Gene Therapy

A group of scientists successfully made a bespoke gene editing medicine for a critically ill baby in just a few months, suggesting CRISPR technology could be used to quickly develop personalized therapies for an array of ultra-rare diseases.

Study results published in The New England Journal of Medicine and presented at a medical meeting in mid-May reveal that a treatment tailored to an infant with a deadly metabolic disorder was safely administered. They also describe early evidence the treatment has helped stabilize the infant’s disease.

Researchers at the Children’s Hospital of Philadelphia and several other institutions designed and developed the treatment within seven months of the baby’s birth. It’s meant to correct a specific genetic abnormality that causes the metabolic disorder, known as CPS1 deficiency for short.

Part of a family of “urea cycle disorders” that disrupt liver metabolism, CSP1 deficiency results in ammonia accumulation that’s toxic to the brain. Treatment, while limited in effect, typically involves diet restrictions, dialysis and certain drugs.

After receiving three doses of the therapy, the baby, named KJ and about 10 months old in May, can consume more protein and requires less supportive medication. KJ has also withstood multiple viral infections that might normally worsen his condition.

“All the milestones that he's reaching, or the developmental moments that he's reaching, show us that things are working,” Nicole Muldoon, his mother, told reporters in a May media briefing.

Longer follow-up is needed to determine how much the therapy actually ameliorates KJ’s disease and improves his long-term health. Doctors also couldn’t yet safely perform the liver biopsy that’s needed to show the treatment’s effects on a genetic level, leaving important questions unanswered.

“We are still in very early days,” said Rebecca Ahrens-Nicklas, an assistant professor of pediatrics at the University of Pennsylvania and study author. Doctors will monitor KJ’s progress, and are considering other ways to evaluate the therapy’s effects without a biopsy.

Yet the findings could carry important implications for drug research. There are more than 7,000 rare diseases, many of which are so uncommon they’re unlikely to be profitable for any companies that develop treatments for them. Gene editing could be a powerful solution, but an expensive development path and slim sales prospects make such medicines tough investment propositions. A large number of biotechnology firms pursuing gene editing are struggling to survive.

Speeding development of gene editing therapies tailored to individuals may be one answer. In an editorial also published in NEJM, Peter Marks, the former head of the Food and Drug Administration office that regulates gene editing, wrote that a “forward leaning, science-based regulatory approach” might address the commercial challenges limiting this approach’s use against these so-called N-of-1 disorders.

The results published May 15, while “very early,” are a clear example, he wrote.

KJ’s case adds to other instances in recent years of researchers designing custom therapies for specific individuals. In 2018, a girl named Mila with Batten disease was given a bespoke medicine made using an older drugmaking technology. Scientists at Boston Children’s Hospital have followed that model several times since.

KJ’s disease is extremely uncommon, affecting an estimated one in every 1.3 million people born. While the condition’s severity can vary, its most serious form takes hold in early infancy and causes a panoply of potentially life-threatening health problems. Liver transplants may help, but babies diagnosed with the disease can suffer irreversible brain damage before they’ve grown enough to receive one. More than half die, according to Ahrens-Nicklas.

KJ experienced high ammonia levels immediately after birth and was quickly put on dialysis. He received supportive care at CHOP, and was closely monitored for serious health problems. The typical plan in cases like his was to wait until he could receive a new liver, she said.

Ahrens-Nicklaus had a different idea, though. For a few years, she had worked closely with Kiran Musunuru, a professor of medicine at UPenn who specializes in CRISPR gene editing. The two were collaborating on ways to develop personalized, gene editing therapies that could turn on enzymes that were defective or missing in people like KJ.

By the time KJ was born, they had already completed multiple “practice runs” of a monthslong process to design and test a corrective therapy, Musunuru said.

Once KJ was diagnosed, “we were ready,” he added.

Within four months, the researchers sketched out what they believed would be the most effective therapy design and met with the FDA to discuss testing it on KJ. They conducted preclinical safety tests over the next two months, and constructed a batch of the drug. The FDA cleared their clinical application one week after filing, enabling Ahrens-Nicklaus, Musunuru and the rest of the team to dose KJ when he was 7 months and 8 months old. KJ recently received third dose of the drug, which is expected to be his final infusion.

“The FDA recognized that this was an unusual circumstance. KJ was very, very sick, and there wasn't time for business as usual,” Musunuru said. “They told us to do as good a job as we possibly could in the limited time we had, and they would take it from there.”

The speedy process represents a “milestone in the evolution of personalized therapies for rare and ultrarare inborn errors of metabolism,” wrote Alexis Komor, an associate professor at University of California, San Diego and Andrea Gropman, a pediatric neurogeneticist at St. Jude’s Children Hospital, in an accompanying editorial.

Still, they noted the “evidentiary” limitations of such N-of-1 experiments that make it harder to gauge whether the treatment is safe, works or provides lasting benefits.

The findings, Komor and Gropman wrote, “offer hope and yet require validation.”

This type of approach can hold hard-to-predict risks. A bespoke gene therapy designed for a person with Duchenne muscular dystrophy wasn’t successful, and the individual died days after treatment. In a “preprint” paper that hasn’t yet been peer-reviewed, the researchers behind that experiment note how its N-of-1 nature made it more difficult to draw conclusions about the cause of the patient’s death.

Marks, who while at the FDA pushed the agency to be more flexible in reviewing rare disease drugs, is still confident in a path forward, however. The study published May 15, he wrote, points to a future in which U.S. regulators could “markedly reduce the complexity and cost of product development.”

Perhaps a gene editing drug for a rare disease could receive an initial approval for its “overall approach,” he said. If so, a slight switch of a single component, like the guiding sequence of RNA, could allow its use in similar-but-different diseases. That “could transform N-of-1 therapy into N-of-many therapies, thus leading to commercial viability of these products for rare diseases,” Marks wrote.

“I don't think I'm exaggerating when I say this is the future of medicine,” Musunuru said. “We very much hope we are showing it's possible to make a personalized gene editing therapy for a single patient, in real time in several months, and it will inspire others to do the same.”

The Food and Drug Administration in November unveiled a new blueprint for the regulation of bespoke drug therapies, announcing a way for these treatments to quickly get to market if they meet certain standards.

Called the “plausible mechanism” pathway, the new framework is designed to help accelerate treatments for serious conditions that are so rare they may only affect individuals or handfuls of people and can’t feasibly be tested in randomized clinical trials. It was announced through an article authored by FDA Commissioner Martin Makary and top deputy Vinay Prasad, and published in the New England Journal of Medicine.

“Critics may contend that there is no need for an alternative pathway and that existing FDA operations are able to address bespoke, transformative therapies,” they wrote. “Unfortunately, the FDA has heard from patients, parents, researchers, clinicians, and developers that current regulations are onerous and unnecessarily demanding, provide unclear patient protection, and stifle innovation. We share this view.”

The FDA intends to issue joint guidance on the new pathway from both of its main drug offices, CDER and CBER, a spokesperson for the U.S. Department of Health and Human Services told BioPharma Dive.

There are more than 7,000 rare diseases, many of which are so uncommon they’re unlikely to be profitable for any companies that develop treatments for them. Solutions might exist, too, in the form of CRISPR gene editing treatments or other types of genetic medicine. But an expensive development path and slim sales prospects make such therapies tough investment propositions. Many biotechnology firms pursuing these types of treatments are struggling to survive.

Yet in recent years, there’ve been multiple instances of academic researchers designing custom therapies for specific individuals. In 2018, a girl with Batten disease was given a bespoke medicine using a type of RNA technology. Scientists at Boston Children’s Hospital have followed that blueprint several times since. And earlier this year, researchers at the Children’s Hospital of Philadelphia and several other institutions designed and developed a CRISPR-based treatment for a critically ill baby named KJ Muldoon within seven months.

Makary and Prasad wrote that baby KJ’s story, in particular, is illustrative of what the FDA aims to achieve with its initiative. In that case, KJ was quickly diagnosed with a rare liver condition. The FDA then processed, in one week, a single-patient “expanded-access” application, enabling KJ’s care team to speedily manufacture and infuse a gene-editing therapy that’s so far helped stabilize his condition.

Several aspects of that process “define” the “plausible mechanism pathway,” they wrote. Qualifying treatments need to be directed at the known biological cause — like a molecular or cellular abnormality — of a disease. Developers must have “well-characterized” historical data showing how the disease might impact patients if left unchecked. Companies must also confirm, via a biopsy or preclinical tests, that a treatment successfully hits or “edits” its target and improves outcomes afterwards.

The FDA will initiate an approval process for developers that meet these objectives in “several consecutive patients with different bespoke therapies,” Makary and Prasad wrote. Companies must then accumulate evidence showing a therapy continues helping a patient without causing serious harm, or negatively impacting a child’s development.

The FDA is initially prioritizing rare diseases, especially those that are deadly or associated with serious childhood disabilities. But the new framework could also apply to common conditions with no “proven alternative treatments" or in cases where new therapies are sorely needed. It could also be available to more than just gene or cell therapies, with Makary and Prasad noting situations where small molecules and antibodies might eventually be beneficiaries, too.

Bespoke therapies are “closer to reality,” they wrote.

