Gene Therapy

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.

Bluebird bio’s new gene therapy, approved in the U.S. on Aug. 17, offers patients with an inherited blood disorder a one-time, potentially curative, treatment option.

But it comes at a price of $2.8 million, making the therapy the second most expensive drug on a single-use basis in the U.S. and among the highest globally.

Bluebird defends its therapy’s worth, citing the clear benefit in clinical testing and the high lifetime costs of treatment for people with severe forms of the disease, called beta thalassemia, for which its drug is approved. At least one independent assessment of the drug, sold as Zynteglo, supports Bluebird’s case.

Still, the price sets a new bar by which other gene therapies in development might be compared. Bluebird’s success or failure in marketing the therapy is likely to be closely watched by other biotechnology companies nearing regulatory approvals for their own genetic medicines.

“This is a very important test for biotech, the payers and all other key stakeholders,” said Luca Issi, an analyst at RBC Capital Markets.

Zynteglo is the third gene therapy for an inherited disease to be cleared for use in the U.S., following a treatment for a type of genetic blindness and another for spinal muscular atrophy. The other two are also expensive, with list prices of $850,000 and $2.1 million, respectively. While sales of the blindness treatment haven’t amounted to much, the spinal muscular atrophy drug has become a blockbuster product for its maker, Novartis.

Zynteglo isn’t expected to match those commercial heights, even with its price tag. It is approved for people with beta thalassemia severe enough to require regular blood transfusions. Bluebird estimates there are between 1,300 and 1,500 patients in the U.S. who fit that criteria and, of those, about 800 to 850 who would be healthy enough to receive Zynteglo.

Tom Klima, Bluebird’s chief commercial and operating officer, estimates about a third of those eligible for treatment are eager to try gene therapy and might consider Zynteglo. Another third will likely wait and see, while the rest may be stable on their current treatment or uninterested in gene therapy, he said.

Given the small numbers of eligible and interested patients, U.S. insurers might not immediately balk at covering Zynteglo, even at its high cost.

“It’s not going to break the system,” Issi said. “I think this is going to be relatively well received by payers in the context of such a small, rare indication.”

Analyst predictions for peak annual sales vary widely, from SVB Securities' forecast of $64 million to Raymond James' estimate of about $200 million.

About three-quarters of eligible patients are on commercial health insurance, according to Bluebird, and most of the rest are covered under Medicaid. Bluebird will refund up to 80% of the treatment’s cost for two years afterwards if patients still need blood transfusions. In clinical testing, about 90% of study participants no longer needed them.

Over time, those blood transfusions can become costly. Patients with severe beta thalassemia often need transfusions every two to five weeks, as well as other medications to manage the iron overload the procedure can cause.  

Bluebird estimates that, over a patient’s lifetime, the cost of treatment and associated care will exceed $6 million, a factor Klima said it considered in setting Zynteglo’s price.

The potential for Zynteglo to offset some of those costs is real, according to David Rind, chief medical officer at the Institute for Clinical and Economic Review, or ICER, a nonprofit that’s become influential in the drug pricing debate.

But, “some of those costs are far in the future,” Rind said. “We don’t view costs 30 years in the future the same way we view $2.8 million today.”

In assessing Zynteglo’s value, ICER did find that the therapy could be considered cost effective at a price of $2.77 million, as long as certain benchmarks were used. But the group also modeled a scenario in which half of the lifetime savings provided by the drug were returned to society and came up with a price range of $1.3 to $1.8 million.

“If you think of the cost offsets for this expensive disease,” said Rind, “[Zynteglo’s price] is giving all of that to the manufacturer and none back to society.”

“I have trouble saying, ‘Gee, this is a terrible price,’” he added. “But this is 0% of the savings going back to society and I’m sad about that.”

Bluebird says it is in advanced negotiations with insurers as well as national pharmacy benefit managers about covering Zynteglo. “We’ve actually gotten positive feedback from payers on our pricing thinking,” said Klima.

The company has been here before. Three years ago, Bluebird won approval of Zynteglo in Europe and priced treatment there at $1.8 million, spread over five years.

But the company struggled to secure reimbursement, facing resistance from national payers. Drugs are often priced lower in Europe as countries there can more effectively negotiate with pharmaceutical companies.

After failing to reach agreements in Germany and elsewhere, Bluebird decided to withdraw Zynteglo from the market and later wound down its European business operations.

