The Food and Drug Administration on June 22 approved the first gene therapy for Duchenne muscular dystrophy, a milestone in treatment for the deadly disease and a calculated gamble the medicine can slow its unrelenting progression.

The regulator granted the treatment, called Elevidys and developed by biotechnology company Sarepta Therapeutics, an “accelerated” clearance, meaning its benefit must be confirmed in further testing. Its use is limited to Duchenne patients who are 4 or 5 years of age, can still walk, and don’t have genetic mutations that might blunt the treatment’s effects or raise its safety risks.

The approval is narrower than Sarepta originally sought, due to limitations in the data the company submitted to regulators. Sarepta estimates that, in any given year, there are about 400 children aged 4 or 5 years old with Duchenne in the U.S., according to a company spokesperson.

The agency based its decision on the therapy’s ability to help patients make a tiny protein, dubbed microdystrophin, that the FDA deems “reasonably likely” to result in a health benefit.

Sarepta must prove that’s the case with an ongoing late-stage clinical trial expected to deliver results by the end of the year. If successful, that trial would support a full approval of Elevidys and could allow Sarepta to expand the FDA’s restrictions to include older children. However, if negative, Celia Witten, the acting director of the FDA office that reviewed Sarepta’s therapy, said last month the regulator could remove the drug from market.

In a statement, the FDA reiterated that position, noting that it would review data from the trial quickly to decide whether any action, like a revised label or market withdrawal, would be required.

“The approval of Elevidys is a watershed moment for the treatment of Duchenne," said CEO Doug Ingram, in a statement. If the Phase 3 study "confirms the benefits seen in our prior trials, Sarepta will move rapidly to submit a[n application] supplement to expand the approved label as broadly as good science permits,” he added.

Though the current approval is relatively narrow in scope and the therapy isn’t a cure, many patient advocates and families see Elevidys as a significant step forward in treatment for a disease that’s frustrated drug developers for decades.

“Even 10 years ago, there wasn't anything in the works like there is today,” said Susan Finazzo, whose two young sons have Duchenne, in an interview. “This gives us hope.”

“It means a lot for the field and really opens up things,” added Jerry Mendell, director of gene therapy research at Nationwide Children’s Hospital and a co-inventor of Sarepta’s treatment, prior to the approval.

Sarepta priced its therapy, a one-time infusion meant to last years, at $3.2 million, making it one of the most expensive medicines in the world.

Duchenne is caused by inherited mutations in the largest known human gene, one responsible for building a protein, dystrophin, that protects muscle tissue from damage by its repeated contraction and relaxation. Without it, the muscles of those with the condition, almost exclusively boys, slowly waste away. People with Duchenne usually lose the ability to walk in their teens and die from heart or lung weakness around age 30.

Many patients rely on steroids to slow the disease, but at the cost of side effects like weight gain, behavioral changes and growth defects. Some can get “exon skippers,” including three drugs sold by Sarepta, which are thought to modestly delay progression.

Patients as well as Duchenne physicians and researchers are hoping gene therapy can work better, such as by more clearly halting or possibly even turning back the disease.

Sarepta’s treatment is the result of decades of research into Duchenne and its underlying genetics. Like other gene therapies in clinical development, it delivers into the body’s cells DNA encoding the microdystrophin protein, which is designed to imitate a form of dystrophin found in people with a milder type of muscular dystrophy known as Becker.

Clinical testing has shown Sarepta’s therapy can produce a large amount of this protein, far above what experts believe is needed to benefit patients. Some participants in Sarepta’s main study are also performing better on certain functional tests than historical data suggests they would otherwise, which experts and advocates take as proof Sarepta’s treatment works.

“What we're seeing is stabilization of a disease that we've never been able to stabilize before,” said John Brandsema, a pediatric neurologist at the Children’s Hospital of Philadelphia, prior to the approval. “That is a tremendous achievement.”

Tim Revell, the father of two boys with Duchenne, said he and others expect Elevidys can help their sons, and that its benefits can last. “We’re hoping and praying” it “can help the older boys live, and the younger boys keep walking,” Revell said in a recent interview.

Sarepta hasn’t proven it can. The only placebo-controlled test to produce results so far did not show the therapy meaningfully improved function. In their review, FDA scientists were skeptical of the treatment, as were some members of an advisory panel the regulator convened last month.

Though a majority voted to recommend an approval, a number of the panelists worried about the FDA clearing a potentially ineffective drug, as there’s a chance people who receive it couldn’t receive another, similar type of gene therapy later on. Treatment was also linked in a few cases to serious liver damage.

“While the risks are low, there was no evidence of benefit,” said Lisa Lee, a panelist and associate vice president for research and innovation at Virginia Tech, at the May meeting. “Without some data showing benefit, we’re basically asking families to shut off any future short- or mid-term possibilities for treatment.” Lee voted against recommending the therapy’s approval.

Still, Duchenne patients are certain to progress without treatment, putting pressure on the FDA to act quickly. “Time is muscle,” said Jennifer Handt, the parent of a boy with Duchenne, wrote in a recent email.

Some top officials within the FDA have advocated for flexibility in exactly these types of situations. At a meeting held by a nonprofit group in March, Peter Marks, head of the FDA office that reviews gene therapies, spoke of the urgency to expedite new genetic medicines for rare and life-threatening diseases.

“We can’t be so careful about our approvals under accelerated approval that we prevent potentially life-saving therapies from getting to market in a timely manner,” Marks said then.

The same month, he had reportedly pushed the agency to schedule the May advisory meeting for Sarepta’s treatment, after learning agency scientists were leaning toward a rejection, according to Stat News.

The FDA ultimately chose a compromise of sorts. It delayed its decision by a month, using the time to narrow its initial approval to a younger group of boys who an after-the-fact analysis of the company’s study results suggested might benefit the most.

An approval now, rather than after Sarepta’s ongoing Phase 3 study reads out at the end of this year, means eligible patients, their families and physicians can consider Elevidys sooner. But it leaves those who are older potentially without a chance to receive the treatment, as they may not meet any expanded criteria the FDA later clears.

“We’re pretty hopeful the Phase 3 will read out positively,” Pat Furlong, CEO of advocacy group Parent Project Muscular Dystrophy, said in a recent interview. “To be honest, I don't think we have the appetite to think differently at this moment.”

