Gene Therapy

Investment in developers of cell and gene therapies nosedived through much of 2024, a sharp drop-off that investors and analysts said reflected manufacturing and drug delivery challenges at a time when biotechnology companies with clear development paths were increasingly favored.

Through last August, makers of cell and gene therapies raised half of a billion dollars across 16 venture rounds, according to data from DealForma published by Nature. Even annualized, those numbers are well below the $8.2 billion in funding brought in by the 121 deals DealForma counted during the sector’s peak in 2021. In 2023, cell and gene therapy developers raised $3.5 billion across 65 deals.

“We’re largely seeing investments shifting to things that are de-risked,” said Jon Norris, a managing director at HSBC Innovation Banking. “Cell and gene therapy is becoming an area we know better, because there are products that have advanced through development, but it still doesn't compare to the number of approvals and drugs commercially available in small molecules or biologics.”

Overall, biotech venture investment ticked higher over the first half of 2024, according to a mid-year report from HSBC Innovation Banking. Yet, regardless of technology or research field, biotechs still face a challenging financing environment entering 2025.

Developers of cell and gene therapies face additional hurdles, however, “given that the kind of capital required to advance these therapies is different from small molecule drugs or biologics,” said Peter Sletteland, a managing director for Silicon Valley Bank’s life science and healthcare practice. “You typically need to spend significant investment in manufacturing.”

Still, he added, cell and gene therapies “garner a lot of attention because of the promise of what they could do.”

Six CAR-T cell therapies have been approved by U.S. regulators to treat cancer and, in some indications, their benefits can be dramatic. But hopes of replicating that success with so-called allogeneic therapies, which use donor cells rather than individual patients’, has been harder to come by than initially envisioned by investors. And uptake of some of the approved CAR-T therapies has been slow, especially as companies work through manufacturing bottlenecks.

In gene therapy, sickle cell treatments Casgevy and Lyfgenia secured milestone approvals from U.S. regulators late last year. But only a few dozen patients have begun the process to receive treatment, reflecting the long manufacturing and infusion times needed for each.

Adoption has also been slow for the hemophilia gene therapies Hemgenix and Roctavian, while other gene therapy developers like Pfizer have hit clinical setbacks.

Patient perception of gene therapy is a crucial barometer. "The therapy has to be worth it, but the question is, are there treatment alternatives?" said Chris Bardon, co-managing partner at MPM BioImpact.

For diseases that have limited treatment options, it may be easy for a patient to consider an intensive cell or gene therapy treatment, which can require arduous chemotherapy preconditioning. But such treatments may by less appealing to people with conditions that are manageable with approved medicines, such as is the case in hemophilia.

"It has been a challenge for investors," Bardon said.

The challenge of developing and selling cell and gene therapies, though, isn’t enough to deter investors and drugmakers entirely.

In cell therapy, for instance, there’s buzz around the potential to target hard-to-treat autoimmune disorders, said Bruce Levine, a cell and gene therapy pioneer at the University of Pennsylvania who co-founded Tmunity Therapeutics and Capstan Therapeutics with colleague Carl June.

“That's the nature of a therapy that, currently, through the cost of goods and services, is expensive to manufacture, but delivers long-term, durable benefit in patients who have failed all other available therapies,” Levine said.

One year on from the landmark U.S. approval of two powerfully effective gene therapies for sickle cell disease, the treatments have been barely used, a sluggish start that reflects the myriad challenges of launching them.

While some several dozen people with the blood disorder have begun the treatment process for one or the other therapy, only two had actually received an infusion through early December, according to the therapies’ developers, Vertex Pharmaceuticals and Bluebird bio. That’s because the process typically lasts at least several months, involving a precise choreography of medical consultations, preparatory treatments and bespoke manufacturing of the two personalized therapies, called Casgevy and Lyfgenia.

Martin Steinberg, a hematologist at Boston Medical Center, said his center had expected to infuse four or five people with one of the therapies in 2024, and maybe a dozen or so a year going forward. Now, however, he thinks that outlook was too optimistic. “While we've had plenty of patients come to us, getting them through the screening process has taken a little bit of work,” he said.

Slow beginnings for new medicines, especially ones as complex as Casgevy and Lyfgenia, aren’t anything new in the pharmaceutical industry. But the plodding uptake over the therapies’ first year on market stands out more starkly against their dramatic benefit, which can be described as something close to curative.

Neither therapy directly fixes the gene mutation that causes red blood cells to warp into sharp-edged scythes in people with sickle cell disease. But through genetic engineering of a patient’s own stem cells, Casgevy and Lyfgenia introduce — in different ways — clever workarounds that improve the health and function of red blood cells. In testing, both therapies generally eliminated the debilitating pain crises people with severe disease routinely experience. As a result, those trial volunteers were able to discontinue blood transfusions and stayed out of the hospital.