“In the U.S., value is received a little bit differently than in Europe,” said Klima. “What we’re seeing so far is payers and the treating community [here] recognize the value of a one-time treatment much differently than the Europeans do.”

Klima said Bluebird is focused only on the U.S., although he said the company would “keep its options open” for the future in other markets like Europe, where there are many more patients with transfusion-dependent beta thalassemia.

One of Bluebird’s chief challenges is its rapidly dwindling funds. The company warned investors in March that was at risk of insolvency in 2022, and in April laid off 30% of its workforce. To stay afloat, it is counting on selling special vouchers granted by the FDA for Zynteglo and another gene therapy that was approved on Sept. 16.

Bluebird’s financial jeopardy is a dramatic reversal in fortune from five years ago, when shares in the company were worth, at one point, 30 times as much as their price in August. 

“This is biotech in 2022, not biotech in 2017 or 2018,” said RBC’s Issi. “They’re cash constrained and they’ve got to make some calls.”

Gene therapies have garnered attention as a promising treatment modality for diseases that have an underlying genetic component. A significant number of promising therapies have entered the clinical pipeline, with a sizable percentage of them utilizing adeno-associated virus (AAV). This particular method sets itself apart from other technologies due to its non-integrating properties, ability to infect a broad range of cell types, and its safety profile.

A critical need that has emerged in the gene therapy manufacturing space is for streamlining and standardization of the viral vector manufacturing process to support the continued emergence of the commercial gene therapy sector, while reducing the significant costs associated with these treatments.

In this webinar, Dr. Richard Snyder, Dr. Kate Torchilin, and Brandon Pence discuss current manufacturing workflows for AAV vectors and identify opportunities for process optimization—both upstream and downstream—to support the manufacture of viral vectors at commercially relevant scales.

Considerations for designing and optimizing upstream and downstream bioprocessing workflows

There are many variables to consider for upstream AAV bioprocess development. These may include producer cell line development, media selection, plasmid construction, plasmid transfection and viral vector harvest. To ensure their manufacturing process can meet clinical and commercial requirements, scientists must optimize their workflows early on in order to address the necessary efficiency and production volumes of their workflows are sufficient to support clinical administration of their drug. To address these challenges, movement away from cumbersome adherent cell lines to suspension-based viral vector production cell lines can easily translate from the initial small-scale requirements of the early discovery phase, over to the large-scale bioreactors needed for commercial scale viral vector production volumes.

When considering downstream process optimization, it is important to utilize the lessons learned from other biologics and apply them to scaling up processes such as purification and formulation. While traditional purification methods such as cesium chloride or iodixanol density-gradient ultracentrifugation are still being used in the field, the multiple, complex processing steps ultimately result in a significant reduction in the final yield. Importantly, scalability of these approaches can be limited. To address some of these challenges, recent advances in affinity chromatography have reduced the number of steps required to purify AAV, boosting yield and reducing processing lead times. POROS™ CaptureSelect™ AAV Affinity Resins are engineered to address the high selectivity and capacity requirements for large-scale downstream purification and can be used for a broad range of naturally occurring and synthetic AAV serotypes.

Latest innovations in advanced analytical tools

The nature of clinical usage of gene therapies often requires direct administration of a viral vector directly to the patient. This means that quality and purity standards are the highest priority when establishing a manufacturing process. Considered a manufacturing impurity, empty and/or partial capsids can affect the efficacy, safety, and transduction efficiency of the final AAV therapeutic product. There are multiple technologies such as anion-exchange HPLC or analytical ultracentrifugation sedimentation velocity (AU-SV) that can be employed for the separation and quantification of empty and full capsids. Additionally, liquid chromatography mass spectrometry (LC-MS) based peptide mapping can be used for capsid identity testing and to verify the primary structure of a therapeutic protein. Next generation sequencing (NGS) is another approach for understanding the identity of the package genome and any other contaminants or residual DNA that may have inadvertently been packaged into the viral particle during the manufacturing process.

Working together to support the advancement and success of gene therapies

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In many respects, this is still in a new and emerging field. As we think about the processes that we develop and the ways in which we ensure that they are both scalable and consistent, it is important that the communication pathways between supplier, manufacturer or developer, and the regulatory agencies remains open and persistent.

Brandon Pence

Vice President, Cell Biology

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Early collaboration and frequent, candid communication across various stakeholder groups in the manufacturing process helps to cement an understanding of challenges and expectations that drug developers face. Engagement between tools providers, technology developers, contract manufacturing organizations and drug manufacturers will allow for open discussion on existing gaps and needs, which in turn facilitates translation of these valuable insights directly over to investments into new product development efforts to support the ever-changing goals of this market.