The diagnosis was news no parent ever wants to receive. Susan and Chris Finazzo heard it twice in two months.

Both of their children, Chase and Dylan, have a genetic disease called Duchenne muscular dystrophy. The progressive condition slowly and unstoppably lays waste to muscles, first stealing away the ability to walk, then weakening the lungs and heart.

The hopes they held for their children’s future were darkened by fears of a shortened life, and dread of when Chase and Dylan would no longer be able to climb a playground slide, dress independently or swallow food.

“You’re just sitting there like, this is not what was supposed to happen,” Susan said. “You’re mourning the death of the life that you thought your child was going to have.”

The Finazzos didn’t accept the outlook doctors gave their sons, though. They trawled through the internet looking for answers to their many questions. They met with patient advocates to learn about experimental medicines being developed, and enrolled Chase and Dylan in a clinical trial of a cutting-edge gene therapy.

“We always say we’re the luckiest of the unlucky,” she said. “This gives us hope.”

The Finazzos are part of a large network of parents and patient advocates who believe the gene therapy, developed by biotechnology company Sarepta Therapeutics, represents a medical breakthrough for Duchenne. The treatment is an infusion meant to change the course of the disease for years, if not permanently. Available medicines, by comparison, are thought to only slow Duchenne’s relentless advance, not halt it, as a gene therapy might.

“There isn’t a parent, family or person with this diagnosis that doesn't go to bed every night and say, ‘Stop the disease right here. Let it be stopped,’” said Pat Furlong, president and CEO of Parent Project Muscular Dystrophy, a prominent patient advocacy group. “The community believes this is a very important step forward.”

In late June, the Food and Drug Administration granted Sarepta’s therapy an “accelerated” approval, a type of clearance that’s used to speed treatments for serious diseases like Duchenne to market. The company’s case was supported by data showing its drug produces large amounts of a potentially helpful protein, as well as signs some study participants are doing better than medical history suggests they should.

“I am not, as I sit here today, aware of an approved therapy under the accelerated approval pathway with more compelling evidence than we have,” said Sarepta CEO Doug Ingram.

Yet the treatment failed an important part of its only placebo-controlled test to date. The effects of the protein it helps produce, a diminutive molecule called microdystrophin, aren’t fully understood. Nor is how long any benefit might last. The approval also set a precedent for other gene therapy developers to follow, raising the stakes of the agency’s decision.

The FDA’s verdict came months before a Phase 3 study will deliver results that either confirm or refute the benefit of a treatment likely to cost more than $1 million. “This is a very, ‘between a rock and a hard place’ situation for the FDA,” said Dae Gon Ha, an analyst at the investment bank Stifel, who covers gene therapy companies, in an interview before the approval.

Buying time

Seventeen years ago, Tim Revell’s son Timothy was having trouble walking.

A whirlwind of brain and blood tests followed, confirming that Duchenne was why Timothy, then 2, had fallen behind his peers. The Revells’ doctor told Tim that all he could do was go home and love his son.

Timothy is one of an estimated 300,000 people worldwide, almost exclusively boys, who have the condition, which is caused by a genetic mutation that stops the body from making a muscle-protecting protein called dystrophin. A few years later, the Revells learned Timothy’s younger brother had it too.

Parents of children with Duchenne have long received the same advice as Revell heard in 2006. “There’s zero hope,” he recalls being told.

Revell became an advocate for drug research and got his sons into earlier clinical trials of Duchenne medicines that ultimately proved unhelpful. In the meantime, he's watched the disease slowly take hold. Timothy lost the ability to walk three years ago.

“Duchenne is like death by 1,000 cuts,” he said. After years of decline, death often occurs in young adulthood, when the muscles of the heart or lungs fail.

There are a few treatments available. Some patients with particular mutations can get drugs known as “exon-skippers,” which help the body produce a shortened form of dystrophin that’s thought — but not proven — to modestly slow progression. Others, like Revell’s sons, aren’t eligible.

However, most rely on steroids, which can slow muscle damage but cause other problems like weight gain, weak bones and behavioral changes.

“It's not a great choice, and it's not an easy one for parents to make,” said Jennifer Handt, whose 5-year-old son Charlie has Duchenne. “The expectation is to hopefully buy a little bit of time until science can give us something more tangible.”

For decades, patient advocates have put their hopes in gene therapy, a way of shuttling replacements for missing or damaged genes into the body to restore needed proteins like dystrophin. Until recently, it had always seemed just out of reach.

“I remember in my first meeting 30 years ago, it was raised, ‘At some point we'll have gene therapy,’” said PPMD’s Furlong, “and it sounded way back then like, ‘Oh my gosh, what will it take to get there?’”

‘A significant adversary’

Jerry Mendell saw his first Duchenne patient in 1969, during a postdoctoral fellowship at the National Institutes of Health.

“We didn't know anything about the disease” then, he said. “Just what it looked like under a microscope.”

What started as a fellowship became a lifelong mission for Mendell, who in the following decades emerged as a top researcher in the field of neuromuscular disease.

In 1989, he and his team at Ohio State University published research that established the steroid prednisone as the standard of care for Duchenne. In the late 1990s, he was the first to test a gene therapy for another neuromuscular condition in humans and later conducted an early gene therapy experiment in Duchenne. More than a decade later, after Mendell became director of gene therapy research at Nationwide Children’s Hospital, the team he assembled invented Zolgensma, a dramatically beneficial medicine for infants born with the rare condition spinal muscular atrophy.

“I understood the potential for gene therapy if we could make it work” for Duchenne, he said. “There were many scientists and clinicians who doubted it, but to me it was the best approach we had.”

Duchenne presents several vexing scientific problems, however.

The disease has been seen as a target for gene therapy since the 1980s, when its genetic roots were first identified. But the gene that encodes for dystrophin is too large to be packaged into the microscopic viruses researchers use to deliver corrective gene therapy. And because Duchenne affects muscle, researchers need to use very high doses to shuttle in enough genetic material to hope for a benefit.

“This disease is a significant adversary,” said John Brandsema, a pediatric neurologist at the Children’s Hospital of Philadelphia. “We have been hammering away at it for decades.”

Scientists have spent years searching for workarounds, “dissecting” the gene and trying to figure out how to make it small enough to fit into the virus, Mendell said.