Updated trial data presented in December at the American Society of Hematology for Casgevy and Lyfgenia show their effects to be meaningfully durable.

The promise of a cure comes with significant trade-offs, however. Treatment with both therapies requires several hospital visits and, all told, a patient’s journey from first evaluation to infusion can stretch as long as a year, depending on how quickly each step goes and whether it’s successful. One step, preparatory chemotherapy with a drug called busulfan, is particularly difficult to bear and can cause infertility. Lyfgenia’s label warns of the risk of blood cancer.

“It’s a complicated process,” said Akshay Sharma, a pediatric hematologist at St. Jude Children’s Research Hospital who helped test Casgevy. “It's not just the patient preparation and manufacturing of the product that takes time, but [also that] centers have to be accredited. Everything from resources to staff and training has to be completed before you can even enroll a patient.”

Vertex and Bluebird have steadily qualified more and more centers to administer their sickle cell therapies, with Vertex now counting 33 as activated in the U.S., and Bluebird 50. But half of U.S. states still don’t have an accredited center that can provide either Lyfgenia or Casgevy, according to maps posted by the companies online.

Many of these hurdles were anticipated upon approval of both medicines, and the slow rollout hasn’t surprised executives at either company, who had set expectations for gradual launches. Both Vertex and Bluebird predict use of their therapies will grow as more treating centers grow accustomed to providing them. Treatment numbers will climb noticeably in the next few quarters, too, as the dozens who began preparations this year move ahead with infusions.

Yet even as barriers come down, the choice of Casgevy or Lyfgenia may not get easier for patients, who have to process an avalanche of new information and weigh the risks they’re willing to tolerate.

At the Children’s Hospital of Philadelphia’s CuRED Clinic, for example, people with sickle cell meet a range of specialists, including hematologists, transplant experts, psychologists and social workers.

“Families walk away with just a treasure trove of information,” said Alexis Thompson, the chief of CHOP’s hematology division. “There are times when we can tell families are almost overwhelmed with the amount of information they have in front of them. They need to pause and think about it.”

Thompson said interest has been high, though. “Overall there has been mostly enthusiasm, some apprehension, but absolutely engagement.”

Conversations also cover the cost of treatment. Casgevy’s list price is $2.2 million, while Lyfgenia’s is $3.1 million. While doctors say insurance companies are generally agreeing to coverage, patients and their families can still be under the impression they have to pay the therapies’ cost. “Some have taken themselves out of the running because they perceive they can’t afford this,” said Thompson.

There’s also hesitation around new treatments, especially in the sickle cell community. “There’s a lot of not only misunderstanding, but also mistrust of the medical research establishment in general among patients with sickle cell,” said Sharma, of St. Jude. “Just because there is a fancy thing that got approved last year, you wouldn’t expect everybody to run towards that to receive it.”

Indeed, sometimes consultations about Casgevy and Lyfgenia become opportunities to fine-tune treatment with other drugs like hydroxyurea, Thompson said. Or patients may be interested in gene therapy, but opt instead to enroll in one of several clinical trials testing newer, experimental medicines.

Other patients may not be good candidates for Casgevy or Lyfgenia, either because their disease is not severe enough, or because they may not be able to easily endure chemotherapy conditioning.

“You wouldn’t take somebody who's having mild disease, and was well managed on their own medications,” said Sharma. “Demand is limited to the number of patients who have severe disease, and that number is not a lot.”

Some 100,000 people in the U.S. are estimated to have sickle cell. Vertex and Bluebird believe somewhere between one-sixth and one-fifth of that total population may be eligible for Casgevy and Lyfgenia, but only a slice will likely seek them out in the first few years.

Steinberg, at Boston Medical Center, believes the current gene therapies will remain something of a niche product for the time being. “As we get more skillful at getting patients through the process, that won’t be as much of a stumbling block. Maybe we will be able to do one a month or so [at Boston Medical Center],” he said. “But it’s still too early for us to know if this is going to be realistic.”

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As obesity and diabetes become global health concerns, demand is skyrocketing for Ozempic, Mounjaro, Wegovy and other glucagon-like peptide-1 (GLP-1) medications that control blood sugar levels and appetite. Facing immense pressure to expand capacity quickly, life sciences companies are seeing how blockbuster drugs can dramatically reshape the industry and require the right real estate and facility strategies to accelerate the journey from laboratory to production.    

Establishing a new GLP-1 manufacturing operation involves a myriad of decisions. To accelerate speed to market, it’s important to understand how operating costs, regulatory approval timelines, talent, access to talent, customers and suppliers, and other factors drive an efficient manufacturing strategy. 

1. Weigh locations versus business, operating and financial strategies 

Whether you’re seeking a GLP-1 manufacturing site or a combined research-and-development (R&D) and production location, consider how well a location aligns with the operating and financial strategies of your business. The top life sciences clusters continue to attract people and companies, although new clusters are emerging in less costly areas that offer both life sciences talent and facilities.  

