Gene Therapy

A research paper published a decade ago touched off a biomedical revolution that has made careers, spawned companies and drawn billions of dollars of investment. Late last year, the gene editing technology that paper described won Food and Drug Administration approval as part of a powerful new treatment for sickle cell disease.

Now Nobel Prize-winning science, CRISPR gene editing is at the heart of the biotechnology industry’s latest Big Bang. It’s adaptable and efficient, putting the precise alteration of DNA within easy reach of academic scientists and drug startups alike.

Since 2012, when research by Jennifer Doudna and Emmanuelle Charpentier was published in Science, more than a dozen biotech companies have sprung forward to capitalize on the possibilities they and other scientists unlocked.

This new generation has joined early adopters CRISPR Therapeutics, Editas Medicine and Intellia Therapeutics, offering various twists and tweaks to improve on the original CRISPR technology. They’re also taking aim at a wider array of illnesses, from ALS to heart disease.

Many are led by or employ scientists and post-doctoral students trained in the laboratories of the University of California, Berkeley and the Broad Institute of MIT and Harvard, the academic institutions most closely linked to CRISPR gene editing research.

The research diaspora mirrors a broader trend in the life sciences. According to Feng Zhang, a member of the Broad and a pioneering CRISPR expert, the lines between academia and industry are “blending” more than before.

“The door is open in both directions,” Zhang said. “We need the flow of talent to be as porous as possible” to speed CRISPR research.

And, as happened with new drugmaking technologies before CRISPR, large pharmaceutical companies have moved in, placing bets on the technology’s potential.

“Large pharma is recognizing that this has the potential to be the future of medicine,” said Benjamin Oakes, co-founder and CEO of Scribe Therapeutics, an early-stage CRISPR drug developer now working with Eli Lilly and Sanofi.

The first glimpse of that future came last December, when the FDA approved that sickle cell treatment, known as Casgevy and developed by CRISPR Therapeutics and Vertex Pharmaceuticals.

A biotech foundation

Often likened to a pair of genetic scissors, CRISPR editing at its simplest involves just a few specialized components. A strip of engineered RNA acts as a guide, shepherding the editing machinery to a corresponding stretch of DNA in a cell. If the sequences match, an enzyme called Cas9 will cut through the DNA double helix at that precise spot.

When this happens, the cell moves to repair the double-stranded DNA break. The process can inactivate the gene in question — useful for treating diseases caused by harmful protein production. Researchers can also take advantage of the cut made by Cas9 to correct the target gene or insert a new one by pairing the editing complex with a DNA template.

Casgevy, Vertex and CRISPR Therapeutics’ drug, relies on the former approach. A patient’s own stem cells are collected and isolated in a laboratory, where CRISPR/Cas9 is used to cut a particular section of a gene called BCL11A.

This disruption causes the cells, once reinfused back into the patient, to produce high levels of fetal hemoglobin, an oxygen-carrying protein which the body stops making soon after infancy. High levels of fetal hemoglobin are thought to counteract the red blood cell sickling that’s characteristic of the disease and the cause of its symptoms.

Before CRISPR, gene editing was limited to older technologies like zinc finger nucleases, and transcription activator-like effector proteins, or TALENs.

Zinc finger nucleases are enzymes that also can cut specific gene sequences, while TALEN-based editing uses the eponymous protein to do the job. But both are expensive and time-consuming to produce and lack CRISPR’s specificity.

“The CRISPR revolution came around at the right time,” said Mitch Finer, CEO of Life Edit Therapeutics and former chief scientific officer of Bluebird bio, which has developed a rival sickle cell treatment to exa-cel. “It’s one protein, and all you have to do is change up the guide RNA. That’s what was so attractive.”

Doudna and Charpentier’s paper, as well as research by Zhang and others, led to the quick formation of a trio of companies focused on turning CRISPR science into new medicines.

Charpentier launched CRISPR Therapeutics in 2013 with Shaun Foy, a venture capitalist, and Rodger Novak, who had been an executive at Sanofi. Around the same time, Doudna joined other leading scientists in the field, including Zhang, George Church, David Liu and Keith Joung, to introduce Editas Medicine.

But Doudna quit Editas in 2014 as the co-founders tussled over who owned the intellectual property for CRISPR/Cas9. She later co-founded Intellia Therapeutics, working with Atlas Venture and Caribou Biosciences, a company she had launched several years prior.

According to Novak, academic innovation provided the necessary spark to start biotech’s CRISPR revolution, particularly as it came alongside the emergence of other technologies like messenger RNA and cheaper gene sequencing.

“Technology wise, around that time, there was some light on the horizon and things came together relatively nicely,” he told BioPharma Dive in a recent interview.

CRISPR Therapeutics, Intellia and Editas drove the translation of CRISPR into the clinic, achieving some of the field’s firsts. Exa-cel, for instance, became the first medicine made with the technology to be tested in humans in a biotech trial. And in 2021, Intellia proved CRISPR could work “in vivo,” or directly inside the body rather than via extracted cells.

But they also hit difficulties, too. Progress was greatest in rare diseases of the eye and blood, areas of the body that are relatively easier to reach — shaping which conditions the companies aimed for first. CRISPR/Cas9, with its proclivity to cut through both strands of DNA, also isn’t the best tool to address every kind of genetic mutation, spurring research into other approaches.

New directions

As gene editing research advanced, scientists unearthed different techniques for editing DNA as well as other CRISPR-associated enzymes to do the job.