Watch the webinar to learn how Thermo Fisher Scientific is supporting the rapidly growing demand for AAV vectors, from both technology development and manufacturing strategy viewpoints.

Four years ago, a small Philadelphia biotech company won U.S. approval for the first gene therapy to treat an inherited disease, a landmark after decades of research aimed at finding ways to correct errors in DNA.

Since then, most of the world's largest pharmaceutical companies have invested in gene therapy, as well as cell therapies that rely on genetic modification. Dozens of new biotech companies have launched, while scientists have taken forward breakthroughs in gene editing science to open up new treatment possibilities.

But the confidence brought on by such advances has also been tempered by safety setbacks and clinical trial results that fell short of expectations. In 2022, the outlook for the field remains bright, but companies face critical questions that could shape whether, and how soon, new genetic medicines reach patients. Here are five:

Can anticipated gene therapy approvals provide a boost to the field?

Food and Drug Administration approval of Spark Therapeutics' blindness treatment Luxturna — a first in the U.S. — came in 2017. A year and a half later, Novartis' spinal muscular atrophy therapy Zolgensma won a landmark OK.

But none have reached market since, with treatments from BioMarin Pharmaceutical and Bluebird bio unexpectedly derailed or delayed.

That could change in 2022. Two of Bluebird's treatments, for the blood disease beta thalassemia and a rare brain disorder, are now under review by the FDA, with target decision dates in May and June. BioMarin, after obtaining more data for its hemophilia A gene therapy, plans to soon approach the FDA about resubmitting an application for approval.

Others, such as CSL Behring and PTC Therapeutics, are also currently planning to file their experimental gene therapies with the FDA in 2022.

Approvals, should they come, could provide important validation for their makers and expand the number of patients for whom genetic medicines are an option. In biotech, though, approvals aren't the end of the road, but rather the mark of a sometimes challenging transition from research to commercial operations. With price tags expected to be high, and still outstanding questions around safety and long-term benefit, new gene therapies may prove difficult to sell.

Will funding keep pouring in?

A record $20 billion flowed into gene and cell therapy developers in 2020, significantly eclipsing the previous high-water mark set in 2018.

Last year, the bar was set higher still, with a total of $23 billion invested in the sector, according to figures compiled by the Alliance for Regenerative Medicine. About half of that funding went toward gene therapy developers specifically, with a similar share going to cell-based immunotherapy makers.

Driving the jump was a sharp increase in the amount of venture funding, which rose 73% to total nearly $10 billion, per ARM. Initial public offerings also helped, with sixteen new startups raising at least $50 million on U.S. markets.

Entering 2022, the question facing the field is whether those record numbers will continue. Biotech as a whole slumped into the end of last year, with shares of many companies falling amid a broader investment pullback. Gene therapy developers, a number of which had notable safety concerns crop up over 2021, were hit particularly hard.

Moreover, many startups that jumped to public markets hadn't yet begun clinical trials — roughly half of the 29 gene and cell therapy companies that IPO'd over the past two years were preclinical, according to data compiled by BioPharma Dive. That can set high expectations companies will be hard pressed to meet.

Generation Bio, for example, raised $200 million in June 2020 with a pipeline of preclinical gene therapies for rare diseases of the liver and eye. Unexpected findings in animal studies, however, sank company shares by nearly 60% last December.

Still, the pace of progress in gene and cell therapy is fast. The potential is vast, too, which could continue to support high levels of investment.

"I think fundamentally, investment in this sector is driven by scientific advances, and clinical events and milestones," said Janet Lambert, ARM's CEO, in an interview. "And I think we see those in 2022."

How will safety scares impact the FDA's oversight?

The potential of replacing or editing faulty genes has been clear for decades. How to do so safely has been much less certain, and concerns on that front have set back the field several times.

"Safety, safety and safety are the first three top-of-mind risks," said Luca Issi, an analyst at RBC Capital Markets, in an interview.

Researchers have spent years making the technology that underpins gene therapy safer and now have a much better understanding of the tools at their disposal. But as dozens of companies push into clinical trials, a number of them have run into safety problems that raise crucial questions for investigators.

In trials run by Audentes Therapeutics and by Pfizer (in separate diseases), study volunteers have tragically died for reasons that aren't fully understood. UniQure, Bluebird bio and, most recently, Allogene Therapeutics have reported cases of cancer or worrisome genetic abnormalities that triggered study halts and investigations.

