Gene Therapy

Bluebird bio has spent the better part of two decades developing gene therapies for rare diseases. This summer, after years of clinical trials, setbacks and delays, two of its experimental treatments could secure approval in the U.S.

Yet Bluebird is in a precarious position. The company warned investors in March that, with cash reserves dwindling rapidly, there is "substantial doubt" about its ability to remain solvent for the coming year.

Bluebird isn't the only cell and gene therapy developer facing a financial bind. Since December, at least nine other biotech companies working in the field have announced layoffs, cost cuts or restructured their research. Two others have sold off their manufacturing operations.

The retrenchment coincides with the sharpest market downturn for publicly traded drugmakers in years, which has forced tough choices on young startups and more established biotechs alike.

"We're seeing valuations for companies take a hit, down to the point that we're seeing multiple companies at negative enterprise value, which really is quite shocking to see," said Nessan Bermingham, a venture capitalist and former CEO of the gene editing biotech Intellia Therapeutics.

The stock market pain is shared by companies in other sectors of the biotech industry beyond cell and gene therapy, but developers of those types of medicines appear vulnerable.

Many aren't yet in the clinic and have yearslong research journeys ahead of them before it's clear whether their experimental treatments are likely to work. Developing and manufacturing gene therapies is also an expensive endeavor, stressing balance sheets at a moment when new investment is harder to come by.

Moreover, a string of clinical and regulatory stumbles has sapped investors' confidence in the ability of gene therapy companies to reliably turn cutting-edge science into approvable medicines.

"It's not a perfect storm, but it's a confluence of a lot of elements driving the issues we're seeing," said Bermingham, now an operating partner with Khosla Ventures.

A challenging environment

For Amicus Therapeutics, a small biotech that for the past three years has built a pipeline of gene therapies, the market downturn hit at an inopportune time.

Last September, in somewhat better times for biotech stocks, Amicus announced plans to spin out its gene therapy business via a merger with a blank-check company. But by February, it was forced to call off the deal, citing "unfavorable market conditions" and an "increasingly challenging environment for stand-alone gene therapy companies."

As a result, Amicus said it would no longer advance multiple gene therapies into the clinic as intended and suspended plans to build a manufacturing plant. Thirty-five employees, or about 7% of the company, were laid off, most of whom had been involved in R&D.

Since December, Sigilon Therapeutics, Freeline Therapeutics, Gemini Therapeutics and Passage Bio have been forced to cut jobs as well. Meanwhile, Generation Bio, Avrobio, Sio Gene Therapies and Graphite Bio have reset their research, prioritizing certain experimental drugs or areas of research while stepping back from others.

"When you are in a position where you have to conserve capital, you are often going to prioritize indications where you believe have a higher probability of success as well as less competitive dynamics," said Luca Issi, an analyst at RBC Capital Markets. "We're going to see more of that."

The gene therapy contraction contrasts sharply with the past several years, during which new gene therapy companies won substantial funding and outlined expansive drug development plans. Since 2018, nearly 50 biotechs working on either cell or gene therapies priced an initial public offering. About half had yet to enter clinical testing at the time of their IPO — Generation and Graphite among them.

While they weren't alone — dozens of other biotechs outside of gene therapy did the same during the same period — those companies are now more exposed as investors adjust their expectations for gene therapy.

"We saw a lot of companies go very early on," said Bermingham. "That's OK when markets are really strong," he added, but "becomes more challenging" in a downturn.

To Gbola Amusa, chief scientific officer at Chardan, the flood of preclinical companies launching IPOs in recent years has meant the average gene therapy biotech is less mature and therefore more susceptible to changing market conditions.

"A lot of the missteps and things we're hearing, sometimes it's because of [scientific challenges]," Amusa said. "The other times it's because of small companies that went public maybe too soon and are basically publicly traded academic enterprises without the capabilities that we would see with bigger biotechs."

