Gene Editing: From CRISPR to Curative Medicine

Stephanie Sirota: Imagine a disease not caused by your environment or lifestyle, but something encoded in your DNA. A single typo, invisible to the naked eye, that affects the quality and length of your life. For decades, medicine could only manage the symptoms of these diseases, if that.

But advances in gene editing pave the way for something different, the ability in certain cases, to address the root cause of disease and to repair that error once and for all, where something microscopic might have a massive impact on the future of medicine.

Like any transformational technology, gene editing didn't arrive fully formed. These tools have evolved over decades. They were always elegant but are now becoming more precise. And it's shaping the next era of genetic medicine. Welcome to the RTW Podcast, where we aim to keep our audience healthy, wealthy, and wise. I have the privilege of speaking to top docs, CEOs, and thought leaders at the intersection of health, technology, and investments.

Today we're excited to welcome the CEO of a company leading the next generation of gene editing technology: John Evans, of Beam Therapeutics. John, thank you for joining us.

John Evans: Thanks for having me, Stephanie.

Gene Editing, Gene Therapy, Base and Prime Editing

Stephanie Sirota: Gene editing and gene therapy are terms that are thrown around a lot and have important distinctions. What are the differences between gene replacement therapy, gene editing, and then can you also go into base editing and prime editing?

John Evans: If you think about medicine over the last 100 years, it begins with small molecules. We had antibiotics, chemotherapy, and then the '70s, '80s, and '90s we had the more synthetically designed drugs.

The second big revolution was using proteins: the workhorses within the cell. And we learned to synthetically make them using recombinant DNA tools.

And this led to the launch of Genentech, Amgen, and many others in the '80s. Now, we have antibody therapeutics, we have enzyme replacement and the diversity of protein therapeutics continues to grow.

For the last couple of decades, we've seen a push towards a third category: genetic medicines.

Now you're using either the RNA or the DNA itself as part of your therapeutic. And that is going to be incredibly powerful, and incredibly programmable, because we know what these sequences do, and we can rewrite them and make them do certain things.

The ability to design your drug becomes more sophisticated. It opens up the possibility of a one-time cure. We can potentially just fix what's wrong at the root cause, the DNA level, and you never have the disease again.

That has gone in a couple of waves. The first wave was gene therapy.

I consider gene therapy mostly to still refer to viral types of mechanisms which can deliver some DNA into your cells that maybe you're missing. And that can compensate for a mutation that you might have.

It's not fixing the problem. It's helping supplement what is missing. The challenge has been viruses are complicated. They're hard to make. They're hard to control. They're not very programmable.

The next wave was always the idea, “Well, wouldn't it be nice if we could rewrite the problem where it exists?”

With gene editing, we're going to try to go into your genes, and make a very specific change in a very specific area of the body that can then permanently change the disease.

They did solve one important problem, which was, “How do I find one address within the genome, and target it?” The most famous, the winning way, has been CRISPR.

CRISPR allows you to very easily target a certain part of the genome, and then when you want to go to another part of the genome for new medicine, it's very easy to reprogram it to do that. So, the targeting precision of CRISPR is really unmatched.

The challenge has been: once you get to the target site, the only thing the original CRISPR could do is cut.

And then prime editing, which is a related technology we're using, as well as others, is designed to fix this second problem, which is once we get there, we want to make a precise change, we want to know the sequence that was there before, find a mutation, rewrite it back to normal, and then be done.

Now, I think for the first time, we're really getting to the point where this technology is mature to have that conversation about customizable, reproduceable genetic cures for mutations.

Where we know the tissue we're targeting, we know the mutation that's causing disease, and we have the technology to precisely rewrite it. That's the era that we are now in, and it's going to only accelerate from here.

Challenges in Gene Editing

Stephanie Sirota: Tell us about the limitations of the earlier gene editing approaches that pushed the field to keep evolving. What are the biggest challenges that you face today, even in this kind of next-gen editing?

John Evans: The challenge has been the original CRISPR. It's like having scissors. So, you just slice the DNA open, but you're not actually repairing it—the cell sort of puts the pieces back together again.

It turned out that was pretty good for scrambling the gene, and kind of turning something off, if it was causing a problem, but wasn't so good at rewriting or repairing.

Base editing, the initial technology that our company pioneered, can do single letter rewriting.

