A cure for hemophilia seemed closer than ever. For many patients, it's now further out of reach.

The surprise rejection of BioMarin's hemophilia A gene therapy delays a decades-long mission to fix the rare bleeding disorder.
Danielle Ternes/BioPharma Dive

The bleeding doesn't show right away. A couple days pass before the skin puffs and the bruises form. But the people who have this disease recognize its early symptoms. A familiar warmth builds in the ankles, knees, hips or wrists, then flares into sharp, sometimes pulsating bursts of pain. For Ryan Hallock, the telltale sign was not being able to move the afflicted joint normally. "It's kind of like getting a hug from a significant other," he said. "You just know what it feels like."

Hallock has a severe form of hemophilia, a rare, inherited disorder that causes excessive bleeding, often from the most innocuous activities. Hallock would get bleeds if he slept on his arm wrong or hit an odd stride while walking. As a teenager, he started taking medication to manage the disease, but hasn't needed any for a while. Before, Hallock would have two to three minor bleeds each year. Since receiving an experimental gene therapy five years ago, the 27-year-old nurse said he's had none.

This week, the Food and Drug Administration was expected to approve, for the first time, a gene therapy for hemophilia. After decades of unfulfilled hopes, the gene therapy called Roctavian could have finally delivered the closest thing yet to a permanent fix for one of the earliest identified genetic diseases.

But in a shocking move, the agency rejected Roctavian on Wednesday and asked its developer, BioMarin Pharmaceutical, for more evidence that it provides a long-lasting effect on bleeding rates.

An approval could have been transformational not only for certain patients, but for BioMarin too. Roctavian is a billion-dollar product by some Wall Street estimates, the kind of asset that could lift up BioMarin, which hasn't been profitable in 21 of its 23 years in business. Now, the Californian biotech likely won't be able to sell its therapy until mid- to late-2022, at the earliest.

Roctavian is not the same gene therapy that was given to Hallock, who has the less common, hemophilia B form of the disease. Rather, it's specifically designed to treat hemophilia A. Clinical studies of Roctavian and other gene therapies have shown these one-time infusions allow some people to go years without reaching for the anti-bleeding treatments they were using every few days.

The chance at a yearslong, maybe even lifelong treatment for hemophilia has doctors and patients excited. Yet, even before Roctavian's upset, their hope also came with a fear that this big leap forward would leave many patients behind, either because their bodies or the healthcare system won't take to gene therapy.

The stakes are higher still, given that Roctavian was poised to be the most expensive drug ever. Should it come to market, and patients who do get treated don't perform as well as expected, a difficult precedent could be set for the next generation of gene therapies to overcome.

"Gene therapy is the future," said Len Valentino, CEO of the patient advocacy group National Hemophilia Foundation. "The worst thing that could happen is we lose the opportunity to develop gene therapy products because people don't believe in them anymore."

A promising target

Broadly speaking, gene therapy tries to fix disease-causing defects in a person's DNA by introducing new, helpful genetic material. As the technology gained legs in the late 1980s, researchers looked for illnesses where it could make a difference. Hemophilia, which affects an estimated 20,000 people in the U.S., rose to the top of the list.

The disorder's genetic links were well established. Mutations in one of the sex chromosomes left the body without proteins critical for clotting blood. The missing protein in hemophilia A is called Factor VIII, while in hemophilia B it's called Factor IX. In both types, patients need only generate small amounts of these proteins to live fairly normal lives, which sets up a manageable goal for gene therapy developers.

Hemophilia patients also desperately needed more treatment options. Blood transfusions had become a staple of care, but inadequate screening measures led to a contamination crisis in the early 1980s that resulted in thousands of patients contracting HIV or hepatitis C.

In spite of the early interest, a series of high-profile setbacks near the turn of the century grounded the field of gene therapy research. Only in the last decade, as scientists came to better understand the technology and how our bodies react to it, has confidence returned.

Workers gather inside BioMarin's gene therapy plant in Novato, California.
Courtesy of BioMarin Pharmaceutical

By 2012, Spark Therapeutics, a company spun out of the Children's Hospital of Philadelphia, had begun human testing of a precursor hemophilia B gene therapy to the one that Hallock would later get. Another, from the Netherlands-based biotech UniQure, emerged soon after.

Hemophilia A gene therapies from Spark, BioMarin and Sangamo Therapeutics followed suit, with BioMarin ultimately taking the lead position. Roctavian was the first of the field to reach regulators, making the FDA's rejection of it consequential both for BioMarin and for gene therapy's role in treating hemophilia.