The solution was found in people with a milder form of the condition known as Becker muscular dystrophy. Patients with Becker have a large deletion in the middle of their dystrophin gene, but are still able to make a shorter version of the protein, explained Timothy Lotze, a pediatric neurology professor and director of a muscular dystrophy care center at Texas Children's Hospital. Published research has described a Becker patient who, while missing nearly half of that gene, was still walking at 61 years old.

Those insights sparked a rush among rival research groups to develop gene therapies built around “micro” or “mini” forms of the dystrophin gene, many of which were later licensed to or acquired by biopharmaceutical companies.

One program from the laboratory of Jude Samulski at the University of North Carolina was picked up by Pfizer. Another, from Jeff Chamberlain at the University of Washington and Dongsheng Duan at the University of Missouri, ended up in the hands of a biotech called Solid Biosciences.

Nationwide’s work, co-invented by Mendell and one of his recruits, Louise Rodino-Klapac, was acquired by Sarepta. It was a decision made by former CEO Ed Kaye, who had unsuccessfully tried to license Zolgensma years earlier.

“I knew Jerry would be first in the clinic and get it done quickly,” he said in a 2019 interview with Xconomy. “In this business, it’s who gets there first that’s important.”

Uncertain benefit

Jennifer Handt wrestled with whether to enroll her son Charlie in one of Sarepta’s trials.

She met with other parents, visited different trial sites and “did her homework,” including vetting the doctor who would treat Charlie.

Still, it wasn’t a decision she made lightly.

“I had that moment of, ‘Is this the right thing to do?’” Handt said.

Early study results from Sarepta had shown the company’s gene therapy could produce levels of miniature dystrophin markedly higher than previously reported in trials of other Duchenne medicines — well beyond the amount that researchers think will alter the disease.

Yet data have been more mixed as to whether those protein levels translate to functional benefits. In some cases, boys who would have been expected to decline on tests evaluating their ability to walk, stand and balance, haven’t yet, which some experts point to as evidence the treatment is working.

“What we're seeing is stabilization of the disease that we've never been able to stabilize before,” said CHOP’s Brandsema, who is an investigator in multiple Duchenne gene therapy trials, including Sarepta’s. “That is a tremendous achievement.”

While Handt couldn’t be sure Sarepta’s treatment would help, Charlie’s disease was certain to progress. “What is our alternative?” she said. “The idea of doing nothing, when we had something, was not an option.”

Still, the gene therapies being developed for Duchenne, including Sarepta’s, use trillions of copies of the viral shells that deliver dystrophin DNA into the body. Though the virus in question has been safely used in scores of gene therapy experiments, prominent researchers have warned higher doses administered intravenously might not be as benign.

Those alarms have some merit. Four children died in a study of a gene therapy for a different type of neuromuscular disease. And while most of the side effects so far associated with Duchenne gene therapy appear manageable with close monitoring and a short course of immune-suppressing drugs, some rare but serious events have caused concern.

One patient died in a trial of Pfizer’s Duchenne gene therapy in 2021. Solid’s research was stalled multiple times due to safety worries. Data to date suggests Sarepta’s gene therapy to be generally safe, but it, too, was linked to one case of serious muscle weakness that researchers believe to be a shared effect among microdystrophin gene therapies. The company has excluded patients with certain mutations from testing in response.

“We have to be very aware that this is an irreversible decision when we do this. It's like transplanting an organ or doing surgery,” said Brandsema. “We cannot take it back once we’ve given it, and the reaction can be significant.”

Echoes of eteplirsen

Seven years ago, hundreds of patients and family members traveled to a Washington, D.C., suburb to testify in support of an emerging treatment for Duchenne.

The drug, known then as eteplirsen and also developed by Sarepta, was up for an accelerated approval. The FDA had gathered a panel of experts to review the evidence.

The data primarily came from a clinical trial of just 12 boys with Duchenne, and reviewers were skeptical. The treatment produced a tiny amount of dystrophin — less than 1% of normal levels — and it was very difficult to discern whether it had an effect.

However, parents, patients and doctors were convinced the drug worked. At the meeting, some chided FDA officials, drawing cheers from the audience. Although the panel ruled narrowly against eteplirsen that day, the agency’s top drug evaluator, Janet Woodcock, overruled her own review team, concluding the dystrophin levels were “reasonably likely” to result in a benefit. Her decision was supported by Robert Califf, the FDA commissioner then and now.

Eteplirsen’s approval caused a rift within the agency. Multiple reviewers left afterwards. In emails made public following the decision, Woodcock was accused by other staff members of flouting agency norms, keeping unusually close ties with Sarepta and patient advocates, and deciding to approve before reviewers had completed their evaluation.

Outside of the FDA, the approval was viewed as an example of the growing pressure patient groups — many of which receive some degree of funding from drug companies — were putting on regulators.

“That advisory committee meeting harmed relationships within the [Duchenne] community, with the FDA, and the perception of our community outside,” PPMD’s Furlong said.

Sarepta still hasn’t completed a required trial to confirm whether eteplirsen, which is now sold as Exondys 51, actually changes the disease’s course.

According to Ingram, the company’s CEO, the post-marketing study requested by the FDA won’t directly answer that question, only whether higher doses might be more beneficial. He pointed instead to real-world evidence presented at a recent medical meeting, as well as a study showing dystrophin levels as low as 0.5% of normal are associated with milder disease. Neither type of data is as conclusive as results from a placebo-controlled trial.

In the meantime, Sarepta has become one of biotech’s most valuable companies, currently worth about $12 billion. It followed a similar blueprint as Exondys 51 to bring two more drugs to market for different subsets of Duchenne patients, and began investing in gene therapy.

“In my view, we wouldn’t have [the gene therapy] today” without Exondys 51’s approval, he said. “It’s clear the FDA did the right thing.”

A new controversy?

In March, Peter Marks, head of an FDA office that reviews new drugs, stood before more than 1,000 researchers, patient advocates and doctors to give a speech on gene therapy.

Marks spoke of the agency’s urgency to speed development of gene therapies for rare and life-threatening diseases, and the tools the FDA had to help. Among those was the accelerated approval pathway, which has been criticized in the years following Exondys’ clearance and only used once before for a gene therapy.

Marks acknowledged the criticism. Some see speedy approvals as “a shortcut,” he said. But “we can’t be so careful about our approvals under accelerated approval that we prevent potentially life-saving therapies from getting to market in a timely manner,” he added.

