A year and a half into a collaboration with Biogen to develop CRISPR-based therapies, Scribe Therapeutics says the companies have made progress beyond the little they have announced publicly.
Scribe disclosed last week that Biogen had exercised an option for a second (unnamed) target through which they aim to treat disease. The first target is a genetic cause of amyotrophic lateral sclerosis (ALS).
Also undisclosed is how much more Biogen will pay Scribe if the second target leads to a successful therapy. The companies’ original collaboration, inked in October 2020, called for Biogen to pay Scribe $15 million upfront, and up to $400 million tied to achieving milestones. Back then, the companies said Biogen had an option for a second “neurological disease target with high unmet need.”
Headquartered in Alameda, CA, Scribe develops CRISPR-based treatments through its genetic modification platform, designed to build and apply its suite of CRISPR technologies in therapeutic areas that include neurodegenerative diseases; ophthalmological diseases; multi-system, muscle, and metabolic disorders; and hematopoietic disorders. That platform aims to address safety, delivery, poor editing outcomes, and the long-running bitter legal battle over who invented CRISPR-Cas9.
To avoid intellectual property uncertainty, Scribe has engineered its own CRISPR effectors—CasX enzymes—that are more capable of delivering CRISPR packaged in a viral vector because the protein is less than 1,000 amino acids (aa), compared with the 1,200–1,400-aa size of Cas9. Those “X-Editing” (XE) molecules are highly engineered CRISPR-based enzymes designed to provide combined aspects of greater efficacy, specificity, and deliverability than current CRISPR genome editing technologies.
Benjamin L. Oakes, PhD, Scribe’s Co-Founder, President and CEO, is among the company’s co-founders—a group that includes 2020 Nobel laureate Jennifer Doudna, PhD, of UC Berkeley. Oakes recently discussed the Biogen collaboration, and his company’s progress in developing its genome editing technology, in an exclusive interview with GEN Edge. (This interview has been lightly edited for length and clarity).
GEN Edge: Ben, why has Biogen agreed to develop this second target with Scribe?
Oakes: I think it’s predicated on the past year of work that we’ve done with them that has been quite successful in demonstrating the power of the technologies we’re building, both from a standpoint of using them in ways that I think no one else has really been able to utilize CRISPR technologies for, as well as demonstrating that what we believe internally is what other folks are seeing externally, in terms of actually having greater activity. We’re able to utilize these in vivo, demonstrating time and time again across models that these technologies are working well.
GEN Edge: What progress have Scribe and Biogen made since the launch of the collaboration?
Oakes: We’ve been focused on pushing forward and identifying ways using CRISPR tools to treat the underlying causes of disease. That first target is in ALS and we remain excited about pushing forward in that area. We’ve also been developing ways of using genome editing and additional genome modification technologies, as well as significantly improving delivery. In all those areas, the collaboration has been really fruitful. We’re excited about all the progress that has been made, even in just a very short time.
GEN Edge: Scribe’s areas of focus now include cell therapy, as in modifications to products that include CAR-T and NK and some other modalities. How is Scribe applying that? Is that to deliver the XE molecules or what?
Oakes: Yes, that’s a really interesting question. We at Scribe are not doing any cell therapy ourselves. We’re very focused on bringing genome editing in vivo. That said, our technologies, our molecules are exceptionally well suited. It’s like the challenge of in vivo cell editing, it’s just quite frankly much more difficult than doing genome editing in a dish. We’re optimizing technologies to be more active, more efficient, and that’s, for treating all of these in vivo disorders, but that makes them ideal molecules for use ex vivo as well.
So the question becomes, if we’re not doing them, how do we make sure that essentially the world can get access to them? We continue to maintain a real interest in finding the right partners to work with. We haven’t announced anything in that area yet, and I can’t promise that we will, but we’re always open to find the right teams that can have the same sort of deep scientific insight and mission that we have, to collaborate with in cell therapy.