Safety setbacks

As gene therapy companies have proliferated, so too has the number of experimental treatments entering clinical testing. According to the latest count by the Alliance for Regenerative Medicine, an industry group, there are more than 200 trials of gene therapies underway, with hundreds more in cell therapy.

One consequence of that progress is that more companies are running into problems in testing, whether due to newly uncovered safety risks or because of lower-than-expected efficacy.

Last year, Bluebird, UniQure and Allogene Therapeutics each halted studies after clinical trial participants developed cancer or, in the case of Allogene, signs of unusual DNA abnormalities. While all three companies were able to exonerate their treatments, the reports resurfaced concerns of whether gene therapy could heighten the risk of cancer.

The Food and Drug Administration has also appeared to be proceeding cautiously, even as it expects to approve more and more cell and gene therapies in the coming years. Last September, the agency convened a panel of experts to discuss one common type of gene therapy, a meeting that Bermingham said raised "orange flags" for companies in the field.

The FDA also issued more clinical holds, or regulatory suspensions, for cell and gene therapy trials in 2021 than in previous years. According to a Feb. 27 note from analysts at Jefferies, cell and gene therapy holds accounted for approximately 40% of those ordered by the regulator last year, despite representing well below that proportion of trials.

Beyond setting back individual companies, the trial halts might also be sparking broader questions about regulatory requirements and whether the field needs to do more work preclinically to assess certain risks.

On the other hand, clinical trial successes from more advanced cell and gene therapy developers could force companies earlier in testing to redraw their plans, particularly as many target some of the same rare diseases.

"I think you're going to see some of the business models and strategies be put under pressure by data that's come out from various groups," said Bermingham.

While more cell and gene therapy companies might restructure as stock prices remain depressed, clinical and regulatory progress from others could restore some of the field's attraction.

Beyond Bluebird's two treatments now up for approval, UniQure and BioMarin Pharmaceutical are expected to soon file for approval of gene therapies for hemophilia B and A, respectively. A sickle cell treatment from CRISPR Therapeutics and Vertex Pharmaceuticals is also nearing an FDA review.

Most large pharmaceutical companies are now invested in cell and gene therapy, too, buoying the partnership and acquisition activity that investors seek when backing new startups.

"Innovation takes time," said RBC's Issi. "We live in a bear market and gene therapy companies, many of them have limited cash. They are thinking creatively of how to continue to innovate."

Article top image credit: Dr_Microbe via Getty Images

Gene therapy companies have been especially vulnerable to a public market downturn that’s shaken the biotech sector. But the difficult environment hasn’t stopped venture firms from betting on the science, as evidenced by the launch of a startup on April 26 that’s raised up to $67 million in early funding.

The company, Apertura Gene Therapy, was built around separate technologies developed at Harvard University and the Broad Institute — two institutions well-known for their contributions to genetic medicine. Apertura believes these tools can help deliver treatments to the right cells and express precise amounts of key proteins, which might help to overcome some of the challenges that have hampered gene therapy research.

“The majority of gene therapy programs would really benefit from better delivery and better expression,” said Dave Greenwald, Apertura’s acting CEO, in an interview. “There's a lot of potential for our technology to be brought to bear.”

Greenwald also serves as vice president of business development at Deerfield Management, an investment firm specialized in healthcare and life sciences startups. Deerfield incubated Apertura over the last year or so, and is singularly supplying its Series A financing round.

Notably, Apertura’s launch comes during one of the most challenging periods in recent memory for the biotech industry. The two main ways in which early investors of drug startups see returns on their investments — acquisitions and initial public offerings — have stagnated, forcing startups to stay private for longer and raise additional financing rounds. Meanwhile, the XBI, a closely watched stock index that includes many of the world’s most prominent biotech companies, has fallen more than 40% over the past year.

Gene therapy developers, some of which have run into issues testing their treatments, appear to have been hit particularly hard by the change in investor sentiment. At least 10 of these companies have announced layoffs, restructurings or other cost-cutting measures since December.