For a combined R&D-production facility, access to top-tier research talent to drive innovation may be a priority that outweighs real estate cost considerations. Given the large volume of potential GLP-1 patients in the United States, such states as Indiana and North Carolina are home to GLP-1 production and R&D because of their life sciences talent pools and facilities. 

2. Expect the unexpected costs 

Unexpected costs can undermine the advantages of an otherwise favorable location. For instance, importing specialized equipment can become a logistical and financial nightmare in an off-the-beaten-path location. Labor trends, tax incentives, speed of regulatory approvals, access to customers and suppliers, business disruption risks, environmental requirements and other factors can also add costs and risk to a location. It’s critical to understand whether the utilities infrastructure is adequate, or whether substantial investments will be needed that will affect return on investment. 

3. Pay attention to global supply chain and logistics considerations 

The pathways for incoming ingredients and the shipment of finished products are interconnected and will play a significant role in shaping your real estate strategy. An effective real estate strategy will consider the supply base, the destination of finished products, the cost and efficiency of both inbound and outbound shipments, and the impact on the overall network of manufacturing operations.  

Supply chain and logistics considerations are particularly important for the complex process of creating a recombinant DNA biologic drug such as GLP-1. End-to-end cold storage logistics is a critical aspect of delivering GLP-1 drugs to patients while retaining product integrity, and not every location will provide robust solutions for the challenge. 

4. Leverage location analytics 

Given the myriad location factors unique to GLP-1 manufacturing, your location decision should make full use of available relevant data—whether your location search is regional or global. Today’s leading location analytics tools can integrate a wide range of data sources to inform highly detailed and sophisticated data visualizations and location analyses. With a platform designed for location data and analytics, you can accelerate speed-to-market with detailed insights about locations and specific options and increase confidence in your decision-making.  

5. Streamline project development and management through partnerships 

When you are seeking to deploy billions in capital investments for GLP-1 production in sites globally, your in-house real estate team will likely be stretched beyond its capacity. An efficient way to expand capacity is to partner with a global project manager that can bring your new manufacturing sites online efficiently and cost-effectively with transparent project data, predictable outcomes and avoidance of regulatory delays. Another way to improve speed to market is to bring in facilities management (FM) experts to provide input on building design, tooling and equipment selection, develop standard operating procedures and more. An experienced global project manager can reduce project timelines while an FM service provider will effectively augment your in-house team. 

Seizing the moment to deliver lifesaving GLP-1 medications 

The growing prevalence of obesity and Type 2 diabetes is creating a major public health crisis in many countries around the world. With GLP-1 innovations, biopharmaceutical organizations have an opportunity to help millions of patients reduce their health risks and improve their well-being, while relieving pressure on public and private healthcare systems. By combining a structured site selection methodology with data and insights, every GLP-1 innovator and manufacturer can streamline the journey to addressing a global health challenge. 

Are you ready to create value with efficient, compelling real estate and facilities that accelerate scientific innovation? Connect with one of our life sciences experts today. 

BioMarin Pharmaceutical on Aug. 5 said it will limit sales of its hemophilia gene therapy Roctavian to the U.S., Germany and Italy in a bid to reach profitability with the slow-selling blood disease medicine.

BioMarin will also pause production at a Roctavian manufacturing site and stop enrolling new patients in clinical testing of the therapy, which won approval in Europe in 2022 and the U.S. last year. The company expects its changes to lower direct Roctavian expenses to $60 million a year by 2025, by the end of which it anticipates the business will be profitable.

While Roctavian was once viewed by analysts as a future blockbuster, demand for the one-time treatment has been scant, reflecting doubts about the durability of benefits it offers and a price tag that’s hampered reimbursement discussions in the U.S. and Europe. Five patients received treatment between April and June, resulting in revenue of $7 million, BioMarin said Aug. 5.

Roctavian’s commercial future has been in the balance as BioMarin and new company CEO Alexander Hardy weighed the therapy’s slow uptake.

In April, Hardy laid out three options BioMarin was considering: staying the course on evidence sales were ramping quickly, reducing spending to ensure a “reasonable” return on investment, or selling Roctavian altogether.

With the new plan disclosed in August, BioMarin is choosing the middle ground and hoping it can increase sales by enough to match a lower level of expenses.

“This decision on Roctavian was based on four conclusions: One, our belief in the therapeutic profile of Roctavian and its role in hemophilia A; second, our understanding that a launch like this takes time; third, signs of progress in the United States, Germany and Italy; and lastly, a revised expense profile that gives us confidence Roctavian will contribute to profitability,” Hardy told investors on a conference call.

Hardy said he expects the pace of treatment in the U.S. to improve as more centers gain experience with Roctavian, which delivers a functional copy of the gene that people with hemophilia A lack. In Germany, the company is working to secure reimbursement following an agreement with the country’s health authorities on pricing, while in Italy Hardy reported “signs of patient demand.”