Their discoveries led to a stream of academic literature on how CRISPR could be improved and made more precise. Zhang and researchers working with him at the Broad studied Cas12 and Cas13. Joung, at his lab at Massachusetts General Hospital, engineered CRISPR/Cas9 systems to better avoid off-target effects. Liu and his team published in 2016 and 2019, respectively, landmark papers on base and prime editing, which offered ways to edit single nucleotides without cutting both DNA strands.

“We now have at our disposal more capabilities, so that we can pick the best one for the disease we're trying to treat,” Zhang said.

He likened the advancements to a bigger toolbox, containing just the right equipment for specific jobs. “If your house didn't have water, there’s a problem with the pipe, and instead of fixing the pipe you get water from somewhere else — that’s the approach that's taken with current sickle cell disease treatments,” Zhang said, referring to exa-cel and Bluebird’s treatment, which uses an engineered virus to add a new gene to patient stem cells.

“With more tools in the toolbox, we'll have a better chance of being able to fix the pipe,” Zhang added.

The discoveries led to new companies, like Beam Therapeutics, which was founded by Liu, Zhang and Joung to develop base editing into medicines. A group of venture investors and life sciences researchers including Joung started Verve Therapeutics in 2018. And Liu later co-founded Prime Medicine around prime editing.

These companies, and others, were launched even as legal battles continued between the Broad and Berkeley over rights to the original CRISPR invention. (Federal patent officials issued a ruling in 2022 determining the legal rights to the foundational technology belong to the Broad.)

The Broad has said it believes in “open access” to CRISPR research. Since 2014, the institution has granted licenses to companies and scientists looking to build on the existing technology.

An expanding group of venture firms, including Arch Venture Partners, F-Prime Capital, GV, Atlas Venture and Newpath Partners, has emerged as common backers of this second generation of CRISPR companies.

The value of private financings also swelled. Early on, CRISPR-focused biotechs raised between $15 million and $43 million in their initial Series A rounds. Their successors often raised much more: Prime Medicine emerged from stealth in 2021 with $315 million in hand from its Series A and B rounds, for instance.

The influx of money helped fund grand ambitions and broad development goals. “I certainly would love to become the next Vertex or Biogen,” Keith Gottesdiener, then the CEO of Prime Medicine, said in a 2021 interview with BioPharma Dive.

Some of these later companies also benefited from going public during a peak in biotech valuations. Beam went out in 2020, followed by Verve in 2021, when it hit Wall Street with one of the year’s largest IPOs. Even in 2022, when the sector was experiencing the beginnings of a funding drought, Prime Medicine was able to pull off an IPO.

Still, these companies haven’t gotten far in the pursuit of treating people. Beam began testing a “first-of-its-kind” gene editing medicine for cancer in September, the first time a base editing medicine has entered human trials.

An expanding ecosystem

CRISPR is now no longer the domain of just a handful of biotechs. A larger ecosystem exists, as more gene editing startups have continued to crop up.

These companies are working with other CRISPR enzymes, such as Cas12, Cas13, Cas14 and CasΦ, and aim to sidestep problems like delivery and off-target editing. (Older gene editing companies, like Editas, Caribou and Beam, are also experimenting with new enzymes, too.)

This fresh slate of Cas molecules has emerged along with a new generation of scientists. Researchers who completed their PhDs and post-doctoral fellowships under gene editing pioneers like Doudna, Zhang and Liu are launching companies of their own.

“Abandoning false modesty, we're UC Berkeley,” said Fyodor Urnov, a professor of molecular and cell biology at UC Berkeley and an expert in genetic medicine. “We're the best public research university in the world. It's an elite training school.”

For example, Janice Chen and Lucas Harrington, two Berkeley researchers who worked with Doudna on a 2018 paper detailing Cas12, founded Mammoth Biosciences with her and a Stanford University colleague, Trevor Martin. Based in the San Francisco Bay Area, Mammoth is now working with both Cas14 and CasΦ proteins, which are smaller than the original enzyme.

“We’re still developing tools to understand what are high standard edits, or what are other off-target edits,” said Chen, now Mammoth’s chief technology officer. “The technology is advancing, but then also the tools to understand the safety profile.”

In its early days, Mammoth focused on both diagnostics and medicines, believing CRISPR could improve upon existing methods in identifying cancer targets or viral infections. The biotech partnered with Vertex in 2021, Bayer a year later and Regeneron in April 2024. It has since trimmed back its diagnostics work.

Like Zhang, Mammoth’s founders see the latest iterations of CRISPR as a toolkit.

“We want to have the right technology available for the disease so we can be driven by the science and the disease biology,” Martin said. Then, “it’s not that we have a hammer, so everything has to look like a nail. We can choose the right technology for the disease, rather than having to fit everything into a certain box.”

Doudna is also associated with other biotechs such as Scribe Therapeutics, which she co-founded with Oakes, one of her former students. Oakes, who once studied zinc finger nucleases, came to Berkeley in 2013 after the publication of that first CRISPR/Cas9 paper by Doudna and Charpentier.

“That problem that we were brute force working to solve was solved in a much more elegant way,” said the Scribe CEO, who co-authored a paper on CRISPR/CasX in 2019.

The backing of young researchers by scientists at Berkeley and the Broad has helped along the evolution of new CRISPR-based technologies. So, too, has the technology’s spread throughout the scientific community, despite the legal battling over CRISPR patents between Berkeley and the Broad.