All of the next generation approaches to cell therapy involve some form of genome editing, whether it’s removing receptors, knocking them out, or knocking things in or turning things up or tuning them down. We are excited about using our CRISPR technologies in that area as well. It’s just not something that we’re doing internally.
GEN Edge: Scribe focuses on CRISPR-based treatments developed through its own platform. How has that focus evolved in the past year?
Oakes: That’s a really good question, I think what we’ve seen is, in each quarter, the broader and broader applicability of our technology. In each of our target areas—CNS, ophtho, muscle, metabolic—we now have demonstrated the ability to edit those organ systems in vivo at a level that is more than sufficient to treat a number of diseases, that really is fit for purpose for a TPP [therapeutic product profile] of a particular type.
What that has allowed us to do is really think more broadly—from a platform standpoint—about exactly where we can apply the technology today, where we think it will expand into strategically, who are the right people to work with, and what are the additional technologies we need to be building to continue to broaden the use case for our core CRISPR enzymes. We’ve been seeing a lot of success in engineering and improving delivery technologies, and we’re expanding to include a couple of new styles of delivery at Scribe, nothing I can talk about more specifically yet. Hopefully in another six months we’ll have some more fruitful discussions there.
We’ve also been expanding well beyond just “genome editing” per se, but using CRISPR to modulate the genome in an additional ways—ways that I think have been shown before, but perhaps not nearly as effectively as what we are able to create.
GEN Edge: What is Scribe’s approach to genome editing? It appears to go beyond simply cut-and-splice.
Oakes: There are a number of additional technologies that folks have really started to show as possible once you have an RNA-guided DNA binding system: You have base editing —the ability to modify single nucleotides and change one into another; epigenetic modification—the ability to tune genes up or tune them down. You also then have things like HDR [homology directed repair] or prime editing, where you have the ability to cut and paste in.
At Scribe, we think of each one of those as just a piece of the pie, part of the puzzle. Each one is actually editing, it’s good at treating some specific diseases and, in fact, is the only way to treat some specific diseases. Base editing maybe is good at treating a smaller subset of diseases, but it’s still very good for treating those. Epigenetic modification is good at treating an entirely other subset of diseases.
At Scribe, we are building the complete package. That is our goal, and that is enabled by engineering. You just mentioned when we talked last that we created millions of enzymes, that we screen them. What’s so interesting is that we can do the same thing for each of those technologies as well, and we have begun to do so. And then, based on the particular therapeutic outcome we want, we can actually take that same diversity of molecules.
Let’s just start with the editor, for example. Rather than selecting it for the greatest activity with high specificity, select it for the greatest specificity, and actually we get different answers. And those answers we can then stack on, ratchet into the holistic X-Editor platform.
Since we last spoke, we’ve taken half-a-dozen additional steps in our enzyme—basically, moving that forward to even greater activity, greater specificity. That’s a process that we consider to be evergreen here, that allows our technologies to be the most broadly applicable out there.
GEN Edge: How have Scribe’s X-Editing molecules evolved since last year?
Oakes: We’ve continued to improve their ability to edit highly active and create more efficacious outcomes as well. It’s not just like, Do you have 80% or 90% editing activity? But it’s, What does that edit actually look like? Does it get you what you want to treat disease? If you treat some diseases, you may want to remove a certain number of base pairs, cause things like exon skipping, or double cut and remove a larger sequence, or actually knock something in. Each of those axes of activity can be engineered on and we may have a molecule that is really good at one but less good at another.
Likewise on specificity: Do you want additional specificity across the whole genome? Do you want additional specificity at a particular base pair in the guide RNA which is 20 nucleotides? Is there a particular base pair that has the ability to exquisitely determine an on-target versus an off target? What we have done is essentially continue to move through sequence space, take this enzyme, add additional changes to it, so that it continues to be better on all of those characteristics holistically.