The comments were notable given the venue. Marks was speaking at the yearly meeting of the Muscular Dystrophy Association, a large nonprofit group that supports research into neuromuscular diseases like Duchenne.

The talk was days after the FDA had scheduled an advisory meeting to review Sarepta’s accelerated approval application — a meeting, Stat News subsequently reported, that Marks called after agency staff appeared ready to reject the treatment. Sarepta had previously said a meeting wasn’t expected.

The conflicting news jarred the patient community, as advisory committees add an element of risk to the review process.

“It made people step back a little bit,” said Debra Miller, head of the advocacy group CureDuchenne, adding that there’s “a real feeling” people need to band together to show the FDA “we're behind this.”

“We all feel there's a really good chance that the therapy is going to be approved,” Miller said.

Still, the tension highlights the risk Sarepta took by seeking an accelerated approval in the first place.

Weighing Sarepta’s case

The decision to file early, rather than wait for the results of the company’s ongoing Phase 3 trial, was made “after a lot of contemplation” within the company, according to Ingram.

One factor was time. If Sarepta waited, at least one more year would pass before the gene therapy could possibly become available. “In the life of a Duchenne kid, that’s a monumentally long time,” he said.

Ingram also pointed to the “totality of the evidence” Sarepta has already compiled. The treatment’s design is based on decades of research on the dystrophin genes of Becker patients, he said. It has been tested in about 150 boys and is supported by biological data suggesting it’s working. Children in the studies are doing better than normally would be expected and the therapy’s benefit may “grow with time,” he added.

Other experts interviewed by BioPharma Dive were supportive of the data as well.

“This looks like a highly beneficial drug with relative risks that can be managed,” said Lotze, of Texas Children’s, who isn’t involved in Sarepta's trials. “I would hope, and somewhat expect, that a treatment like this might halt further progression of disease or markedly slow it.”

Still, Sarepta’s closest competitor, Pfizer, chose to wait for results from a Phase 3 study before deciding whether to file an application for its gene therapy.

The reason, according to its development head of rare neurologic diseases, Dan Levy, is that it’s challenging to tease apart a drug’s effect by comparing the performance of Duchenne patients to historical data.

The patients who join a clinical trial and the ones involved in the “natural history” studies that document disease trajectory could be different. There are also biases and confounding factors that can skew results of the primary test used to measure Duchenne’s progression.

“We believe the good data is going to come from a placebo-controlled, randomized clinical trial,” Levy said. “We’ve received general guidance from regulators around that.”

There are other issues regulators and panelists wrestled with. Clearing Sarepta’s treatment signals some degree of comfort on the part of the FDA with medicines that use “truncated,” rather than full-sized, genes. Yet the gene Sarepta’s treatment delivers isn’t identical to a gene of a Becker patient, raising questions about its impact. The company also hasn’t clearly shown a correlation between microdystrophin expression and patients’ performance in the clinical trials.

More glaringly, the treatment didn’t improve physical function in its only placebo-controlled test, an outcome Sarepta blamed on bad luck during the process for randomizing patients between drug and placebo groups.

The timing of Sarepta’s Phase 3 trial results adds another wrinkle. Sarepta designed the study with various adjustments meant to boost its odds of success. 

Ingram is confident the trial will succeed. Still, he said Sarepta would carefully weigh the data if it fails. “We would of course do the right thing for patients,” he said, when asked by BioPharma Dive whether the company would withdraw the treatment in the event of a negative result.

‘Not the end game’

Christine Miller was cautiously optimistic when she enrolled her 7-year-old son George, who has Duchenne, in one of Sarepta’s trials. (At her request, BioPharma Dive changed her and her son's name to protect their privacy.)

School had become difficult for George. He couldn’t keep up with other kids during soccer, and lagged behind on the playground. Miller sensed George was frustrated with his body.

Miller turned to a gene therapy trial for help. She didn’t expect George to suddenly “walk an extra mile,” or be cured. She hoped he might be able to walk, play and visit the beach for a little longer. More time as a healthy kid before a better drug comes along.

“Time is the one thing you don't have with Duchenne,” she said. Like other parents of children involved in Sarepta’s trials, Miller was hesitant to discuss how her son has responded to treatment, fearful of jeopardizing the study. He’s “in line with the data Sarepta has published,” she said. “That’s meaningful.”

Patient advocates are similarly wary of overstating what gene therapy might do, or how widely it’ll be available if approved. The results so far have been less predictable than people anticipated, said CureDuchenne’s Debra Miller. Some patients may not be eligible because of safety reasons, age, or the state of their disease. Others will be ruled out because their bodies’ immune system may react to the virus that delivers Sarepta’s treatment.

Advocates don’t expect the therapy’s effects to last forever, either. They’re already pointing to newer technologies that might overcome gene therapy’s limitations, or ways people might get a second dose if the effects of the first wane.

“A few years ago, there was a great expectation that this was going to be a ‘one-and-done’ [therapy],” Miller said. “We’ve been sobered. We know this is not the end game.”

Doctors are also trying to manage families’ expectations. After speaking with the heads of various neuromuscular clinics, Lotze, of Texas Children’s, said many large centers will treat only one or two patients per month so they can closely watch those who receive treatment.

Brandsema, too, is girding for conversations in which he’ll have to tell desperate parents to wait months before their child can get access; that a treatment isn’t just one infusion, but a lifetime of monitoring afterwards.

“Beyond everything else, we have to make sure that we keep everybody safe,” Lotze said.

Mendell acknowledges the questions facing the treatment he helped invent. “That’s what science is: show me, prove it,” he said.

Yet Mendell takes a longer view. For decades, he’s diagnosed boys with Duchenne and watched them slowly waste away. In 1999, he “dreamed that someday we would be where we are today,” he said.

Now, Mendell talks of the boys he believes he’s helping and of the hugs he gets after a child shaken by a life-threatening diagnosis feels “new stature” after treatment.

“There is no better feeling,” he said.

Editor’s note: This version of the story has been updated to reflect the Food and Drug Administration’s June 22 approval of Sarepta’s gene therapy.

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The Food and Drug Administration in late June approved the first gene therapy for the most common form of hemophilia, clearing the way for what patients, doctors and the medicine’s developer hope could be a one-time treatment for the rare bleeding disorder.

