The Food and Drug Administration in November approved the first gene therapy for a type of hemophilia, giving people with the inherited disorder a treatment option that could potentially keep their bleeding in check for years while also allowing them to skip the infusions that have been the standard of care.

The therapy, called Hemgenix and developed by the Dutch biotechnology company UniQure, is for the less common “B” form of hemophilia, which is estimated to represent about 15% of all patients with the disease.

“Gene therapy for hemophilia has been on the horizon for more than two decades,” said Peter Marks, head of the FDA’s Center for Biologics Evaluation and Research, in a statement. “[The] approval provides a new treatment option for patients with hemophilia B and represents important progress in the development of innovative therapies for those experiencing a high burden of disease associated with this form of hemophilia.” 

Australian drugmaker CSL, which licensed Hemgenix from UniQure and will market the drug, set the treatment’s list price at $3.5 million, making it the most expensive medicine in the U.S. on a single-use basis. 

In a statement, the company said it is confident that the price “will generate significant cost savings for the overall healthcare system and significantly lower the economic burden of hemophilia B.” 

The Institute for Clinical and Economic Review, an influential nonprofit that assesses drug costs, previously estimated Hemgenix could be cost effective at a price of $2.9 million. The group cited the therapy’s benefit in clinical testing, as well as the high cost of current treatment.

Hemophilia B is caused by missing or low levels of a critically important protein called Factor IX that the body needs to effectively clot blood. Depending on the amount of Factor IX present, people with the condition experience spontaneous or excessive bleeding that can cause serious health complications.

To prevent this, treatments consisting of replacement Factor IX are taken routinely — a regimen that many patients consider burdensome to daily living. (While women can have hemophilia B, most individuals who experience symptoms are men.)

“Anecdotally, what we hear from the gentlemen who have gone through this treatment is they’re really enjoying not having to think about their hemophilia anymore,” said Steven Pipe, a professor of pediatrics and pathology at the University of Medicine who led the main trial testing Hemgenix. “You’re not doing infusions anymore. You’re not scheduling your life around your prophylactic therapy.” 

In that study Pipe helped run, 54 adult men with severe or moderately severe hemophilia B were given Hemgenix and tracked for changes in their Factor IX levels, as well as bleeding rates and use of standard replacement therapies. 

After 18 months, treatment raised Factor IX levels to amounts that were, on average, typically considered equivalent to “mild” hemophilia. The annualized bleeding rate was sharply reduced and participants were largely able to stop taking replacement Factor IX. 

Meant to be a one-time treatment, Hemgenix is designed to replace the gene that encodes for Factor IX and is defective in people with hemophilia B. A specially engineered virus, known as AAV5, is used to shuttle a functioning version of the gene into the liver, where it’s taken up by cells and spurs production of Factor IX. 

Its development has been years in the making. Hemophilia was one of the first diseases identified as a good candidate for gene therapy. A landmark 2014 study of a treatment similar to Hemgenix showed the potential for long-term bleeding control. 

UniQure, which was originally known as Amsterdam Molecular Therapeutics, extended that research, first developing and testing a prototype gene therapy using the AAV5 virus. It then tweaked that version further to make what’s now approved as Hemgenix. (In testing, Hemgenix was known as AMT-061, or etranacogene dezaparvovec.) 

In 2020, UniQure sold rights to Hemgenix to CSL for $450 million upfront, with additional payments promised depending on the achievement of regulatory and commercial milestones.

Development was stalled, however, by a case of liver cancer in one study participant, which prompted the FDA to temporarily suspend testing. UniQure later determined the cancer was unrelated to treatment, but the delays pushed back when it and CSL applied for regulatory approval. 

Michigan’s Pipe noted that many people with hemophilia have hepatitis C or other liver problems that raise their risk of cancer. He pointed to the longer follow-up for participants in the 2014 study and the earlier work UniQure did with Hemgenix’s predecessor as further evidence of the low cancer risk. 

“We still need to do epidemiological follow-up on a global scale for patients who undergo gene therapy to make sure that we don't see some accumulating safety signal in malignancy or any other adverse event risk,” he said. 

CSL’s therapy is also under review in Europe. There, European regulators have approved a gene therapy from BioMarin Pharmaceutical for the more common hemophilia A.

The FDA is set to make a decision on BioMarin’s treatment, called Roctavian, next year. The agency originally planned to consult an advisory committee, but in November the company disclosed the FDA is no longer planning to do so.

Until this August, just two gene therapies for inherited diseases were available in the U.S. Now, in the span of one month, that count has doubled, with the Food and Drug Administration approving new treatments for a rare blood condition and a childhood brain disorder.

The agency’s decisions, delivered Aug. 17 and on Sept. 16, represent a turnaround for the gene therapy field after a series of setbacks had slowed progress. They also offer a lifeline to the treatments’ developer, the Massachusetts-based biotechnology company Bluebird bio, which is running out of money and earlier this year warned investors it may not be able to stay afloat.

Selling the two gene therapies could help Bluebird survive. More broadly, the company’s success or failure launching the treatments will be a signal to other gene therapy developers nearing the FDA, among them CSL, BioMarin Pharmaceutical and PTC Therapeutics.

“We've had to cross this desert for years and, all of a sudden, we have the two-fer from Bluebird,” said Geoff MacKay, CEO of a gene therapy biotech called Avrobio. “For those of us who have been in the field for a decade plus, this is an incredible period of time.”

Bluebird’s development of its newly approved treatments dates back just as long, to when the company, then named Genetix Pharmaceuticals, was an early explorer of gene therapy. Renamed in 2010, the company came to be seen as a leader in the field, which after many lean years was benefiting from improved scientific tools and renewed investor interest.

FDA approvals of the first two gene therapies, a blindness treatment called Luxturna and the neuromuscular disease therapy Zolgensma, in 2017 and 2019 were a further proof point, spurring predictions of a coming wave of gene-based medicines.

More recently, though, gene therapy development has been marked by renewed questions around safety, manufacturing missteps and more conservative regulatory decision making. Bluebird hasn’t been immune. It has run into repeated delays due to disagreements with the FDA over gene therapy production, while cases of cancer in its clinical trials slowed testing further.

That Bluebird was still able to persevere and win back-to-back approvals is an encouraging sign for other companies in the field, according to MacKay. The FDA and its advisers were also willing to balance the cancer risk associated with Bluebird’s treatments against their benefits, suggesting a degree of comfort with gene therapy technology more broadly.