Two of the five patients treated in the second quarter were located in Italy; the other three were in the U.S.

BioMarin declined to give specific patient or revenue guidance in August, although the company would likely need to treat several dozen patients to break even on $60 million in expenses. The list price for Roctavian in the U.S. is $2.9 million, while in Germany BioMarin agreed to a price that equates to about $900,000 in per-patient revenue.

BioMarin also didn’t detail what it plans to do with Roctavian rights in countries other than the U.S., Italy and Germany. In its statement, the company indicated that “expansion into other markets” will depend on progress in the three it’s chosen.

BioMarin’s pared-down vision for Roctavian contrasts with the high potential the company and many outside it ascribed to hemophilia gene therapy. Long a goal for the gene therapy field, treatments like Roctavian promise to control bleeding for many years, freeing people with the disorder from regular infusions of so-called factor replacement therapy.

But the arrival of newer and longer-lasting drugs like Roche’s Hemlibra and Sanofi’s Altuviiio have given patients new options, possibly lessening the appeal of gene therapy. Sales of Hemgenix, a gene therapy for the less common “B” form of hemophilia, have also been slow.

Roctavian’s sluggish sales have put the focus more squarely on another new BioMarin drug, Voxzogo, that’s approved to treatment a form of dwarfism. According to the company, roughly 3,500 children were on the drug at the end of the second quarter, and it is now BioMarin’s top-selling product.

Regenxbio has aligned with the Food and Drug Administration on an abbreviated approval path for an experimental gene therapy the company is developing for Duchenne muscular dystrophy.

Following discussions with the agency, an existing Phase 1/2 study has been expanded into a pivotal trial that can support an accelerated approval, Regenxbio said Nov. 18. The study will evaluate Regenxbio’s gene therapy in about 30 Duchenne patients at least 1 year old and won’t include an active placebo as a comparator.

Notably, the therapy’s main study goal will be to produce, after three months, at least 10% of normal levels of a diminutive protein, microdystrophin, that’s thought to help Duchenne patients. Previous pivotal studies of Duchenne gene therapies from Pfizer and Sarepta Therapeutics were placebo-controlled and hinged on an evaluation of motor function that, for Regenxbio, is an exploratory measure.

Regenxbio was a latecomer in the biotech industry’s development of gene therapies for Duchenne, a deadly muscle-wasting disease with no cure. But stumbles by more advanced competitors have positioned the company as the closest threat to Sarepta Therapeutics’ Elevidys, which is available for most Duchenne patients despite clinical results that raised doubts about its effectiveness.

Like Elevidys, Regenxbio’s RGX-202 is designed to produce microdystrophin, a tiny version of the muscle-protecting protein Duchenne patients lack. But the therapy is packaged into a different type of microscopic virus. It also produces a larger version of the protein that more closely resembles normal dystrophin, “which we expect to lead to improved function,” CEO Curran Simpson wrote in an email to BioPharma Dive.

The company says early data hints at such potential. The handful of patients treated with RGX-202 at two different dose levels in Regenxbio’s trial have produced, on average, higher levels of microdystrophin than did those given Elevidys in Sarepta’s testing. Expression levels in children 8 years or older — kids who are expected to already be declining — are the highest observed in a clinical test of a Duchenne gene therapy, the company claimed.

A snapshot of data from five patients — two of whom were 8 or older — additionally showed either stabilization or improvement on a measure of motor function called the North Star Ambulatory Assessment, or NSAA, after nine months to one year. No serious adverse events have occurred so far. The most common drug-related side effects were nausea, vomiting and fatigue, the company said.

The results show “a distinct therapeutic profile with the potential for enhanced benefits compared to other [Duchenne] gene therapies,” wrote Michael Kelly, the chief scientific officer of advocacy group CureDuchenne, in an email. (Regenxbio is a sponsor of CureDuchenne as well as other patient groups.) 

Sarepta and Pfizer have struggled to prove microdystrophin production can alter Duchenne’s trajectory. Elevidys failed to show a meaningful difference in NSAA scores after a year in two placebo-controlled trials. Pfizer quit developing a Duchenne gene therapy after a failed Phase 3 trial that showed no correlation between microdystrophin levels and function.

Those results have fueled questions about microdystrophin as a predictive marker. But Peter Marks, the head of the agency’s gene therapy office and the official who overturned other reviewers in approving Elevidys, remains confident. At an academic symposium in early November, Marks noted he’s “not willing to throw out microdystrophin entirely,” which signaled the FDA is still open to streamlined approvals for microdystrophin gene therapies, wrote RBC Capital Markets analyst Brian Abrahams.