Sponsored content

By Mirus Bio LLC

Viral-based gene therapies (GTs) represent a new frontier in medicine, offering hope to patients who previously had few, if any, treatment options. As therapeutic developers increasingly target polygenic indications with larger patient populations, including Parkinson’s disease, they have the potential to impact millions of lives.

Successfully delivering on the promise of GTs, however, requires developers to find a cost-efficient manufacturing strategy that meets patient demand.

“Most of the industry historically has standardized around 200-liter bioreactors, but higher dosing and larger patient populations are pushing manufacturing demand to 1,000+liter bioreactors,” explains Fletcher Malcom, Head of Strategy, Product and Business Development at Mirus Bio LLC. “If developers can’t find a cost-efficient way to scale up production, they risk undermining the commercial viability of their programs.”

The challenges: Scaling upstream adeno-associated virus (AAV) gene therapy manufacturing

Developers and manufacturers looking to move beyond the standard 200-liter bioreactor scale must overcome a crucial bottleneck: The stability of their transfection complex.

Transfection complexes, composed of plasmid DNA and transfection reagents, have an extremely short window of stability. When using standard reagents, manufacturers must prepare the transfection complex and add it to the bioreactor within minutes to achieve the optimal titer for the resulting therapeutic.

Beyond 15-30 minutes, the transfection complexes increasingly aggregate, becoming too large to effectively cross the cell’s plasma membrane thus reducing transfection efficiency.

This results in a race against time, particularly as manufacturers look to scale up production. For a 200-liter bioreactor, you may only need to add 10 liters of transfection complex within a time frame of 5-10 minutes to hit the optimal efficiency targets; But for a 1,000-liter bioreactor, the complex size jumps to 50 liters and you have the same 5-10 minutes to deliver the complex.

“At that volume, the transfection complex solution is difficult to deliver quickly to a production bioreactor,” says Malcom. “Essentially, you have an upper limit to the transfer flow rate whereby adding the solution faster to comply with the short time window risks damaging the complex. Damaging the transfection complex reduces upstream titer and therefore it becomes a real balance when increasing bioreactor size to 1000L or greater while not sacrificing productivity per liter.”

As a result, manufacturers face:

• Limits on scalability: Short time windows to deliver the transfection complex don’t expand or scale with large volume processes.
• Stressful work environments: Employees who struggle to deliver large volumes of transfection complex within a tight time frame.
• Increased variability in performance: Nuances or even small deviations during the complexation delivery step can negatively impact yield and titer.

The solution: Improve transfection complex stability to reduce time-sensitivity

Developers must find ways to improve the stability of the transfection complex solution to make scale-up easier and to enable scaling to 1000L and beyond. Enhanced complex stability increases the timeline during which staff can add the complex to the production bioreactor, enabling better consistency of results while also reducing the risk of error.

“With the introduction of Mirus Bio’s innovative VirusGEN Stabilizer additive, you can extend the stability of the transfection complex six-fold — from 30 minutes to three hours,” Malcom says. “That means less scrambling to add the solution to your bioreactor and more opportunities to scale up production into the thousands of liters.”

Mirus Bio’s transfection reagent and enhancer technologies also enable manufacturers to achieve higher titers and percentages of full capsids, thereby increasing the overall productivity of the manufacturing process.

“When you’re manufacturing in the thousands of liters, being able to reduce the transfection complex to 2% of culture volume instead of 5% goes a long way in streamlining your workflow and making life easier for your staff,” Malcom says.

The result: More opportunities to streamline your manufacturing process

Enhancing transfection complex stability provides an opportunity for manufacturers to boost outcomes across their programs, including:

• Productive manufacturing at scale: Manufacturers can increase capacity while maintaining a high level of productivity.
• Less risk due to more forgiving workflows: Reduce the impact of delays in the complexation process by increasing stability.
• Manage manufacturing costs: By reducing the risk of a wasted batch due to transfection complex instability and more easily realizing the efficiencies of scale in manufacturing.

Scale with peace of mind: Mirus Bio’s transfection reagent and enhancers

Scaling up manufacturing doesn’t have to be painful — and the optimal reagents and enhancers can help you reach your goals, Malcom says. “We can make it easier to manufacture AAV at scale by extending the time window for transfection complex stability to help you achieve greater performance, usability and cost-efficiency that sets your commercialization plan up for success.”

Learn more about how we can help you optimize recombinant AAV production.

In June, a 51-year-old man treated in a clinical trial with an experimental gene therapy became dangerously sick. The developer of that treatment, Sarepta Therapeutics, informed the Food and Drug Administration his case could be life-threatening. 

The man died from acute liver failure a few weeks later, which Sarepta reported to the FDA on July 3 as a matter of course. Little has seemed to go by the book since. 

Liver injury is a known risk of the kind of gene therapy used to treat the man, who had a muscle-weakening disease called limb-girdle muscular dystrophy. Two other patients with a different kind of muscular dystrophy, Duchenne, and treated with a different Sarepta gene therapy, approved as Elevidys, also died of liver failure this year. In response to those earlier deaths, Sarepta stopped shipping Elevidys to certain older Duchenne patients. 

But Sarepta didn’t consider the 51-year-old man’s death to be “material,” a regulatory term describing when an event is important enough to require public disclosure. The death went unreported publicly until July 17, one day after Sarepta had held a conference call to discuss a business restructuring that will shelve the limb-girdle treatment, along with several others. 

Wall Street analysts who cover Sarepta were furious over the lack of transparency, forcing Sarepta to hastily hold another conference call, on July 18, to explain why it hadn’t disclosed the man’s death, which raises serious questions about the safety of that gene therapy and, potentially, Elevidys. 

The FDA appeared angered as well. Despite knowing about the most recent patient death for weeks, and having already discussed Elevidys labeling changes with Sarepta, the agency on July 18 asked Sarepta to stop shipping the drug to Duchenne patients. In statements, the FDA implied it was looking at a common component between Elevidys and the experimental therapy. 

Sarepta initially refused the FDA’s request, saying it will continue shipping Elevidys for younger Duchenne patients who can still walk — a group for whom the company claims treatment remains supported by available evidence. Three days later, it begrudgingly agreed. 

The standoff between Sarepta and the FDA, while brief, has few precedents. Analysts see rising risk the FDA formally attempts to withdraw Elevidys from market, which could divide a patient community that has for years helped Sarepta push for greater regulatory flexibility at the agency. For the gene therapy field, meanwhile, the brewing crisis comes at a time when investment has dried up and its future appears fragile. Here are five questions about what might come next: 

What does Elevidys’ future look like now?

Some backstory first: The FDA first approved Elevidys in June 2023, granting it accelerated clearance for Duchenne patients who were 4 or 5 years old and could still walk. One year later, the agency expanded the treatment’s OK to include ambulatory and non-ambulatory Duchenne patients who were 4 years of age or older. 

Both decisions were controversial, as Sarepta’s trial data for Elevidys didn’t prove the therapy could significantly improve motor function. But the Duchenne community mostly embraced Elevidys, propelling it to the fastest market launch of any gene therapy approved in the U.S. 

Safety concerns prompted by the recent deaths could now change that. But without Sarepta’s cooperation, the FDA’s options for stopping Elevidys sales altogether are limited. And those it does have at its disposal are likely to take time. 

In first refusing the FDA’s request to halt sales, Sarepta maintained there has been no new information indicating greater safety risk in younger, ambulatory patients. Both of the Elevidys patients who died were teenagers whose disease had eroded their ability to walk. 

The distinction is clinically important as Elevidys is dosed by weight, so younger, lighter patients receive less of the drug. And as they’re earlier in their disease course, the treatment window to forestall further damage may be greater.

The distinction also has regulatory implications. In June 2024, when the FDA expanded Elevidys’ approval it did so by converting its accelerated approval to full for ambulatory patients. In non-ambulatory patients, Elevidys’ clearance remains “accelerated,” which indicates Sarepta is required to produce further evidence of its benefit in this group.

The FDA has more tools at its disposal to request market withdrawal of therapies under accelerated approval than it does for those under traditional OKs. But even here, its power to compel drugmakers to stop sales of a product is attenuated by a process requiring regulatory notice, comment periods and public hearings. 

In one high-profile case, the FDA needed two-and-a-half years to pull a preterm birth drug from market. Another, more recent case that occurred after 2023 legislation granted the FDA more latitude still took 232 days. 

Analysts seem to think the FDA might still try. “We don't believe FDA is likely to let go without a fight — and while we can't predict timing (not much precedence in this occurring), there is a good chance the FDA at some point forces this from the market,” Cantor Fitzgerald analyst Kristen Kluska wrote in a recent client note. — Ned Pagliarulo

Why did the FDA wait to step in?

The FDA claimed on July 18 that it took “swift action” by suspending multiple Sarepta trials and requesting the company halt all Elevidys shipments. It took those steps following “new safety concerns” that the agency said showed patients may be exposed to “unreasonable and significant risk of illness or injury.”

“We believe in access to drugs for unmet medical needs but are not afraid to take immediate action when a serious safety signal emerges,” FDA Commissioner Martin Makary said in the statement. 

According to Sarepta, the FDA had known about the latest death, which occurred in June, for two weeks. But the FDA didn’t take action until July 18, after news of the death became public through reports and a conference call from Sarepta.

There were “no new or changed safety signals” regarding Elevidys, Sarepta added, noting how the most recent death occurred with an experimental therapy that’s manufactured differently and administered at a different dose. Both treatments use the same viral vector for delivery into the body, however.