We’ve also continued engineering other characteristics that rather than having a single enzyme that’s better for activity, better for specificity, and maintains that deliverability, might have slightly different aspects, so it might change its targeting range. The targeting range of A CRISPR enzyme is determined by its PAM [protospacer adjacent motif] interacting domain. The PAM interactive domain is the only hard-coded region of the CRISPR enzyme. It actually is what the enzyme uses to find a site of DNA and begin to unwind it, and that unwinding allows the guide RNA then to interrogate that site and say, do I match or not?
For example, with the original Cas9 molecule, that PAM was GG. Therefore, you could only bind very frequently, but you can only bind at sites that had GG in front of them. At Scribe, with the X-Editing platform, we’ve been broadening out the targeting range of our enzymes by essentially engineering PAM specificity. That allows us to exclusively position our genome editing tools to once again better create a more efficacious therapeutic outcome… so that a larger percentage of edits actually achieve what you want them to achieve from a therapeutic standpoint—removal of a toxic sequence or breaking a gene.
GEN Edge: Given how the markets have been since last year, when Scribe had just raised its $100 million Series B financing, was Scribe lucky to have raised the capital when you did? Or did you anticipate that the market would go downhill?
Oakes: Oh no. Could anyone have anticipated things were going to look this bleak?! Overall, we raised capital when we did because we had hit a number of critical milestones in terms of demonstrating the efficacy of our technology, signing up the right partners and getting the right pieces in place. We were fortunate to partner with the folks who we did when we raised that capital.
The markets are bleak right now, especially biotech. I think there is a real reckoning that’s happening more broadly with how a number of these companies have been created, and what is actually underpinning that valley. I don’t think that that is wrong at some level. I think that companies like Scribe are few and far between, where we’re actually building entirely new things that fundamentally can unlock access or unlock therapeutics that were not before possible, and make them safer, more effective. There was a lot of excitement in biotech, and there’s a lot of organizations that created companies. We’re now going to see the separation of who’s actually building something real and who’s not.
At the same time, it’s an interesting macro-development that I think is, apart from that, also somewhat unrelated: We’ve just had COVID. Biotech has never been more important than it was in the past two years. The fact that the broader markets look like this is surprising. I think it’s an over-correction in many ways, given just how impactful biotechnology has been. You see that on the balance sheets of many of the larger organizations that had real impact over the past two years.
We recently hired a CFO by the name of David Parrot, who has really been a fantastic addition, and is helping me and other folks at Scribe continue to grow the organization. We’re continuing to grow along a number of distinct lines in terms of manufacturing, as well as drug development. We’re still rapidly hiring.
GEN Edge: David was brought in, reportedly, to lead an IPO. In light of the market, the company has held off pursuing that offering. Is that still possible this year?
Oakes: I think that any biotech organization ultimately has to be public, and that is where essentially you can access the amount of capital necessary to develop drugs. We have a wide diversity of drugs available that we’re currently building. So, if we’re not just making a single antibody, like many other organizations out there, we will need to be able to access even greater streams of capital.
That said, we have no need of doing that right now. I think like everything we do at Scribe, our goal is to be intentional about it. It’s to make sure that everything is in place and set up so that when the opportunity presents itself, we can execute on it. It’s not in a way to rush towards an IPO. I think that has been one of the challenges with the market recently.
GEN Edge: What’s the current the headcount, and how much is that expected to grow this year?
Oakes: We’re about 60 people today. In terms of growth, we’re anticipating adding at least another 20 before the end of the year. Our total equity capital is just over $120 million.
GEN Edge: Is there any move to a Series C financing?
Oakes: We are always open to talking with organizations who share our engineering mission and the vision that the future of medicine can be different. I’d say yes, absolutely. But at the same time, there’s no need right now. We’re taking a really opportunistic approach to this. We feel comfortable with the place we’re in right now, from a cash burn and capital standpoint. But at the same time, we are always looking for the right partners.
When it comes to investors, we believe in the long-term vision that Scribe has and is continuing to develop: To build the entire technology suite that can modify the genome in any way, in the diverse variety of tissues that we want to target.