BioMarin Pharmaceutical, the California-based company behind the therapy, plans to sell it under the brand name Roctavian. It’s specifically meant to treat hemophilia A, which is caused by genetic mutations that inhibit the production of a key blood-clotting protein known as Factor VIII.

The company has set a list price of $2.9 million in the U.S., higher than the therapy’s cost in Europe, where it’s priced at about €1.5 million and has been approved since last August.

The FDA’s decision concludes a prolonged journey to the U.S. market for Roctavian. BioMarin originally filed an approval application at the end of 2019, supported by evidence from a large clinical trial that showed its therapy sharply reduced bleeding rates and the need for Factor VIII infusions in patients with severe hemophilia A.

In spite of these results, the agency unexpectedly rejected BioMarin’s application and asked the company to collect at least two years’ worth of data on each participant in that trial. Notably, the safety and long-term effectiveness of gene therapies have been a focal point for the FDA and other drug regulators. There’s also been signs that the effects of BioMarin’s therapy may wane with time.

BioMarin met this request, but late last year said the agency now also wanted to see three-year data. The company submitted those results shortly after, but, in order to allow enough time for a proper review, the FDA pushed back its review deadline to June 30.

With approval now in hand, BioMarin’s focus will turn to ensuring a successful launch of its therapy. Though the company has seven other marketed drugs, it hasn’t been profitable for most of its 26 years in operation. But analysts believe Roctavian could be the tipping point. Joseph Schwartz of SVB Securities has forecasted around $2.2 billion in peak annual sales.

BioMarin and other gene therapy developers have argued that, dosed just once, these treatments could be more cost-effective than regular Factor VIII replacements or newer, longer-acting medicines. Roche’s hemophilia A drug Hemlibra, for example, carries a list price of about half a million dollars, and has gained popularity because it can be administered as infrequently as once every four weeks.

BioMarin’s therapy won’t be available to all hemophilia A patients in the U.S., however. The FDA approved it only for patients with severe disease who test negative for a type of antibody that attacks the virus Roctavian uses to deliver its helpful genetic material into cells.

Previously, BioMarin estimated that about 20% of patients in the U.S and 30% globally would be ineligible for Roctavian because of these antibodies.

The FDA’s nod for Roctavian comes less than a year after the agency approved Hemgenix, the first gene therapy for the less common “B” form of hemophilia. It was developed by the Dutch biotech UniQure and is sold in the U.S. by CSL Behring, at a list price of $3.5 million.

Developing a new drug is a long, expensive process that comes with a high risk of failure, often because would-be medicines are unsafe or ineffective.

For companies specializing in cell or gene therapies, an equally pressing concern is figuring out how to reliably make their products. Unlike small molecule or antibody drugs, genetic medicines typically involve a variety of specialized parts woven together through a complex process.

"Ex vivo," or outside-the-body, treatments can involve a multi-week process for collecting, multiplying and modifying a patient's cells in a laboratory. Even the simpler "in vivo" therapies have multiple pieces, including engineered viruses and synthetic genetic material, that are challenging to produce at scale.

The approvals of a dozen cell- and gene-based medicines for cancer and inherited diseases in recent years has given young drugmakers a path to pursue. But most of those approvals were won by large pharmaceutical or biotechnology companies that invested heavily in manufacturing. Startups, by contrast, don't yet have that luxury.

Still, cell and gene therapy research is booming. More than 2,200 clinical trials testing these types of treatments were ongoing globally as of last year, according to the Alliance for Regenerative Medicine. The surge has often outstripped the capacity of large contract manufacturers, leaving startups facing waitlists that can stretch one to two years.

A growing group of new manufacturers aim to help. Since 2017, at least half a dozen companies have launched with plans to ease the "bottlenecks" slowing down aspiring cell and gene therapy developers. Many have been started by veterans of the young field and gotten the backing of top venture firms. Here's what they aim to accomplish and how their work is progressing:

What are the main bottlenecks in cell and gene therapy manufacturing?

Cell and gene therapies involve materials that aren't used in many of the other products the pharma industry is well-versed in producing.

Scientists design synthetic genetic material to deliver into patients, either via their own cells, benign viruses known as vectors or specially made bubbles of fat. Constructing these treatments is tricky even in a research setting, where small amounts of such material might be required for early experiments. But it's much harder for companies running clinical trials, or preparing for mass production.

Manufacturing delays can wreak havoc on young companies, causing them to miss milestones that could endanger future funding. Established gene therapy biotechs like UniQure or BioMarin Pharmaceuticals have spent years and millions of dollars to build their own plants. But startups and academic labs — where a number of the approved cell and gene therapies originated — can’t afford that.

“Academics have truly cutting-edge research, and I have been blown away by some of the creative ideas, novel modalities and breakthrough innovations that came about,” said Ran Zheng, the CEO of Landmark Bio, a Massachusetts-based company that caters to cell and gene therapy developers. “But that information needs to be translated into therapeutics, and this is the biggest, and probably the first, hurdle [startups] have to overcome.”

Turning to contract manufacturers like Thermo Fisher and Catalent can be a solution, but brings problems of its own. Transferring technology from a small lab to a larger organization can be arduous and require troubleshooting for glitches that arise in the process.

Big CDMOs may also prioritize more lucrative work with larger biotech and pharmaceutical firms. And they're struggling to meet the surging demand for cell and gene therapy manufacturing tools themselves.

Building up capabilities internally can be costly for startups. Viral vectors, for instance, are expensive to make and handle.

“You often see companies trying to own their own manufacturing and unfortunately, in this environment, if the product’s not successful, that's a heavy capital and operating expense to carry,” said Mike Paglia, a senior executive with ElevateBio, a richly funded startup that helps manufacture cell and gene therapies.

How are these startups trying to change that?

Rather than compete directly with larger CDMOs, some manufacturing startups aim to provide a more cost-efficient path for companies to develop in-house production capabilities. To appeal to younger biotechs that may need them, they are building relationships earlier and providing more services to attract first-time founders and small teams.

Many of these conversations take place long before an application to begin human testing, so these smaller manufacturers work to teach startups about raw material control strategies and set realistic timelines to gather early clinical data.

“Traditional CDMOs are like a kitchen, you'll give them a recipe and they make an entree,” said Zheng, who previously worked in manufacturing and operations at Orchard Therapeutics and Amgen. “That’s all they do. We're not like a kitchen where you just simply state the recipe. We actually ask our clients what ideas they have and we develop the recipe with them.”