“The more clarity, the more this is a well-traveled path, the more it facilitates drug development [and] changes investor confidence,” MacKay said in an interview ahead of the Sept. 16 FDA clearance.

But as a result of its setbacks, Bluebird is arriving on the market in a precarious position. Its stock price has tumbled precipitously over the past five years and its funds have dwindled to such a low level that the company was forced to acknowledge the risk of insolvency. To save money, Bluebird laid off 30% of its staff and moved its headquarters. In March, it lost its chief financial officer and her replacement will depart this fall.

Neither of its new gene therapies, called Zynteglo and Skysona, are expected to become big sellers, despite prices that rank as among the most expensive for any drug. Bluebird will charge $2.8 million for Zynteglo and $3 million for Skysona, although it has offered to reimburse part of Zynteglo’s cost if patients don’t benefit.

The company expects to treat about 50 patients initially with Zynteglo, and eventually many more of the estimated 850 or so who are healthy enough to receive the treatment. The market for Skysona, which treats a brain disorder called cerebral adrenoleukodystrophy, is smaller still, with Bluebird anticipating it will treat about 10 patients each year.

The next step for Bluebird will be convincing insurers to cover its therapies, which would likely otherwise be out of reach for patients and their families. While it’s confident it can do so, the company ran into significant difficulties in Europe, where Zynteglo and Skysona were approved previously, and later withdrew both products from the market.

“With Zynteglo, we are several weeks into our launch now and we are getting a lot of positive feedback from payers,” said Tom Klima, Bluebird’s chief commercial and operating officer, on a call with analysts Sept. 19. The company has signed multiple contracts so far.

“We feel confident that payers will support Skysona,” he added.

Crucially for Bluebird, the approvals of Zynteglo and Skysona both came with so-called priority review vouchers granted by the FDA. These vouchers can be used to shorten regulatory reviews for new drug applications and may be sold to other companies. Recently, they’ve commanded prices between $100 million and $110 million, giving Bluebird an opportunity to secure significant funding that’s not dilutive to its existing shareholders.

“We do not need them because the therapies we develop have priority review in general,” said Bluebird CEO Andrew Obenshain in an interview. “So we will sell both — sequentially, though, not all at once.”

Bluebird held $218 million in the bank as of June 30, and expects its restructuring efforts will bring its cash burn down to about $60 million per quarter by the end of this year. That level of spending will be sufficient to launch Zynteglo and Skysona, as well as prepare to file for approval of a third gene therapy for sickle cell disease next year, the company’s outgoing CFO Jason Cole said on the Sept. 19 call.

In recent years, gene and cell therapy treatments researched since the 1970s have advanced significantly. Since the first cell and gene therapies were approved for clinical use in the U.S. in 2017, we’ve seen a shift in medicine, as these potentially lifesaving, one-and-done treatments are finally reaching patients. 

Members of the American Society of Gene and Cell Therapy have been instrumental in this progress, so we’re always adding programming and other benefits to help them further the field. If you’re not familiar with ASGCT, or if you haven’t been a member in a while, we’d like to show you why now is the best time to join.

By joining us in 2023, you can leverage these career-building resources: 

Share your research at the ASGCT Annual Meeting, the premier event for professionals in cell and gene therapy. We want to see what you’ve been working on in the lab! Send us an abstract for the opportunity to present your work live and in person at the 26th Annual Meeting in Los Angeles, CA. The Annual Meeting has always been our biggest event, and now we’re expanding it to four full days. That means more time to share your discoveries at the largest gathering of the field’s professionals. ASGCT members receive discounted registration.

If you’re selected to present an abstract at the meeting, you’ll be able to discuss your work with thousands of colleagues and leaders in the field. Your research is the most exciting part of the meeting—it shows what’s possible for people with rare diseases who may have no other treatment options. Have a late-breaking discovery? We’ll have a separate submission window for data that is high-impact, groundbreaking, innovative and newsworthy. 

Depending on your ASGCT membership type, you may be eligible for awards or free Annual Meeting registration when you submit an abstract. Associate members who are first and presenting abstract authors always receive free registration. They may also be eligible for Meritorious Abstract Travel or Underrepresented Population Travel awards. Learn more about awards here.

Win an award for a high-impact project. When it’s not Annual Meeting season, you can still apply for awards to support your work. Every year, ASGCT gives out six $100,000 Career Development Awards, which support independent transformative pilot studies in cell and gene therapy. In 2021, we began offering three Diversity, Equity and Inclusion Awards. Created to promote justice and equity in the field, the DEI awards total $250,000 and support the work of ASGCT members from underrepresented populations. Check out these awards and others, like our new Science Communication and Best of Molecular Therapy awards, on our website.

Publish your work in the Molecular Therapy family of journals. As an ASGCT member, you can get your research published in one of our four field-leading journals at a reduced members-only rate. In 2021, the impact factor of our flagship Molecular Therapy increased to 12.9—the highest value in its history. Additionally, all four journals rank above the 80th percentile in their top category. Become a published author and submit your research to our respected journals today!

Expand your skills to advance your career. Our event offerings have continued to grow in the last couple of years so we can provide our members with the latest knowledge about the field. We started the free-for-members Insight Series last year as a way to dive deeper and further explore committee-selected topics, like long COVID, AAV gene therapy and the ethics of inserting genes into the human genome. We also offer free monthly professional development events with speakers covering early-career topics like building a successful team, starting your own company and crafting an elevator pitch about your scientific work. We don’t expect to stop in 2023. 

Miss an event or want to watch something again? Members always have on-demand access to all archived events.

Advance Your Career—and the Field as a Whole—Today: Join ASGCT to Become Eligible for These Benefits and More

We rely on our members to help us advance the field and we hope you’ll consider joining our society. Anyone with a demonstrated professional interest in the field is invited to ASGCT. If you’re looking to connect with peers, develop your professional skills or share and win an award for your work, become a member now.

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.”

Despite safety concerns and pushback from drug regulators, gene therapy continues to be an area of interest to biopharmaceutical dealmakers, as shown by a recent spate of activity.

In mid-October, Akouos, a Boston-based developer of gene therapies for hearing loss, agreed to be bought by Eli Lilly in a deal that could be worth north of $600 million. Less than a week later, on Oct. 23, Applied Genetic Technologies Corp. said it would be taken private through an acquisition by the life sciences investing company Syncona.

And the following day, the Japan-based pharmaceutical firm Astellas Pharma announced a $50 million investment in Taysha Gene Therapies, which is advancing treatments for rare neurological disorders.