“Licensing the technology, on a non-exclusive basis for different areas, has been really, really good,” said Zhang, of the Broad. “It’s accelerated research and application development.”

Setbacks and public sentiment

The rapid growth of the gene editing sector has come with its share of research stops and starts.

As the initial companies raced to begin clinical trials, federal regulators in the U.S. proceeded more warily. In 2018, the FDA paused Vertex and CRISPR Therapeutics’ plans to start their first study of exa-cel. Editas also ran into delays when the FDA imposed a partial clinical hold for its sickle cell disease therapy in 2021.

Both Beam and Verve had similar problems as they tried to advance their base editing programs into clinical testing, receiving clinical hold orders from the FDA last summer and fall.

The temporary pauses reflected regulatory caution on the safety of CRISPR gene editing and its use in humans. In particular, the FDA appears to be closely watching tests of in vivo CRISPR medicines for any signs CRISPR changes could be inadvertently made to sperm or egg cells  — so-called germline edits.

“Our view is that this is the FDA taking a very considered view of the space,” said Intellia CEO John Leonard in response to questions on an August 2023 call about a request made by the agency.

Intellia conducted testing of its first in vivo candidate outside of the U.S., and scrapped plans to include U.S. patients in testing of its second following the FDA’s ask. The company is opening up U.S. trial sites as part of a late-stage study it recently began.

Other safety concerns have cropped up too, such as with Graphite Bio’s sickle cell treatment nula-cel, which the company stopped testing after reporting a serious side effect.

In most cases, though, the FDA has lifted the holds it’s imposed, allowing testing to advance and paving the way for the agency’s review of Casgevy.

That treatment’s approval again put CRISPR gene editing squarely in the public eye. While biotechs are using the technology to treat diseases solely via edits to somatic cells, the field is still shadowed by the actions of Chinese scientist He Jiankui. In 2018, He stunned the scientific world by announcing he had edited a pair of embryos that were implanted and brought to term, sparking condemnation and renewed calls to restrict germline editing.

Even before the controversy, the Broad had put in place safeguards against experiments like He’s. Now, the institution maintains “any human clinical use must be consistent with all laws and regulations,” and does not license their technology for editing human egg and sperm cells.

Looking ahead

Even as a down biotech market has stressed young drugmakers, gene editing companies continue to draw investment.

Prime’s IPO, for example, raised $175 million last October — a rare IPO success in a down year. New gene editing companies continue to emerge, too, such as Tome Biosciences and Tune Therapeutics.

Others, meanwhile, are applying CRISPR principles in different ways. Boston-based Chroma Medicine, which raised $135 million in venture funding this March, is crafting drugs to alter the epigenome.

From an R&D perspective, researchers in the field hope to make advances in several areas. First, prove that CRISPR-based gene editing can work in a wider variety of diseases. Many of the initial programs are for eye-related conditions, sickle cell disease or beta thalassemia, but there are many other possible targets, said Urnov, who co-founded Tune and consults with Vertex.

Second, delivery remains a challenge. Current genetic medicines can readily reach those parts of the body that are easily accessible, such as the eye, blood or liver. As a result, diseases affecting other tissues, like the muscle and brain, remain challenging to treat, even if the genetic errors causing them are well understood.

And there are still concerns about the possibility of off-target edits with CRISPR-based therapies. The FDA’s approval of Casgevy suggested some comfort with this risk.

From an industry perspective, commercialization of genetic medicines remains a question mark. While they promise dramatic benefits, their high price tags and complex manufacturing could present marketing hurdles. Outside of Novartis’ spinal muscular atrophy drug Zolgensma, sales of the gene replacement therapies approved to date have not taken off.

“The for-profit sector really understands how to commercialize medicines where you put the patient on a lifetime of treatment,” said Urnov. With gene therapy, most patients will likely receive treatment once.

“At the end of day, patients aren't going to care about the modality,” Chen said. “They just want to know: is it safe and does it work? That's the ultimate end goal.”

Ned Pagliarulo contributed reporting.

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.

Sponsored content

By Fortrea

In 2015, Evelyn Villareal received gene therapy at just eight weeks old, which successfully halted her progression of spinal muscular atrophy type 1, a fatal genetic disease. Gene therapies make a difference for children diagnosed with a rare disease and can offer solutions for unmet medical needs. Understanding their unique challenges can help gene therapy developers design and execute better clinical trials.

Advancing life-changing pediatric gene therapies requires navigating several challenges related to both the therapeutic area as well as the patient population. These include:

Open-label studies

For ethical reasons, these studies often have no placebo control, stressing the importance of control groups. Historic or contemporary control groups can be considered (e.g., patients who are declining participation in the gene therapy trial are followed per standard of care). A natural history study in early clinical development can also be considered, per FDA guidance.¹

Natural history studies can help explain the natural course of rare diseases substituting for the control arm of a study. Early regulatory advice and collaboration regarding choice of control group and the potential use of natural history data will be critical.

Enrolling vulnerable subjects

Traditional clinical trials are usually first conducted in less vulnerable populations before moving into pediatrics. As there might be no adult patients with the disease, these studies might enroll pediatric patients in the first-in-human study which raises ethical and safety concerns that need to be addressed.

Without an existing regulatory precedent, sponsors need to generate robust preclinical data and engage regulators, but also KOLs and patient organizations when creating their clinical development plan.