While the treatments being tested were later cleared in the three latter cases, the FDA was sufficiently alarmed to convene a panel of outside experts to review potential safety risks last fall. (Bluebird recently disclosed a new hold in a study of its sickle cell gene therapy due to a patient developing chronic anemia.)

The meeting was welcomed by some in the industry, who hope to work with the FDA to better detail known risks and how to avoid them in testing.

"[There's] nothing better than getting people together and talking about your struggles, and having FDA participate in that," said Ken Mills, CEO of gene therapy developer Regenxbio, in an interview. "The biggest benefit probably is for the new and emerging teams and people and companies that are coming into this space."

Safety scares and setbacks are likely to happen again, as more companies launch additional clinical trials. The FDA, as the recent meeting and clinical holds have shown, appears to be carefully weighing the potential risks to patients.

But, notably, there hasn't been a pullback from pursuing further research, as has happened in the past. Different technologies and diseases present different risks, which regulators, companies and the patient community are recognizing.

"We're by definition pushing the scientific envelope, and patients that we seek to treat often have few or no other treatment options," said ARM's Lambert.

Will in vivo gene editing take another step forward?

Last June, Intellia Therapeutics disclosed early results from a study that offered the first clinical evidence CRISPR gene editing could be done safely and effectively inside the body.

The data were a major milestone for a technology that's dramatically expanded the possibility for editing DNA to treat disease. But the first glimpse left many important questions unanswered, not least of which are how long the reported effects might last and whether they'll drive the kind of dramatic clinical benefit gene editing promises.

Intellia is set to give an update on the study this quarter, which will start to give a better sense of how patients are faring. Later in the year the company is expecting to have preliminary data from an early study of another "in vivo" gene editing treatment.

In vivo gene editing is seen as a simpler approach that could work in more diseases than treatments that rely on stem cells extracted from each patient. But it's also potentially riskier, with the editing of DNA taking place inside the body rather than in a laboratory.

Areas like the eye, which is protected from some of the body's immune responses, have been a common first in vivo target by companies like Editas Medicine. But Intellia and others are targeting other tissues like the liver, muscle and lungs.

Later this year, Verve Therapeutics, a company that uses a more precise form of gene editing called base editing, plans to treat the first patient with an in vivo treatment for heart disease (which targets a gene expressed in the liver.)

"The future of gene editing is in vivo," said RBC's Issi. His view seems to be shared by Pfizer, which on Monday announced a $300 million research deal with Beam Therapeutics to pursue in vivo gene editing targets in the liver, muscle and central nervous system.

Will pipeline overlap force companies to make hard choices?

With more and more cell and gene therapy companies launching, the pipeline of would-be therapies has grown rapidly, as has the number of clinical trials being launched.

Yet, many companies are exploring similar approaches for the same diseases, resulting in drug pipelines that mirror each other. A September 2021 report from investment bank Piper Sandler found 21 gene therapy programs aimed at hemophilia A, 19 targeting Duchenne muscular dystrophy and 18 going after sickle cell disease.

In gene editing, Intellia, Editas, Beam and CRISPR Therapeutics are all developing treatments for sickle cell disease, with CRISPR the furthest along.

As programs advance and begin to deliver more clinical data, companies may be forced into making hard choices.

"[W]e think investors will place greater scrutiny as programs enter the clinic and certain rare diseases are disproportionately pursued," analysts at Stifel wrote in a recent note to investors, citing Fabry disease and hemophilia in particular.

This January, for example, Cambridge, Massachusetts-based Avrobio stopped work on a treatment for Fabry that was, until that point, the company's lead candidate. The decision was triggered by unexpected findings that looked different than earlier study results, but Avrobio also cited "multiple challenging regulatory and market dynamics."

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, although that may now be delayed.

Sticking to that timeline would put Bluebird well ahead of rival therapies, according to an analysis by the investment bank Raymond James. The next closest is CRISPR and Vertex's treatment, which Raymond James analysts think could be submitted for approval in two to three years. Testing, after a slower start, is now moving quickly, however. 

Behind that, genetic medicines from Aruvant Sciences and partners Sanofi and Sangamo Therapeutics are on track to be filed in three to five years, according to Raymond James.

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.

An experimental CRISPR-based medicine from Intellia Therapeutics reduced biological markers of disease and relieved symptoms in patients with a rare condition called hereditary angioedema.