Some clients start from near the beginning, working with these newer manufacturers from the moment they identify a lead candidate.

ElevateBio and Landmark Bio both help startups with laboratory studies to ensure that, down the line, they’re familiar with how to transfer their drugmaking technology to the companies that might eventually produce their therapies.

Paglia, who previously worked at Bluebird bio, said the biggest hurdle for him and his former colleagues was transferring their technology to contract manufacturers.

“Whether it was manufacturing our lentiviral vectors or cell therapy products, it took tremendous amounts of oversight to get those processes right because of the infancy of the industry,” he said.

Still, outsourcing to a dedicated manufacturer can save biotechs millions of dollars in the long term, Paglia said, allowing them to put that money toward additional clinical studies. That has meant steady demand for CDMOs, and created business for new startups trying to help.

Manufacturing startups have also attracted academics and nonprofits that struggled to get time with larger CDMOs. Landmark has worked with researchers who have received National Institutes of Health grants, for example.

Ultimately, improving manufacturing might give companies an opportunity to rethink how they price cell and gene therapies, which are some of the costliest medicines to make. The few companies that have reached market have noted these high costs in setting price tags that range from hundreds of thousands to millions of dollars.

Who are the startups in the space?

At least six biotech startups have launched since 2017 to address shortfalls in cell and gene therapy manufacturing.

The most richly funded, ElevateBio, has raised about $1.3 billion since it began working with drugmakers. It’s also spun out its own biotech startup with Boston Children’s Hospital to develop more convenient alternatives to current cancer cell therapies.

More recently, Ascend Cell & Gene Therapies in the U.K. emerged from stealth armed with $130 million in funding and led by industry veterans. It’s focused on adeno-associated viruses, a heavily used type of viral vector, and has acquired some of its capacity and technology from the struggling Freeline Therapeutics.

“AAV manufacturing is complex and needs teams that show real expertise and ownership,” said one of Ascend’s founding investors, Tim Funnell of Monograph Capital, in a statement on the company’s launch. “This led many advanced modality biotech developers to build their own internal CMC capabilities. However, these companies are now finding it difficult to sustain and fully utilize their facilities.”

There are smaller ventures, too. A pair of University of Pennsylvania researchers who worked on the cell therapy Kymriah and the gene therapies Zolgensma and Luxturna launched VintaBio in April. Months before in January, biotech startup creator Versant Ventures debuted Vector BioMed to help supply startups with the "lentiviral" vectors often used in ex vivo treatments.

What’s the status of their work?

With demand for more CDMOs at an all-time high, these startups are partnering with drugmakers straight out of the gate. Though many rely on capital infusions from venture firms, they also can generate cash from their work early on, bringing returns to investors well before a typical biotech might.

Landmark Bio had its first customer “even before we put a sign on the door,” Zheng said in October. In early June, it announced a partnership with InnDura, a new biotech company focused on “natural killer” cell research.

ElevateBio, having been around for some years, boasts a larger client list, noting in a May fundraising announcement that it added more than 15 new biopharmaceutical partners over the past year. Its subsidiary Life Edit Therapeutics is collaborating with large drugmakers like Novo Nordisk and Moderna.

VintaBio has a 22,500-square-foot facility in Philadelphia that’s now open for business, while Vector BioMed is working out of Gaithersburg, Maryland.

Shape Therapeutics is somewhat different, as it’s working on its own research, too. But it has also hinted at playing a manufacturing role, developing a new kind of cell line for producing adeno-associated viruses and indicating plans to build a factory where other companies can make their therapies.

CRISPR pioneer Feng Zhang is again making a mark in biotechnology, this time with a new startup focused on expanding the kinds of diseases genetic medicines can treat.

Aera Therapeutics officially debuted Feb. 16, announcing a combined Series A and B funding of $193 million. The company, which is headquartered in Boston, is formed around technology that’s meant to help solve one of genetic medicine’s most vexing challenges.

Gene therapy, which encompasses RNA-based medicines as well as gene replacement and gene editing applications, has been a hot area of research for biotech startups and pharmaceutical giants alike over the past decade, spurred by its potential to create powerful, long-lasting treatments for many diseases.

However, delivering gene therapies to the right area of the body for them to work remains a major obstacle. Infused genetic medicines are often limited to diseases of the liver, where they will usually end up, or to “ex vivo” applications, involving the modification of cells outside of the body.

Genetic medicines are also expensive to develop and manufacture, due in part to the high costs of the components that make them work, such as engineered viruses.

In 2021, Zhang's lab at the Broad Institute of MIT and Harvard identified a collection of proteins in the human genome that could form “capsid-like” structures capable of transporting genetic cargo within the body. One of the proteins, known as PEG10, could be engineered to "package, secrete and deliver specific RNAs," according to a Science journal article published that year.

He took that research to Bob Nelsen of Arch Venture Partners and Issi Rozen of GV, two investors with experience building gene editing companies. In September 2022, Zhang tapped former Alnylam Pharmaceuticals executive Akin Akinc to become Aera’s CEO and, more recently, longtime Alnylam leader John Maraganore to be its chairman.

The company isn’t yet working on building a pipeline of medicines, Akinc said. Instead, it’s first spending time developing its technology and identifying potential applications.

“The greatest unmet need today in terms of the genetic medicine space is delivery,” Akinc said in an interview with BioPharma Dive. “Ultimately, what we're after is a genetic medicine, and that means combining those two.”

Akinc claims Aera can address the safety and immunogenicity issues sometimes seen with current gene-based treatments. Aera is starting with human proteins, which its researchers hypothesize could lower the risk of provoking unwanted immune responses.

Cracking the code for delivery may also lead to new targets, perhaps in the central nervous system, heart or lungs, Akinc said. And it could also help with some of the problems associated with manufacturing the complex medicines.

“We’re less interested in trying to do a different way of solving a problem that's already been solved with lipid nanoparticles or viral vectors,” Akinc said, referring to the two most common ways to deliver genetic medicines.

Aera’s platform is built on work done in Zhang’s lab, where he also developed the research that led to the formation of Editas Medicine and Beam Therapeutics. Some of that technology also comes from a biotech it acquired called VNV, which Akinc described as doing “similar work” to Aera.