Sarepta was already under fire for waiting weeks to disclose the most recent death, a decision CEO Doug Ingram last week said was because the company believed it was “neither material nor relevant.” Its share price has been decimated as a result. 

Yet the agency’s delayed response was “puzzling” and “perplexing,” according to analysts on Wall Street. They suggest the FDA reacted only in response to “recent headlines,” wrote Leerink Partners’ Joseph Schwartz, and hint at a “shift towards decision-making influenced more by social factors than by science or regulatory precedent.”

“This makes it increasingly more difficult to anticipate how [the FDA] will govern moving forward,” Schwartz added, noting how the “optics” look bad “both for the agency and the company.” — Ben Fidler

Where does Sarepta go from here?

Sarepta posted net yearly losses for much of its history, but finally became profitable in 2024 because of Elevidys. The company expected that financial success to continue in the coming years, predicting in February that its overall revenue would reach $2.9 billion to $3.1 billion in 2024. Analysts anticipated Elevidys would surpass $2 billion on its own, enabling Sarepta to afford pursuing more than 40 programs based on gene therapy, gene editing and RNA technologies. 

Those projections have quickly fallen apart. Sarepta revised and suspended its financial guidance after halting Elevidys shipments to non-ambulatory patients and, last week, cut nearly 40% of its workforce along with several drug programs. Gene therapy research, once a main focus, has been whittled down to a single prospect for limb-girdle muscular dystrophy. 

The biotechnology company is now counting on a trio of “exon skippers” for Duchenne, which it suggested could bring in $900 million annually, and Elevidys, which it said at minimum should generate about $500 million per year. An RNA-focused collaboration with Arrowhead Pharmaceuticals could yield more medicines in the future. 

But Sarepta could face more financial peril. It has about $1 billion in debt due in 2027 and intends to speak with lenders this week to determine whether any of the myriad recent developments might constitute a “material adverse event” that could trigger financial fallout, executives told Leerink’s Schwartz. The company would need to make “sizable organizational cuts” to pay its debts and remain viable if Elevidys were to be removed from the market entirely, Schwartz wrote.  

Even now, investors are wondering whether Sarepta can pay its debts without more cuts, Schwartz added. 

The company could face competitive threats to its exon-skipping drugs as well as Elevidys in the near future, further threatening its core business. And the clinical holds announced by the FDA will at minimum likely delay the arrival of its next-closest product to market, a gene therapy for limb-girdle dystrophy, wrote William Blair analyst Sami Corwin on Monday. — Ben Fidler

How will the Duchenne community respond?

Several Duchenne medicines have been approved by the FDA over the last decade or so.

These medicines have offered hope to a community of patients, caregivers and advocates facing a lethal disease that slowly robs children of their ability to walk and function independently. They’ve also tested the FDA, spotlighting the tricky decisionmaking involved in evaluating treatments for rare, deadly conditions and the pressure patient groups — many of which receive funding from drug companies — can put on regulators. 

That community is now at the center of a high-stakes standoff between a company and its regulator. In the last few months, they’ve heard of multiple deaths in clinical trials, potentially changing how they see the risk-benefit balance of Elevidys. They’ve seen access for Elevidys restricted and clinical trials put on hold. And now, they’ve received conflicting reports from Sarepta and the FDA about Elevidys’ market status.

“Families who have fought tirelessly for access to this therapy, those who have already received it, and those who are in line to receive it are now left with more questions than answers,” wrote Parent Project Muscular Dystrophy, a prominent patient advocacy group, in a July statement. PPMD is “urgently seeking answers and calling on both Sarepta and the FDA to provide clarity and transparency.” 

“These developments are painful, and they’ve shaken the hope that many families have carried for years,” added the Muscular Dystrophy Association, another large advocacy organization, in a separate statement in late July. 

Should the FDA try to withdraw Elevidys altogether, it could start a messy fight with an educated and mobilized patient community that has influenced past agency decisions — the kind of spat an optics-conscious agency might want to avoid. 

Such a move would also counter some of the messaging from Makary and Vinay Prasad, who now runs the FDA’s Centers for Biologics Evaluation and Research. Prasad was highly critical of his predecessor Peter Marks’ decision to twice overturn agency staffers in approving and then broadening use of Elevidys. But, like Marks, he and Makary have promised FDA flexibility in reviewing rare disease gene therapies. — Ben Fidler

What are the implications for the gene therapy field? 

The patient deaths, and Sarepta’s handling of them, come as the gene therapy field faces its own crisis.

Developers of these medicines are having trouble demonstrating they can reliably profit off of their sale. Logistical, financial and administrative hurdles are hampering adoption of approved therapies, which in turn is crimping the outlook of those in development. The slump in investment that’s holding back biotech writ large is hurting gene and cell therapy companies even more acutely. 

This newest episode presents two challenges. Firstly, the patient deaths bring the surface safety concerns that have stayed simmering underneath gene therapy ever since the 1999 death of Jesse Gelsinger in one of the field’s early clinical trials. Elevidys, and Sarepta’s experimental limb-girdle treatment, use a type of engineered virus — called AAV for short — that’s become a go-to method for delivering functional genes to target cells. Researchers have warned, though, that high doses of these therapies present notable risks, which now appear back in the spotlight.

Cantor Fitzgerald analyst Eric Schmidt wrote in a July 18 note that he’s heard concerns from investors and companies that Sarepta’s decision to discontinue swathes of its gene therapy research “would be another difficult setback for the AAV platform.”

Sarepta’s lack of disclosure may carry consequences of its own, too. “Fears are running high that Sarepta’s downfall could be a Theranos/Vioxx/Gelsinger-type of event that further poisons generalists against the sector,” Schmidt added, referencing how biotech safety scandals of the past led to declines in investment. 

“In what other industry can a company's revenue projections drop from ~$5B to near nothing in weeks?” he added. “Where else are investors so reliant on management to provide accurate information? And how can an industry that claims to put patients first have gone so far afield?”

Sarepta’s credibility problems are of its own making, of course, but for a sector that desperately needs investors to regain confidence in its potential, there may be knock-on effects. — Ned Pagliarulo

Anyone looking for evidence of genetic medicine’s enormous promise need only read of KJ Muldoon. The 10-month-old infant headed home from a Philadelphia hospital this week, dressed in a celebratory cap and gown, after his life-threatening disease was successfully treated with a bespoke CRISPR therapy.

While baby KJ is not cured, the treatment has stabilized his disease, a rare liver condition known as CSP1 deficiency, to such extent he’s able to resume eating a normal diet. Doctors, who hurriedly designed and constructed KJ’s custom therapy in a matter of months, have backed off supportive medications and hope he’ll no longer need a liver transplant.

“Each year, 10 million babies are born with one of about 10,000 known rare genetic diseases, many of which are, in principle, now treatable with genetic medicines,” David Liu, a pioneering CRISPR scientist whose laboratory helped in KJ’s treatment, said at a meeting hosted by the Food and Drug Administration in early June.

“The opportunity created by this perfect storm moment in scientific, medical, regulatory and manufacturing innovation is to provide on-demand genetic treatments like KJ’s at scale.”

Yet Liu and 22 other gene therapy experts and advocates who attended the June roundtable didn’t travel to the regulator’s headquarters in White Oak, Maryland to extol the field’s advances. By and large, they came to warn of a crisis.

There are now dozens of approved cell and gene therapies in the U.S., some of which offer near-curative potential for serious diseases like spinal muscular atrophy, sickle cell disease and acute lymphoblastic leukemia. However, the sector that’s produced these therapies is struggling.

Investors have soured on genetic medicine as developers struggle to prove they can profitably sell the complex and often hugely expensive treatments. Biotechnology companies are cutting research, laying off staff and, in some cases, shutting down. Large pharmaceutical firms are no longer willing to bet billions of dollars they can surmount the regulatory and reimbursement hurdles that stand in the way of many of these therapies. And academic labs, still bursting with promising new ideas for technologies like CRISPR, now fear their projects will wither on the vine.

“We estimate that over 100 rare disease gene therapy products that had reached clinical stage have been discontinued since 2023 — not because of treatment failure, but because of the risk of market failure,” said Terence Flotte, dean of the University of Massachusetts’ T.H. Chan School of Medicine and president of the American Society of Cell and Gene Therapy.

“The scientific advances that we have witnessed are just nothing short of spectacular. It’s not hyperbole,” said Crystal Mackall, a professor at Stanford University and founding director of the cancer cell therapy center there. “Despite this unconditional scientific success, the field is really struggling to deliver these therapies to all patients who can benefit.”

Their warnings found a receptive audience in FDA leadership. Commissioner Martin Makary and top official Vinay Prasad, who leads the office that oversees cell and gene therapies, were sympathetic to experts’ arguments and pledged to help.

“We are going to continue the successes of the FDA in facilitating the regulatory process for these conditions and these products,” said Makary. “We’re also going to try to improve by creating more efficiencies.”

Prasad, who in the past has criticized the FDA’s accelerated approval of a gene therapy for Duchenne muscular dystrophy, showed support for flexible trial designs and endpoints when appropriate for the disease or treatment.