In the field of genetic disease, that turns out to be really useful, because about half of all mutations that cause disease are caused by single letter changes.

It's a single A that should be a G, or a single T that should be a C. And that's the only change we have to make. With prime editing, and related systems, we now have the ability to do short range rewriting.

Now we can tackle some of the other kinds of mutations that cause disease. Where do we go from here? We can't yet insert an entire gene, right? There's definitely efforts to expand the amount of genetic material we can insert into the genome safely.

These genetic tools, as they've gotten more sophisticated, they are also more challenging to get to the right cells in the body.

That is a limiter, as well. So, the second area that we're really focused on is delivery. Right now, we can get very reliably to the liver. There are lots of liver diseases or diseases that are mediated by the liver. So that is a big focus.

The blood, through either outside of the body or inside of the body, access is definitely there. Immune cells are there. But we're not yet at the place where I can get everywhere I want to go.

We really want to get to the brain, muscle, heart, lungs. The techniques to start to do that are starting to be clearer.

I actually expect there will be an inflection in the delivery technologies that are possible in coming years.

In Vivo and Ex Vivo

Stephanie Sirota: That's really important, because the field started with editing these genes outside of the body, ex vivo, and now we've made it possible to actually do this in vivo. What was the breakthrough that cracked the code to do it inside the body?

John Evans: There's been several breakthroughs. You know, one is doing it outside of the body, we call that ex vivo. It works really well.

You can take those cells, and you put the genetic editing machinery in there, make an edit, and put the cells back in. In blood, for instance, we do that in the context of a transplant. The challenge is simply that the cost of goods on that is very significant.

The transplant is very rigorous, and is tough for patients. The very sickest patients, that makes a lot of sense. There are efforts to make transplant and ex vivo approaches a lot more accessible. But in parallel, there's always the idea of, “Well, wouldn't it be nice to have a vector that will go inside the body, find the right place, and then get the stuff into the right cell?”

Instead of viral gene therapy delivering the gene, and trying to express it for the rest of your life, what if the virus could just deliver the gene editing equipment?

And express it for a few days, the edit gets made, now the DNA is fixed, and you've already fixed the problem. We did some of that.

You just still have the challenge that viruses are difficult to work with. We have really invested more in the lipid nanoparticles.

And this was pioneered most famously by Alnylam delivering short RNA oligos, and then by Moderna delivering longer mRNA in the context of vaccines and otherwise. Now we're using that same technology to try to deliver gene editing. And it works great.

It's well tolerated; it's a simple infusion in a couple of hours. Billions of people who have been dosed with these sorts of things, if you include the vaccines, and the many thousands by Alnylam in genetic medicine context, give us a lot of understanding that they can be quite reliable. We're looking at where you even have the ability to re-target these particles to go to other parts of the body.

And in vivo is literally a couple hour infusion, out-patient procedure, and off you go, and in a couple of days, when the editing is complete, you may be rid of your disease forever. Anytime you can do it in vivo, you would prefer to. I think ex vivo will be reserved for the more complicated, tricky types of things.

It is really the dream of medicine that we're finally starting to achieve here.

Stephanie Sirota: It is a dream, actually. Do you think about gene editing as a puzzle, more akin to traditional medicine, or is it an engineering problem?

John Evans: Why not both? It certainly is medicine. We have to think about the patients that are appropriate. We focus a lot on safety, dose, and efficacy. You have to do this carefully.

At the same time, I think unlike maybe the small molecule world, and the protein world, it is a lot more like engineering.

We can program in with a short RNA sequence, where the CRISPR will go.

And then the edit is very predictable. An A base editor's just going to find an A. It's going to turn to a G every time. It won't do anything to your other bases.

If it works, you can iterate on it. And then it should be applicable to all possible applications of that editor, and that's indeed what we see.

The same is true with delivery. Let's say a lipid nanoparticle can deliver our base editor to the liver once, and it did so safely and achieved its editing goals.

If I change the targeting element, so that now I have a new medicine, it's going to go to a different gene, and make a different edit, it's not going to change the way I manufacture that product. It's not going to change the way it's tolerated in preclinical studies or in people.

We add up a lot of little changes you end up with sort of an exponential curve.

What is A1AT Deficiency?

Stephanie Sirota: One of Beam's main focuses is A1AT deficiency, or Alpha-1 antitrypsin deficiency. At a patient level, what does living with that disease actually look like?

