‘No tolerance for failure’: An oral history of the first CRISPR medicine

‘No tolerance for failure’: An oral history of the first CRISPR medicine

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.

CRISPR researcher Emmanuelle Charpentier stands in a laboratory at the Helmholtz Centre for Infection Research in Braunschweig, Germany, on May 19, 2015.

Peter Steffen/Picture-Alliance/DPA/AP

 

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.

CRISPR Therapeutics co-founder Rodger Novak stands for a photo.

CRISPR Therapeutics co-founder Rodger Novak

Permission granted by CRISPR Therapeutics

 

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.

A scientist at Vertex Pharmaceuticals works in a laboratory in San Diego, California, on March 4, 2015.

A scientist at Vertex Pharmaceuticals works in a laboratory in San Diego, California, in 2015.

Gregory Bull/AP

 

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.

Samarth Kulkarni and Bill Lundberg stand in front of a research poster at the American Society of Hematology’s annual meeting in 2016.

Sam Kulkarni, then CBO of CRISPR Therapeutics, and Bill Lundberg, formerly the company’s chief scientific officer, stand by a poster at the American Society of Hematology’s annual meeting in 2016.

CRISPR Therapeutics

 

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.

Samarth Kulkarni, CEO of CRISPR Therapeutics, speaks in front of employees at the opening of the company’s former office in Cambridge, Massachusetts in 2017.

Sam Kulkarni, CEO of CRISPR Therapeutics, speaks in front of employees at the opening of the company’s former office in Cambridge, Massachusetts in 2017.

CRISPR Therapeutics

 

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.

CRISPR Therapeutics CEO Sam Kulkarni stands for a photo

CRISPR Therapeutics CEO Sam Kulkarni

Permission granted by CRISPR Therapeutics

 

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.

Vertex Pharmaceuticals headquarters building in Boston, Massachusetts, on Sept. 21, 2017.

Vertex Pharmaceuticals headquarters building in Boston, Massachusetts, on Sept. 21, 2017.

Bill Sikes/AP

 

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.

Vertex Pharmaceuticals executive David Altshuler stands for a photo.

Vertex Pharmaceuticals’ Chief Scientific Officer David Altshuler

Permission granted by Vertex Pharmaceuticals

 

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.

Victoria Gray, the first person with sickle cell disease to receive Casgevy, speaks with her physician, Haydar Frangoul.

Victoria Gray, the first person with sickle cell disease to receive the therapy now approved as Casgevy, speaks to Haydar Frangoul, a hematologist and trial investigator

Victoria Gray

 

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.

Gene therapy researcher Kathy High stands for a photo

Researcher and CRISPR Therapeutics board member Katherine High

Permission granted by AskBio

 

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.

Crescent-shaped red blood cells from a person with sickle cell disease are viewed under a microscope in 1972.

Crescent-shaped red blood cells from a person with sickle cell disease are viewed under a microscope in 1972.

F. Gilbert/CDC/AP

 

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.

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.

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