The benefit risk assessment is critical and needs to be carefully discussed with potential patients and families when seeking their consent for participation.

Different pediatric age groups often require different assessments in terms of the tools and questionnaires, which may also change during long-term follow-up (LTFU). Studies can also, for example, try to use as much standard of care sampling as possible for collecting safety samples.

Studying a gene therapy product

Because children are growing, it is important to choose the right vector. For example, nonintegrating vectors will only be expressed temporarily in dividing tissues, so the effect of the gene therapy will not be sustained over time. However, when only a temporary effect is desired, nonintegrating vectors would be good candidates to consider.

Currently, gene therapy repeat dosing is not possible due to the development of neutralizing antibodies to the vector. Research is ongoing to optimize vector design and to address the challenges of immunogenicity to the vector.

Gene therapy trials may require an invasive administration (e.g., intracerebral) of the investigational product, pre-treatment with immunosuppression, multiple assessments during visits and/or long hospital stays for treatment/post treatment. These factors should be considered when determining how to best support the patients and caregivers while reducing participation burden.

Incorporating a market access strategy

Early contact with stakeholders (e.g., payors, patient advocacy groups) can help understand interest in new therapies and guide sponsors to develop their early strategy.

Looking ahead to improve outcomes

Promising areas continue to advance gene therapies for children with rare diseases. Expanding newborn screening programs is critical for early diagnosis and treatment improving patient outcomes. An increasing number of highly complex gene therapy trials will involve very young pediatric patients, which could eventually lead to the possibility of fetal gene therapy. Finally, improvements in vectors, reducing immunogenicity, enhancing tissue specificity and less invasive procedures could support easier product administration.

---

Reference

1. U.S. Food and Drug Administration. Rare Diseases: Natural History Studies for Drug Development. Draft Guidance for Industry. March 2019. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/rare-diseases-natural-history-studies-drug-development

The Food and Drug Administration’s approval Dec. 8 of two gene therapies for sickle cell disease opens up their use by as many as 20,000 people in the U.S.

But in their first year on the market, and maybe for a year or two after that, physicians expect the uptake of the powerful, but complex treatments to be gradual at best.

“I think it'll be a slow ramp up,” said Akshay Sharma, a pediatric hematologist at St. Jude Children’s Research Hospital who was an investigator in testing. “Most of us clinicians are taking a very cautious approach, because many of us are looking for long-term data before we start saying, ‘Hey, everybody should get it.’”

The reasons are many. Fewer than 100 people received the therapies in clinical testing, the earliest treated of whom have now been followed for four or five years. While the data show dramatic benefit — treatment eliminated the pain crises associated with sickle cell — there are still outstanding questions on safety and on their use in sicker individuals, such as those who have a history of stroke.

The personalized treatments are also cumbersome to manufacture and require “conditioning” chemotherapy beforehand that carries risks of its own, particularly infertility. They’ll be among the most expensive medicines sold, too, priced at $3.1 million for Bluebird Bio’s Lyfgenia and $2.2 million for Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy. Working out payment and getting insurers onboard may take time.

"I anticipate very few patients that first year for both products, maybe for the first couple of years,” said Alexis Leonard, also a pediatric hematologist at St. Jude’s.

Who should receive gene therapy?

While sickle cell is considered a rare disease, it still affects an estimated 100,000 people in the U.S., a figure President Joe Biden cited in a statement hailing Lyfgenia and Casgevy as “major breakthroughs.”

The indications approved by the FDA — 12 years or older with recurrent sickle cell crises — significantly shrink the number of people who could receive treatment. Vertex estimates about 16,000 people will be eligible, while Bluebird believes that number to be higher than 20,000.

Notably, the FDA did not restrict use of either Lyfgenia or Casgevy in people who have matched stem cell donors, the only other curative therapy for the blood disease. (Regulators in the U.K., where Casgevy was approved weeks prior, chose to exclude these individuals from the drug’s approved labeling.)

People with matched stem cell donors were not enrolled in testing of either treatment, so insurers might balk at paying for gene therapy in these individuals.

“I don't know if I would be as enthusiastic in recommending this over a matched sibling donor transplant,” said Sharma. “But the label clearly doesn't say that.”

Physicians also expressed uncertainty about treating sickle cell patients with a history of stroke with either therapy. Bluebird did enroll five such people in its trial before changing its study criteria, while Vertex excluded them.

“Stroke is a major indication for transplant so that should change,” said John Tisdale, a branch chief at the National Institutes of Health who specializes in sickle cell research, at a Monday session during the American Society of Hematology’s annual meeting. “The companies have been reluctant to accept the risk of [central nervous system] bleeding while trying to figure out if the approach works.”

Vertex’s study also capped the age of participants at 35, meaning physicians wanting to prescribe Casgevy won’t have data on its use in older individuals with sickle cell, who may have more organ damage as a result of their disease. They may also be unable to tolerate the chemotherapy conditioning.

How quickly can centers get up to speed?

Initially, only a handful of treatment centers around the country will offer Casgevy or Lyfgenia.

Vertex will initially make its drug available at nine sites across six states and Washington, D.C., while Bluebird said Dec. 8 that 27 centers in 12 states are ready to receive patient referrals. Both companies envision a broader network, but discussions at ASH made clear that the process for onboarding new hospitals will take time.