Greenwald, however, is taking a long-term view, betting that interest in gene therapy research will be there once the downturn is over. “The financial markets for biotech are certainly not where they were a year ago. And we do keep a close eye on that,” he said.

“That being said … we haven't wavered in our support of the company,” Greenwald added. “I am hopeful that whatever correction we're going through right now abates, and the tide turns back to positive news and outcomes for innovative companies like Apertura.”

Apertura isn’t alone in its ambitions. Multiple other startups, including Generation Bio, Stride Bio, Affinia Therapeutics and Dyno Therapeutics, have launched in recent years with the goal of improving gene therapy technology.

But while these companies have attracted interest from private investors and larger pharmaceutical firms, their work mostly remains in the earlier stages of drug discovery and research. And in some cases there have been setbacks. Generation Bio, for instance, lost more than half its market value in December after animal studies produced results that disappointed investors.

Apertura is early in its journey as well, though Greenwald and others argue that the company’s blend of technologies helps to differentiate it from competitors.

“The fundamentals of why we founded Apertura haven't changed. We know there's a ton of potential in gene therapy; we're only scratching the surface of it,” said Kristina Wang, a board member and director of the company’s corporate development.

One of Apertura’s platforms, created in the lab of Ben Deverman, the senior director of vector engineering at the Broad Institute and Harvard, focuses on the viral shells used to shuttle gene therapies into cells. Specifically, it’s meant to create shells that are customized to certain diseases.

Apertura’s other technology was developed in the lab of Michael Greenberg, chair of the neurobiology department at Harvard Medical School, and it revolves around “fine-tuning” the amount of activity genetic medicines trigger once inside the target cells.

“Our platform is unique in that it allows us to do multiple things simultaneously. Those two approaches,” said Deerfield’s Greenwald, “actually work together hand in hand.”

Greenwald added that the technologies could be used to advance gene therapies for “a wide variety of genetic diseases,” though Apertura isn’t yet disclosing which diseases it plans to go after or when any of its programs might enter human testing.

In the meantime, the company will deploy the funding from Deerfield.

According to Greenwald, the up-to-$67 million figure was a “very deliberate number” that was based on “the appropriate amount to raise at this stage for the company.” He said Apertura could have been brought in front of other investors, but Deerfield felt it had the capacity to nurture and finance the company on its own.

That stance could change, though.

“At the appropriate time, we're certainly open to exploring other options,” Greenwald said.

Article top image credit: DKosig via Getty Images

After more than two decades of successes and failures, the promise of cell and gene therapy to treat the root cause of many human diseases is now starting to redefine modern medicine. CRISPR genome engineering technology is at the forefront of transforming next-generation cell and gene therapies and personalized medicine.

Re-engineered viruses and non-viral vectors, which are used to deliver therapies, have mitigated some of the adverse reactions experienced in earlier studies. Patients receiving these therapies are experiencing greater benefit with fewer adverse reactions.

A lot of this progress has been enabled by the precision genome editing tool CRISPR. “Saying CRISPR has revolutionized gene therapy is not hyperbole,” says Scott Burger, MD, principal for Advanced Cell and Gene Therapy, a consulting firm specializing in cell and gene therapy product development. “Most gene therapy has focused on gene replacement until recently. CRISPR allows one to potentially approach gene therapy from the standpoint of editing: correcting mutations that cause disease.”

In recent years, CRISPR has shown great potential for developing safer and more effective CAR T-cell therapies, sickle cell disease treatment, as well as targeted therapies for other genetic and non-genetic diseases. However, transforming promising bench results into actual therapy involves several steps and hurdles.

Although CRISPR presents new questions for regulatory agencies, as well as serious ethical issues related to germline modification, CRISPR gene-editing technology may solve problems that have plagued cell and gene therapy development since its inception, as well as issues that have sprouted during the recent cell and gene therapy boom.

But what current challenges remain in this field? And how can CRISPR address them?