John Evans: When you get infected, your body mounts a very strong defense to fight off the germs. But that can have collateral damage. And particularly it can lead to lung tissue destruction.

And so, to stop that, we have this protein called Alpha-1 antitrypsin that blocks that. When you have this mutation, you're making an abnormal form of that protein, which isn't secreted as much to the blood stream.

So, your protection level is quite low. You get this gradual lung loss. You basically have emphysema (COPD). And it's progressive over time.

And it can ultimately lead to double lung failure and transplant. That mutant protein is getting stuck in the liver and causing toxicity there. You end up with progressive liver failure.

End stage disease, you can end up needing liver transplants. And there's no good options that can solve all of those issues.

About 100,000 patients in the U.S. have the severe form of this disease.

We then make a base editor just for that one mutation. And we can use that same base editor over and over again.

Stephanie Sirota: You've developed BEAM-302. In broad terms, how does this treat patients with Alpha-1?

John Evans: BEAM-302 is a base editor for that single letter misspelling, delivered in a lipid nanoparticle. It's a two-to-three hour drug infusion. Very simple.

And then the first place things go when they're in the blood stream is to the liver. So, we're trying to get to the hepatocytes: the metabolic production cells within your liver. Once we enter those, the editor goes to the nucleus, and it literally checks every base, every letter in the genome. It finds that one misspelling.

It makes an edit. And then all of this stuff washes away, within a couple of days, max, the change has been made to your DNA.

For a first product, that's really attractive. That change is in a gene for a protein that we have ubiquitous in our blood streams. It's constantly produced. And it's designed to protect you when you're sick.

With BEAM-302, if we can just fix that one letter that's wrong, you're going to start creating normal protein.

Your levels will be higher. Your lungs will be protected. Because we're fixing it in its normal location, the gene will turn on even more when you're sick, which is what it's supposed to do. And we stopped producing the mutant form of the protein, so your liver will get relief as well.

It will be a durable change for the life of the patient.

Stephanie Sirota: When do patients typically get diagnosed with this, and when does it start to impact a person's life?

John Evans: Your 30s, I think people start to notice a decline. Certainly, by the 40s, it starts to be more acute.

Diagnosis, unfortunately, trails that by quite a bit. Up to a decade.

There's a lot of patients who are currently undiagnosed, who are just in COPD clinics, and just have been lost to follow up. We've had patients find out they were Alpha-1, based on just the 23-and-Me test.

Stephanie Sirota: When you decide what disease you want to develop a drug for, do you think about diseases that have some kind of standard of care, or targeting diseases that have nothing?

John Evans: We have focused generally on the places where people are not very satisfied with those therapeutic options. They're not curative, they're still progressing. Sickle cell, Alpha-1 are both great examples of that, where there really is a desperate need for better options. Because then, you can bring something transformative to the table, which is going to be motivating for the patients, physicians, and regulators.

Stephanie Sirota: And for investors, too, by the way. (LAUGH)

John Evans: Well, exactly.

Gene editing also brings the one and done.

I think patients will ultimately still prefer that. I also think the health care system would prefer that, because a chronic medicine for life, if it's a branded specialty medicine, is quite expensive.

Stephanie Sirota: It will save the system a great deal of dollars down the road.

John Evans: Yes. It is a function of avoiding other expensive biotech and pharmaceutical products, health care expenses, hospitalizations and the constant crises that these patients go in and out of. But it's also a function of restoring someone to society. They can now get a job, have a family.

We're treating people in adulthood, or in childhood, and they're going to have a lot of years ahead that are really different if they can get this kind of cure.

All of that is value, ultimately, to the health care system, that's quite important, and underappreciated about this category. The moral imperative, the patient impact.

Stephanie Sirota: And the impact on the immediate family members and those who have to become the primary caregiver for the patient.

Safety in Gene Editing

Now, despite the incredible progress that has been made, what about some of the concerns around safety, especially around what is maybe relatively small, but exists nonetheless? The unintended genome editing, how do you approach the skepticism? How do you allay some of those fears? And is it different if you're talking to patients versus investors?

John Evans: With medicine you always start with safety first.

And then you ask the question of, "Have I delivered efficacy?" We have a lot of rigorous standards to apply.

The real answer to that is just going to be time and data. We're probably six or seven years into the first gene edited patients with CRISPR.