Roctavian's approval chances rested on two clinical trials of patients with severe hemophilia A, defined as having less than 1% the normal amount of clotting protein.

The smaller, earlier trial found treatment nearly eliminated bleeds in the 13 patients given higher doses of the therapy, a benefit that has persisted through several years of follow-up. Within months of infusion, clotting protein rose to levels almost as high as people without hemophilia. That was much more than the 5% of normal that researchers initially hoped to see, according to lead investigator John Pasi.

"To be honest, we thought that was hugely optimistic," said Pasi, who also directs the hemophilia center at The Royal London Hospital. "We ended up with results that knocked the ball right out of the park, and that has had a huge impact on changing people's perceptions of what gene therapy can deliver."

BioMarin was then able to replicate those promising results in a larger study. A preliminary analysis showed similarly sharp reductions in bleeding rates, factor use and a rise in protein activity.

Longer follow-up, however, has also eroded some enthusiasm. Updates last May and this June showed Roctavian's effect appeared to wane over time, although protein levels were still much higher four years after treatment compared to when patients started. Additionally, the updates measured less protein activity from the high dose of Roctavian than what was seen in earlier testing.

According to BioMarin, the FDA wants to see two years of follow-up data from all patients in the larger study before it gives the greenlight to Roctavian, a task that can't be completed until November 2021. CEO Jean-Jacques Bienaime said agency staff had "never, ever discussed" such a requirement in "any meetings we had with them." Bienaime said he suspects the differences in protein activity seen between the smaller and larger studies are what pushed the FDA to want more data on durability.

The agency's apprehension may also have to do with the fact that Roctavian probably can't be given a second time, so if its effects diminish, patients may have to either wait for a different gene therapy to come along or go back on older treatments.

"The reward is quite high if they're successful, but patients really need to understand all of these issues before going into it and not think it's a one-and-done approach," said Robert Sidonio, a pediatric hematologist at Children's Healthcare of Atlanta. Sidonio has consulted for both BioMarin and Spark.

Not for everyone

Researchers were already planning to follow Roctavian-treated patients for years to provide continual updates on safety and durability. Ahead of Wednesday's FDA decision, the therapy was generally viewed as long-lasting but not necessarily curative — a disappointment to some, though still an attractive option for those who've grown tired planning their lives around multiple weekly infusions.

Hallock, for example, said that since receiving Spark's drug, it's been a relief to go on hikes with friends or short trips with his wife and daughter without doing the math on how long beforehand he should infuse. Not having to keep needles around the house, or deal with getting his replacement factor treatment through airport security, are a few more perks he's noticed.

"I think most patients would consider that to be worth it," said Courtney Lawrence, an assistant professor of pediatric hematology at Johns Hopkins Children's Center.

Ryan Hallock and his daughter. Years after receiving a gene therapy, Hallock says he's been pleased with the results.
Courtesy of Ryan Hallock

Others aren't so sure. Valentino expects that, excitement aside, many patients will be slow to choose gene therapy because of the uncertainties surrounding its long-term effects.

Gene therapy is also irreversible, something that Michelle Rice, who has mild hemophilia, has seen weigh on her two adult sons as they consider whether it's the right treatment for their severe disease.

"This is a community that doesn't necessarily jump at the next bright, shiny thing," said Rice, who works alongside Valentino as the head of external affairs at NHF. "Gene therapy is kind of a bell that you can't unring. It's a big commitment. So the decision becomes much, much harder."

And in some cases, patients don't get much choice. The pivotal studies of Roctavian didn't enroll patients with HIV infections, active hepatitis infections or "inhibitors," a phenomenon in which the body develops antibodies to attack replacement factor protein.

It's unclear whether these patients, who typically are at greater risk of health complications, will be cleared to receive Roctavian if it comes to market. BioMarin had expected an approval from the FDA to cover about 2,400 patients with hemophilia A in the U.S., a minority of the total population.

Another type of antibody will further limit who's eligible for hemophilia gene therapy. For these treatments to work, they must get the genetic instructions for making factor protein into cells. Most accomplish that by using certain viruses like a shipping service. This group of "adeno-associated viruses," or AAVs, have been shown to safely deliver genetic cargo.

Yet, like with most viruses, the immune system sometimes sees AAVs as invaders and deploys antibodies to stop the threat. If present, these antibodies will not only neutralize the gene therapy in question, but every other gene therapy that uses the same viral vehicle.

The problem is made worse by the fact drugmakers pull from a small crop of about a dozen AAVs. Roctavian uses genetically engineered AAV5, as does UniQure's hemophilia B gene therapy. Patients therefore don't need many types of antibodies before they're ineligible for the bulk of gene therapies now in development.

