceutical Alliance (pCPA) then take place. After successful negotiation, public drug plans ultimately decide whether to fund the new drug and enter their own agreement with the drug manufacturer.

As of writing this story, the pCPA completed its negotiation with the drug manufacturer, Novartis. The fate of patients who are in need of Luxturna now rests in the hands of the provinces and territories, which are not obliged to accept the pCPA agreement and still have to negotiate the details with Novartis. This month, Quebec announced public coverage of Luxturna effective Sept. 28, 2022.

Christina turned to her insurance company, Canada Life, as Luxturna was on the list of drugs covered by her plan. The process of applying for coverage took about a year.

The whole process is backwards," she says. After submitting forms, there is no way of contacting the insurance company, no phone number, no email, you've got to wait for their response in snail mail."

Ultimately, the Cordeiro twins were told they did not meet criteria for Luxturna and were denied coverage. For privacy reasons, Canada Life declined to comment on the basis of their decision.

As parents, we started losing sleep," recalls Kevin. We were ready to liquidate our house to pay for treatment."

Inherited retinal disease specialists Dr. Elise Heon and Dr. Ajoy Vincent were the doctors that had diagnosed the children.

The twins needed treatment imminently," Heon says. In teenagers with the specific RPE65 mutation the rate of photoreceptor loss accelerates to thousands a day, so it was a critical time."

Insurance companies rely on their own internal experts as well as recommendations from Health Canada and CADTH to determine which patients should have access to coverage.

CADTH recommended that the costs of Luxturna be covered in those patients with the specific RPE65 mutation who meet strict criteria on vision testing, and who have sufficient viable retinal cells.

The Cordeiro twins did not meet CADTH's criteria on vision testing.

Kertes argues that specific vision testing criteria stem from clinical trials but that these trials are designed to maximize effectiveness and safety and do not mean that patients outside those strict criteria won't benefit from the treatment."

In the real world," he says, we try to offer treatment to those many patients within and beyond the criteria who we know will benefit and if withheld will lose vision that they will not get back."

Adds Vincent: The demonstration of progressive vision loss and the presence of viable retinal cells are better criteria to determine eligibility for treatment than the particular visual testing ones."

CADTH recommended a reduction in the price of Luxturna by 74 per cent because its cost-effectiveness was difficult to determine with no long-term data on the treatment effects.

There is controversy around the durability of Luxturna. Published data shows results can be maintained for at least four years. Dr. Stephen Russell, professor of ophthalmology at the University of Iowa and principal investigator of the Phase 3 Luxturna trial in the U.S., says although not yet published, our data suggest improvements in vision with Luxturna are sustained in most up to nine years so far."

Durhane Wong-Rieger, president and CEO of the Canadian Organization for Rare Disorders, says the problem with Luxturna is the cost is being compared against no treatment or best supportive care which is really cheap, but what if we consider the cost of blindness to society, well, then the treatment would absolutely be cost-effective."

In Canada, when you have an alternative treatment that is already being paid for, it is easier to get a new drug funded than when you don't have a treatment. Isn't that sad?

Here we have a miracle treatment, even if it isn't 100 per cent, a first of its kind, so good that 95 per cent of patients are getting it in the U.S., and Canada says, Sorry, we can't figure out how to make it cost-effective because guess what, we are currently paying nothing.

Companies with novel therapies are saying they are not coming to Canada, due to this reimbursement issue. Canada is sitting on the outskirts, we are setting up a reputation where advanced therapies, innovative therapies, gene therapies are not even coming to Canada. Our patients are going to miss out on the best and newest life-changing treatments."

After the rejection by his wife's insurance, which happened to be the same as his own, Kevin, at a loss for how to help his boys, approached his union business manager, Jack Oliveira, at LIUNA Local 183. The local represents more than 58,000 construction workers and their families in the GTA.

I am not the kind of person to back up from a fight that easily," Oliveira says. It was very important for Kevin's kids to get light again.

We were ready to have an emergency meeting with the trustees and get it off the fund and we could deal with the insurance companies down the road. I guess they understood our point."

Chris McNeil, the administrator of the benefit program of Local 183, says we make sure the plan is there for the members and their eligible dependants in their time of need. Our members work hard and deserve the best."

After some exchanges, Chris says, Canada Life reversed their decision and made Luxturna available for all members of Local 183."

I still remember the day that I called Kevin to tell him his boys were going to receive their treatment," recalls Oliveira. Kevin said he was just waiting for someone to price his home. It's a good thing he didn't have to do that."

Nathan recalls: My dad called me at school and told me to get Andre and go to the bathroom so he could tell us something. We aren't allowed to answer our phones at school but I saw it was my dad calling."

We got worried that something was wrong, my dad was crying on the phone," says Andre. He told us he just found out that we were going to get the treatment to save our vision."

Before surgery, Nathan was apprehensive. I had accepted that I would have to live with this my whole life. When I heard about the treatment I didn't know how to feel because I didn't know what it would be like without it."

Nathan says he had trust in Dr. Heon, as she had been there every step of the way.

On June 17 and July 8 this year, Andre and Nathan, now 13, were the first children to receive Luxturna in the country under the direction of a team of doctors, IRD specialists Heon and Vincent and retinal surgeons Kertes and Dr. Rajeev Muni. (One adult was previously treated.)

Kertes said of this moment, I have been waiting my entire professional career for something like this. We have seen many advances in ophthalmology, but this one is huge and just the tip of the iceberg."

Andre says that after surgery it's not great, but you have to know that in a while you are going to be able to see and have experiences that you never had. Now I've been able to see planes and stars which is kind of cool, I couldn't see that before."

My vision in the night has gotten so much better," reports Nathan. I can be in my room and it can be dark and I can find my way around."

Christina says her boys no longer wake her up if they need something at night and Kevin, with a deep sigh, says we are all sleeping much better ... but our fight is not over. We need to help the other 40 or more patients with the mutation who are losing vision while waiting for Luxturna in Canada."

Radha Kohly is a Toronto-based ophthalmologist and freelance journalist