He also noted the agency accepts that cell and gene therapies don’t always comes with transformative potential. “We understand that progress is not always made in a single leap,” he added. “We will consider incremental steps forward, because those add up.”

The assembled experts came with lists of possible solutions. Carl June, a famed immunologist and cell therapy researcher at the University of Pennsylvania, called for the U.S. to borrow from the two-tier regulatory system used in China, which allows for medical institutions to more rapidly start first-in-human trials under the supervision of local review boards.

Don Kohn, a University of California, Los Angeles scientist who has developed gene therapies, asked the FDA to reduce the requirements for “comparability” testing when companies transition production from academic to commercial settings. 

Others emphasized the importance of regulatory awards, like the priority review vouchers granted by the FDA to developers of certain therapies, who often sell them for needed capital. And many called for the agency to share more feedback and lessons learned from the applications they receive from industry. 

Behind all of their suggestions was a consistent concern: If regulators don’t help solve the field’s problems, the U.S. risks losing its leadership in developing the kinds of treatments that can cure diseases.

“If we don’t adapt, the next generation of treatments will emerge abroad,” said June. “The future of medicine with cell and gene therapy is at stake.”

Their message seemed to be heard by Makary and Prasad, who noted that many of the issues raised are on their radar at FDA. Prasad, for instance, noted that they hope to redact and make available more internal documents to aid developers’ understanding of what the FDA is looking for. 

“This is not a horse and pony show to say we did this,” added Makary. “This is an honest listening session.” 

BioMarin Pharmaceutical is giving up on the hemophilia gene therapy Roctavian, announcing in October plans to offload a first-of-its-kind medicine once expected to become a future blockbuster.

In a statement announcing the company’s third-quarter earnings, CEO Alexander Hardy said BioMarin will “pursue options to divest Roctavian and remove it from our portfolio.” BioMarin still believes Roctavian “has an important role to play in the treatment of hemophilia A” and is evaluating “out-licensing options” as a result, Hardy said. 

“This decision is consistent with BioMarin’s portfolio strategy and offers the most promising opportunity for ensuring continued patient access to Roctavian,” Hardy added in the statement. 

The announcement culminates what’s been a fast fall for Roctavian since its launch began four years ago. 

Roctavian’s approval in Europe in 2022 and in the U.S. a year later were scientific milestones, the culmination of years of research developing a genetic medicine for hemophilia A. As a one-time, long-lasting treatment, Roctavian was billed as an alternative to the chronic therapies people with hemophilia A use to prevent bleeding. It was also seen as a clear example of the potential economic bargain of a gene therapy that, despite a high initial price tag, might alleviate the need for supportive care patients would receive instead. 

At the time, many Wall Street analysts viewed the product as a blockbuster-to-be. Leerink Partners analysts once projected $2.2 billion in peak sales, and BioMarin was similarly optimistic, estimating early on that the therapy would generate anywhere from $50 million to $150 million in 2023. 

Instead, Roctavian has become a cautionary tale of the challenges drugmakers can face selling a gene therapy. BioMarin quickly and sharply slashed its revenue forecasts for 2023 and ended up recording $3.5 million in product sales that year. The therapy accounted for only $26 million in 2024, and just $23 million over the first nine months of 2025, the company said Monday.

Hardy has previously cited the “complexity” of getting patients on treatment as a reason for Roctavian’s commercial performance. But doubts about the durability of its benefits and a price tag that made reimbursement discussions challenging also slowed its sales trajectory.

BioMarin wasn’t alone in reporting sluggish sales, either. Pfizer cited weak demand in choosing to stop selling a gene therapy for the less common hemophilia B. Uptake has also been slow for CSL’s Hemgenix, another hemophilia B gene therapy. 

In August 2024, BioMarin pared down Roctavian spending rather than choosing to sell it altogether, with Hardy at the time citing signs of launch progress in the three countries — the U.S., Germany and Italy — the company chose to focus on. 

Nearly three dozen states have signed onto a U.S. government initiative designed to help improve access to gene therapies that can eliminate serious symptoms of sickle cell disease, but remain little-used because of their high price tags. 

The Centers for Medicare and Medicaid Services said in mid-July that 33 states, plus the District of Columbia and Puerto Rico, will participate in the “Cell and Gene Therapy Access Model” to centrally coordinate insurance coverage for the treatments. Between 50% and 60% of people with sickle cell in the U.S. have Medicaid coverage and the participating states represent about 84% of Medicaid beneficiaries with the condition, the agency said. 

Two such treatments, Vertex Pharmaceuticals’ Casgevy and Bluebird bio’s Lyfgenia, were approved by the Food and Drug Administration in December 2023 after proving in testing to be able to free people with severe sickle cell from the serious bouts of pain they experience. However, the treatments are complex to administer, involving a monthslong process and a “preconditioning” chemotherapy step that comes with the risk of infertility. They also cost $2.2 million and $3.1 million, respectively, raising concerns about their affordability and the impact on state Medicaid budgets. 

Since approval, uptake of both treatments has been slow. In its last quarterly report, Vertex attributed $14.2 million in revenue to Casgevy and said that, through May 1, cells had been collected from about 90 patients seeking therapy. Bluebird was taken private this year — partly due to challenges selling its gene therapies — and in its last public financial report, said 17 patients had started on Lyfgenia through the first nine months of 2024. 

The CMS program could help boost these figures by having the government negotiate what’s known as “outcomes-based agreements” with product manufacturers. These deals link payment to the health benefit a treatment is supposed to deliver. If that benefit doesn’t materialize, the insurer is issued a rebate or reimbursed. 

Some insurers have long used outcomes-based deals for certain gene therapies, and represent a way to lower the financial risks associated with treatments typically carrying a nine-figure price tag. But the CMS model, which was initially hatched during the Biden administration and picked up by the Trump administration earlier this year, would coordinate the negotiation of a specific framework across many states so each one doesn’t have to arrange its own deal.

The federal government will also cover a “defined scope” of fertility preservation services and other costs, such as travel expenses. It could provide up to $9.55 million in additional support per state, as well, to help with outreach and data tracking, as outcomes-based deals require the collection of extensive information. CMS could expand the program to cover “other diseases with high-cost, high-impact therapies” too, the agency said. 

“This model has the potential to improve health outcomes for patients with sickle cell disease while also ensuring state and taxpayer dollars are being used more effectively,” said Abe Sutton, CMS’ deputy director and the head of its innovation center, in a statement. 

UniQure, the Netherlands-based gene therapy developer, lost a majority of its value in November after disclosing that the Food and Drug Administration seemed unlikely to review — at least in its current state — an approval application for the company’s most advanced research program.

UniQure met extensively with the FDA to ensure the agency would be receptive to its application for “AMT-130,” a gene therapy designed to treat Huntington’s disease. And the parties seemed to be in alignment. Last April, the FDA gave AMT-130 a special classification that would speed up its review timeline.

Then, in September, UniQure unveiled results from a mid-stage clinical trial that wowed investors and the research community. The company said it was “eager” to discuss these data with the FDA and planned to formally file for approval in 2026.

But after a meeting with agency staff, UniQure said the FDA doesn’t see those results as adequate enough to support approval. “This is a key shift from prior communications,” the company said in a statement, and as such the timing of a submission for AMT-130 “is now unclear.”

Huntington’s was the first genetic disease mapped to a specific chromosome. Yet, despite knowing its root cause for more than 40 years, drugmakers have struggled to create effective therapies for the nerve cell-destroying illness. That track record made UniQure’s data all the more exciting. Its trial found that, among 12 participants who were given a high dose of AMT-130 and followed for three years, signs of disease progression appeared to slow by 75%.

While the results delighted investors — UniQure’s share price tripled on their unveiling — lingering concerns about the path to approval also tempered some of the enthusiasm.

Vinay Prasad, head of the FDA office that regulates gene therapies, has criticized the ways in which the agency has tried to expedite the review of certain genetic medicines. He was also a central figure in the FDA’s request to Sarepta Therapeutics’ to pause distribution of Elevidys, a gene therapy for Duchenne muscular dystrophy.

Paul Matteis, an analyst at the investment bank Stifel, spoke to UniQure executives and confirmed Prasad was not in that recent meeting between the company and the FDA. Still, “it's hard to believe that this [UniQure] about face happened without him knowing or being involved,” he wrote in a note to clients.

Matteis added that the FDA’s new position is “very surprising” and could weigh down the shares of other companies developing gene therapies. “Really the broader takeaway here for us is that FDA — and our ability to predict the FDA — is about as uncertain as it's been in the past decade or longer,” he wrote.

UniQure isn’t the only drugmaker to be recently blindsided by the FDA. Last summer, the agency rejected approval applications from Replimmune and Capricor Therapeutics, which, respectively, have been developing a melanoma treatment and a first-of-its-kind cell therapy for heart-related complications of Duchenne.

The CEOs of both companies said the FDA’s decision surprised them, especially because they had met with agency staff to make sure there was agreement on the necessary steps to tee their medicines up for approval.

Mani Foroohar, an analyst at Leerink Partners, wrote in a note to clients that the UniQure news “fuels worry on how much weight can be put on prior regulatory alignment with the agency.”

Each year, a small number of babies are born mostly, if not fully, deaf because one of their genes isn’t working.

The gene normally makes a protein that the hairs in our inner ears need to relay sound signals to the brain. Without that protein, people with this rare form of hearing loss often rely on cochlear implants for their entire lives.