To some on Wall Street, these deals are a positive sign for an area of drug research that drove immense excitement several years ago, but has since weathered setbacks. Safety scares like those seen in clinical trials run by Pfizer, UniQure, Bluebird bio and others drew scrutiny from the Food and Drug Administration, which last year held a special meeting to discuss the risks of gene therapy.

Safety hasn’t been the only issue, either. In recent years, experimental treatments from Biogen, Sarepta Therapeutics and Amicus Therapeutics came up short in key trials testing their effectiveness. And for Editas Medicine, positive, albeit early, results from a study of its CRISPR-based gene editing therapy were met with disappointment from some investors, with company shares subsequently sliding in value.

To Dae Gon Ha, an analyst at the investment firm Stifel, the fresh string of deals could be seen as a “boon” for gene therapies targeting rare diseases. “We agree that an onslaught of [mergers and acquisitions] in such a short period can add a much-needed sentiment shift to a sector that's been in investors' penalty box for much of 2022,” he wrote in an Oct. 25 note to clients.

However, Ha also wrote that these deals don’t necessarily mean the gene therapy space is “out of the woods yet.”

For example, Ha noted how these deals are “noticeably smaller” in value — both in comparison to the gene therapy acquisitions seen a few years ago, like that of AveXis and Spark Therapeutics, and to other, more recent ones targeting different drugmaking technologies.

Several factors may have influenced these lower deal values. A record amount of funding flowed into gene therapy research over the last few years, leading to the creation of more companies, many of which are still relatively small. Akouos, for instance, was founded in 2016, and by the end of this February had just over 100 employees.

But with greater competition, and amid a historic downturn in the biotechnology stock market, money has been harder to come by, forcing a number of companies to cut costs and trim their workforces. As a result, some gene therapy developers could be more willing to consider cheaper offers.

The investment firm Cantor Fitzgerald reviewed five gene therapy acquisitions, including Lilly’s planned purchase of Akouos, and found the more recent ones have taken longer to agree upon final costs. Cantor analyst Kristen Kluska wrote that her team suspects “most of this is driven by recent weakened market conditions.”

Given the setbacks experienced by the gene therapy field, the newer deals may also suggest buyers are more interested in programs that are “de-risked” to some degree. In the case of Akouos, the FDA in September cleared the company to begin human testing of its most advanced therapy — a milestone that regulatory filings show prompted Lilly to renew acquisitions talks.

Akouos also had a narrow focus, which has been true of other gene therapy acquisitions. Nightstar Therapeutics, purchased by Biogen for roughly $800 million, was developing treatments specifically for eye diseases, while Audentes Therapeutics and Prevail Therapeutics, bought respectively by Astellas and Lilly, centered their research around neurological conditions.

In spite of the caveats, the three deals from the past month could at least signal a growing comfort from buyers and investors “in the risk/reward profile of gene therapy, companies' compelling valuation, or both,” according to Ha.

“In sum, the recent transactions and announcements are undoubtedly encouraging for the sector,” Ha wrote, “but the acquirer's selectivity of assets, capital commitment, and what the acquirer ultimately brings to the table buffer greater enthusiasm, in our view.”

Gene editing startup Prime Medicine raised $175 million in a mid-October initial public offering that was a rare market debut for a genetic medicine company amid an IPO slowdown. 

The Cambridge, Mass.-based startup on Oct. 20 sold about 10.3 million shares at $17 apiece. Its IPO is the sector’s sixth-largest by proceeds in 2022, and the biggest this year for a company not yet in human trials, according to BioPharma Dive data.

Though the number of biotechnology companies hitting Wall Street has slowed to a trickle in 2022, gene editing companies like Prime may have better luck due to the past successes of Beam Therapeutics and Verve Therapeutics, said Kevin Eisele, a managing director at investment firm William Blair.

Plunging stock prices shook the biotech sector this year. Young companies attempting to go public found little appetite for the sky-high valuations that were common in 2020 and 2021’s bull run of IPOs. Some investors described that period as resulting from "a lack of discipline.”

Recently, companies have been more likely to try and prolong the cash raised in Series B rounds or raise additional private funding before making a debut on the Nasdaq. A few have opted for alternatives such as reverse mergers.

Though the rate of biotechs going public remains slow, the market hasn’t scared off all companies.

According to Eisele, the appetite for gene editing IPOs is “immense.”

“It's a technology that has the ability to really serve patients who have debilitating genetic diseases that don't necessarily have a lot of alternatives, and so the market opportunity here is really exciting,” Eisele said.

Though a company like Prime is still early in its drug discovery, it is partnered with Beam and could attract larger drugmakers as well, he said.

The ability of companies like Beam — which was co-founded by Prime co-founder David Liu — and Verve to hold their values despite the downturn could help whet investor appetite. Both are among the few companies that went public in 2020 and 2021 and are still trading above their initial stock price.

Prime's IPO is the 19th in the biotech industry this year, compared to more than 90 this time last year, according to data from BioPharma Dive. Prime’s IPO follows on the heels of Third Harmonic Bio’s successful public offering in September. A cancer drug startup, Acrivon Therapeutics, filed to go public on Monday, and two other small drugmakers, Intensity Therapeutics and Alopexx, are scheduled to price offerings this week.

Prime is a “platform” biotech, built around a gene editing technology it will use to develop several medicines, rather than a “product” biotech concentrated more closely on a single drug. 

Prime initially aimed for a roughly $160 million IPO after raising more than $315 million in private financing, regulatory filings show. The company priced within its projected $16 to $18 per share range, but raised its IPO total by selling about 1.6 million more shares than intended, a sign of investor interest in the offering. That figure could climb higher if underwriters exercise their right to buy another 1.5 million shares at the IPO price.

Prime claims its “prime editing” is more precise than other CRISPR-based gene editing techniques. Though it shares some similarities with CRISPR, it can swap out specific DNA letters as well as edit out or add sequences of nucleotides.

The company has 18 research programs across diseases of the blood, liver, ear, eye and lung. None are in human trials. Its IPO filing did not reveal when it expects to begin its first Phase 1 trial.

When Misty Lovelace was a baby, her eyes were drawn to the light.

She could not focus on faces, only sources of light. Her grandmother Cynthia Lovelace, who would become her main caretaker, suspected vision problems.

By age three, Misty was diagnosed as legally blind. School systems struggled with how to handle her. She was intelligent and intuitive, but people would treat her as if she had a learning disability.

As she got older, Misty started carrying a lamp with her at school. She would put her lunch under it to see what she was about to eat. She learned Braille and used a cane to navigate. When she visited the doctor for checkups, her prognosis seemed to get worse.