By the time we're reaching market with these drugs, those numbers are even higher. So, we'll have incredibly good long-term follow-up to convince people that this is generally safe and effective.

We have incredible science to show us what we're doing.

A small molecule that touches every single protein in your whole body is probably doing a lot of things that are hard to track and hard to assess. And you're taking it for life.

So, you have to worry about the chronic, ongoing pressure you're putting on some of those systems. With editing, you have basically 3 billion bases in your genome. It's a fraction of a thumb drive. And that's it. All we have to do is figure out, you know, are there any off-target edits of any kind?

What would be the consequence of that? We have assays that are biased and unbiased and go very, very deep. So, we learn every single possible change that could ever be seen.

It is an incredibly precise system. For the most part you see very little off-target effect. If you do see it, you then just want to make sure you've done your homework on it, right?

Your genome is actually not very static, I hate to tell you. It is changing all the time. You go out on the beach in the sun, you're picking up hundreds of genetic changes.

The kind of changes that we observe with gene editing are well below those sorts of things. More importantly it's very predictable.

Nothing would ever proceed if it was remotely close to being worrisome. Every gene editing program that you see in the clinic now has already passed those very rigorous filters.

I think this will go from serious genetic diseases to more common diseases to even disease prevention in the broader population.

AI and Beam Therapeutics

Stephanie Sirota: Disease prevention, that sounds great. I'm curious how you think about technology and data science and AI and whether you've incorporated better tech and more advanced and rigorous data analysis to help you make key decisions.

John Evans: Yes. We have a very sophisticated tech platform at Beam. We have an amazing computational biology team, as well as an automation and robotics team. I think both of those are going to be big trends in biotechnology for the future.

We generate vast amounts of data with every single experiment.

You can then start to apply AI to it to do machine learning on that data. That's proprietary insight. And we use that in the design loop as we make new gene editing systems, as we predict the possible profile of a new editor medicine, off-target biology, preparing regulatory filings.

I think that will only grow. All that said, there's a little bit of an enthusiasm for AI that gets a little beyond itself. I think we only understand 20% of biology, you know? It's awfully hard to build a world model to just sketch out the rest of the 80% and hope you're right.

AI needs to just be tightly integrated with a sophisticated wet lab environment. You're generating really good data. And yes, it runs through some AI and some computation. But then you're back to the lab to validate that. That's the loop that ends up being the most productive in biology.

Stephanie Sirota: Investors certainly are very excited about how AI is going to impact drug discovery and is it happening now.

Can we shift over to FDA? There have been challenges on rare disease and genetic medicines and some moving the goal post. How has your dialogue with FDA been throughout this period? What do you hope for going forward?

John Evans: Whenever you have an administration changeover, you always see a lot of change.

I think it's much more instructive to look at the things that didn't change. Because the things that didn't change show you there's a consensus behind the scenes among the parties. The direction of travel for the policy environment is moving in the direction to support what we're doing.

And I'm very, very excited about that. And this is bipartisan, right? So, a lot of these ideas started under Peter Marks, who served under Trump 1, he served under Biden.

What does this look like for medicines like ours?

I've shown you that I can edit a certain gene in the liver, in animals and then in people, and I've shown that that can be safe and manufactured effectively, and we understand the off-target profile.

There's a little bit that's different every time.

But most of it is not. This FDA, they understand that. And they say, "Yeah, yeah, no, maybe you shouldn't have to do the 95% again every time, right? You should just show me the 5% that's new."

Stephanie Sirota: Is that the biggest point that gives you more confidence today than you had five years ago?

John Evans: It does. If we didn't have that feature, we wouldn't be having any of these conversations for sure.

Stephanie Sirota: Because you would be starting from scratch every single time.

John Evans: That platform approach is really critical. So that'll allow us to go much faster and treat more diseases more quickly.

Maybe everybody doesn't have the same mutation, right? Maybe that's a mix of different editors for different mutations. And this starts to build even on some of the pioneering work that was recently done at the University of Pennsylvania in CHOP, the Children's Hospital of Philadelphia, where they took our technology: base editing.

And they did a custom editor for a baby. They knew it had a mutation that was going to be very life-threatening, a rare condition called urea cycle disorder. They were able to take a known lipid nanoparticle, a known base editor, design a custom guide RNA, and kind of moving mountains with the FDA, because this was still a little bit early. Some of these pathways were not in place.