“We got approval [Friday], but that doesn't mean that all these centers are ready to provide the therapy,” said Leonard, of St. Jude’s, who presented at ASH Dec. 9 on the topic. She noted a survey of 50 hospitals by the National Alliance of Sickle Cell Centers. Only 32 had participated in a gene therapy clinical trial, which Leonard described as an experience gap.

Prospective treating centers need comprehensive care teams that can include pain specialists, pulmonologists, infectious disease doctors and social workers. They also need access to a blood bank, space to draw and collect patient stem cells, cell processing facilities and fertility preservation services.

“The first step to getting these therapies is you have to be a qualified treatment center,” said Leonard. “We actually went to the Vertex and asked them, ‘What's your definition?’ And we got a very wishy-washy, no answer.”

In an email, a Vertex spokesperson said the company has been in “close dialogue” with all of its targeted authorized treatment centers. Many of these prefer to complete contracting discussions until after Casgevy’s approval, the spokesperson added.

Are there alternative treatments?

Matched bone marrow transplants can be a curative option for sickle cell. But only a small minority of patients, about 15% or so, have a donor who’s a suitable genetic match. Even then, the transplants still require patients to be healthy enough to undergo preconditioning with the toxic chemotherapy busulfan. 

Research presented at ASH Dec. 11 suggested haploidentical, or half-match, transplants could be used in more patients, and with a gentler conditioning regimen. Haploidentical transplants use stem cells from family members such as parents, aunts, uncles or cousins, greatly broadening the pool of people who may be donors for a person with sickle cell. 

The study, which was funded by the NIH, found that haploidentical transplants with a modified, less toxic regimen still led to good outcomes. 

Adetola Kassim, director of Vanderbilt University's adult sickle cell disease program and an investigator, described how the studied procedure boosted hemoglobin levels as well as gene therapy. He noted, too, that transplants are about one-fifth the cost of the new therapies. 

“The ideal curative therapy profile should offer protection from sickle cell related complications,” Kassim said during a Monday presentation at ASH. “[But] it also must be accessible and available to most patients.”

More broadly, researchers are looking at other ways to prepare patients for gene therapy, such as by using medicines known as antibody-drug conjugates for conditioning. Not only could these drugs be gentler on older people or those with organ damage, they could also preserve fertility. Further out, gene therapies involving an inside-the-body, or “in vivo” approach, could sidestep preconditioning altogether. 

Ultimately, gene therapy offers new promise for treating sickle cell, said Tisdale. The NIH scientist included in his presentation a nod to Rodrick Murray, an early volunteer to receive sickle cell gene therapy in the U.S. 

Murray was declared sickle cell-free two years after therapy, but died in 2020 from complications of leukemia he developed from preconditioning. The data recorded while tracking his treatment effects helped doctors adjust the treatment for later clinical trial participants.

“He told me he wanted to do this not for himself, but for other patients with sickle cell disease,” Tisdale said. “I was really happy to be in communication with his wife … on Friday to let her know he succeeded.”

The Food and Drug Administration on April 26 approved a new gene therapy for hemophilia, clearing Pfizer’s Beqvez for certain people with the less common “B” form of the bleeding condition.

Beqvez is for adults with moderate to severe hemophilia B who currently use drugs to prevent bleeds or have repeated, spontaneous bleeding. Eligible individuals also must be tested to determine whether they have antibodies that neutralize Beqvez’s effects.

Pfizer set the treatment’s list price at $3.5 million, a company spokesperson confirmed. That matches the cost of Hemgenix, the other available gene therapy for hemophilia B. Pfizer will offer insurers a warranty providing “financial protections” if Beqvez doesn’t work or its effects don’t last, the spokesperson wrote in an email, without providing details.

FDA approval of Beqvez was years in the making for Pfizer, which has sought to have a presence in gene therapy.

The treatment came to Pfizer through a licensing agreement with Spark Therapeutics — now a unit of Roche — a decade ago. It was one of several deals Pfizer struck to build a gene therapy portfolio, and is the first to yield a marketed product, with approvals in Canada and now the U.S. The company also has experimental therapies for Duchenne muscular dystrophy and hemophilia A in late-stage testing, although it sold off other earlier-stage projects to AstraZeneca.

“The road to this breakthrough has been a 40+ year effort in which we have worked to advance the hemophilia treatment paradigm,” wrote Mikael Dolsten, Pfizer’s top scientist and head of research and development, in a post on LinkedIn.

Beqvez arrives as existing hemophilia gene therapies have fallen short of expectations.

Last year, the FDA approved two other, similar treatments: CSL and UniQure’s Hemgenix, and BioMarin Pharmaceutical’s Roctavian for hemophilia A. Both were seen as would-be blockbuster medicines, showing in testing the ability to keep bleeding in check for years. They were also important test cases for the economic viability of gene therapies — pitched as long-lasting alternatives to existing treatments and financial bargains for the healthcare system despite their high prices.

Yet, at least so far, their adoption has been slow. Sales of Hemgenix haven’t been large enough for CSL to break out in investor presentations. Roctavian only generated $3.5 million in sales in 2023 and $800,000 in the first three months of 2024, causing BioMarin to weigh divesting the drug altogether. CEO Alexander Hardy cited the “complexity” of selling Roctavian, a multi-step process that requires a “motivated patient” as well as supportive insurers and physicians.

“The handwriting is on the wall regarding Roctavian,” Piper Sandler analyst Christopher Raymond wrote in a note earlier this week, calling the drug a “commercial flop.”