"[The doctor] would take her little face and he'd put his hands on her face and say, 'Misty, I'm so sorry, there's nothing more we can do for you, honey. You're going to wake up in the dark one day,'" Lovelace recalled.

"It'd be like looking through a tunnel. And all of a sudden that tunnel goes out."

Misty has Leber congenital amaurosis, or LCA, a genetic disorder that often manifests at a young age, causing vision loss. In Misty's case, and for approximately 1,000 to 2,000 other people in the U.S., the disease is caused by mutations in a gene called RPE65.

What Misty didn't know as her vision got darker was that a scientist and doctor duo at the Children's Hospital of Philadelphia had already spent years working on a gene therapy for her disease.

The gene therapy, which would eventually become known as Luxturna, was not an overnight success. Decades of research and setbacks preceded the landmark U.S. approval of Luxturna four years ago, the first the Food and Drug Administration had ever granted to a gene therapy for an inherited disease. While Luxturna is not a cure for blindness, treatment has brought sustained improvements in sight, particularly in lower light, for several patients who spoke with BioPharma Dive. As a result, they've needed less help in educational and social environments, and have more independence.

Their experience with Luxturna is proof of gene therapy's potential as well as its limitations. As the first gene therapy of its kind, Luxturna also holds lessons for a field that's grown dramatically since its December 2017 approval.

A gene therapy first

Lovelace said she never stopped trying to find a way for Misty to regain her sight. The possibility gave her hope as she watched her granddaughter adjust to a life that, for her, was almost in total darkness.

A call from Jean Bennett was a lifeline.

Bennett and her husband, Albert Maguire, met at Harvard Medical School in the early 1980s. The two began researching gene therapy together, attempting to treat blindness in mice. Soon they were testing their approach on Briard dogs with the same defective RPE65 gene that causes LCA in humans.

By 2007, their gene therapy was ready to be tested in people — a high-stakes proposition for a field that had largely been shut down nearly a decade before. After 18-year-old Jesse Gelsinger died during a 1999 gene therapy study, many questioned whether such research was safe. The success Bennett and Maguire had with Luxturna was a large part of gene therapy's journey back to the forefront of biomedical research, aided by improvements in how such treatments are designed and delivered.

Testing began at the Children's Hospital of Philadelphia, where Misty was recruited as a study participant. At age 12, she took her first flight out of Kentucky and received the gene therapy in both eyes, starting with the one with worse vision.

"We didn't know if I was going to get worse, stay the same or get better," she said. "But in my mind, I was going to be completely blind by 18, so what's knocking a couple years off?"

The improvements were almost immediate, however. Lovelace recalls her granddaughter commenting on her wrinkles as soon as the eye patches from the procedure were removed. Misty could make out the fine hairs on the manes of horses, her favorite animal and hobby. Rainbows and stars, though, she found underwhelming.

More than eight years later, Misty says she's grateful she "took the leap," attributing to Luxturna her independence and ability to pursue a career as a horse trainer.

Results from early participants like Misty led to the formation of Spark Therapeutics and a larger clinical trial in Pennsylvania and at the University of Iowa that gave the biotech company the evidence needed to approach the FDA.

On Oct. 12, 2017, a panel of scientists and FDA advisers unanimously endorsed the gene therapy, with Misty one of several individuals who shared their stories. The FDA followed with an approval on Dec. 18, a gene therapy milestone.

"For many of us, this is exactly the type of disease that we hoped that gene therapy would someday treat," Wilson Bryan, director of an FDA office tasked with reviewing Luxturna, said at the time. The next year, Luxturna was also approved in Europe.

It's unclear how many people have received Luxturna since. A Spark spokesperson told BioPharma Dive the company does not disclose that information. In 2019, the company told the Philadelphia Business Journal it had shipped 75 vials of the gene therapy in its first year post-approval. (One vial is used per eye.)

Spark is now owned by the Swiss pharmaceutical company Roche, which does not disclose sales of Luxturna. In February, however, Roche reduced the accounting value of Luxturna, citing "reduced sales expectations."

'This is not a cure'

Luxturna consists of one hundred and fifty billion copies of the corrected RPE65 gene encoded into modified viruses, which are delivered into the eye via about 0.3 milliliters of liquid. Those few drops are injected underneath the retina and, over the course of a week, the viral particles shuttle the functional gene into the patient's eye cells. Once inside, the gene instructs the cells to produce a protein that's otherwise missing, helping restore visual function.

"This is not a cure," said Jason Comander, a physician at Massachusetts Eye and Ear in Boston who has administered Luxturna. "It will not make your vision normal," he added, "and there's a small chance that it could hurt your vision." Comander consults with other drugmakers and in 2019 received a nominal amount from Spark.

Luxturna also benefits each patient differently. Comander said the vast majority gain some night vision, while others report improvements in central or side vision. Some see more substantial improvements — one of his patients was able to see in up to one thousand times dimmer light than in pre-surgery exams. Many have been able to walk without canes and read without using Braille after surgery.

Their vision isn't perfect, however. Some recipients, Misty included, are still considered legally blind and unable to drive. How long the benefit of gene therapy treatment will last is still unclear, though a recent study co-authored by Maguire and Bennett indicated "improvements were maintained up to 3 to 4 years" after Luxturna.

Comander, who was in his residency while Luxturna was tested, said seeing Maguire administer the therapy affirmed his decision to go into the practice. Now, Comander has done close to a dozen surgeries; his youngest patient was 4 years old at the time of treatment and his oldest was in their 30s. While younger patients saw greater improvements, each patient's eyes functioned better in lower light following treatment.

For Comander, Luxturna was an inspiration, one that he said has helped fuel greater interest in gene therapy. "Many careers have been dedicated to expanding on the success of Luxturna, and it's made a huge difference in the field," he said.

Since Luxturna's clearance, Novartis won FDA approval in May 2019 for a spinal muscular atrophy treatment known as Zolgensma, making it the second gene therapy for an inherited disease available in the U.S. A handful of other gene therapies are in late-stage testing and, behind them, are an expanding pipeline of experimental medicines for a constellation of genetic conditions. In 2020 alone, the FDA received more than 230 applications from cell and gene therapy developers to begin clinical trials, the head of the agency's biologic drugs division said in 2021.

"It's like he's a new kid every day"

Gordon "Creed" Pettit was one of the kids who couldn't get into clinical trials for Luxturna. His mother, Sarah St. Pierre-Pettit, brought him from Florida to the University of Iowa a number of times. But he couldn't get through the tests needed to qualify him for treatment.

