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.”

Sarepta has asked the Food and Drug Administration for an “accelerated” approval, a type of clearance that’s used to speed treatments for serious diseases like Duchenne to market. The company’s case is 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. An approval, if granted, would set a precedent for other gene therapy developers to follow, raising the stakes of the agency’s decision.

The FDA is expected to issue its verdict by late June, 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. In May, the regulator convened a group of outside experts to discuss it — a meeting reportedly scheduled because of intra-agency disagreement about the strength of Sarepta’s application. The experts narrowly recommended the FDA grant an OK.

“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.

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 would signal the FDA’s comfort with medicines that use “truncated,” rather than full-sized, genes, said Stifel analyst Ha. 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. The risk of a study failure months after an approval could give regulators pause, however.

One former senior FDA official, who was granted anonymity to discuss the agency’s forthcoming decision, speculated the regulator might ask panelists to vote on whether a decision should be delayed until Sarepta releases data.

“The fact that they have a trial reading out relatively soon after the [decision] date is a big problem,” the official said. An approval would “let the genie out of the bottle. You’re not going to be able to put it back in if that trial is negative.”

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.

Sometime this spring, a person with the inherited blood disease beta thalassemia received an infusion containing hundreds of millions of their own stem cells. These cells had just completed a round-trip journey to a drug manufacturing facility, where they were equipped with a modified gene capable of fixing the patient's condition.

The infusion was the first commercial use of a gene therapy approved by the Food and Drug Administration in August. Called Zynteglo, the treatment is the result of more than a decade of research by biotechnology company Bluebird bio. Its approval offered validation to Bluebird and to the broader gene therapy field, which over the past two years has struggled through safety concerns as well as clinical and regulatory setbacks.

Zynteglo's approval, as well as three other FDA OKs since, has gene therapy developers looking ahead. "If you take a step back, I think that what we've gone through in the last couple years is just part of a maturation process," said Faraz Ali, the CEO of Tenaya Therapeutics and an executive at Bluebird from 2011 to 2016.

That process is still playing out, though, and this year companies in the space face a number of important questions. Here are five:

Will approvals lead to commercial successes?

The recent gene therapy approvals — for Zynteglo, Bluebird’s Skysona, CSL’s Hemgenix, Krystal Biotech’s Vyjuvek — are more than the FDA granted in the five years previous.

Others could soon follow. The industry group Alliance for Regenerative Medicine, or ARM, predicts 2023 could bring at least five more gene therapies for rare diseases to the U.S. market, including potential new treatments for sickle cell disease, Duchenne muscular dystrophy and hemophilia A.

But regulatory clearances lead to the even harder test of marketing complex, expensive and unfamiliar treatments. While Novartis’ relative success with Zolgensma — the second gene therapy OK’d in the U.S. — shows what’s possible, the industry has had a poorer commercial track record in Europe, with several companies later withdrawing approved medicines. Bluebird, for instance, pulled from European markets both of the treatments that it is now trying to sell in the U.S.

Geoff MacKay, CEO of the gene therapy developer Avrobio, described 2023’s key theme as “commercial viability.”

“We are at a tipping point in gene therapy supported by real data, real milestones and real patients’ lives changed,” he added in an email.

Accomplishing that will be the challenge faced by Bluebird and CSL as well as any other biotech companies that secure an FDA approval.

They’ll face scrutiny over pricing. Both Bluebird and CSL set list prices of several million dollars for their therapies, citing the years of benefit they’re expected to deliver for patients. So far, insurers don’t appear to be pushing back strongly, but that might change when the gene therapies in question affect larger numbers of people.

They’ll also need to prove that they can reliably produce at larger scale treatments that in clinical testing were used only in scores of patients.

“Like all areas of medicine, there will be both winners and losers, but progress through 2023 will provide more clarity on the recipe for success,” MacKay said.

Can the FDA hire fast enough to stay ahead of the growing field?

Behind the gene therapies on the cusp of U.S. approval is a pipeline of experimental therapies swelled by the dozens of biotech companies that jumped into the field over the past decade.

It makes for a lot of work for the FDA, which must weigh in on clinical trial starts and provide regular counsel to companies throughout the development process. At the same time, the FDA center that oversees gene therapies has had difficulties keeping staff, stretched thin by the pandemic and its related vaccine review workload.

“They’ve clearly had some turnover,” said Timothy Hunt, head of ARM. “That has led to some challenges.”

The agency will be getting reinforcements, however, with a planned uptick in hiring following new user fee agreements with drugmakers. The Center for Biologics Evaluation and Research, or CBER, stands to gain nearly 200 new staff over the next two fiscal years.