Developers have urged patience. On an earnings call in February, CSL executives claimed patient referrals have been accelerating and said the company is confident more people will receive its drug as a result. BioMarin hasn’t given up entirely either. On a Wednesday call with investors, Hardy said the company remains focused on understanding “what the Roctavian opportunity is.”

Aamir Malik, Pfizer’s chief U.S. commercial officer, said in a Friday statement that Pfizer will lean on its “more than 40 years of experience in the hemophilia space.”

The company is “proactively working with treatment centers, payers, and the hemophilia community to appropriately help ensure the healthcare system is prepared to readily deliver Beqvez to the patients who can benefit from it,” Malik said.

Beqvez is currently under review in Europe. Pfizer also has an antibody drug for hemophilia A and B that’s being evaluated by regulators in the U.S. and Europe.

Orchard Therapeutics said in late March it will offer a new gene therapy to children with a rare, devastating disease at a record-setting wholesale price of $4.25 million. 

The therapy, Lenmeldy, won Food and Drug Administration approval to treat patients with early-onset metachromatic leukodystrophy, or MLD. The disease, which most often attacks infants between six months and two years of age, robs patients of the ability to walk, talk and function in the world, killing most of its earliest victims within five years of onset.

Lenmeldy’s price tag will leapfrog those of the two most expensive gene therapies available in the U.S. CSL and UniQure’s hemophilia treatment Hemgenix costs $3.5 million, a price that Pfizer recently matched with its rival treatment Beqvez.

Gene therapy makers like Orchard are counting on insurers to recognize the value proposition of their products. Unlike traditional pharmaceuticals that might be taken regularly for the rest of a person’s life, gene therapies carry the promise of a long-lasting treatment that can alter the course of a disease and offer significant savings for the care needed to treat patients.

The argument doesn’t always work. Difficulty winning reimbursement forced gene therapy maker Bluebird bio to pull out of Europe in 2021. More recently, BioMarin has struggled with the launch of its hemophilia gene therapy, scaling back projections significantly. Orchard itself gave up on a gene therapy called Strimvelis in 2022.

But Orchard sees a different trajectory for Lenmeldy, in part because of its long-term data. Researchers have 12 years of follow-up on the earliest patients treated with Lenmeldy, the longest duration of any gene therapy launched in the U.S. Orchard also plans to develop outcomes- and value-based agreements designed to share risks with payers.

In studies, Orchard found that all patients with pre-symptomatic late infantile MLD treated with Lenmeldy were still alive at age six, compared with just 58% of such children historically. In addition, 71% of treated children could walk at age five without assistance and 85% had normal language and performance IQ scores. That has not been seen with untreated children.

“MLD places an enormous emotional and economic burden on families and caregivers – who face substantial wage loss and added expenses each year as the disease progresses – all while dealing with the unquantifiable anguish of losing their child,” Bennett Smith, Orchard’s senior vice president and general manager of North America, said in the company’s statement. Gene therapy can be “transformative,” he said.

In the March 20 release, Orchard highlighted the findings of the Institute for Clinical and Economic Review, which found that Lenmeldy had the highest value-based price of any treatment it has evaluated. Still, Orchard priced its therapy above the $2.3 million to $3.9 million cost-effectiveness threshold determined by that group.

Orchard, which was acquired by Kyowa Kirin this year, is setting up five treatment centers across the U.S. to administer Lenmeldy. The first, in Minnesota, is in the final stages of qualification and has already treated several children on a compassionate use basis. Four others, in Atlanta, Philadelphia, San Francisco and Texas, are in the process of qualification.

The U.S. government will test whether centrally coordinating insurance coverage can help people with sickle cell disease access expensive new gene therapies for the inherited blood condition.

Two such treatments were recently approved by the Food and Drug Administration after testing showed they can eliminate the crises of pain people with severe sickle cell often experience. However, they respectively cost $2.2 million and $3.1 million, raising alarm about their affordability and impact on the budgets of state Medicaid agencies, which cover an estimated 50% to 60% of people living with sickle cell in the U.S.

The Centers for Medicare and Medicaid Services, which oversees the Medicaid program, last year proposed a pilot “access model” for pricey cell and gene therapies. On Jan. 31, they confirmed sickle cell will be the pilot’s initial focus and released new details about how such a program will work.

Through the model, CMS will negotiate what’s known as an “outcomes-based agreement” that links payment for a drug to the health benefit it delivers. In sickle cell, for example, the targeted outcomes could be continued elimination of pain crises over time.These crises can require hospitalization and cause a constellation of other damaging symptoms.

If the targeted health benefit isn’t achieved, outcomes-based agreements typically require drugmakers to rebate or reimburse the insurer for some of the therapy’s cost.

These types of agreements are not new, nor is their application to gene therapies, which are often priced in the millions of dollars. But CMS’ model aims to coordinate the negotiation of a sickle cell-specific framework across many states, rather than each state agency negotiating their own.

This might help solve some of the resource constraints state agencies face implementing outcomes-based agreements, which require extensive collection of financial and clinical outcomes data.

“If each Medicaid program were to negotiate [coverage] independently, there would have been discrepancies in what different Medicaid programs would have paid for the same product, in turn resulting in differences in access,” said Akshay Sharma, a pediatric hematologist at St. Jude Children’s Research Hospital who helped run a trial of one of the new therapies, Vertex Pharmaceuticals’ Casgevy.