The agency has now agreed to such a path for Regenxbio. In doing so, it’s endorsed a smaller trial than either Sarepta or Pfizer ran, with an open-label design that compares findings to historical controls. Timed tests of how quickly patients walk or stand up are secondary goals, as they were for Sarepta and Pfizer.

NSAA scores have been pushed down in the statistical hierarchy, however. On a Nov. 18 conference call with analysts, CEO Simpson said that the decision wasn't driven by the FDA, but was instead based on historical data from other trials. Some analysts have argued, for instance, studies need to run for longer to show a meaningful difference in NSAA scores.

“The general view has been that [NSAA] is a cruder measure, where there's just less sensitivity to detect a potential drug effect,” Simpson said.

The news is a “net positive” for other Duchenne gene therapy developers, alleviating investor concerns that accelerated approvals may be unavailable to other companies, wrote Leerink Partners analyst Joseph Schwartz, in a Nov. 18 note to investors.

Peter Marks is again at the center of a controversial Food and Drug Administration decision on a gene therapy for Duchenne muscular dystrophy. Twice now, the high-ranking FDA leader has pushed aside objections from agency reviewers to grant an approval to Sarepta Therapeutics' treatment for the muscle-wasting condition.

In mid-June, the FDA substantially broadened use of that treatment, called Elevidys. The decision makes Elevidys available to approximately 80% of people in the U.S. with Duchenne, which has limited treatment options and no cure. The agency also converted Elevidys’ accelerated approval to full, securing its place on the market. Previously, Elevidys was only approved for a specific group of boys 4 or 5 years of age.

“Families facing Duchenne have an urgent need for treatments that will delay the progression of the disease and this represents a significant treatment option for many boys and young men with Duchenne,” said Debra Miller, CEO of the patient advocacy group CureDuchenne, in an emailed statement.

But documents published by the FDA expose a rift within the agency over Elevidys. Three FDA review teams and two top officials recommended Sarepta’s application be rejected due to insufficient and conflicting clinical data. They were overruled by Marks, head of the FDA center that reviews gene therapies, who found the results supportive enough to broaden Elevidys’ label. It’s now cleared for Duchenne patients over the age of 4 with mutations to a specific gene, regardless of whether they can still walk.

“I come to a different conclusion regarding the overall interpretation of the data,” Marks wrote in a memo.

Marks has been a pivotal voice in the review of Elevidys. Before the regulator cleared it last year, he pushed the FDA to schedule an advisory meeting after learning agency scientists leaned towards rejecting the treatment outright, according to reporting by Stat. He then later overruled FDA reviewers in granting an accelerated approval.

Marks made those decisions while on a public campaign to communicate the agency’s flexibility in evaluating gene therapies for deadly diseases like Duchenne. Marks recently spoke at multiple meetings held by patient advocacy groups, noting how the FDA’s thinking has changed to become more patient focused. The regulator aims to speed development of rare disease gene therapies, he said, and views accelerated approvals as a valuable tool to accomplish that goal.

Even so, FDA reviewers once again wanted to reject Sarepta’s application. Elevidys has twice missed the main goals of placebo-controlled trials, failing to meaningfully improve motor function compared to a placebo after one year. Agency staff remain skeptical of the connection between the muscle-protecting, “microdystrophin” protein Elevidys produces and treatment benefit, documents show. They additionally found Sarepta's main supportive evidence — a series of apparent benefits across secondary measures like how quickly a person can stand up — inconclusive.

Lola Fashoyin-Aje, director of clinical evaluation within the FDA’s gene therapy office, described those findings in another memo as “exploratory,” “possibly due to chance” and argued they should only be considered “hypothesis generating.”

“In some cases, the results of these analyses have yielded conflicting results, further illustrating the unreliability of exploratory analyses to support regulatory decision-making,” Fashoyin-Aje wrote. She added that, if an association between microdystrophin expression and improvement in physical function exists, “the data provided to date do not demonstrate it.”

Fashoyin-Aje made her case in support of the FDA’s clinical, clinical pharmacology and statistical review teams, which all determined that the evidence Sarepta generated doesn’t prove Elevidys effective or support broadening its use.

Notably, they rejected Sarepta’s arguments that Elevidys’ benefits on secondary measures in its main trial make up for the fact its primary outcome was negative. Because that primary statistical test failed, the secondary findings are “misleading” and “cannot guide any stakeholders — including patients, family members and caregivers, and prescribers — in making informed decisions” about Elevidys’ potential benefits, wrote clinical reviewers Mike Singer and Xiaofei Wang.

“We cannot reliably distinguish if these results are due to actual effects of Elevidys, or to chance alone,” they wrote.

Marks took an opposite view, finding Sarepta’s secondary study findings “compelling.” He also argued that historical data suggests even a small benefit compared to a placebo in someone with Duchenne is “clinically meaningful.”

Making Elevidys widely available now, rather than waiting years for a superior product to emerge, could positively impact lives, he added.