In the full eBook, we address the following issues and potential solutions:

• Circumventing the CDMO
• Overcoming regulatory hurdles
• Avoiding reagent inconsistencies

Click here to read the full CRISPR Revolution in Cell & Gene Therapy eBook.

Article top image credit: metamorworks via Getty Images

Gene therapy developer Bluebird bio will lay off about 30% of its employees in a restructuring plan aimed at keeping the struggling company solvent into the first half of next year.

The restructuring, announced in early April, will reduce Bluebird's 2022 operating costs by 35% to 40% and save $160 million over the next two years. The company now expects its cash burn to be less than $340 million this year, slightly less than what it currently has on hand.

The workforce reduction "cuts across all parts" of the company, while they will be concentrated in Bluebird's administrative, research, process and sales teams, chief communications officer Sarah Alspach said. The company employed 518 full-time staff at the end of January, according to a regulatory filing.

For years a leading gene therapy developer, Bluebird entered 2022 in financial peril.

A string of clinical, regulatory and commercial setbacks lengthened the company's road to profitability, while its research spending has remained elevated. At the same time, Bluebird's share price has tumbled over the past year, making it more difficult to raise cash on the public market.

Even as Bluebird soon may win Food and Drug Administration approval for two gene therapies, the company last month warned investors there was "substantial doubt" about its ability to remain solvent though the end of 2022. Its top financial executive, Gina Consylman, resigned.

Bluebird is counting on those approvals, and the special vouchers it could receive if the FDA clears both products, known as beti-cel and eli-cel. The vouchers, which speed up drug reviews, are awarded to the developers of drugs for certain neglected or rare diseases and can be sold for tens of millions of dollars.

Still, the FDA approvals aren't certain. The two drugs, developed for rare blood and brain diseases, respectively, have been slowed in the past by safety concerns and testing of eli-cel is currently on hold. They're being evaluated at a two-day meeting of FDA advisers in June, which could influence the FDA's review. The agency previously pushed back its target decision dates for both medicines.

With its future in the balance, Bluebird has turned to reducing costs. The restructuring announced in early April is aimed at getting Bluebird through the FDA's decision dates for beti-cel and eli-cel, as well as the submission of an FDA application for lovo-cel, a potential drug for sickle cell disease. In addition to cutting jobs, Bluebird also is narrowing its research and ending investment in projects aimed at making gene therapies safer to administer and easier to produce.

The company said it will maintain some "targeted" research on so-called in vivo gene therapy, which involves treatments that modify genes inside the body. (Beti-cel, eli-cel and lovo-cel are made from patient cells genetically engineered in a laboratory.)

Bluebird is still evaluating other options, including "public or private equity financings," the company said. Bluebird's shares trade at a fraction of the nearly $180 peak they reached in 2018.

Bluebird's restructuring is the latest in a series of retrenchments by gene and cell therapy developers during the biotech sector's steepest downturn in years. For example, Orchard Therapeutics and Taysha Gene Therapies also announced layoffs in late March and early April.

Article top image credit: "Numbers And Finance" by Ken Teegardin is licensed under CC BY-SA 2.0

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."

Article top image credit: Danielle Ternes/BioPharma Dive

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."

Article top image credit: Permission granted by Ed Shipman for Mass Eye and Ear

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."

Article top image credit: Danielle Ternes/BioPharma Dive

The Food and Drug Administration advised developers of gene editing medicines to carefully assess potential safety risks in animal and human studies of their experimental treatments, issuing in mid-March draft recommendations that spell out the agency's thinking on research in the fast-moving field. 

"While the potential of such products for the treatment of human disease is clear, the potential risks are not as well understood," the FDA wrote in the 19-page document, which follows previous recommendations for gene therapies that don't edit DNA directly. 

Wall Street analysts who cover biotech companies developing gene editing treatments viewed the FDA's guidance as straightforward and without any major surprises. However, shares in one company, Verve Therapeutics, fell by more than 10% following the guideline's release on concerns the recommendations might affect its clinical trial plans. 