From there, it was a waiting game until Luxturna's approval. Soon after the FDA's decision, Pierre-Pettit brought Creed to Audina Berrocal at the Bascom Palmer Eye Institute in Miami.

Creed was Berrocal's first Luxturna patient. As a pediatric retina specialist, Berrocal said Spark sought her out in the fall of 2017. To date, she's performed a dozen surgeries, all of which have yielded positive results.

"Of all the things I've done in my career, this has been the most amazing and the most rewarding in the sense that we are changing the genetics, the DNA of a person, and we're allowing them to do things that before they couldn't do," Berrocal said. Berrocal consults with other drugmakers and has contributed to published research on Luxturna. In 2018 and 2019, she received nominal payments from Spark.

But treatment, even when positive, can come with adjustments, too. In Creed's case, he was overwhelmed by the sudden change, at first telling his mother he wished he had his old eyes back.

With time, however, Creed has started challenging himself more. "I think most of the gains were at the beginning," Pierre-Pettit said. "Whatever Luxturna did is done. But now that he finally feels confident with himself, he's putting Luxturna to the test now."

For Creed, that means being more social and inquisitive about the world around him. Now 12 years old, he hasn't mentioned wanting his old eyes back for years.

"It's still almost like a new kid every day, like a new baby that sees something new," his mother said.

A sky-high price tag

From a young age, Luke Ward told his mother, Stephanie Joachim, about his dream of playing soccer. But the sport — as well as many other daily tasks — seemed out of reach.

His vision problems were apparent from birth. While his twin sister could track people with her eyes, Luke stared only at sources of light. When he started walking, he needed to put his hands out to stop himself from running into walls.

Genetic testing revealed Luke had LCA. His doctor said he'd be legally blind by kindergarten. Around the same time, Joachim read an article about Luxturna, but was too late to get Luke enrolled in clinical testing. By the time the FDA approved the therapy, the family had already decided that Luke was getting Luxturna.

But Joachim was anxious after learning Luxturna's price tag of $425,000 per eye. "I was just flabbergasted and I was like, 'You know what, it's fine. We have the best health insurance,'" she said.

To the family's disappointment, and as other Luxturna patients have experienced, insurance denied the request and cited the therapy's then "newness" as a reason.

At some point in the process, however, Luke's file crossed the desk of an anonymous person who was "so moved from Luke's story and from Luke's pictures, he volunteered to pay for Luke's surgery," Joachim said.

Luxturna's cost was criticized when the therapy was approved and has remained an issue within the patient community since. Shortly after the FDA gave its OK, Spark announced a program with health insurer Harvard Pilgrim and affiliates of Express Scripts, through which the company agreed to pay rebates if the drug doesn't help patients meet certain thresholds.

In a statement to BioPharma Dive, Spark said it offers a "range of patient services and payment models to help navigate and support access" to Luxturna, but did not respond to questions on the number of times rebates have been paid.

"Parents shouldn't be paying for this out of pocket," Berrocal, who was also Luke's surgeon, said.

Berrocal told Luke he's the "poster child for Luxturna," Joachim said. He can play sports with his twin sister, including soccer and tee-ball. He started kindergarten this year and has no issues seeing the whiteboard. He still has visual impairments, though, including his peripheral vision. His mother says they keep their shoes tucked out of the way in the house to prevent Luke from tripping.

"This is what we have, and it's working"

Four years after its approval, Luxturna continues to be sought out by patients. Joachim says she's received messages from people in Spain, South Africa and the U.K. inquiring about Luke and his progress.

And as Luxturna keeps working, other drugmakers hope to replicate its success. The eye, in particular, is the focus of many gene therapy developers, as it's easy to access and targeting it doesn't carry as many safety risks as other organs. Novartis, which sells Luxturna in Europe, AbbVie, Biogen and Johnson & Johnson are all exploring gene therapies for the eye.

Research into gene editing is advancing as well. In September, Editas Medicine shared preliminary results from the first trial testing a CRISPR gene editing treatment that does its work inside the body. Treatment appeared safe, although the efficacy results were mixed, with several patients experiencing little improvement in vision. The treatment uses CRISPR editing to restore the function of eye cells in people with another form of LCA known as type 10.

Berrocal believes Luxturna represents the beginning of what genetic medicine can offer to patients with many inherited diseases, not only those of the eye.

"20 years from now, we could look back and say, 'Oh my god, that was so rudimentary. Look how much you have advanced,'" she said. "But we have to start somewhere, right? And in 2021, this is what we have, and it's working."

Two children who received a Novartis gene therapy for their neuromuscular disease died following treatment, spotlighting its risks and renewing questions about the safety of genetic medicines like it.

The patients developed acute liver failure between five and six weeks after infusion with the gene therapy, called Zolgensma and approved to treat spinal muscular atrophy, a rare, inherited condition that in its most severe form is often fatal by age two.

While acute liver injury is a known risk of treatment with Zolgensma, these are the first cases that led to patients’ deaths, Novartis said in a statement emailed to BioPharma Dive in mid-August. News of the deaths was first reported by STAT.

The company said it has notified regulators, including the Food and Drug Administration, in all countries where Zolgensma is used, and will inform physicians where allowed by health agencies. Novartis will also update the therapy’s labeling to include mention of the deaths, which occurred in Russia and Kazakhstan.

The deaths followed tapering of steroids that are used alongside treatment to manage safety risks, Novartis said.

“While this is important safety information, it is not a new safety signal and we firmly believe in the overall favorable risk/benefit profile of Zolgensma, which to date has been used to treat more than 2,300 patients worldwide across clinical trials, managed access programs, and in the commercial setting,” said Novartis in its statement.

Zolgensma was approved in the U.S. in May 2019, becoming just the second gene therapy for an inherited disease cleared by the FDA. It offers dramatic benefits, keeping alive children who otherwise would be expected to die. In clinical testing, treatment also helped patients sit and stand, as well as reach other developmental milestones that typically wouldn’t be achieved.

Along with two other drugs from Biogen and Roche, Zolgensma has helped transform the outlook for infants born with spinal muscular atrophy, which is caused by mutations in a key gene and leads to severe muscle weakness. Prior to the three medicines’ approval, there were no treatments for the disease.

But, like other gene therapies, Zolgensma comes with safety risks as well as questions about how long its benefits will last.