They got the permission to treat the baby. And that baby is now, transformed—at home, learning, growing, developing—and has, at most, a mild form of that same condition.

So, it's really an unbelievable demonstration.

Stephanie Sirota: The story of the baby treated at University of Pennsylvania, CHOP, is remarkable.

The future is pretty bright. I'm curious if you think about competition. If you are first to the market, should anyone even try to target those same diseases? Should they go after other diseases? How do you see industry evolving?

John Evans: Long-term, I think we save the system money.

I feel really good about our pipeline being something that can lead to commercial sustainability in a meaningful amount of time.

Our initial indications are large enough. You know, sickle cell is 100,000 people. Alpha-1 is 100,000 people. PKU is 20,000 people.

You'll get to some peak revenue. You'll be there for a while. And then there's some tail.

These opportunities are plenty large enough that there will be some competition. May the best technology get to the most patients at the end of the day.

On competitive advantage: people get a little overly focused just on technology and miss the point that to build a leading gene editing company it's going to be a multi-factorial recipe.

So, you definitely need the best technology. You need the IP around that. You create a moat. You need a team that can go deep and continue to improve it and optimize these things.

We also need the delivery technologies. You need manufacturing. We built our own manufacturing facility in North Carolina.

You need capital. For better, for worse, it's expensive to do this still.

And then you need the best products. There are a reasonably small number of really attractive first opportunities. And that's kind of where we're pointing. And the choice that you make on constructing your pipeline and your portfolio will be quite significant.

Stephanie Sirota: Your company is just shy of $3 billion market cap. What does your runway look like?

John Evans: At the last report we had $1.25 billion in capital. We said runway was to mid 2029. So, you know, over three years of runway here.

We have BEAM-302, which is our lead program there. We announced that the FDA had aligned with us for an accelerated path to market based on the data that we've already shown, which is so exciting.

John Evans’ Journey into Biotech

Stephanie Sirota: Well, I certainly wish you all the success. I'm curious. You were an English major (LAUGH) at Yale.

John Evans: Yes, I was.

Stephanie Sirota: I was an English major at Columbia. So here we are talking about biotech. How did you find your way to Beam?

John Evans: I probably would have taken the LSAT and become a corporate lawyer like most of my friends. But I took the year off from school to do a cappella singing, which is a whole other story.

And I got a job to support myself in West Haven at Bayer Pharmaceuticals.

I gradually moved from big pharma to coming to Cambridge and working mostly on small molecules. And then shifting to this ‘genetic medicines’ side of things.

It's hard to make a biotech company. You've got to go a decade or more. You've got to defy the odds. You have to raise a lot of money and spend it. And somehow come up with a franchise that has commercial value that can be an incredibly valuable business.

You really want to stack the odds in your favor. And for me, that means highest possible probability of success. Get rid of risk wherever you can. And you want timelines that are going to be more accelerated.

There's a flywheel, where if we can take the risk out early, it stays out.

Stephanie Sirota: Now, challenges and setbacks make us stronger. What has been your biggest challenge as CEO?

John Evans: The balance between breadth and focus, right?

The unmet need out there is so great. We could make a big difference. At the same time, in biotech you really do need to focus on getting one flywheel running first before you're trying to spin ten of them.

Stephanie Sirota: Well, thank you so much. And I want to extend the invitation next time you are in New York. I didn't know that you are an a cappella singer. We at RTW get pretty competitive in karaoke. And so, you should really join us for one night. You're going to be on my team. (LAUGH)

John Evans: That would be great. I would be happy to do it.

Credits: The RTW podcast was produced and recorded by Devon Leaver at the RTW Headquarters in New York and edited by Dominique Guerra, with Production Coordinator, YingYu Lin, and production support by Annabelle Chan. Executive Editorial Advisor was our Partner, Chief Business Officer Stephanie Sirota, and our Research Consultant was Managing Director and Research Analyst, Piratip Pratumsuwan.

This interview was given by John Evans, CEO of Beam Therapeutics, and moderated by Stephanie Sirota, Partner and Chief Business Officer at RTW Investments. 

Statements reflect RTW's views and opinions as of the date hereof and not as of any future date. All expressions of opinion are subject to change without notice and are not intended to be a forecast of future events or results.

The views expressed by guests are their own and their appearance on the program does not imply an endorsement of them or any entity they represent.