“During this time, the availability of this gene therapy option may help slow or prevent irreversible decline that might otherwise occur in both ambulatory and non-ambulatory individuals, particularly since the latter have few or no alternative treatments available to address their imminent further decline in function over time,” Marks wrote.

In making that judgment, Marks is reprising the role of another longtime FDA official, Janet Woodcock. Eight years ago, Woodcock overruled agency reviewers to grant accelerated approval to Exondys 51, a drug also developed by Sarepta, because it was “reasonably likely” to help some people with Duchenne. Her decision was supported by Robert Califf, the FDA commissioner then and now.

Woodcock’s call was similarly divisive within the FDA and led multiple reviewers to depart afterwards. Some accused Woodcock of skirting agency norms and having unusually close ties with Sarepta and with patient advocacy groups, whose influence over drug regulation has grown.

Marks’ decision to broaden Elevidys’ approval could also reverberate.

“The lasting impact of the approval will likely shape the FDA and gene therapy space for some time,” wrote Tim Lugo, an analyst at the investment bank William Blair, in an investor note in mid-June “We believe a more patient focused and less adversarial FDA review process is likely to continue across several areas in the agency, especially for heterogenous and deadly diseases with few good treatment options.”

Intellia Therapeutics stopped work on one of its principal drug research programs and announced plans to lay off more than one-quarter of its staff in a January restructuring meant to prioritize resources around its two most advanced experimental medicines.

The discontinued program, dubbed NTLA-3001, targets a rare lung disease known as alpha-1 antitrypsin deficiency. Intellia had begun a Phase 1/2 clinical trial testing the therapy in August. Alongside NTLA-3001, the company is also ending “select research-stage programs.”

Intellia will additionally prepare for a change in its scientific leadership as Laura Sepp-Lorenzino, the company’s chief scientific officer since May 2019, plans to retire at the end of the year. Birgit Schultes, who’s led Intellia’s immunology and cell therapy work since 2017, will take Sepp-Lorenzino’s place as CSO.

The restructuing means that, for the second time in a row, Intellia is starting the new year with layoffs and research cuts.

In January 2024, the CRISPR gene editing company said it would eliminate 15% of its workforce and pause some exploratory research. A few months prior, Intellia had nixed an earlier program for alpha-1 antitrypsin deficiency, also known as AATD.

At the time, Intellia said it intended to focus on enrolling pivotal studies of its two lead programs, launch new clinical trials and experiment with new gene editing and delivery tools.

This time around, Intellia’s primary concerns look a bit different. The company will prioritize clinical execution for those two programs, targeting the rare diseases hereditary angioedema and transthyretin amyloidosis, and “advance commercial readiness” to prepare for launching those medicines.

Both of those programs, dubbed NTLA-2002 and nex-z respectively, are now in Phase 3, and Intellia hopes to complete or speed enrollment into those trials.

“Our early clinical data for both NTLA-2002 and nex-z support novel, highly differentiated product profiles that directly address the significant unmet needs of patients and prescribers in HAE and ATTR,” said Intellia CEO John Leonard in a Jan. 10 statement. “We understand the significant potential of our late-stage programs, and within a challenging market environment, have made a difficult decision to focus our resources predominantly on NTLA-2002 and nex-z where we have the greatest opportunity to create significant, near-term value.”

Intellia was one of a handful of companies targeting AATD with new drugmaking technologies like CRISPR. Wave Life Sciences, Korro Bio and ProQr are all developing RNA medicines for the disease, which can damage the liver as well as lungs.

Beam Therapeutics, meanwhile, expects to soon share initial trial data for an AATD therapy that uses what’s known as base editing to correct the disease-causing mutation.

The environment for gene editing companies has darkened over the past year or so. Several others have been forced to lay off staff and pare back their research plans in response to funding constraints or shifting market expectations.

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.

About two years ago, the Food and Drug Administration approved a personalized gene therapy for an ultra-rare childhood brain disorder despite concerns treatment might inadvertently trigger cancer.

Those concerns are now back in the spotlight, as new study data published Oct. 18 in The New England Journal of Medicine document seven cases of blood malignancies in young boys given the therapy, called Skysona.

The cases are among 67 boys with cerebral adrenoleukodystrophy, or CALD, who were enrolled in studies of Skysona. In the months and years after treatment, six developed myelodysplastic syndromes, or MDS, a form of bone marrow cancer, and one developed acute myeloid leukemia, according to the study authors.

All of the cases were previously disclosed by Skysona's developer, Bluebird bio, to study investigators and to the FDA, which updated the treatment's labeling in April. Bluebird has also shared details of some of the cases at medical meetings.

However, the paper is the fullest assessment yet of the safety of Skysona, which the FDA cleared in Sept. 2022 on the condition Bluebird confirm its benefit with additional data.