Results from an early-stage clinical trial, presented at a Sept. 16 medical meeting, showed Intellia’s gene editing treatment, known as NTLA-2002, lowered levels of a protein implicated in the disease by an average of 65% and 92% among six patients given a low or a high dose, respectively.

For the three patients on the lower dose, who were followed for four months afterwards, treatment cut by 91% the number of inflammatory attacks they experienced. These attacks, which are painful and life-threatening, are a hallmark of the disease, often abbreviated as HAE.

Intellia’s results add to an early, but growing, body of evidence indicating CRISPR gene editing within the body may be a safe and effective way to treat disease.

The biotechnology company’s data last year in a disease called transthyretin amyloidosis, or TTR, were viewed as a landmark moment for the Nobel Prize-winning technology. They proved that genetic instructions for CRISPR editing tools could be shuttled into a patient’s cells, where they cut DNA encoding a harmful protein and reduced its production.

Intellia achieved that goal by building on the progress of others like Alnylam Pharmaceuticals, which validated a genetic target for TTR and spent years figuring out how to develop a drug that could stifle it. Intellia went after the same target but used CRISPR gene editing, aiming to provide a one-time fix for a disease that currently requires chronic therapy.

Intellia is now following a similar blueprint with HAE.

Drugs from Takeda, CSL and others are approved to treat or prevent the disease’s swelling attacks. But they have limitations, as they don’t completely ward off the attacks and must be taken for life. Still, they’ve proven that lowering production of plasma kallikrein — a protein involved in blood clotting and other processes — can lead to fewer swelling episodes.

The data Intellia presented Sept. 16 are the first indication NTLA-2002 can do that, too, by making a cut to a gene that encodes for kallikrein. The results are limited by the small number of patients involved and short follow-up, however.

“We have already observed within only weeks of dosing just how profoundly genome editing can impact the disease itself,” said Intellia CEO John Leonard on a conference call.

The study was designed to test whether treatment is safe and to help find the best dose to advance into further testing. Still, the results give an early glimpse of NTLA-2002’s effectiveness, allowing preliminary comparisons to existing treatments.

The three patients who received the low dose had experienced an average of 1 to 7 attacks per month in a screening period prior to the study’s start. Two of the three haven’t had an attack since being treated. The third, who began the study with a much higher monthly attack rate, has been attack free since week 10 post-treatment.

Two patients were able to stop taking preventive drugs, while the other wasn’t receiving prophylactic treatment after getting NTLA-2002.

Data on the attack rates for the three patients on the high dose aren’t yet available and will be presented in November, Intellia said.

Importantly, treatment did not lead to a significant increase in liver enzymes in any patients, which was a concern previously highlighted by analysts. Intellia did report low-grade and short-lived liver enzyme spikes in some patients, though.

Liver enzyme elevations can be a warning sign of more serious side effects and, in August, Intellia altered the design of its TTR trial due to increased liver enzyme counts.

Nonetheless, the results met expectations. Luca Issi, an analyst at RBC Capital Markets, wrote in a note to clients that Intellia’s results surpassed protein and attack rate reductions seen in testing of drugs from Takeda and Ionis Pharmaceuticals. In those studies, patients’ kallikrein levels were lowered by about 60% to 70% and attack rates by 73% to 90%, according to Issi.

Intellia is now testing a mid-range dose and plans to enroll more patients in a Phase 2, placebo-controlled portion of the study that should begin in 2023. Chief medical officer David Lebwohl noted that breakthrough attacks have historically been observed in patients with 60% reductions in kallikrein, and Intellia is aiming higher.

“Our objective would be to eliminate all attacks,” said CEO Leonard. “That's certainly what we're shooting for.”

Despite the data, shares in Intellia sank in early trading Sept. 16. During its conference call, Intellia noted that the liver enzyme elevation previously reported in the TTR trial was judged to be a more serious "Grade 4," or potentially life-threatening, adverse event. The patient was asymptomatic, Intellia confirmed to BioPharma Dive in an email after publication.

Separately, Intellia reported additional results for its TTR medicine in patients with a form of the disease that affects the heart rather the nerves, which was the focus of the company’s first readout. Data showed two tested doses of Intellia’s drug lowered levels of a protein associated with disease progression by over 90%.

A gene editing medicine designed to treat two blood disorders has continued to perform strongly in clinical testing, with the latest results showing that, in the vast majority of treated patients, it alleviates the symptoms and burdens of both diseases.