The risk of liver injury, in particular, is mentioned on the FDA’s product labeling, which instructs doctors to assess liver function before infusing Zolgensma and to administer steroids before and after to manage increases in liver enzyme counts.

Two previous cases of acute liver failure have been reported following Zolgensma treatment, but the affected individuals were treated with steroids and continued to make developmental gains months later.

Liver damage is also a broader concern for gene replacement therapy, which involves infusing billions of inactivated viruses loaded with a functional copy of the gene that’s missing or mutated in inherited diseases like spinal muscular atrophy. These gene-carrying viruses often end up in the liver, which has raised alarms among researchers about the use of particularly high doses.

In a separate trial testing an Astellas gene therapy for another neuromuscular condition known as X-linked myotubular myopathy, four boys died after developing liver damage following treatment. Elevated liver enzyme counts have also been reported in trials of gene therapies for hemophilia and Duchenne muscular dystrophy.

An FDA meeting in September 2021 focused on liver risks with these kinds of gene therapies, but experts on the agency’s advisory committee stopped short of recommending research be slowed or redirected.

The two deaths reported by Novartis could further shape discussion of gene therapy safety, as well as how regulators view the balance between a treatment’s benefits and risks.

Sickle cell disease is one of the world's most common inherited blood disorders, though that isn't reflected in the number of treatments for it. Three new drugs hit the market between 2017 and 2019. But before those additions, nearly two decades had passed since the Food and Drug Administration last approved a sickle cell medicine.

Now, a handful of companies are looking to not just treat the disease, but potentially cure it. Their goal, broadly, is to fix the mutations that cause sickle cell through the use of cutting-edge gene editing technologies. One of these treatments has already advanced to the final stage of human testing, and is expected to be submitted for approval in late 2022 or early in 2023.

A one-time, possibly curative treatment would be momentous, as the median life expectancy for someone living with sickle cell is estimated to be between 45 to 55 years in the U.S. The disease also causes strokes, organ damage and episodes of severe pain known as vaso-occlusive crises. Genetic medicines developed by Bluebird bio and by CRISPR Therapeutics and Vertex Pharmaceuticals have shown promising signs that they can mostly eliminate vaso-occlusive crises, although further testing is needed to better understand if they have limitations or if their effects might wear off over time.

Such treatments raise tough questions, though. Gene-based treatments are very expensive and fairly difficult to make, which presents a major problem in sickle cell given that many people with the disease live in lower-income countries. Drug developers like Novartis say they're tailoring their work to address some of these issues, but it's unclear how well they'll be able to remedy long-standing problems of access and equity.

How is sickle cell treated?

Sickle cell is caused by mutations in the gene that creates hemoglobin, the protein on red blood cells responsible for carrying oxygen.

Patients therefore experience the disease differently depending on their genetic make-up. Those with two copies of the mutated gene have more serious symptoms, like anemia, which happens because sickled red blood cells die much sooner than their healthy counterparts.

Sickled cells are also hard, sticky and misshapen, so they pose the threat of clumping together and causing a stroke.

In more severe cases, the symptoms require patients to get blood transfusions. There are also a few medications available specifically for complications of the disease, in particular the painful episodes that happen when sickled cells clog a blood vessel. The FDA approved a drug called hydroxyurea in the late 1990s for adults experiencing these vaso-occlusive crises. Then it approved another, an oral powder, in 2017.

In 2019, the FDA cleared two more medicines for market: Novartis' Adakveo, which helps reduce the frequency of vaso-occlusive crises, and Global Blood Therapeutics' Oxbryta, which is meant to inhibit red blood cells from sickling and breaking down. Novartis and Global Blood set the monthly list prices for their drugs between $7,000 and $10,400.

Additionally, a cure for sickle cell exists in the form of bone marrow transplants, though the treatments can cause life-threatening side effects and even death.

How could gene therapy be used?

As with other diseases, genetic medicines for sickle cell are being positioned as long-lasting and, potentially, curative treatments. 

If the therapies now showing promise continue to prove effective over time, they could eliminate the long-term symptoms of sickle cell, allowing patients to go without blood transfusions. Lessening or removing the need for blood transfusions would both lower the cost of care as well as avoid the related buildup of iron in the blood, which can require separate treatment.

Gene-based treatments could also prevent vaso-occlusive crises — a main reason for hospitalization among sickle cell patients, who sometimes need strong painkillers like opioids.

Some clinical studies of sickle cell gene therapies are enrolling children. However, should any therapy come to market, older children or adults would likely be the first recipients, given the risks and uncertainties. 

Which companies are working on gene therapies?

A handful of companies have ushered genetic medicines for sickle cell into clinical trials, with the majority still in earlier stages. The farthest along is Bluebird's LentiGlobin, which is designed to deliver an engineered version of the gene that codes for hemoglobin.

To make LentiGlobin, Bluebird takes a patient's stem cells, uses special viruses to outfit them with the corrected gene and then reinfuses them.

This is different from the gene-editing approach favored by several other main developers. At least two sets of partners — CRISPR and Vertex, and Novartis and Intellia Therapeutics — are using the Nobel Prize-winning CRISPR-cas9 technology to get stem cells to produce high levels of what's known as fetal hemoglobin. Fetal hemoglobin is a form of the vital protein, but it stops being produced roughly six months after a person is born. Gene editing, in theory, keeps the switch for this protein on, helping remedy the main problems associated with sickle cell.

Genetic medicines have already shown promise treating sickle cell. A small study of Bluebird's found that, after treatment, hemoglobin levels were close to what's considered normal, and almost no patients experienced vaso-occlusive crises or acute chest syndrome, another symptom of the disease.

CRISPR and Vertex gave a similarly positive update on their program last month. The companies' said that the small group of sickle cell patients given their therapy, named CTX001, had yet to experience vaso-occlusive crises following treatment. Data also suggest their therapy can have a long-lasting effect.

The breakthroughs didn't come without setbacks, however. Bluebird's LentiGlobin program has faced multiple delays tied to manufacturing and safety concerns. In February 2021, the company halted two of its sickle cell studies after one participant developed leukemia and another appeared to have a disease of the bone marrow. Bluebird has since conducted an investigation and determined its therapy was "very unlikely" to be related to the cancer case.

In April 2021, Bluebird said the bone marrow diagnosis had been revised to a condition known as transfusion-dependent anemia.

What's next?

Bluebird was allowed to resume its sickle cell studies in June 2021. Prior to the study halt, the company had said it planned to ask for approval in late 2022, but now expects to do so in the first quarter of 2023.