At the time of the approval, researchers had reported three of the MDS cases, which were discussed at length by a group of experts the FDA convened to advise it. The panel ultimately voted unanimously in favor of Skysona, citing what they saw as convincing evidence of its benefit treating CALD.

Before Skysona, there was no medicine specifically for CALD, which causes progressive degeneration in the brain and, if unaddressed, typically leads to death in a child's second decade of life. The disease is linked to the X chromosome, so it affects boys.

Those past disclosures mean the cancer cases documented in October won't come entirely as a surprise to treating physicians or the broader patient community. Still, they give doctors a more complete sense of how Skysona's risks balance against its benefit, which could inform treatment choices for CALD patients. (In some, stem cell transplants from a matched sibling donor can stabilize the disease.)

"These troubling events raise the bar for offering eli-cel autologous gene therapy for cerebral adrenoleukodystrophy," wrote Cynthia Dunbar, chief of the translational stem cell biology branch at the National Heart Lung and Blood Institute, in an editorial also published Oct. 18. Skysona was previously called eli-cel.

The main NEJM paper shows five of the six boys who developed MDS went on to receive a stem cell transplant, which is typical for treating MDS. Four remain free of MDS with any recurrence of CALD symptoms, while one died from apparent graft-versus-host disease nearly two years after his transplant. The sixth boy with MDS is awaiting a transplant, researchers said.

The boy who had leukemia is also alive following a stem cell transplant.

In all seven cases, researchers determined the cancers were “probably mediated” by the engineered virus Bluebird used to construct Skysona, which is built from patient stem cells.

There are a number of ways researchers can insert helpful new genes into such cells; the way Bluebird chose involves a lentivirus that semirandomly integrates into the stem cells’ genome. Malignant cells in six of the patients had lentiviral DNA within two genes linked to the development of cancer. The seventh case is still being investigated.

When Skysona development began, scientists weren’t sure which cells in the brain needed to express the helpful gene the therapy would deliver. So they added genetic components to their lentivirus shuttle that ensured subsequent gene expression would be strong across the variety of cell types that arise from the transplanted stem cells.

In her editorial, Dunbar hypothesizes that these components, known as a “promoter,” could be to blame, citing a meta-analysis of several hundred patients treated with other lentiviral gene therapies that found no cases of blood cancer.

But other factors could be at play, too. Six of the cases were in one study that used a different chemotherapy regimen to prepare patients for infusion of Skysona. There were also some differences in how stem cells were mobilized into the blood for collection between the two main studies that supported Skysona’s approval.

“The way these factors individually, in combination, or with other unidentified variables interact with one another to lead to genotoxicity is unclear,” the authors of the main NEJM paper wrote.

Skysona’s benefits are easier to document. A third paper published in NEJM Wednesday detailed efficacy results from the 32 patients enrolled in the Skysona study from which only one cancer case emerged. At the most recent evaluation, neurological function scores were stable in 30 of the 32 patients, and 26 had no major functional disabilities — results that Dunbar, in her editorial, called “very promising.”

"There is still a role for Skysona,” said Christine Duncan, a senior physician at Boston Children’s Hospital and medical director of clinical research in the gene therapy program there, who was first author on one of the NEJM papers. “But it needs to be one that is very thoughtful and the family needs to be given all the information.” 

According to Bluebird, 11 patients have so far initiated treatment with Skysona since it’s been available commercially. The treatment process takes some time, so it’s not clear if all five who started recently have actually been infused with the therapy, which carries a list price of $3 million.

“The well-being of patients with CALD treated with Skysona, or who are considering gene therapy following a diagnosis of CALD, is our top priority,” Bluebird said in an emailed statement.

“Bluebird is committed to ensuring that treating physicians have access to the most up-to-date safety information to support informed decision making.”

Bluebird also sells two other gene therapies: one, called Zynteglo, for severe beta thalassemia, and another, called Lyfgenia, for sickle cell disease. Both therapies use a different lentivirus that contains a different promoter.

One patient enrolled in studies of Lygenia previously developed leukemia, but researchers determined it was unlikely to have been caused by treatment. People with sickle cell have a higher risk of leukemia.

All told, 41 patients had started the process for one of Bluebird’s three treatments through late September, and the company expects another 40 more to do so in the fourth quarter. Their uptake is critical for Bluebird, which has faced persistent funding concerns over the past two years. On Sept. 24, it announced plans to lay off about a quarter of its workforce.

A medicine built around a more precise form of CRISPR gene editing appeared to work as designed in its first clinical trial test, developer Beam Therapeutics said Nov. 5. But the death of a trial participant could renew concerns about an older drug used alongside Beam's genetic medicine.

Beam’s medicine uses a technology known as base editing to activate a gene in stem cells collected from people with sickle cell disease, an inherited blood condition that can cause debilitating pain and a constellation of other symptoms.