Presented June 11 at a high-profile medical conference, the results represent another milestone for the therapy’s developers, Vertex Pharmaceuticals and CRISPR Therapeutics, which hope to ask for approval in the U.S., U.K. and Europe before the end of the year.

If approved, the therapy, now known as exa-cel, would become the first marketed medicine based on CRISPR, the landmark gene editing technology that won a Nobel Prize in 2020. It would also provide a new treatment option for patients with sickle cell disease or beta thalassemia.

While a small number of medications are cleared for use in these diseases, the only cure for them are stem cell transplants. The procedure is risky, though, and isn't available to many patients. Exa-cel may serve as another, perhaps more attainable fix, especially if Vertex and CRISPR can keep generating supportive evidence.

So far, the companies have released data on 75 treated patients, almost all of whom are now living without the most serious and impactful effects of their illnesses.

In sickle cell, genetic mutations give rise to misshapen red blood cells, which cause painful and sometimes life-threatening blockages known as vaso-occlusive crises. Beta thalassemia, meanwhile, is also an inherited condition, but one that hinders production of an oxygen-carrying protein called hemoglobin. In severe cases, patients require regular blood transfusions to survive, which can lead to the toxic buildup of iron in their organs.

The trial data presented June 11are from 31 patients with sickle cell and 44 with beta thalassemia who are dependent on blood transfusions. In the two years leading up to the study’s start, the sickle cell patients experienced about four severe vaso-occlusive crises annually, whereas those with beta thalassemia received, on average, 36 units of red blood cells.

Since they were infused with exa-cel, none of the sickle cell patients have reported any crises, and all but two of the beta thalassemia patients have stopped transfusions. Transfusion volume did decrease in those remaining two patients, though, by 75% and 89%, respectively.

Notably, the amount of time trial participants have gone without these health issues varies. At the cutoff for data presentation, some had been followed for roughly three years, others only a month or two. It will therefore take more time for researchers to develop a complete picture of Vertex and CRISPR’s therapy.

Two beta thalassemia patients experienced so-called serious adverse events considered to be related to exa-cel treatment. Vertex and CRISPR previously reported one of those events, a potentially life-threatening immune reaction. Researchers are now saying that another patient showed low blood platelet counts and slower-than-expected engraftment of neutrophils — a type of while blood cell.

However, they noted that all of these serious adverse events resolved, and that none were seen in the sickle cell patients. No deaths have occurred and researchers haven’t detected any signs of cancer, a key concern for gene-based treatments.

To make their therapy, Vertex and CRISPR harvest stem cells from a patient, then genetically engineer them to reactivate a form of hemoglobin the body normally stops making after infancy. High levels of this protein have been associated with better outcomes for sickle cell and beta thalassemia patients.

For exa-cel to work, it must then be introduced back into the bone marrow. To do this, the patient is treated with a chemotherapy-based regimen meant to create space in the marrow for the engineered cells. But such regimens can be extremely difficult on patients. Prior results from the exa-cel trial found one patient, for example, experienced bleeding in the brain that researchers attributed to the precondition process.

While trial results continue to show promise, Vertex and CRISPR are changing how they measure treatment success, introducing new study goals for exa-cel in both sickle cell and beta thalassemia.

Before, the treatment’s goal was to reduce the transfusion burden for beta thalassemia patients and boost fetal hemoglobin levels for sickle cell patients. Now, it’s centered around independence from red blood cell transfusions and freedom from severe vaso-occlusive crises. A Vertex spokesperson said these adjustments “reflect the potential clinical impact of a one-time therapy like exa-cel.”

For Vertex, the successful development and approval of exa-cel could help offset recent setbacks in some of its other drug programs. While there are approved medicines for sickle cell and beta thalassemia, as well as logistical challenges ahead for a complex, outside-the-body treatment like exa-cel, the company appears confident in the commercial prospects for its therapy. This confidence was demonstrated last year, when Vertex agreed to pay CRISPR at least $900 million more for a larger cut of future sales.

Vertex and CRISPR aren’t the only drug developers to see an opportunity treating blood disorders with genetic medicines. Bluebird bio, Editas Medicine, and partners Sanofi and Sangamo Therapeutics, among others, are working on cellular and genetic therapies for sickle cell and beta thalassemia.

On June 10, advisers to the Food and Drug Administration unanimously endorsed Bluebird’s gene therapy for beta thalassemia, convinced by its powerful effect in freeing treated most patients from blood transfusions. The FDA is expected to make a decision on the therapy, called beti-cel, by August.

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."