But right alongside Bluebird are CRISPR and Vertex, which expect to finish submitting an application for their treatment by the end of the first quarter. 

Behind that, genetic medicines from Aruvant Sciences and partners Sanofi and Sangamo Therapeutics are also moving forward.

In the meantime, there are many uncertainties to contend with. Researchers are still trying to understand whether genetic medicine will work for all sickle cell patients, or whether it'll live up to its potential as a lifelong fix for the disease.

Even if these treatments do reach the market, they'll likely still face challenges. For example, therapies currently in development use toxic conditioning regimens to prepare patients' bodies for cell reinfusion, and that may restrict who's able or willing to receive them.

In a recent note, analysts at Stifel wrote that they see the toxic regimens as "limiting the commercial opportunity" for the kinds of treatments being developed by Bluebird, Vertex and CRISPR. "We of course view these events in the context of profound efficacy," the analysts wrote, "but even so, we don't expect the risk/benefit of these agents to resonate with younger, more mild patients."

A decade has passed since the first scientific paper emerged describing a new way to alter DNA with a bacterial defense system known as CRISPR. Two of the authors, researchers Jennifer Doudna and Emmanuelle Charpentier, are now Nobel laureates, and the gene editing technology they pioneered birthed a group of biotechnology companies now testing it as a way to potentially cure a range of inherited disorders.

But innovation happens fast in the biotech industry. Even before the first CRISPR drug developers complete their clinical trials, new startup companies aiming to surpass them are following quickly in their footsteps. “Base” and “prime” editing, touted as more precise tools, have attracted sizable investment. So has another approach targeting the RNA molecules that help turn DNA into proteins. All represent ways to broaden the reach of genetic medicine.

The latest twist may come from a field of research, known as epigenetics, that’s intrigued drug researchers for years. Here’s where things stand:

What is epigenetic editing, and how does it work?

Epigenetics studies the proteins and chemicals that turn genes on and off, without altering the underlying DNA.

For years, scientists and drugmakers have tried to find the right molecular switches that cause a gene to make a protein, and use that information to treat disease. For instance, a chemically linked configuration of carbon and hydrogen atoms — known as a methyl group — can bind to DNA and change how, or whether, certain genes are “read” by specific proteins. Chemical changes to proteins called histones that hold onto DNA can also alter gene expression.

So far, that knowledge has led to limited drug development successes in the form of a few chemical-based cancer medicines. Merck & Co.’s lymphoma drug Zolinza targets a protein that affects the chemical makeup of histones. Epizyme’s soft tissue cancer drug Tazverik, meanwhile, blocks an enzyme involved in gene expression.

But in many cases it's been difficult to determine which switches control what genes, or how to get to them without causing other problems. Using new computing tools and advances in genomic research, a number of biotech companies pushed ahead with research, and are now joined by others seeking to use CRISPR-based tools. Their idea is to use CRISPR components to turn genes on or off, or to alter the expression of several at a time without cutting into or changing DNA.

What advantage would epigenetic editing offer over existing technologies?

The first iteration of CRISPR is often likened to “molecular scissors.” But, relative to the genetic changes researchers might want to make, the scissors’ blades are somewhat blunt. By cutting through DNA’s double-stranded helix, CRISPR can make accidental, off-target edits, which could have real health risks, such as damage to genes that suppress cancer.

Newer approaches are designed to make more pinpoint changes. Base editing can alter single nucleotides, or “letters,” in a gene, but only for certain combinations. Prime editing is more flexible still, capable of swapping any DNA letters as well as editing out specific sequences of nucleotides.

However, both approaches involve breaking or rewriting DNA in one way or another. Epigenetic alterations don’t, meaning they might be reversible and could help developers to more subtly dial up or down gene expression. Proponents of the approach believe these capabilities may allow gene editing to be used for a wider range of diseases, including complex conditions beyond the reach of existing technologies. But that hasn’t yet been proven.

Which companies are working on it, and who is backing them?

Over nine months into July, three biotechs planning to edit the epigenome have launched with significant funding.

Chroma Medicine was seeded by Atlas Venture and Newpath Partners and is based on the work of MIT scientist Jonathan Weissman, who co-founded the company along with gene editing specialists David Liu and Keith Joung.

Tune Therapeutics, co-founded by Duke University researcher Charlie Gersbach and another gene editing pioneer at UC Berkeley, Fyodor Urnov, is backed by New Enterprise Associates and led by the former CEO of Precision Biosciences.

In July, Chroma and Tune were joined by Epic Bio, which revolves around the research of Doudna disciple Stanley Qi of Stanford Medicine. The startup is funded by Horizons Ventures and led by Amber Salzman, who has headed multiple genetic medicine companies, most recently Adverum Biotechnologies.

Sangamo Therapeutics, a publicly traded company best known for its work on an older gene editing method known as zinc fingers, is also working on epigenetic editing through alliances with Novartis and Biogen.

What is the status of the technology?

Work at all three of the startups is in the earliest stages. Only Epic has said which diseases it intends to target, specifically two forms of genetic vision loss, an inherited disease that causes high cholesterol, a liver disorder called alpha-1 antitrypsin deficiency and a type of muscular dystrophy. Human testing on the neuromuscular disease treatment could reportedly begin in 2023.

Chroma and Tune, which both launched since late 2021, have yet to disclose specific development plans.

Sangamo, meanwhile, has published preclinical research on epigenetic editing techniques in Alzheimer’s and Huntington’s disease. Both are targets of its 2020 collaboration with Biogen.

Gene therapy could dramatically alter how dozens of inherited diseases are treated. It's also transforming how the academic institutions working in this growing field move research from the laboratory to the clinic.

Private sector skepticism a decade or more ago spurred institutions like the University of Pennsylvania and Nationwide Children's Hospital to advance experimental projects much further before selling their ideas to biopharma companies — a departure from the previous model of identifying a molecular target and letting industry do the heavy lifting.

As a result, university technology transfer officers are much more involved in the technical and commercial details of preclinical drug development, from assembling financing and creating private companies to building manufacturing capacity. The product is a host of new startups, such as AveXis, Spark Therapeutics and Bamboo Therapeutics, that in recent years have been swallowed up by large pharmaceutical companies.

"The old way is, 'I have a patent, I'm going to throw it over the fence to you and you throw me a sack of money,'" said John Swartley, managing director of the University of Pennsylvania's Penn Center for Innovation, in an interview. "This is completely different. This is co-development."

"We're directly involved over multiple years in helping to move the technology forward. And our commercialization partner is going to take it hopefully all the way to the market."