But in the near future, genetic medicine may offer another option. In October, fresh results from a small clinical trial showed that, among a dozen children given a gene therapy from Regeneron Pharmaceuticals, most are now hearing well enough to not need help from implants.

Encouraged by those results, Regeneron moved forward with plans to submit an approval filing to the Food and Drug Administration.

“To have a therapy that gets kids back to essentially normal hearing in many cases, it's game changing for all of us in the field. It’s just super exciting,” said Lawrence Lustig, a trial investigator, hearing specialist and department chair at Columbia University Medical Center.

Hearing loss is often categorized by the softest sound level a person can register. On one end of the scale is normal, then mild, moderate, severe, and finally “profound,” or the most impaired. Regeneron last presented early, positive findings from its study last February, at which point researchers had collected six months of follow-up data on five children, three of whom were hearing at normal or near-normal levels.

Six-month data is now available for 12 participants. Of them, nine hit the study’s main goal by demonstrating their hearing was in the moderate to normal range at that time point. One of the remaining three had no improvement, while the two others had “positive changes.” Lustig noted that one of those latter children did end up in the moderate class almost a year after treatment.

The trial enrolled children of varying ages. The oldest could probably drive a car, while the youngest, at 10 months, was perhaps just learning to walk. In a paper published in The New England Journal of Medicine, study investigators wrote how Regeneron’s therapy appeared beneficial across this group — “contrary to prevailing views” it might only be effective when given early in life.

The trial also assessed different configurations of ear treatments. Three children, for example, got the therapy in both ears. Everyone else only got it in just one. Four entered the study already having a cochlear implant in one ear, whereas some got the devices as part of the experiment.

The first trial participant, the 10-month old, was in that latter group. Her parents noticed changes within a few weeks post-treatment. She was reacting to hand claps and her name, and became more aware of speech and whispers. By the 24-week mark, her hearing had improved to normal levels, the study authors wrote.

At 72 weeks, researchers briefly turned off her implant to pinpoint how the therapy-treated ear was functioning. They found her speech perception had continued to improve. On a formal test, she identified with complete accuracy a series of two-syllable words like “mommy” and “cookies” without requiring visual cues. Later, at 96 weeks, she scored 70% on a single-syllable word test.

Another, 28-month-old participant got Regeneron’s therapy in one ear and no treatment in the other. Nearly a year later, her parents reported “spectacular” progress. They said their daughter could now respond to distant sounds and understand speech in noisy environments. She could also count to 10 and use more than 100 words — what they described as “unimaginable” improvements, according to the NEJM paper.

The therapy, code-named DB-OTO, is constructed with tiny, disarmed viruses, which deliver functional copies of that malfunctioning gene directly into the inner ear.

It’s an advantageous target, because people can develop antibodies that attack these viruses and, in turn, nullify the whole gene therapy. But a natural barrier separates the cochlea from the bloodstream, where most antibodies are on patrol. Indeed, 10 participants tested positive for neutralizing antibodies at the start of Regeneron’s study, yet these proteins didn’t appear to interfere with the gene therapy’s effectiveness.

DB-OTO is administered via the same surgical approach used for cochlear implants — a very calculated design feature. Jonathan Whitton, the global program head for Regeneron’s hearing research, said one key objective was to create a product surgeons would immediately feel comfortable with and know how to deliver.

So far, DB-OTO looks generally safe. Researchers have documented 67 so-called adverse events, including 17 deemed related to delivery procedures. Almost all were minor, short-lived and “the kind of things you would see in any sort of ear-related surgery,” like pain or nausea, according to Lustig.

There were, however, two serious events. One participant experienced instability while walking. Another developed a severe bacterial infection in an ear that got a cochlear implant but not DB-OTO. Both resolved without causing additional health problems.

The trial results naturally raise questions, like why some patients responded better than others.

And, as is the case with most gene therapies, researchers aren’t sure exactly how long the effects of DB-OTO last.

“This is the first time this has ever been done. What's going to happen five, 10 years down the road? Will we have to re-dose? These are all big questions we're going to have to answer,” Lustig said. “But at least even in our long-term kids out over a year, the results are holding and, if anything, improving.”

Should DB-OTO reach the market, insurance companies will surely take a close look at the durability of what’s bound to be an expensive medicine. In the U.S., list prices on gene therapies stretch from hundreds of thousands of dollars to several million.

The Regeneron team, though, views the apparent benefits as worth the likely high cost.

“What we're talking about, really, is: what's the value of hearing?” said Whitton. “My expectation is most people see massive value, having hearing connect you to your environment, to others, to your families.”

Whitton previously served as the head of clinical research at Decibel Therapeutics, the original developer of DB-OTO that Regeneron bought for $109 million in 2023. One of only a few all-out acquisitions in Regeneron’s almost 40-year history, Decibel proved to be a harbinger of the company’s growing interest in genetic medicine.

In the months and years since, Regeneron has expanded a gene editing pact with Intellia Therapeutics, purchased a slate of cell therapies from 2Seventy Bio, and paid $100 million for access to Mammoth Biosciences’ CRISPR technology. The company also attempted to snag some of 23andMe’s assets as the DNA testing firm went through bankruptcy proceedings.

Such deals place Regeneron at the center of a field that is both cutting-edge, but also one that investors decidedly cooled on over the past few years.

Even with supportive clinical data, Regeneron may well face challenges selling a product like DB-OTO.

David Risinger, an analyst at the investment firm Leerink Partners, laid out some of the potential obstacles in a note to clients in 2024. He wrote that around 20,000 people in the U.S. and European Union have hearing loss caused by the mutations addressed by Regeneron’s therapy. Yet only those who don’t already have cochlear implants in both ears would be eligible for DB-OTO.

Additionally, at least three other companies are developing their own gene therapies for this condition, making for a “crowded competitive landscape.” One of those companies, Akouos, was acquired by Eli Lilly in a deal that, at the high end, could be worth roughly $610 million.

Eli Lilly has agreed to buy Verve Therapeutics for $1 billion, betting on the promise of one-and-done gene therapies to treat cardiovascular disease. 

The deal announced in mid-June offers Verve stockholders $10.50 a share, plus a contingent value right worth another $3 a share. The non-tradeable CVR would pay out if the company’s experimental VERVE-102 treatment advances enough to dose a patient in a Phase 3 trial within 10 years of the transaction’s closing.

For Lilly, the acquisition offers greater control of a pipeline it’s already invested in. The company inked a deal with Verve in 2023 to develop a product now known as VERVE-301 that’s still in preclinical research. Later that year, Lilly bought other Verve opt-in rights from Beam Therapeutics that include the program for VERVE-102.

“The deal makes sense for Verve shareholders and makes sense given the exposure Lilly has to Verve’s entire disclosed pipeline,” William Blair analyst Myles Minter wrote in a note to clients. Lilly is also stepping in at a time when Verve shares are undervalued, Minter said.

Verve went public in 2021 with one of the largest initial offerings of the year in the biotech industry, raising almost $270 million by selling shares at $19 each. As an investment boom continued that year amid high hopes for gene therapies, Verve’s shares soared above $70.

But the company’s lead product, VERVE-101, encountered safety concerns and Verve decided to scrap it in favor of a successor, VERVE-102, that used a different lipid nanoparticle for delivery of the treatment. That product has shown early promise.

Even so, Verve shares have been hurt by a general slump in investment in cell and gene therapy companies. “Eli Lilly is getting a bargain here,” Minter wrote. Still, the 67% premium is “a win for Verve shareholders and the gene editing space more broadly, which has been under significant macro pressure in a difficult funding environment.”

The CVR is likely to pay out, Minter said. The timeframe of 10 years shouldn’t be an issue; dosing in a Phase 3 trial is more dependent on continued demonstration of safety in earlier-stage research, he wrote. 

The larger question for Lilly is whether patients and doctors will embrace genetic medicines for cardiovascular disease, when more traditional treatment options are readily available. Other companies have struggled in that situation.

Verve counters that many patients drop off standard medications, putting themselves in danger of complications like a heart attack. The company’s lead product is administered as an infusion, which also sets it apart from the complicated administration process that underlies high-profile gene editing treatments such as Vertex’s Casgevy.

Verve’s medicine “could shift the treatment paradigm for cardiovascular disease from chronic care to one-and-done treatment,” Ruth Gimeno, Lilly’s group vice president for diabetes and metabolic research and development, said in the company’s press release.

The last line of this century’s most important biomedical research paper contained a hint of the scientific revolution to come. An ancient bacterial defense system, the researchers wrote in 2012, could be adapted to offer “considerable potential for gene targeting and genome editing applications.”

The past decade has proven those words a dramatic understatement. The bacterial defense system, dubbed CRISPR, is the foundation for a flexible and powerful gene editing tool that’s allowing scientists to reimagine how to treat disease. A new generation of biotechnology companies has come of age translating that research into medicines that can turn genes off or on, or even rewrite DNA code directly.

“I think CRISPR is one of the most fundamental innovations in life sciences we have seen over the last 20 years,” said Rodger Novak, co-founder and former CEO of CRISPR Therapeutics, one of the first biotechs formed to develop CRISPR-based drugs.