The past year has brought the first clinical trial data for two CRISPR gene editing medicines used to alter the DNA of cells inside the body. The results, from Intellia Therapeutics and Editas Medicine, add to the gathering evidence supporting another CRISPR drug from CRISPR Therapeutics and Vertex that edits patient cells outside the body. 

Behind those three companies — some of the first formed to use CRISPR to develop human medicines — are a growing group of biotechs seeking to edit DNA directly to treat disease. For example, Beam Therapeutics, which is exploring a more precise form of gene editing, recently began its first clinical study, while Verve plans to do the same later this year. 

The recommendations issued by the FDA, which are in draft form and could be revised, are meant to help guide those companies as they move forward. 

"Over the past 10 years, the level of interest in human [gene editing] as a scientific technology used in the treatment of human disease has increased substantially, and there has been rapid development of gene therapy products incorporating [gene editing]," the FDA wrote. 

The guidance lays out the agency's understanding of specific gene editing components, as well as its expectations for how companies will manufacture and test them. In particular, the document details what information companies should provide the FDA when seeking clearance to begin human testing.

Many different gene editing techniques are covered by the guidance, including CRISPR as well as older methods such as zinc-finger nucleases and transcription activator-like effector nucleases. The guidance also applies to gene editing that doesn't involve breaking both strands of DNA, such as the base editing being advanced by Beam and Verve. 

Throughout the document, the FDA emphasizes the potential for unintended safety consequences to gene editing, such as "off-target" modifications, and advises companies on how to monitor and control for them. In clinical testing, for instance, the agency recommends that companies stagger the enrollment of study participants to better assess any side effects that might emerge. 

Notably, the FDA also calls on companies to track trial volunteers for at least 15 years to study whether gene editing carries risks that only appear later. The agency called for similarly long follow-up in past guidance on gene replacement therapies. 

On the whole, analysts viewed the document as unsurprising. Steven Seedhouse, of Raymond James, described it as "pretty straightforward" in a note to clients, while Stifel's Dae Gon Ha said it was "generally benign without layering any major burden on sponsors." 

However, one section of the guidance specified that companies should choose the patients they hope to treat carefully and generally recruit only those for whom no other acceptable treatments are available into "first-in-human" trials." That could potentially affect Verve, which is developing a gene editing treatment for heart disease. 

Yet the FDA notes that "in some instances," patients with less advanced disease may be appropriate to enroll into first-in-human trials. 

"We actually think [Verve's] strategy is aligned with the FDA given a stepwise approach focused on genetically defined diseases resistant to current [standard-of-care] first ... followed by secondary prevention in patients' [with] prior [cardiovascular] events and ultimately primary prevention," wrote Luca Issi, an analyst at RBC Capital Markets, in an investor note. 

Article top image credit: Getty / Edited by BioPharma Dive

An infusion of an experimental CRISPR gene editing medicine has shown early promise as a treatment for a rare inherited condition, an encouraging finding that marks the latest, significant step forward for a technology awarded a Nobel prize in 2020.

Treatment with the medicine, which was developed by Intellia Therapeutics and Regeneron Pharmaceuticals, dramatically lowered levels of a misshapen protein that causes the disease transthyretin amyloidosis. Side effects in the six patients enrolled in Intellia's study were few and mild.

The results, which were published in The New England Journal of Medicine in June 2021, were the first clinical evidence that CRISPR gene editing can be used successfully inside a person's body to treat disease.

"This is a landmark event in modern medicine," said Kiran Musunuru, a professor of medicine at the University of Pennsylvania who specializes in CRISPR gene editing and wasn't associated with the study. "I think it's going to open the door to a whole new class of therapies."

While encouraging and powerful proof of concept, the initial data from Intellia's study don't yet answer many of the most pressing questions facing CRISPR. It's unclear how long the effects researchers observed will last, or whether they'll vary as more patients are treated. The long-term safety consequences of gene editing are also unknown.

Additionally, multiple drugs are available in the U.S. to treat transthyretin amyloidosis, potentially complicating Intellia's path forward with regulators, doctors and patients.