Arch and GV, which both bet big on gene editing company Prime Medicine, are joined by Lux Capital in leading Aera’s private financing rounds. The cash raised so far will be put to building out its team, currently numbering roughly 50 employees, Akinc said.

The company’s board of directors also includes Maraganore, former Vertex Pharmaceuticals president Vicki Sato and ex-Agios Pharmaceuticals CEO David Schenkein.

Maraganore, who advises several other biotechs, among them Beam and Orbital Therapeutics, said Aera’s technology could be “disruptive for the future of genetic medicine.”

“I'm trying to make new Alnylams, and companies like Orbital, Beam and Aera are great examples of companies I think have the potential to be the Alnylam of the future," Maraganore said.

People with the blood disorder sickle cell are anticipating the arrival of two gene therapies that could dramatically reshape their disease, potentially offering something approaching a cure.

Insurers, too, are preparing for the treatments, which are expected to carry price tags in the seven figures. While five other expensive gene therapies are already available in the U.S., sickle cell is far more prevalent than the inherited diseases they treat, affecting an estimated 100,000 people in the country. Many are covered through Medicaid, the federal insurance plan for people with limited income.

An experimental model proposed by the Centers for Medicare and Medicaid Services last week could help state agencies better afford those medicines, as well as offer a testing ground for payment schemes that could apply to other pricey gene therapies. Yet the timeline for its implementation might mean it comes after the first sickle cell gene therapies reach market.

“Sickle cell is a call to action,” said Michael Sherman, chief medical officer of Point32 Health, the parent company of Harvard Pilgrim Health Care and Tufts Health Plan.

“Without these kinds of models, we’re going to see access issues,” he added. “The Medicaid state agencies, like other parts of the financing system, were never designed with this sort of upfront shock.”

The gene therapy model is one of three pilot programs CMS will test in the coming years in response to an executive order from President Joe Biden directing the agency to find further ways to lower prescription drug costs. Administration officials described these programs as building on last year’s Inflation Reduction Act, which gave Medicare the authority to negotiate prices for a limited number of drugs.

Under the gene therapy model, state Medicaid agencies could delegate authority to CMS to coordinate multistate frameworks to pay for gene therapies based on how much patients benefit from treatment. In sickle cell, for example, payment could be contingent on whether patients remain free of the pain crises they regularly experience.

These types of payment schemes, typically known as outcomes-based arrangements, are already used in some cases for the currently available gene therapies. But budget limitations and federal price reporting requirements have limited their use within Medicaid, indirectly shaping how they’re designed for private insurers, too.

“There’s a lot of benefit, I think, to having both more of a centralized purchaser or negotiator across Medicaid programs … and having more centralized data collection,” said Stacie Dusetzina, a professor of health policy at Vanderbilt University Medical Center. “I think it also gives CMS a little bit of an upper hand at the negotiating table.”

Jeff Marrazzo, the former CEO of gene therapy developer Spark Therapeutics, agrees that a centralized approach in Medicaid could help.

“What I’ve observed is that state Medicaid agencies … generally have experienced more challenges with providing access to cell and gene therapies,” he wrote in an email. “This is due in part to the cost density of cell and gene therapies, but also because these organizations lack the infrastructure required to implement alternative pricing, reimbursement, and access models.”

Marrazzo cited data collection as one example, noting that some state agencies might lack the ability to appropriately track clinical outcomes for patients treated with a gene therapy.

CMS envisions testing several different types of outcomes-based arrangements, including an annuity model where continued payment is based on continued benefit. (To date, gene therapy developers have favored a rebate-based approach, where a certain percentage of their treatment’s cost is returned to the insurer if a specific outcome is not achieved.)

Five years ago, Spark proposed a similar annuity-based idea to help insurers pay for its then newly approved gene therapy Luxturna, for a type of childhood blindness. Spark priced the treatment at $425,000 per eye and sought to offer an installment payment plan, proposing the CMS run a demonstration project around Luxturna.

Its ability to do so was limited by Medicaid rules requiring drugmakers give the program the “best price” they offer on their products. In the event a patient didn’t benefit from treatment, and an insurer therefore didn’t owe the remaining installment payments, Spark would have had to report that fractional cost as its best price.

CMS recently tweaked its policy, allowing drugmakers to report multiple “best prices” in the context of outcomes-based arrangements. “This was an important first step,” Marrazzo wrote. “Along with the [recent] policy change, I do believe CMS providing a more centralized approach could lead to more annuity models being taken up, particularly by Medicaid plans.”

The agency plans to focus the model on a specific disease, and indicated sickle cell as a likely candidate. Behind the advancing sickle cell treatments is a growing pipeline of other gene therapies in development.

“Our concern has been that, for some of these more rare diseases, we haven't seen the access that we would like to see. Sickle cell is one of them,” said CMS Administrator Chiquita Brooks-LaSure on a call with reporters last week. “One of the reasons we're so excited about this model is because we think states need some assistance from us to really be effective in the space.”

But CMS doesn’t envision launching the gene therapy model until 2026 at the earliest, years after the two gene therapies now nearing market are expected to be approved. Their developers — Bluebird bio and partners Vertex Pharmaceuticals and CRISPR Therapeutics — are currently preparing approval applications that they expect to finish filing with the FDA this quarter.

Under current timelines, CMS would begin developing the model this year and announce model specifications in 2024 and 2025, with implementation following the year after. The agency would then track metrics like gene therapy spending, use and change in access over time to evaluate its success.

To some, earlier would be better. “Being in a business, I don’t understand why it takes two years to announce model specifications,” Sherman said.

The planned model is also voluntary, so CMS would need to rely on participation from both state Medicaid agencies and from drugmakers. The latter group, CMS argued in its report, would be enticed by the prospect of simpler market access.

That access could come with some tradeoffs, however. “It may be a little bit less attractive because of the inability to command the highest possible price, especially if there is a large population that's going to be treated and many Medicaid programs are interested in joining together into this kind of one model,” Dusetzina said.

Vertex Pharmaceuticals is mulling several options for pricing its experimental gene editing therapy for sickle cell disease ahead of an expected regulatory decision later this year, executives told investors on an Aug. 2 conference call.

The company, which developed the treatment with CRISPR Therapeutics, is currently talking through payment and reimbursement with both government and commercial insurers, aiming to have coverage in place upon a U.S. approval.