For people with sickle cell, the future is now. On Nov. 16 and Dec. 8, regulators in the U.K. and U.S. approved Casgevy, a near-curative treatment developed by CRISPR Therapeutics and Vertex Pharmaceuticals for the inherited blood condition. It’s the first CRISPR gene editing medicine to win clearance for commercial use.

Casgevy’s journey to approval is a remarkable story of scientific discovery, bold bets and steady perseverance. To Stuart Orkin, a professor of pediatrics at Harvard Medical School whose research outlined how CRISPR could be used to treat sickle cell, it is a “great example of the way things should go.”

“In academia, we do discovery. The role of pharma and biotech, in my view, is to take these discoveries and bring them to patients,” said Orkin. “We made our discoveries. They did the trials. They didn’t mess it up.”

CRISPR Therapeutics and Vertex’s achievement with Casgevy happened more quickly than is usual in biotech, where scientific breakthroughs are often only the beginning of a long and arduous process. Alnylam Pharmaceuticals, the pioneer of a gene silencing method of drugmaking known as RNA interference, needed 16 years to turn an academic discovery into the first RNAi medicine. Casgevy’s first approval, by comparison, came 10 years after CRISPR Therapeutics’ founding.

“It happened a lot faster for gene editing,” said John Maraganore, Alnylam’s founding and now former CEO. "Opening up the door for a new modality is an epic moment."

Casgevy’s success wasn’t a sure thing, though. The drug’s story is also one of patent battles, safety scares and stock gyrations. Other companies tried to apply CRISPR to sickle cell, but came up short.

This oral history of Casgevy’s development is based on nearly two dozen interviews with the scientists, executives, physicians and sickle cell patients who helped make the medicine a reality. All titles are presented based on the principal relevant roles held by speakers during the time of each chapter, unless unchanged. Interviews have been condensed and edited for clarity.

Chapter 1 The Beginnings (2012 - 2015)

The discovery of CRISPR by Emmanuelle Charpentier, Jennifer Doudna, Feng Zhang and others sparked a frenetic race to capitalize on the technology’s potential. Scientists, investors and executives set about to construct business plans for building new gene editing companies — work that resulted in the creation of Caribou Biosciences, CRISPR Therapeutics, Editas Medicine and Intellia Therapeutics.

While it was clear to many that CRISPR was an important new tool, there was disagreement over how quickly and broadly it could be applied, or even how it compared to existing editing techniques like zinc fingers and TALENs.

Simeon George (CEO, SR One): It was 2012 when the first paper from Charpentier and Doudna was published. Within the first six, 12 months, there was clearly a sense that this could be transformative. It had the potential to have this laser-guided approach to treat, repair and possibly cure. Even from those early days, it looked like a step change from everything we'd seen before. There was immediately this sense of wonder around the technology.

Rodger Novak (co-founder and CEO, CRISPR Therapeutics): But it was certainly not the case that the industry, in particular VCs, were all over CRISPR when the paper hit in 2012. There were some believers. But it was so early, it was actually pretty difficult in the beginning to convince people that this is real.

Rachel Haurwitz (CEO, Caribou Biosciences): Both zinc fingers and TALENs had left investors convinced that genome editing is a really hard thing. At that point in time, you basically had to have a PhD in genome editing to do it. There was a fundamental skepticism that this was any different.

Even among those who were willing to think a little more creatively, many expected only one or a small number of relevant use cases, not this incredibly broad toolbox. To be quite honest, what has panned out far surpasses the picture I was capable of painting back then. And yet, the picture I painted was far too vast; people didn't think it could be real.

Rodger Novak: If we had had CRISPR alone, this would have been tough. But messenger RNA was out there and we had much cheaper gene sequencing opportunities. Technology-wise, around that time, there was light on the horizon and things came together nicely.

Nessan Bermingham (entrepreneur in residence, Atlas Venture): If CRISPR had been there 10, 15 or 20 years before, I'm not sure we would have gotten the attention that we got at the time, because, if you think about genetic medicines, there had already been so much work done. Go back to things like small interfering RNA therapies or antisense oligonucleotides. Go back to what was going on with gene therapy. People were able to connect the dots.

Twenty years before, we didn't have the technologies that were required to allow us to move so rapidly. The timing was very fortunate.

Shaun Foy (co-founder, CRISPR Therapeutics): When we were speaking with scientists and drug developers in the beginning of 2013, all of them got the technology. There were different views on whether it would be translated in a decade or sooner. A lot of people thought it would take much longer than what transpired.

When it came to pitching though, we really didn’t have to pitch for the seed. I reached out to Nessan and he wanted to give me a term sheet right away. And I was speaking with Jerel Davis, and Versant [Ventures] got it fairly quickly.

Nessan Bermingham: Shaun reached out to me and said, ‘What do you think?’ I basically said, ‘We'll give you a term sheet.’ He had been working with Versant and flagged it to them at the same time.

Shaun Foy: It was very complicated at the time: exciting new technology; a number of important experts who were circling around different companies; a number of different investors who were interested in building companies; very complicated sets of personalities and a complicated intellectual property landscape.

We were pretty focused when it came to the investors. I knew we were going to work with Versant and/or Atlas. We never really entertained conversations with any other investors.

Nessan Bermingham: We put a term sheet down and Versant put a term sheet down. Things got to a point where it was clear that Versant and Atlas had slightly different visions on how to build the company moving forward, leading to a more competitive position as to who would lead the deal.

I spent a tremendous amount of time with the team and started to build out the overall initial strategy for the company. One of the areas that they really were focused on was ex vivo applications, which has led to [Casgevy]. But I really felt we should be moving in vivo also.

Shaun Foy: We had thought that Atlas would be part of the seed financing in October 2013 but in the end this didn't happen. Versant were very keen to finance the story initially themselves and, although Atlas had done a lot of work on the story, we actually had much deeper relationships within Versant so this made sense to Rodger and myself.

Atlas continued to work with the story on the basis that they would join in the [next] round. By the time that came around several months later Versant had decided they wanted to take the entire round themselves and in the end we didn't get Atlas into the deal. Nessan went off to found Intellia.

Nessan Bermingham: Ultimately, Versant paid more than we were willing to pay and structured the deal in a way that was attractive to the founders also. And we, Atlas, decided to step out of the process.

Fast forward, literally weeks, we then reached out to Caribou and that ultimately led to the formation of Intellia.

Shaun Foy: We didn't need to pitch anybody else until the end of 2014. By then, we were totally in this CRISPR craze. Every group is knocking on your door. We had something like 10 lead investors that were offering term sheets to cut each other out.

Simeon George: After the first meeting with the founders of CRISPR Therapeutics, it was clear this was the company to invest in. Everyone was using the same technology, by and large. But with these founders the vision was: ‘We want to be the first company to actually develop a medicine.’ Rather than falling in love with the science, they were crystal clear around product development.

From that point on, it was about the financing. How do you cobble together a round? There were questions around IP. There were questions around doing a partnership early on. Ultimately the round that we led, the Series A, frankly looks like it should have been a no brainer. Why would you not invest? But it wasn't an easy round to put together.

Shaun Foy: I really believed at the beginning that [CRISPR] should be one company, and that we should have the key scientists that were involved in the technology, patent estate all under one roof. But over the course of the spring and summer of 2013, it was pretty clear that there was so much interest in the technology that people wanted to do their own thing.

In hindsight, it’s been better for patients to have multiple companies working on this. It’s hard to imagine how one company could get all the work done efficiently.

Chapter 2 Charting a course (2014 - 2016)

Thousands of human diseases are caused by genetic mutations. In theory, CRISPR gave researchers and drugmakers the means to fix many. But which to pick? That choice faced CRISPR Therapeutics, Editas and Intellia early on.

CRISPR Therapeutics’ first choices were sickle cell and beta thalassemia, diseases caused by errors in the genetic code for hemoglobin, a vital oxygen-carrying protein. Prior to CRISPR’s discovery, Stuart Orkin had identified a gene, BCL11A, that offered a way to treat both conditions, presenting CRISPR Therapeutics with a valuable roadmap.

Rodger Novak: CRISPR was an entirely new technology. It was not, as some people illustrated, just like editing a Word document. There are so many more complexities. So one thing we asked at the very beginning was, what indication could we go after that reduces complexity while addressing a really important unmet medical need?

Shaun Foy: We wanted to focus ex vivo and on knockout strategies for a variety of reasons, but [mainly] to remove technology risks.

We were trying to identify diseases where there's high unmet medical need and where you could edit a small number of cells and have a big impact. And the two diseases that we looked a lot at were knocking out CCR5 in HIV and knocking out BCL11A. We even had initial conversations with Gilead about the idea of knocking out CCR5.

Rodger Novak: We engaged a firm focused on questions like this. Three or four months later, after a lot of interviews, they came back with a proposal of 10, maybe 20 different indications. I just recently looked back at this and not a single one did we pick. It’s a good lesson learned.

So we came up with sickle cell and beta thalassemia. The next challenge was the board, which said, ‘Oh my God, how can you do that? Look at Editas. Look at Intellia. And then there's Bluebird bio.’ In the end I convinced them that the main focus was simplicity.

You need to differentiate one way or another. It’s relatively irrelevant who's out there otherwise. You should know about it; you should educate yourself. But if you believe in your approach, and you truly believe you can differentiate, then go for it. And that’s what we did.