"We have effective tools that suppress [the protein] at this point," said John Berk, a physician who treats amyloidosis at Boston Medical Center and associate professor of medicine at Boston University School of Medicine. "And we have the luxury of regulating them."

Improving prospects

Transthyretin amyloidosis, or ATTR for short, can either be inherited or acquired. The less common hereditary form is estimated to affect some 50,000 people worldwide. Its telltale sign is the buildup of misfolded clumps of TTR, a protein the body normally uses to ferry vitamin A.

ATTR impacts each patient differently but is consistently progressive, worsening over time. Some have nerve damage that begins with toe numbness and creeps upwards, causing health problems like a loss of bowel control or compromised mobility. For others, the disease corrodes the heart, leading to heart failure and death within a few years. Many have elements of both.

For many years, the only treatments were liver transplants or a generic drug called diflunisal that could stabilize the transthyretin protein and slow nerve damage.

Since 2018, however, three new medicines have won approval in the U.S. Alnylam Pharmaceuticals, a pioneer of a gene silencing method known as RNA interference, secured Food and Drug Administration clearance of an infused medicine called Onpattro that can improve nerve function. Akcea Therapeutics followed with Tegsedi and Pfizer's Vyndamax, which is similar to diflunisal, was OK'd for ATTR patients with heart problems.

"When these drugs were approved it was like, 'Oh finally, at least there's something we can do,'" said Mary O'Donnell, the president of the nonprofit Amyloidosis Foundation.

But the drugs have limitations. O'Donnell says patients often have trouble accessing or covering the costs of Vyndamax. Onpattro requires a multi-hour infusion every three weeks so its effects won't wane, along with steroids to prep patients for each treatment. Tegsedi can have a negative impact on kidney function and blood-clotting platelets. All three must be taken for life.

Those drugmakers, and others, are working on longer-lasting and more convenient options. But none offer the potential of gene editing, which is meant to permanently halt, or even reverse, the disease's downward course.

"When we think about what gene editing can bring, it's not just convenience," said Intellia CEO John Leonard. "This is about improving prospects."

The first look

The clinical success of Onpattro and Tegsedi proved suppression of the TTR gene could change the trajectory of the disease.

In some ways, Intellia is building on what Alnylam has already done. Alnylam spent years figuring out how to safely and effectively deliver RNA drugs into cells. The biotech finally succeeded by focusing on the liver, a large organ that filters blood, and using tiny fat bubbles known as lipid nanoparticles to get them there.

"I think what Intellia has done is sort of take the playbook from Alnylam," said Berk, of BU. Berk has been an investigator in the trials of multiple approved ATTR drugs and advised Intellia in the past.

Like Alnylam, Intellia uses lipid nanoparticles to shuttle its medicine into the liver. Inside each, however, are the genetic instructions for CRISPR editing tools. Once absorbed into liver cells, those instructions are deployed to precisely cut the segment of DNA that encodes for TTR, thereby breaking it and halting production of the harmful protein at its genetic source.

Intellia is co-developing its treatment with Regeneron, which partnered with the smaller biotech in a wide-ranging alliance signed in 2016. 

As with other drugs just beginning testing in humans, Intellia's trial was primarily designed to find the optimal dose to move into further testing — one that strikes the right balance between safety and efficacy. Intellia is enrolling adults between 18 to 80 years old with inherited ATTR and symptoms of nerve damage. Some, not all, have heart damage. They'll be tracked for two years.

The results published in NEJM are from three patients who received a low dose and three given a higher one. After four weeks, results from the first three on the lower dose showed TTR protein levels fell by an average of 52%. For the three given a higher dose, the reduction was much greater — on average 87%, with a range of 80% to 96%.

Those latter numbers surpass the 80% reduction reported in testing of Onpattro, an important bar for efficacy.

"It's not just that it worked, it's that it worked so well," said Musunuru, of UPenn. For TTR levels to fall by up to 96%, he added, essentially all of the liver's cells must be edited.