A paper published earlier in JAMA in March 2020 quantifies the shift. Together, hospitals, universities and the National Institutes of Health sponsored 206 of the 341 identified gene therapy trials that were active in 2019. Biotech and pharma companies led the remaining 135.

Measured by funding, hospitals, universities and the NIH had a hand in more than 280 of those studies, as some trials had multiple funders. Fourteen trials were funded by other federal sources or non-profit charities.

Hospitals and universities were most active in early-stage studies, with industry sponsoring only 22% of Phase 1 trials. But, in gene therapy, those initial human tests can hold more weight, as the benefits of a genetic fix can be quickly apparent.

"This is a sign that the model of drug development that was prominent in the past — academia does basic science and finds some targets and then pharma develops the actual drug product — is pretty different with gene therapy," one of the paper's authors, Walid Gellad, director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, wrote to BioPharma Dive.

The changing academic model also raises questions about the rich price tags being sought by drugmakers for gene therapies, given the greater role played by universities and other non-profit entities.

"The paper, I think, informs discussions about how high prices really need to be in order to encourage private risk taking for gene therapies — it may be a different number than for other drugs that have less late stage involvement by academia and NIH," wrote Gellad.

University involvement in gene therapy development was driven in part by the private sector's reluctance to get involved in a therapeutic approach perceived, until several years ago, as risky. The death of Jesse Gelsinger in a Penn gene therapy trial in 1999 inflicted severe reputational damage on the field, driving away drugmaker interest.

Scientists kept the faith, and their institutions carried the field forward for years afterward. When Swartley began working at Penn in 2007, one of his first meetings was with the university's gene therapy director James Wilson, who was in charge of the tragic trial that led to Gelsinger's death.

"From an external perspective, from an industrial perspective, there was almost nothing happening," he said. "But it was evident from the kind of research that Dr. Wilson and his colleagues were sharing with us, they made a very convincing case that this was going to rapidly shift into a more of a developmental paradigm."

"They were anticipating a tremendous amount of industry interest when that shift occurred," Swartley added. "It turned out to be very prophetic."

At the University of North Carolina, the situation was similar in the early part of the 2000s. The institution reached a slightly different solution, however, spinning out companies like Asklepios BioPharmaceutical to advance gene therapy beyond the walls of the university laboratories.

"We had a lot of vector technology, but the market was not receptive to gene therapy at the time," said Kelly Parsons, associate technology commercialization director at UNC, in an interview. "We had a startup company that had to work very diligently to try to establish the merits of gene therapy."

Asklepios is now owned by Bayer, and some of its gene therapy work was earlier folded into a Pfizer-owned Duchenne muscular dystrophy project that was previously developed by Bamboo Therapeutics.

But the time spent building the knowledge and expertise at universities or closely affiliated startups has been one of the reasons why big pharmas have rushed into the space. By advancing the technology, the universities reduced the risk of failure, making pharmas more willing to buy in.

"We had a recognition that if we wanted the for-profit sector and the investment sector and the [venture capital] world to give gene therapy a chance, it was important as an institution we were able to start that process of de-risking the asset," said Matthew McFarland, vice president of commercialization and industry relations at Nationwide, in an interview.

Doing so was a greater commitment than they expected. "What we did is say: 'What stage would these assets need to get to before external dollars would be interested in investing?'" he said. "And the reality is, oh my gosh, you have to de-risk it all the way to the point it's ready to go into the patients."

That included the initial Phase 1 study of the spinal muscular atrophy gene therapy now known as Zolgensma, which was licensed to AveXis and later acquired by Novartis.

More broadly, development included building production capabilities compliant with Good Manufacturing Practices, which govern quality and consistency standards for finished drug products, and a regulatory team that was able to prepare Investigational New Drug applications within the hospital's technology transfer office.

Building up manufacturing expertise has resulted in a new business for Nationwide: the for-profit Andelyn Biosciences, which will run a commercial scale gene therapy production facility.

Solving the manufacturing question is something many academic gene therapy centers are still grappling with as they near the point of handing off to private-sector partners. Biopharma companies want to have confidence that the therapies manufactured by university scientists will work as well in clinical trials and in wider use as they did in earlier study.

"There's no university that has the ability to ramp their early production manufacturing production to a level to get enough doses … that industry doesn't have to recapitulate it," said Jim O'Connell, director of technology transfer at the University of Florida's UF Innovate, in an interview. "It's notorious for university labs, small molecules and others, to not be able to have their work reproduced out in the real world."

This very question may have been behind data quality issues for Zolgensma. In 2019, Novartis was chastised by the Food and Drug Administration for having submitted manipulated preclinical data, a scandal that the Swiss pharma tied to AveXis co-founder and former Nationwide trial investigator Brian Kaspar. Through his lawyer, Kaspar has denied all wrongdoing.

"Academic institutions have got to ask themselves: How far into this do we want to go?," said O'Connell. "It's going to have a whole bunch of costs that universities aren't used to taking on. How do we share the expense? How do we share the risk appropriately?"

Thorny questions notwithstanding, the increased investment has led to better returns for universities. Technology transfer offices interviewed by BioPharma Dive report the licensing deals are much richer for gene therapies that have advanced to human testing or near it — money which gets returned to scientists and their departments to fund new research.

Returns aren't equally shared, however. Schools blessed with research that is sought-after by private industry flourish, while others struggle, said Lee Vinsel, a Virginia Tech assistant professor who is writing a book called "The Innovator's Delusion."

Indeed, broadly speaking, universities reported a little more than $3 billion in licensing revenue in 2017, but spent $68 billion, according to the Association of University Technology Managers. Less than 1% of licenses yielded more than $1 million in revenue.

Moreover, Vinsel argues the potential for licensing revenue incentivizes universities to only conduct research the private sector wants to license.

"One reason why we need federal funding and university research is to do basic science that corporations aren't going to pay for and do," Vinsel said. "If we tack more university research towards the profitable, who is going to do this basic work, including research that could really help society but will enrich no one?"

McFarland of Nationwide, however, points to less lucrative licenses it has signed, such as a device to prevent pressure ulcers in patients with tracheostomies, along with a mental health research and treatment facility the institution has launched, as ventures that were enabled by bigger deals like in gene therapy.

"If we can take that return and continue to foster research not only in [gene therapy] but even further spread that out and have an impact across all of research," he said.

"There are a lot of times when we're not the office of tech commercialization, but instead we're the office of tech realization, because what we go into is just about getting it out there to the public, and we're not going to get a return on it."