Data shared by Beam from the first handful of patients treated in the trial show the company successfully edited those cells in a laboratory. When later reinfused back into patients’ bodies, they matured into red blood cells that were more durable and less likely to warp into the sharp-edged crescents associated with the disease.

However, one of the patients died from lung damage that was judged by their physician and the trial’s monitoring committee as related to an old chemotherapy drug commonly used prior to stem cell transplants. The Food and Drug Administration also reviewed the case. 

Called busulfan, this drug is known to be toxic. But it is effective at creating an opening in the bone marrow for newly edited stem cells to take root, a necessary step for infusing gene editing therapies like Beam’s.

“This is a sad outcome and it really underscores the real risks of doing myeloablative transplant with chemotherapy,” said Beam CEO John Evans in an interview. “These risks are well known. This includes significant toxicities that are possible and the rare, but real, risk of mortality.”

Still, he added, those risks must be weighed against the urgent health threats posed by severe cases of sickle cell, which can cause strokes as well as heart and lung damage. The disease can also shorten a person’s lifespan.

The patient’s death highlights the challenges developers like Beam face in advancing cutting-edge gene editing techniques that still require the blunt tools of decades past. Treatment with Casgevy, a CRISPR therapy that was approved for sickle cell in a U.S. first last year, also involves use of busulfan, as does Lyfgenia, a competing genetic therapy that’s built in a different way from Casgevy.

Adoption of both therapies since they became available has been slow, which may in part be due to patient concerns over the risk of infertility with busulfan.

Beam is working on a solution to sidestep busulfan and, on Nov. 5, also released data from testing in monkeys showing how it may work.

Rather than busulfan, Beam used an antibody drug targeting a protein, CD117, that’s expressed on the surface of stem cells. Binding to this protein is meant to suppress and eliminate diseased cells in the bone marrow. The second part of Beam’s solution involves an engineered stem cell product that’s very similar to Beam’s first-generation medicine. In addition to editing the stem cells to fix sickle cell, however, Beam also alters them in such a way its antibody can’t bind to CD117.

In preclinical testing, Beam was able to successfully edit stem cells and get them to engraft in the monkey’s bone marrow using only antibody conditioning.

Beam plans on doing further testing in monkeys before starting a Phase 1 study of its anti-CD117 antibody in healthy volunteers. If all goes well, the company would then evaluate the antibody together with the stem cell product in people with sickle cell and beta thalassemia, another inherited blood condition.

“This is clearly the future,” said Evans. “It would not only make this process much safer for all patients because you’ve gotten rid of chemotherapy, it also expands the addressable population by three- to four-fold.”

Beam estimates that its antibody and second-generation sickle cell medicine, BEAM-104, are several years behind its first-generation candidate, which it calls BEAM-101.

Progress from BEAM-101 will help to speed along development BEAM-104, Evans said. The Nov. 5 trial data on BEAM-101 are therefore an important proof point for the company and its base editing technology.

The main outcome Beam tracked involves measuring in the blood a fetal form of the oxygen-carrying protein hemoglobin. Production of this fetal hemoglobin is turned off in the first few months after birth as the body transitions to adult hemoglobin, which, in people with sickle cell, is deformed in such a way that it sickles red blood cells.

With BEAM-101 — and BEAM-104 — the company is essentially trying to recreate a condition known as hereditary persistence of fetal hemoglobin. It does this by using base editing to change a single “letter” in genes that control fetal hemoglobin’s promotion.

Data from the first four patients with a month or more of follow-up show that BEAM-101 led to significant levels of fetal hemoglobin and, correspondingly, lower levels of sickled hemoglobin. In two patients with a bit longer follow-up, treatment led to elimination of nearly all red blood cells expressing only sickled hemoglobin by the second month.

This effect should protect the treated patients from the pain crises typical of sickle cell. So far in testing, none have been reported, Beam said.

There were no side effects classified as severe or serious that investigators judged to be related to BEAM-101. The participant who died had received BEAM-101 treatment several months before developing lung dysfunction.

Participants, who ranged in age from 19 to 27 years, all had a history of sickle cell-related pain crises in the two years prior to screening for enrollment in the study.

As the data are early and from only a few patients, it’s difficult to judge whether BEAM-101 might ultimately be competitive or superior to Casgevy or Lyfgenia. Evans pointed to early signs of easier treatment processing, such as faster time to engraftment, that may eventually differentiate BEAM-101. And he noted how a few patients treated with those two approved therapies still experience the occasional pain crisis.

“Clearly, there’s a little bit of depth of cure to be had,” Evans said.

The company plans to present data from more patients at the American Society of Hematology’s annual meeting in December. The results disclosed Nov. 5 come from an abstract published online ahead of the conference.

Overall, Beam has enrolled 35 patients in the expansion cohort of its Phase 1/2 study testing BEAM-101. Along with hemoglobin levels, the company will also track the proportion of patients who are free of pain crises for 12 or more months.