The model, Sharma added in an email, could also help establish “parity” in access across the country.

The framework established by CMS would include the target clinical outcome measure, pricing rebates and a standard coverage policy. States interested in participating could then opt into the negotiated terms, although they’d be responsible for their share of the therapies cost.

"By negotiating with manufacturers on behalf of states, CMS can ease the administrative burden on state Medicaid programs so they can focus on improving access and health outcomes for people with sickle cell disease,” said Liz Fowler, head of the CMS Innovation Center, in a statement.

CMS envisions the pilot program beginning in 2025, one year earlier than initially floated when the agency first announced its intention to create the model. It’s requesting interested states to submit a letter of intent by April, and for drugmakers to apply by May.

The implementation timeline could still create hurdles, as both Casgevy and Lyfgenia, the other sickle cell gene therapy approved by the FDA, are currently available in the U.S. CMS noted that, prior to the model’s launch, current Medicaid access policies will apply.

In a statement, a Vertex spokesperson said the company is “actively engaged” with CMS on the pilot, describing it as an “important tool to help address longstanding inequities in care by facilitating access and funding for potentially curative therapies for the sickle cell community.”

A spokesperson for Bluebird Bio, which sells Lyfgenia, said the company looks forward to working with the agency on the program. Bluebird is currently offering an outcomes-based agreement it created specifically for state Medicaid agencies. 

“Given the flexibility that exists for states today and the urgent need for those living with sickle cell disease, it’s imperative that states uphold their obligation to provide timely, equitable access to gene therapy for Medicaid patients beginning at FDA approval and not delay access to 2025 or beyond,” the spokesperson added in an email.

Notably, CMS also anticipates addressing other barriers to treatment with sickle cell gene therapies. Both Casgevy and Lyfgenia require a “preconditioning” chemotherapy before they are infused that comes with substantial risk of infertility. In testing, Vertex and Bluebird paid for fertility preservation services, like egg freezing, but are not currently able to do the same for patients covered by Medicaid.

Under the model, CMS would require manufacturers to include a “defined scope” of fertility preservation services for people receiving sickle cell gene therapy.

The agency also plans to offer optional funding to states that promote comprehensive sickle cell treatment, such as with behavioral health or care management services. Participation in the model is voluntary, CMS said.

Casgevy and Lyfgenia are both personalized cellular treatments, built from hematopoietic stem cells extracted from each patient. The cells are genetically engineered to effectively detour around the mutation that causes the disease’s characteristic red blood cell sickling. Casgevy does this via CRISPR gene editing, while Lyfgenia uses a benign virus to insert functional gene copies into the cells.

Once infused, the modified stem cells mature into red blood cells that are resistant to sickling, preventing the blockages that result when misshapen cells pile up in blood vessels.

Vertex, which partnered with CRISPR Therapeutics to develop Casgevy, set the cost of its treatment at $2.2 million, while Bluebird’s Lyfgenia costs $3.1 million. On a single-use basis, they are among the most expensive drugs available in the U.S. However, their developers argue the benefit they offer more than offsets the years of expensive medical care people with severe sickle cell would otherwise need.

Outside of Medicaid, commercial insurers are beginning to roll out their own policies. Some Blue Cross Blue Shield plans, for example, will cover both Lyfgenia and Casgevy.

Developing a new drug is a long, expensive process that comes with a high risk of failure, often because would-be medicines are unsafe or ineffective.

For companies specializing in cell or gene therapies, an equally pressing concern is figuring out how to reliably make their products. Unlike small molecule or antibody drugs, genetic medicines typically involve a variety of specialized parts woven together through a complex process.

"Ex vivo," or outside-the-body, treatments can involve a multi-week process for collecting, multiplying and modifying a patient's cells in a laboratory. Even the simpler "in vivo" therapies have multiple pieces, including engineered viruses and synthetic genetic material, that are challenging to produce at scale.

The approvals of a dozen cell- and gene-based medicines for cancer and inherited diseases in recent years has given young drugmakers a path to pursue. But most of those approvals were won by large pharmaceutical or biotechnology companies that invested heavily in manufacturing. Startups, by contrast, don't yet have that luxury.

Still, cell and gene therapy research is booming. More than 2,200 clinical trials testing these types of treatments were ongoing globally as of last year, according to the Alliance for Regenerative Medicine. The surge has often outstripped the capacity of large contract manufacturers, leaving startups facing waitlists that can stretch one to two years.

A growing group of new manufacturers aim to help. Since 2017, at least half a dozen companies have launched with plans to ease the "bottlenecks" slowing down aspiring cell and gene therapy developers. Many have been started by veterans of the young field and gotten the backing of top venture firms. Here's what they aim to accomplish and how their work is progressing:

What are the main bottlenecks in cell and gene therapy manufacturing?

Cell and gene therapies involve materials that aren't used in many of the other products the pharma industry is well-versed in producing.

Scientists design synthetic genetic material to deliver into patients, either via their own cells, benign viruses known as vectors or specially made bubbles of fat. Constructing these treatments is tricky even in a research setting, where small amounts of such material might be required for early experiments. But it's much harder for companies running clinical trials, or preparing for mass production.

Manufacturing delays can wreak havoc on young companies, causing them to miss milestones that could endanger future funding. Established gene therapy biotechs like UniQure or BioMarin Pharmaceuticals have spent years and millions of dollars to build their own plants. But startups and academic labs — where a number of the approved cell and gene therapies originated — can’t afford that.