Bill Lundberg (Chief scientific ofifcer, CRISPR Therapeutics): We didn't start with awe over our brilliant technology platform. We started with: What's the medical problem that we want to try to solve? Let's really truly understand it. Fifty years of sickle cell and beta thalassemia research have really shown what that problem is. It's one of the best understood diseases.

Simeon George: The company and founders were looking very closely at a number of applications. We were also waiting and trying to think about how to prioritize ‘low-hanging fruit.’ Frankly, there isn't low-hanging fruit when you're bringing a new technology forward.

Everything looks obvious in hindsight. At the time, there was risk. We had to take a leap. You don’t know what you don’t know.

Sam Kulkarni (Chief business officer, CRISPR Therapeutics): We’ve seen a lot of platform companies live and die by the choices they make on the initial indications they go after. It wasn’t clear in 2014 and 2015 what was going to work and what wasn’t.

It was clear ex vivo was more likely to work and sickle cell fit because the genetics were known.

Bill Lundberg: We fully understood [sickle cell and beta thalassemia’s] disease biology and pathophysiology. We knew what we had to change. There were all these human genetic variants showing, if their genetics are just a little different, the patients are better. Then it was just an engineering question.

[President John F.] Kennedy challenged the country to get a man on the moon by the end of the decade. He knew he could do that, because he knew the discoveries were solved. All you had to do was just strap five Saturn V rockets together and you’d get there. That’s where we were. We had all the pieces.

Rodger Novak: Without the innovation from academia, [there was] no chance at the time. At the same time, we did build out within CRISPR a very strong research organization. We came to the conclusion that if we don't master the technology and rely almost exclusively on innovation out of academia, we don't stand a chance.

Bill Lundberg: We weren't sure where to edit. And we did these incredibly large experiments looking at a large number of possibilities. We had to simultaneously optimize for a number of different characteristics. Which guide do we use? Do we make synthetic guides? Do we transcribe? Do we need to put some funky nucleotides on the front? How do we introduce it into cells?

We didn’t know. It came down to two different approaches. Ultimately, we chose the one we chose, for various reasons, but we didn’t know that until the very end. We were simultaneously parallel processing everything up until the time we needed to lock down processing and manufacturing. We had huge arguments over whether to spend extra millions of dollars.

On the financing side, for the first year or so, we had a lot of headwinds. Investors were like, ‘This is a Nature paper, why is it going to work? Look, another Science paper, but this isn't a medicine.’ And then it flipped. Suddenly, we had a huge amount of tailwinds. That subsequent financing climate was really helpful.

Tirtha Chakraborty (Head of hematology, CRISPR Therapeutics): Once the platform was built, we [started] the therapeutic work. When preclinical development started, pharmacological models didn't exist. We had to build them from scratch. If I think about how many things didn't exist before this program started, it's quite unreal that it all happened.

Bill Lundberg: [With] a really complicated system, we needed to to simplify [it]. Any complexity equals risk. It really came down to taking as many risks off the table, [such as by] taking cells out of the body.

Simeon George: I felt in those early days that, relative to our small peer group — the other companies that were in Boston, that were well capitalized, that had a lot of noise around them — we were the odd one out. I didn't feel like we got the same level of attention or that there was the same excitement in those first few years. And in part [that was because] we were coming out of Europe.

Bill Lundberg: The pressure came from the other companies who were claiming they were going to radically revolutionize the world. It was clear to me we needed to put our head down. But then it was like, ‘Oh, wait, Editas is going to cure every disease and they're starting with eye diseases. Maybe we should go into eye diseases.’ That kind of pressure is hard. It takes real commitment. You have to trust the reasons why you’re going down the path, stay focused and continue to deliver.

Chapter 3 CRISPR’s ‘wild ride’ (2015 - 2019)

The promise and acclaim of CRISPR gene editing meant added scrutiny for CRISPR Therapeutics and its peers. The first few years of the biotechs’ existence were dogged by a bitter patent battle between the University of California, Berkeley, and the Broad Institute of MIT and Harvard over who invented the technology. The field was divided in two camps, with CRISPR Therapeutics and Intellia aligned with Berkeley, and Editas with the Broad.

The companies also faced questions about gene editing’s implications for society, and skepticism from investors as they prepared initial stock offerings. Once public, their stocks rose and fell on news of academic findings suggesting safety concerns to CRISPR, or on delays in their efforts to reach clinical trials.

Simeon George: In the early years, the IP estate and how we were prosecuting it was a meaty topic. We all felt it was going to get resolved. If you look to the history of monoclonal antibodies and how this plays out, generally speaking companies can coexist, whether it's by cross licensing or specific composition [patents] that give you coverage for targets.

Sam Kulkarni (CEO, CRISPR Therapeutics): People billed it as a [battle] for IP that's worth billions. Sure, the IP is worth billions, but that doesn't reflect what would actually be transferred. We went through that with the Alnylam story and the patent battle around RNAi.

I’m confident that ultimately this is going to be a footnote in the CRISPR story, just like it’s a footnote in the antibody story. If you look at all the antibody drugs now, does anyone remember the IP battles?

Simeon George: Everything about CRISPR has been heightened, accelerated, done in a way that is unusual. Of all the deals that I’ve worked on, this has been the most squarely in the broader ecosystem’s eye, if you will.

The lay audience has some sense of CRISPR and what's happening. This technology is very well reported across scientific publications through to the BBC, The New York Times, etc.

The company, the team, the board, investors have had to be hyper aware of all of the noise and extraneous things that are around us.

Rodger Novak (board chair, CRISPR Therapeutics): Intellia and Editas went public [before CRISPR Therapeutics], which may have helped get the message out. Today you couldn’t do this. It was a special time.

But there was also a lot of skepticism. The IPO was probably the most tiring week of my life. I would put it this way: It was so hard that in the end, when we succeeded [with the IPO], we were too tired to have a real party. We didn't even ring the bell.

Bill Lundberg: [Ethics] was another topic we talked about a fair amount. Do we have an ethical basis to continue to provide these therapies? That was a pretty straightforward conversation.

[But] there was another element: What's the rest of the world going to think of the ethics? Is the U.S. Senate suddenly going to decide that this is a terrible technology and shut it all down? Is popular culture going to blow this way out of proportion? There was a large amount of uncertainty in all of these areas.

We consulted with an ethics center at Stanford University about this. And then in a precompetitive approach, Nessan and I went to D.C. and met with the Office of Science and Technology Policy and had the opportunity to educate.

We felt we had to defend ourselves, educate, and get the message out to protect our ability to do this [research].

Nessan Bermingham (CEO, Intellia Therapeutics): The [U.S. intelligence community] put out a piece about bioterrorism and [CRISPR] as a threat. We spent a lot of time navigating that and the implications around it. It really became, for a short period of time, problematic and a threat to us. We thought about whether we’d actually be prevented from moving these technologies forward.

Sam Kulkarni: It was a wild ride. Our stock would go all the way down based on publications in academia.

But we dosed the first few patients and that was really key. In the early days, it’s hard to find these patients — new platform, new technology, unproven, etc.

Chapter 4 A ‘powerful partnership’ (2016 - 2021)

Venture capitalists weren’t the only ones who saw value in CRISPR. Large pharmaceutical companies moved in quickly to license the technology and partner with CRISPR Therapeutics, Intellia and Editas.

Stuart Arbuckle (Chief commercial officer, Vertex): We very early on recognized that this was going to be a generational technology and wanted to work with one of the companies. CRISPR Therapeutics was the one we selected because we thought they were the best fit for Vertex.

David Altshuler (Chief scientific officer, Vertex): It was as obvious to me as, like, where my kitchen is, that the combination of BCL11A in sickle cell and CRISPR was a possibility. When I joined Vertex, [former CEO] Jeff Leiden and I talked about what the business opportunities were. We agreed this was the right thing to do.

When we were talking to the different CRISPR companies, it was absolutely necessary to do sickle cell. We felt that that was the best opportunity.

Sam Kulkarni: The logic was, this is all new and tricky so having two parties stress test it might lead to a better product. Most biotechs don’t think about how much money they need to spend. They think about one or two years. We knew that it was going to cost over a billion dollars to develop through approval. How do we finance it all? And that was why we did a 50-50 deal with Vertex.

I think Vertex initially wanted to license the technology. They wanted to make it their own product, similar to what Biogen had done with Sangamo Biosciences. But, for us, the 50-50 partnership made a lot of sense because we had a lot of value to bring and wanted to make sure we had a lot of ownership in how the program progressed.

Nessan Bermingham: Bayer, Vertex, Regeneron, Novartis; they were playing all three [CRISPR] companies. It was basically shopping by the parties to see where they would get the best deal and where they were philosophically aligned on how to move the technology forward.

We spent a lot of time talking with Vertex. Ultimately CRISPR Therapeutics did the deal with them. In retrospect, our focus at Intellia was going in vivo and CRISPR Therapeutics was certainly more focused than we were on ex vivo applications.

David Altshuler: Bulk delivery is incredibly hard in all genetic medicines, getting the thing to where it belongs. In sickle cell, you could do ex vivo gene editing. There was so much known about bone marrow transplant and about what would happen.

Rodger Novak: A number of factors come into play when you do a partnership like that. The input cannot be just economic. There must be some kind of enabling. Vertex, at the time, was purely [a] small molecule [company]. But they had a very committed, smart team and it became clear they wanted to enter this field.