"That's essentially saturation editing," he said. "That's a home run."

Reported side effects, which included headaches, nausea and an infusion-related reaction, were minor. Abnormalities on lab tests for blood clots or elevated liver enzymes — a key concern given the stress the treatment could put on the liver — were "barely detectable," Intellia's Leonard said.

Intellia's results are the first glimpse at how well the company's treatment might work. They do not yet prove CRISPR gene editing can benefit patients any more than existing drugs. While Onpattro and Tegsedi require chronic dosing, they've already been shown to keep transthyretin levels down for multiple years, with their effects leading to better health outcomes for patients with polyneuropathy. It's unclear whether greater TTR suppression would offer an improvement.

"Kudos to Intellia for crafting a CRISPR/cas9 that worked," said BU's Berk. "The novelty is employing new biology to suppress TTR — but the concept of TTR suppression in this disease is well established."

Berk is wary of permanently driving down transthyretin levels, as Intellia's medicine is designed to do, even though that hasn't yet been shown to negatively affect people other than requiring vitamin A supplements.

The potential for accidental, off-target edits to DNA also exists, which could have real health risks such as damage to a gene that helps suppress cancer. Laboratory testing of extremely high doses of Intellia's medicine in human liver cells found no evidence of off-target editing and researchers expect the DNA changes introduced by treatment to be "of low risk." But that may not be known definitively for years. Study participants will have long-term monitoring for safety.

"It's exciting to see that there's evidence of efficacy," said Matthew Wheeler, a Stanford University cardiologist who specializes in genetics and works at Stanford's Amyloid Center. "But there are a lot of safety-related questions that are unanswered."

Wheeler also remains concerned about the potential of gene editing-induced changes being passed on to children, although Intellia's treatment isn't meant to affect sperm or egg cells.

The FDA appears to have taken a stricter stance on genetic medicines for diseases that already have effective treatments. The agency, for instance, is requiring lengthier follow-up for multiple gene therapies in development for the blood disease hemophilia. It's not known what the regulator will require of a gene editing treatment for ATTR. So far, the FDA has asked developers to prove benefits beyond TTR reduction.

"We will draw from some of the work that's been done by others," said Leonard.

Intellia intends to test an even higher dose as well as prove its treatment can similarly lower TTR levels in people with heart damage. A dose will then be selected for pivotal testing in both types of patients, so the drug "can be approved for patients with whatever form of amyloidosis," Leonard said.

CRISPR's reach

Intellia's results are the latest milestone in a string of research landmarks set since 2012, when a paper from Jennifer Doudna and Emmanuelle Charpentier laid out the biochemical components of how CRISPR gene editing worked.

Scientists in academic labs and biotech companies like Intellia have harnessed the tool, which is both more powerful and easier to use than previous methods, across medicine and agriculture. The outpouring of research has made many careers as well as led to immense controversy, such as when Chinese researcher He Jiankui shocked the world with his announcement of the birth of two girls from embryos edited by CRISPR.

Other CRISPR-focused biotechs have made history before Intellia, which was founded by Doudna and others. CRISPR Therapeutics entered clinical testing with a CRISPR gene editing medicine first. Study results over the past year and half have proven its treatment can dramatically alter, and potentially cure, the blood diseases beta thalassemia and sickle cell.

But the biotech creates its treatment by editing patient cells outside the body. Those cells are modified using CRISPR and then reinfused. The complex process has safety risks of its own and limits the reach of gene editing to diseases that can be treated through altered stem cells.

That's why Intellia's results represent a step forward for CRISPR. The inside-the-body approach involves its own set of challenges, most notably delivering the medicine to the right place and ensuring the right cells are edited. But proving it can be done opens a new chapter in gene editing research.

Intellia has several experimental treatments meant to edit genes with a single infusion. So does Editas Medicine, which last September reported initial results for an in vivo CRISPR treatment it's developing for a rare form of genetic blindness. Verve Therapeutics, which Musunuru co-founded and went public last year, also has an inside-the-body gene editing treatment for heart disease that could enter clinical testing next year.