“This is going to be a big area of emphasis at the FDA,” Commissioner Robert Califf told investors and industry professionals attending the J.P. Morgan Healthcare Conference in San Francisco in January. “There’s a very nice increase in budget for CBER to hire a bunch of people.”

“So we do have jobs, those of you who are tired of investing or whatever,” he quipped.

Additionally, the FDA elevated the division in charge of gene therapies specifically — the Office of Therapeutic Products — to “super office” status, giving it more autonomy and authority.

Drugmakers are watching closely. “The expansion of [OTP] paired with increased regulatory maturity and a promising stream of regulatory activity ... is a signal to the industry that the door is open for innovation,” wrote Avrobio’s MacKay.

How will gene therapy startups fare in a prolonged downturn?

Genetic medicine companies weren’t spared from last year’s biotech market reversal, with more than a dozen cell and gene therapy specialists forced to cut jobs over the course of 2022. That count included relatively large and mature companies like BioMarin Pharmaceutical and Bluebird, as well as high-profile startups like Passage Bio and Tasyha Gene Therapies.

With this year’s financial outlook uncertain, the sector may see more consolidation, particularly given the often expansive pipelines that many gene therapy biotechs touted when markets were more favorable. Taysha, for instance, once listed 18 programs in its pipeline and boasted of plans to launch a product every two to three years.

Gene therapy development is also expensive, requiring biotechs to make costly choices around manufacturing.

Already, Editas Medicine, a leading biotech in CRISPR gene editing, in January announced plans to cut back investment in several clinical-stage therapies and lay off 20% of its staff.

“Oftentimes you see that the corners of the sector that are the most cutting-edge ... get it a little bit more disproportionately than others,” said Hunt, of ARM. “But I think it’s balanced out by the realization that the FDA and the [European Medicines Agency] are rewarding innovation.”

MacKay also noted the field’s recent regulatory and clinical progress, but added that he expects investors to remain wary.

“The data will eventually pull the public markets along, but it may take a long time,” he wrote. “Until then, this tough financing environment will spur more restructuring, consolidation, pipeline reprioritization, M&A, market de-listings and, unfortunately, bankruptcies.”

What do recent clinical holds say about the FDA’s views on gene editing?

If all goes to plan, 2023 could see the first FDA approval of a CRISPR gene editing medicine. CRISPR Therapeutics and Vertex Pharmaceuticals currently expect to finish submitting an application to the agency by the end of March, potentially setting up a consequential decision from the regulator later this year.

Developed for sickle cell and beta thalassemia, CRISPR and Vertex’s medicine builds on the long history of stem cell transplantation, using the gene editing technique to modify a patient’s own stem cells in a laboratory, or ex vivo.

An approval would represent a remarkable achievement for a field catalyzed by scientific breakthroughs made just a decade ago. Already, developers have moved quickly to explore gene editing directly inside the body, or in vivo. Intellia Therapeutics, for one, has reported clinical trial results for CRISPR medicines used in vivo to treat two rare genetic diseases.

But in the U.S., there are some signs of caution from the FDA when it comes to in vivo gene editing. The agency has put on hold a study by Verve Therapeutics that uses a newer iteration of CRISPR-based gene editing inside the body, for example.

Safety is of paramount concern when editing genes, both because of the theoretical potential for off-target changes to DNA and the permanence of such modifications.

“Regulatory agencies quite rightly should be cautious,” said Editas CEO Gilmore O’Neill. “That is their job. I think it is our job to make sure that, as we advance our new technologies — and advancing in vivo is an example — we need to be very rigorous about our approach to managing risk.” (Editas is now prioritizing in vivo gene editing.)

Still, the go-slow approach contrasts somewhat with outside the U.S., where Intellia is conducting its studies and Verve has begun human testing of its medicine.

“We're the first in front of the agency with this kind of product,” said Verve CEO Sek Kathiresan, referring to a base editing medicine in a January interview. “So we're really working it out in real time with them in terms of regulatory expectations for this product."

Kathiresan noted Verve is working through the FDA’s questions following the study hold and said “it’s a matter of when, not if” it can address the agency’s questions.

Can the business model work for ultra-rare conditions?

Many genetic disorders being targeted by gene therapy developers are uncommon, affecting several thousand or a few hundreds of people in a given country. Others are rarer still, found in only a few dozen individuals or even just one or two people — conditions sometimes referred to as “n of one” diseases.