“Academics have truly cutting-edge research, and I have been blown away by some of the creative ideas, novel modalities and breakthrough innovations that came about,” said Ran Zheng, the CEO of Landmark Bio, a Massachusetts-based company that caters to cell and gene therapy developers. “But that information needs to be translated into therapeutics, and this is the biggest, and probably the first, hurdle [startups] have to overcome.”

Turning to contract manufacturers like Thermo Fisher and Catalent can be a solution, but brings problems of its own. Transferring technology from a small lab to a larger organization can be arduous and require troubleshooting for glitches that arise in the process.

Big CDMOs may also prioritize more lucrative work with larger biotech and pharmaceutical firms. And they're struggling to meet the surging demand for cell and gene therapy manufacturing tools themselves.

Building up capabilities internally can be costly for startups. Viral vectors, for instance, are expensive to make and handle.

“You often see companies trying to own their own manufacturing and unfortunately, in this environment, if the product’s not successful, that's a heavy capital and operating expense to carry,” said Mike Paglia, a senior executive with ElevateBio, a richly funded startup that helps manufacture cell and gene therapies.

How are these startups trying to change that?

Rather than compete directly with larger CDMOs, some manufacturing startups aim to provide a more cost-efficient path for companies to develop in-house production capabilities. To appeal to younger biotechs that may need them, they are building relationships earlier and providing more services to attract first-time founders and small teams.

Many of these conversations take place long before an application to begin human testing, so these smaller manufacturers work to teach startups about raw material control strategies and set realistic timelines to gather early clinical data.

“Traditional CDMOs are like a kitchen, you'll give them a recipe and they make an entree,” said Zheng, who previously worked in manufacturing and operations at Orchard Therapeutics and Amgen. “That’s all they do. We're not like a kitchen where you just simply state the recipe. We actually ask our clients what ideas they have and we develop the recipe with them.”

Some clients start from near the beginning, working with these newer manufacturers from the moment they identify a lead candidate.

ElevateBio and Landmark Bio both help startups with laboratory studies to ensure that, down the line, they’re familiar with how to transfer their drugmaking technology to the companies that might eventually produce their therapies.

Paglia, who previously worked at Bluebird bio, said the biggest hurdle for him and his former colleagues was transferring their technology to contract manufacturers.

“Whether it was manufacturing our lentiviral vectors or cell therapy products, it took tremendous amounts of oversight to get those processes right because of the infancy of the industry,” he said.

Still, outsourcing to a dedicated manufacturer can save biotechs millions of dollars in the long term, Paglia said, allowing them to put that money toward additional clinical studies. That has meant steady demand for CDMOs, and created business for new startups trying to help.

Manufacturing startups have also attracted academics and nonprofits that struggled to get time with larger CDMOs. Landmark has worked with researchers who have received National Institutes of Health grants, for example.

Ultimately, improving manufacturing might give companies an opportunity to rethink how they price cell and gene therapies, which are some of the costliest medicines to make. The few companies that have reached market have noted these high costs in setting price tags that range from hundreds of thousands to millions of dollars.

Who are the startups in the space?

At least six biotech startups have launched since 2017 to address shortfalls in cell and gene therapy manufacturing.

The most richly funded, ElevateBio, has raised about $1.3 billion since it began working with drugmakers. It’s also spun out its own biotech startup with Boston Children’s Hospital to develop more convenient alternatives to current cancer cell therapies.

More recently, Ascend Cell & Gene Therapies in the U.K. emerged from stealth armed with $130 million in funding and led by industry veterans. It’s focused on adeno-associated viruses, a heavily used type of viral vector, and has acquired some of its capacity and technology from the struggling Freeline Therapeutics.

“AAV manufacturing is complex and needs teams that show real expertise and ownership,” said one of Ascend’s founding investors, Tim Funnell of Monograph Capital, in a statement on the company’s launch. “This led many advanced modality biotech developers to build their own internal CMC capabilities. However, these companies are now finding it difficult to sustain and fully utilize their facilities.”

There are smaller ventures, too. A pair of University of Pennsylvania researchers who worked on the cell therapy Kymriah and the gene therapies Zolgensma and Luxturna launched VintaBio in April. Months before in January, biotech startup creator Versant Ventures debuted Vector BioMed to help supply startups with the "lentiviral" vectors often used in ex vivo treatments.

What’s the status of their work?

With demand for more CDMOs at an all-time high, these startups are partnering with drugmakers straight out of the gate. Though many rely on capital infusions from venture firms, they also can generate cash from their work early on, bringing returns to investors well before a typical biotech might.

Landmark Bio had its first customer “even before we put a sign on the door,” Zheng said in October. In early June, it announced a partnership with InnDura, a new biotech company focused on “natural killer” cell research.

ElevateBio, having been around for some years, boasts a larger client list, noting in a May fundraising announcement that it added more than 15 new biopharmaceutical partners over the past year. Its subsidiary Life Edit Therapeutics is collaborating with large drugmakers like Novo Nordisk and Moderna.

VintaBio has a 22,500-square-foot facility in Philadelphia that’s now open for business, while Vector BioMed is working out of Gaithersburg, Maryland.

Shape Therapeutics is somewhat different, as it’s working on its own research, too. But it has also hinted at playing a manufacturing role, developing a new kind of cell line for producing adeno-associated viruses and indicating plans to build a factory where other companies can make their therapies.