Still, it's never easy to be the junior partner, because even if we brought the knowledge, we brought the asset, you're considered by a company like Vertex as a junior partner.

Bill Lundberg: We were a small company and limited in dollars, experience and expertise. We had talked to and came very close to doing a deal with a different company around gene editing opportunities. [But] Vertex recognized the power of the human genetics that underlied the basis for this approach to sickle cell and beta thalassemia. There was a connection and appreciation there.

Bastiano Sanna (chief of cell and genetic therapies, Vertex): We, as a strategy, work only on diseases for which the underlying mechanism or cause is known. Sickle cell is one of them. It is the oldest described genetic disease in the history of medicine.

So it's really well known what the cause is. It's also known that if you increase levels of fetal hemoglobin you pretty much get rid of all the clinical consequences of sickle cell.

We chose CRISPR as the technology as opposed to, for example, viral methods, because of three reasons. One is its precision, targeting only a particular region of the genome. That of course has consequences in safety, because you know exactly what you're cutting. [The second is] efficacy, because you know the effect. [And the third is] persistence, because once those cuts are made, they are for life.

Tirtha Chakraborty: It was a powerful partnership. Vertex having been there, done that, gave a lot of power to CRISPR Therapeutics as a smaller entity that was learning how to do these things.

In 2021, after six years of working with CRISPR Therapeutics, Vertex amended their collaboration, paying $900 million to own a greater share of the profits (and the costs).

Sam Kulkarni: We realized [taking on commercialization] would have meant we'd have to hire 200 people in commercial and change how we operate. Companies like Alnylam have talked about what it meant to go commercial and how it transformed the company.

What was important to me was that we continued to be driven by research and translation as a company, and that’s what everyone spends their time on. This was the best solution. Vertex already had an established footprint and capabilities to commercialize this. They brought a lot of capital and money for CRISPR Therapeutics. They allowed us to focus on what really matters.

Chapter 5 Testing and results (2019 - 2023)

Early in 2019, CRISPR Therapeutics and Vertex treated the first beta thalassemia patient with Casgevy. Soon after, they treated the first sickle cell patient. The milestone came after years of preclinical research and manufacturing preparations and, while hopes were high, the outcome wasn’t certain.

Over time, early results trickled out and the companies enrolled more patients in their twin studies testing the drug in the two blood diseases.

Haydar Frangoul (hematologist, Sarah Cannon Research Institute): The preclinical data looked good. But in science, preclinical data doesn't always translate to human outcomes. So when we dosed the first patient, we were on pins and needles trying to figure out how high their fetal hemoglobin would go, and whether it would translate into clinical benefit.

Sam Kulkarni: You find a patient, then you have to collect their cells, go through manufacturing and dose them. You’re sitting on the edge of your seat for almost a six month-long journey.

You don't really know how the manufacturing goes for about two or three weeks. The key part was making sure we have the drug product manufactured. And that was probably the most nerve-wracking part of all this. Once we had the drug manufactured, the actual infusion of the patient was less climactic.

Simeon George: The biology made sense. I believed in the technology. [But] there were leaps we were taking. So there was a cautious optimism. When we first saw that clinical data though, jaws dropped. I trained as a physician and it’s literally rewriting medical textbooks. I'm not even that old. When I was in medical school, I wouldn't have imagined this.

Victoria Gray (First person with sickle cell treated with Casgevy): I didn’t want to wait. There was an urgency for me, because my life was hard. My kids began to have a fear of me dying. Their behaviors had changed in school. I knew I had to do something.

The beginning [of treatment] was still hard. I experienced body aches because of the [preparatory] chemotherapy. I didn't feel an immediate change. It was about eight months before I felt a real difference.

But within that eight months, I wasn't going to the hospital. That was new, to have an eight-month stretch without going to the emergency room or being in the hospital.

Rodger Novak: After about three months into treatment for the first patient, their fetal hemoglobin levels were so much above what I had expected. I said, ‘Oh my God, this works.’ And then I got very nervous for the next data point.

Sam Kulkarni: It was an exhilarating feeling to hear not just that the patient is doing well, but that the levels of fetal hemoglobin were remarkable. It surprised even us on the team how well it worked.

We wanted to get these remarkable data out and decided to do a company event. A lot of the company found out real time together with the rest of the world. When we finished, people had this mix of excitement, relief, joy for the patients and a feeling that we had actually built something at this company.

But it wasn't champagne glasses. We weren’t already celebrating. We kept saying to the team, ‘It’s early days. Let's just watch this.’ We needed to make sure the effects were durable. We wanted to make sure we didn’t take our eyes off the ball.

Stuart Orkin (hematologist, Boston Children’s Hospital): When they published the first paper on the data, I guess my feeling was, ‘Yeah, that's the way it should have gone. I'm glad they didn't screw it up.’ I wasn't surprised at the result, because we knew that that's what it should have been. But there was a sense of relief that it all went well.

Sam Kulkarni: The moment when I realized this was a drug was when I saw nine-month data for more than three patients. It seemed to work.

Katherine High (board member, CRISPR Therapeutics): At the board level, there were probably more discussions, not about the quality of the data, but the best way to make the product available.

In the U.S., we perform about 25,000 bone marrow transplants or so per year. And there are 100,000 people with sickle cell. It's not as if those 25,000 people won't need transplants anymore. They will. So we needed to figure out how to add additional capacity.

Stuart Orkin: They did what we described in the 2015 paper. What they did — I don't want to diminish. I want to give them full credit — is the clinical execution of that, the scale-up, the quality control and the safety and all of that.

It is essential in this field because there's no tolerance for failure.

Victoria Gray: [Before] I was going to the hospital every four to six weeks to get a catheter placed in to pull out four to five units of my blood, and get replacement [blood] to keep me healthy. That was the routine.

I no longer have to do that. My blood counts remain stable. And I don’t experience pain at all from sickle cell disease.

Chapter 6 The first CRISPR medicine (2023)

After four years of testing, Casgevy’s benefit was clear. The treatment could eliminate the debilitating pain crises people with sickle cell frequently experience. Those with severe beta thalassemia could go without the regular blood transfusions they previously required.

The U.K.’s Medicine and Healthcare products Regulatory Agency was the first to issue a decision, clearing Casgevy for certain people with either disease 12 years or older on Nov. 16 The FDA followed on Dec. 8 and approved the therapy for people with sickle cell. Its decision in beta thalassemia is expected next year. The therapy will cost $2.2 million, Vertex said. 

Sam Kulkarni: If I look back and think that, within a decade of starting a company, that we have our first approved drug, it’s just incredible.

The journey that CRISPR has been through is unlike any other. If you think of the great biotech companies right now, if you think about Alnylam or Regeneron or Vertex, they all generally took about 15 to 20 years to get their first drug approved. We’ve been able to get there much faster.

It wasn’t always a straight line. There were twists and turns that both Vertex and us navigated.

Rachel Haurwitz: To see the field actually have a first approved CRISPR-edited product plants a flag that CRISPR is here in a consequential way.

Today our world is largely two kinds of assets: small molecules and monoclonal antibodies. We are on the precipice of there actually being three legs to that stool. The third leg is genetic medicines and CRISPR is an incredibly important part of that.

Tirtha Chakraborty (chief scientific officer, Vor Biopharma): Monoclonal antibodies cannot hit anything inside the cell. Small molecules can to some extent, but they have their own limitations. CRISPR technology completely changes the world because it can get inside a cell and hit targets that were completely undruggable before. You don't need to hit a protein molecule. You can hit a part of the genome that will never be expressed in the form of a protein or RNA.

Today, we know a large part of the genome is not expressed, but plays really important roles. How do you manipulate the part that has been hiding away from all the drugs? Newer technologies exist because the previous systems have failed to address those problems.

That said, CRISPR is a classic nucleic acid therapy. Any nucleic acid therapy requires a powerful partnership with delivery technology. The success of CRISPR as a platform also brings the need for evolution.

Rodger Novak (venture partner, SR One): This goes back to academia. Thousands of labs have driven the innovation of CRISPR gene editing. You almost have the entire life sciences academic field applying a technology all together. I don’t think we’ve seen a technology democratized to this extent, except for PCR testing.

CRISPR is one of the most fundamental innovations in life science we have seen over the last 20 years. It will have a huge impact on the future.

Emmanuelle Charpentier (co-founder, CRISPR Therapeutics): This milestone certainly underscores the importance of fundamental research in the field of microbiology. I am truly amazed at the speed at which CRISPR research and applications have developed to get us to this historic moment.

My most sincere acknowledgment goes to the team at CRISPR Therapeutics for their efforts and commitment to develop the CRISPR/Cas9 technology.

Stuart Orkin: The approval is final gratification, coming full circle. I started at a time when we could barely clone genes and we had no conception whatsoever that we'd ever be able to do what we're capable of doing now. It's validation of what I've done as a career.

David Altshuler: When I was an intern at Mass General and working in the ICU, I admitted a young man who had a sickle cell crisis. He died later that day. His sickle cell had made one of his bones die, and the bone marrow went into his bloodstream. I never forgot it.

This is not a CRISPR story. CRISPR is a means to an end. The end is helping people with sickle cell.

Ben Fidler contributed reporting.