These types of discussions are standard practice ahead of a Food and Drug Administration decision. But they are more complicated for Vertex and CRISPR’s therapy, which is called “exa-cel” and envisioned as a one-time, potentially curative treatment for severe sickle cell and beta thalassemia, another genetic blood disorder. Like other gene therapies that have been launched in the U.S., it is expected to be expensive, possibly around $2 million per treatment by one estimate.

“We are considering a range of different options,” Stuart Arbuckle, Vertex’s chief operating officer, said on Wednesday’s call. “If you ask one payer what they’re looking for, you get one answer. If you ask another payer, you get another answer.”

“Right now, we’re in listening mode and designing what the nature of our payment models will be,” he added. “But I think the key word is flexibility.”

Drugmakers have previously launched gene therapies with pricing schemes meant to defray the risk of paying a seven-digit price tag, only for treatment not to work. For example, Bluebird bio said it would reimburse up to 80% of the $2.8 million cost for its beta thalassemia treatment Zynteglo if treated patients didn’t improve as expected.

However, these “outcomes-based” models can be challenging to make work in practice, particularly within Medicaid, the federal insurance plan for people with limited income. The Centers for Medicare and Medicaid Services recently proposed a model to help state Medicaid agencies explore outcomes-based payment, but it’s not set to be in place until 2026.

“Without these kinds of models, we’re going to see access issues,” Michael Sherman, chief medical officer of Point32 Health, told BioPharma Dive in an interview earlier this year. “The Medicaid state agencies, like other parts of the financing system, were never designed with this sort of upfront shock.”

Approximately two-thirds of patients with sickle cell or beta thalassemia have government health insurance, with the majority covered by Medicaid, Vertex estimates.

The company has been in contact with the Medicaid administrators in all 50 states, Arbuckle said Wednesday. It’s focusing in particular on the 24 states with the highest sickle cell prevalence. He called CMS’ proposed model “clear evidence of the federal government's recognition of the potential transformative value of gene therapies like exa-cel to treat sickle cell disease.”

Vertex is also having discussions with commercial insurers, which Arbuckle described as “encouraging.”

Still, the company is setting expectations for a relatively slow launch. Treatment requires a monthslong process of extracting patient stem cells, editing them in a laboratory and then reinfusing them back into the body.

Before that final step happens, patients must also receive a “conditioning” chemotherapy regimen that’s meant to clear space in the bone marrow for the edited stem cells to take root. This can be toxic and may factor into many patients’ decision-making around whether to pursue gene therapy.

“This launch we do expect to be slightly slower in uptake rates than in cystic fibrosis,” said Arbuckle, referring to the company’s past experience with cystic fibrosis drugs. “We continue to believe there's a lot of interest. It's a big market opportunity and we see [the therapy] as a multibillion-dollar opportunity in the future.”

Analysts at RBC Capital Markets expect the conditioning regimen and other market challenges to limit adoption of Vertex and CRISPR’s therapy to a “narrow niche of very severe patients willing to undergo the procedure,” according to a recent investor note.

They currently estimate a “conservative” $900 million in out-year annual sales.

The FDA split its review of Vertex and CRISPR’s therapy, considering the drug’s use in sickle cell and beta thalassemia separately. The agency expects to decide on approval in the former indication by Dec. 8, and in the latter by March 30.

Before those dates, the FDA will convene a panel of independent advisers to discuss the therapy’s merits, Vertex confirmed Tuesday.

As a top regulator at the Food and Drug Administration, Peter Marks isn’t responsible for weighing the cost of the treatments his teams review. But he is worried that some of the drug industry’s most promising medicines may not reach patients with uncommon diseases if companies can’t figure out how to sell them.

There are an estimated 7,000 rare diseases, many of which affect only small groups of people. Genetic medicines, including RNA-based drugs and gene replacement therapies, could offer a powerful way to treat, and potentially even cure, some of them. But for would-be developers, diseases affecting only a few dozen people might not represent a large enough market to justify the cost of developing and selling a new treatment.

“We're not going to find enough philanthropic groups to foot the bill for gene therapies for the hundreds upon hundreds of different diseases that need to be addressed,” said Marks, head of the FDA’s Center for Biologics Evaluation and Research, at a conference hosted by the Alliance for Regenerative Medicine on Oct. 12.

“We're gonna have to find a way to make this commercially viable so that industry can find a way forward towards this."

According to Marks, commercial viability for a gene therapy means administering roughly 100 to 200 treatments a year, a threshold that could be difficult to clear in a single country for rare conditions like severe combined immunodeficiences or adrenoleukodystrophies.

“It has not escaped our attention at FDA that there have been some clouds on the horizon in gene therapy,” said Marks, noting instances when gene therapies were taken off the market or returned by their developers to the original academic researchers.

In Europe, for example, first GSK and then Orchard Therapeutics abandoned one of the first gene therapies approved there, a treatment called Strimvelis for a condition known as ADA-SCID. Only a few dozen patients were ever treated, and Orchard has also handed back rights to a successor treatment. More recently, Bluebird bio withdrew two gene therapies from the EU market after running into difficulties securing reimbursement in several European countries.

Bluebird recently won FDA approval for both of those therapies in the U.S. One, to be sold as Skysona at a cost of $3 million, is for an inherited condition known as CALD that affects about 50 boys each year. Bluebird has said it expects to treat around 10 each year.

In his remarks to the conference, known as the Meeting on the Mesa and attended by many in the cell and gene therapy field, Marks highlighted a few areas where the FDA could help ease hurdles for ultra-rare disease treatments.

The agency is currently putting together a “cookbook” for developing and manufacturing of bespoke gene therapies, which could help academic groups more easily transfer treatments they’re working on to industry. It’s also looking into how to use non-clinical and manufacturing data from one application to speed the review of others that share similar technology.

“There are certain pieces of gene therapies that are not like your typical small molecule drug, because they're reused repeatedly,” Marks said.

Automated manufacturing could be another solution to help lower the costs of production, which are significantly higher for cell and gene therapies than for other more established drug types.

The FDA is also hoping to get on the same page with other regulators so that developers could be more confident a product they gain approval for in one country would have a good chance of success in others.

“Some of [these problems] may relate to how we can make gene therapies for small populations more widely available,” Marks said. “What may be a tiny population in the U.S. becomes a reasonable sized population when you go globally.”