For many of these conditions, the promise of genetic medicines can be great. Treatments for several types of severe combined immunodeficiency, for instance, could be curative. But, despite developing powerfully effective treatments, drugmakers have backed off, deprioritizing SCID gene therapies.

Even the prospect of being able to price treatments in the millions of dollars might not be enough, if companies need to spend much more to collect the needed evidence and can only treat a few patients.

“When you’re talking about dozens of patients, it is tricky to think through how you can capture the appropriate value to the patient,” said ARM’s Hunt. “That has been hard and will be tricky in the future.”

A down market in biotech makes the financial calculus even harder, potentially forcing companies to prioritize projects with greater chances of earning a return on investment.

It’s a problem that regulators are watching, too.

“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 Peter Marks, head of the FDA’s CBER, at a conference in October.

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

He put forward a few proposals for how his agency could lower hurdles for developing therapies for ultra-rare diseases, such as using data from one application to speed review of others using the same technology.

Meanwhile, in the U.S., Bluebird will put the model to the test. It expects to treat only 10 patients a year with its newly approved gene therapy Skysona, for a rare childhood brain disease.

Jacob Bell and Ben Fidler contributed reporting

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      1. Metadata fields are unified, not redundant

Author-submitted metadata vary widely.  Manual curation of field names can enforce alignment to a set of well-defined standards.  Our curators identify hundreds of columns containing frequently-used information across studies and combine these data into unified columns to enhance cross-study analyses.  This unification is evident in our TCGA metadata dictionary, for example, where we unified into a single field the five different fields that were used to indicate TCGA samples with a cancer diagnosis of a first-degree family member. 
 

      2. Data labels are clear and consistent

Unfortunately, it’s common that published datasets provide vague abbreviations as labels for patient groups, tissue type, drugs or other main elements. If you want to develop successful hypotheses from these data, it’s critical you understand the intended meaning and relationship among labels. Our curators take the time to investigate each study and precisely and accurately apply labels so that you can group and compare the data in the study with other relevant studies. 

      3. Additional contextual information and analysis

Properly labeled data enables scientifically meaningful comparisons between sample groups to reveal biomarkers. Our scientists are committed to expert manual curation and scientific review, which includes generating statistical models to reveal differential expression patterns. In addition to calculating differential expression between sample groups defined by the authors, our scientists perform custom statistical comparisons to support additional insights from the data.
 

     4. Author errors are detected

No matter how consistent data labels are, NLP processes cannot identify misassigned sample groups, and such errors are devastating to data analysis. Unfortunately, it’s not unheard of that data are rendered uninterpretable due to conflicts in sample labeling presented in a publication versus its corresponding entry in a public ‘omics data repository. As shown in Figure 2, for a given Patient ID, both ‘Age’ and ‘Genetic Subtype’ are mismatched between the study’s GEO entry and publication table; which sample labels are correct? Our curators identify these issues, and work with authors to correct the error before including the data in our databases.

 

Figure 2. In this submission to NCBI GEO, the ages of the various patients conflict between the GEO submission and the associated publication. What’s more, the genetic subtype labels are mixed up. Without resolving these errors, the data cannot be used. This attention to detail is required, and can only be achieved with manual curation. 

 At the core of our curation process, curators apply scientific expertise, controlled vocabularies and standardized formatting to all metadata. The result is that you can quickly and easily find all applicable samples across data sources using simplified search criteria. 

Dig deeper into the value of QIAGEN Digital Insights’ manual curation process

Ready to incorporate into your research the reliable biomedical, clinical and ‘omics data we’ve developed using manual curation best practices?  Explore our QIAGEN knowledge and databases, and request a consultation to find out how our manually curated data will save you time and enable you to develop quicker, more reliable hypotheses. Learn more about the costs of free data in our industry report and download our unique and comprehensive metadata dictionary of clinical covariates to experience first-hand just how valuable manual curation really is. 

References:  

1. Callahan TJ, Tripodi IJ, Pielke-Lombardo H, Hunter LE. Knowledge-based biomedical data science. Annu Rev Biomed Data Sci. 2020; 3:23–41.  

2. H. Sarih, A. P. Tchangani, K. Medjaher and E. Pere Data preparation and preprocessing for broadcast systems monitoring in PHM framework. 6th International Conference on Control, Decision and Information Technologies (CoDIT). 2019; 1444–1449.  

3. Big data to good data: Andrew Ng urges ML community to be more data-centric and less model-centric (06/04/2021) https://analyticsindiamag.com/big-data-to-good-data-andrew-ng-urges-ml-community-to-be-more-data-centric-and-less-model-centric/