"Until now we really didn't have any evidence that if you put CRISPR or any gene editing tool directly in the human body, it would be both effective as well as — as far as we can see from this study — safe," he said. "This is the first clinical trial that convincingly shows that yes, [in vivo] gene editing can work and can work very well."

Article top image credit: del Aguila III, Ernesto. (2018). "CRISPR Cas9" [Illustration]. Retrieved from Flickr.

Shares of Bluebird bio fell sharply in early August as the biotech company, already in the midst of a major reorganization and just getting past a serious challenge to one of its leading programs, disclosed two more significant setbacks.

The first is that another of Bluebird's more advanced programs has been placed on clinical hold because of safety concerns. According to the company, a patient treated with its eli-cel gene therapy has developed a kind of bone marrow cancer known as myelodysplastic syndrome. Bluebird said the disease was likely "mediated" by eli-cel's design, which uses a so-called Lenti-D lentiviral vector, or LVV, to deliver helpful genetic material into stem cells extracted from patients.

Though they're considered safer than what was used in the earlier days of gene therapy research, lentiviruses like the ones Bluebird uses are still thought to pose potential risks. These viruses integrate with the genetic code of cells, but if they do so incorrectly, it may trigger unwanted mutations that could, at least in theory, lead to cancer.

Bluebird knows the risks well. In early 2021, two clinical studies of its gene therapy for sickle cell disease — a therapy that also uses lentiviral vectors — were put on hold after one patient developed leukemia and another looked to have myelodysplastic syndrome. The trials have since been resumed, after an investigation concluded the myelodysplastic syndrome case was a misdiagnosis and the cancer case was "very unlikely" to be tied to Bluebird's therapy.

According to Bluebird, the clinical hold for eli-cel shouldn't impact its other programs targeting rare blood diseases and cancer. The compnay has submitted eli-cel for FDA approval and expects a decision by September. 

Eli-cel is meant to treat a rare metabolic disorder known as CALD, which is caused by mutations in a specific gene. Regulators in Europe last month cleared the treatment under the brand name Skysona for use in treating certain children with CALD.

"Given what we know, we remain confident that eli-cel can offer hope for patients and families impacted by this devastating disease who have very few treatment options," Bluebird CEO Nick Leschly said in an Aug. 9 statement.

Meanwhile, Bluebird also disclosed alongside its second quarter earnings plans to wind down operations in Europe.

The decision, according to Bluebird, has to do with challenges the company's faced making money from its Zynteglo gene therapy. Zynteglo treats a blood disease known as transfusion-dependent beta-thalassemia, and was given conditional authorization in Europe in mid-2019. But it wasn't until this February 2021 that the first patient was treated outside of a clinical trial and Bluebird hasn't earned any material revenue from sales since.

That's partially because Bluebird and payers can't agree on Zynteglo's price, which starts at $1.8 million. The figure hasn't sat well with certain health authorities, as was evident in April, when Bluebird said it was withdrawing Zynteglo from the German market due to disagreements with regulators there, who reportedly offered to pay up to $950,000 in the event treatment is successful.

Bluebird's announcement suggests this problem isn't isolated to just a few European countries, either. The company said that, moving forward, its severe genetic diseases business will focus on the United States market, its core three programs for sickle cell, beta-thalassemia and CALD, and programs exploring new disease targets that would be suitable for "in vivo" LVV technology.

"European payers have not yet evolved their approach to gene therapy in a way that can recognize the innovation and the expected life-long benefit of these products," Andrew Obenshain, Bluebird's president of severe genetic diseases, said in the Aug. 9 statement.

Bluebird said it's planning an "orderly wind down of operations in Europe," and is considering licensing rights to its gene therapies outside the U.S. to a company with "European experience and capabilities."

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."

Article top image credit: Permission granted by University of Pennsylvania