As such, hemophilia doctors worry a substantial portion of patients can't receive gene therapy because they already have antibodies. A presentation BioMarin made in January cited estimates that about 20% of patients in the U.S, and 30% globally, would be ineligible for Roctavin for this reason.

"To have expression and then lose it five to six weeks later. That will be very difficult, I think, for a patient to accept," Sidonio said.

Insurers on the fence

Insurance companies will also be hard pressed to accept such an outcome, as the starting price for Roctavian looked likely to fall within the $2 million to $3 million range. While insurers now have more time to figure out payment methods, they may still try to limit risk by restricting access to gene therapy to just the patients who have the most severe disease or whose bleeding isn't controlled with currently available options.

"That's what we're worried about," Sidonio said, "having to bleed into your next therapy."

Gene therapy does, however, offer certain advantages that incentivize insurers to cover it. A one-time treatment that can keep clotting protein levels up for an extended period of time may save the healthcare system money, since replacement factor and other hemophilia drugs often cost hundreds of thousands of dollars per year. Hemlibra is one of the newer drug options, and has grown popular because it can be taken as infrequently as once a month. It comes at an annual list price of about $450,000.

These offsets have helped gene therapies for other rare diseases secure coverage. The Zolgensma gene therapy, approved last year to treat spinal muscular atrophy, has overcome insurance barriers despite carrying a list price of $2.1 million. Until Zolgensma came along, the only treatment option was a drug priced at $750,000 for the first year of treatment and $350,000 each year thereafter.

"Even a gene therapy that comes in at a couple million dollars, presuming durability, can be worthwhile financially speaking," said Michael Sherman, chief medical officer at Harvard Pilgrim, a New England insurer.

Still, hemophilia isn't like other rare diseases. It affects more patients than what's typical for a gene therapy target, meaning insurers that didn't have a patient eligible for Zolgensma likely can't say the same for Roctavian. If enough patients qualify for and are interested in BioMarin's drug, that would present a budget challenge for payers.

Hemophilia also has north of a dozen treatments approved by the FDA, with a new slate of long-lasting options inching closer to market. This abundance puts added pressure on BioMarin and the other leading gene therapy developers to set prices that won't surprise insurers.

"We're all excited about this for the sake of the patients," Sherman said. "But if the pricing were to be egregious, there is the option to wait for the next gene therapy or to keep people on traditional hemophilia drugs."

Cure is a big word

Hallock has several things in common with Eric Burgeson. Both are in their late 20s, living with severe forms of hemophilia. They found replacement factor mostly kept their diseases in check, allowing them to go about day-to-day activities like work or exercise without much issue.

But a key difference is Burgeson, a program coordinator at the Hemophilia Federation of America, has not gone through gene therapy.

Burgeson said he trusts the technology and understands its appeal. Yet he's always been a "slow adopter" of new treatments — hence why he's taken the same kind his entire life. Though there are times when his medication seems less effective, Burgeson said it's hard to shake the fear that switching to something else could open the door to bigger complications, such as inhibitors developing or insurers denying coverage.

Michelle Rice and her oldest son, Lance. Rice's sons have severe hemophilia, and have been mulling whether gene therapy might be right for them.
Courtesy of Michelle Rice

These fears run deep in the hemophilia community. BioMarin, if it eventually gets the FDA's stamp of approval, will try to ease them with a successful launch of Roctavian, but that could be tough on several fronts. For example, of the 150 or so hemophilia treatment centers in the U.S., relatively few participated in the clinical trials of Roctavian. Getting the others up to speed on how to administer the therapy presents challenges that are made more daunting by the current pandemic.

"There isn't going to be a reason why someone has to come in right away to do this," said Sidonio, who foresees Roctavian being a niche product used in less than 5% of eligible patients.

Burgeson, too, expects uptake to be slow, with many taking a wait-and-see approach to Roctavian and gene therapy more broadly.

"Gene therapy seems to be this golden hope," he said. "But for something that severe, to just dip your toes in it? I don't see anywhere near the majority of the population being on this for the first decade of its availability."

Of course, some patients will still seek out Roctavian.

For those who do, doctors and patient groups say it's critical to set appropriate expectations. Gene therapy won't work for everyone. Patients might only get one shot at it. And it may not have the lifetime effect with which it's become synonymous.

"If it were me — and my oldest son has talked to me about this — I would always be waiting for when it's going to stop working," Rice from the NHF said. "And that sounds like I'm not a fan of gene therapy. I absolutely want to see gene therapy come to fruition. I just want to make sure that people understand what it is and what it isn't."

"Cure, to me, is a really big word."