Lipid nanoparticles (LNPs) have successfully entered the clinic to deliver messenger RNA (mRNA); in particular, LNP-based mRNA vaccines are now in clinical use against COVID-19. But, the buck doesn’t stop with SARS-CoV-2. Instead, it’s the springboard for delivering genetic medicines for much-needed clinical indications that cannot be fixed with traditional pharmaceuticals.

ReCode Therapeutics is an integrated genetic medicines company developing disease-modifying therapeutics using its powerful LNP delivery technology. The company’s pipeline includes lead programs for patients with life-limiting genetic respiratory diseases, including cystic fibrosis (CF) and primary ciliary dyskinesia. ReCode is leveraging its proprietary LNP platform and nucleic acid technologies and utilizing systemic and direct delivery for mRNA-mediated replacement and gene editing in target cells.

Recently, ReCode announced a new $80 million Series B round of financing co-led by Pfizer Ventures and EcoR1 Capital with participation from a syndicate of world-class life sciences investors. The company plans to advance its mRNA and gene correction therapies into the clinic for CF and primary ciliary dyskinesia.

This funding will also propel ReCode’s proprietary non-viral lipid nanoparticle (LNP) delivery platform to generate a deep pipeline of therapies that target the lung, liver, and other tissues and expand internal manufacturing capabilities to support research and clinical programs.

GEN Edge spoke with CEO & President David J. Lockhart, PhD, to discuss how ReCode came together as a merger between two companies and how they plan to harness LNPs for genetic medicines.

GEN Edge: David, how did ReCode come together?

Lockhart: Recode 2.0 was formed a year and a half ago. The new Recode was formed by merging the original ReCode—a small company out of Dallas—with a company in California called TranscripTx. TranscripTx was formed years earlier when the prominent biotech investor, OrbiMed, was interested in starting an  mRNA therapy company. It turns out it is an important area. They reached out to me, and together we started the company and began developing mRNA drugs for genetic respiratory diseases.

When we were at TranscripTx, we became experts on everything to do with the mRNA, the genetic respiratory diseases, and the animal and cell models. But we were buyers of LNPs. We tested LNPs from companies all over the world. That experience ended up serving us well because we were very familiar with what everybody else’s LNPs could do. Earlier at TranscripTx, we had licensed LNPs that we thought could be useful for our lead programs. And then about two years ago, we met the ReCode team out of Dallas, which was also pitching to venture capitalists to raise some more money, just like we were at TranscripTx.

We ended up pitching to some of the same people who knew what both of us were talking about. A couple of our investors called me, and we met with the Recode 1.0 folks. My initial reaction was that it was too good to be true. Their LNPs could do things that I didn’t think you could do! It became clear pretty quickly that the better idea, rather than having each of these companies go their own way and raise money independently, was for us to combine because both companies worked on genetic respiratory diseases like CF. The original ReCode 1.0 had a grant from the Cystic Fibrosis Foundation. TranscripTx worked on a related condition called primary ciliary dyskinesia, a disease with much overlap with CF.

We had a management team at TranscripTx that knew how to build companies, developed drugs before, and got them into the clinic and to approval. That wasn’t the case for the original ReCode. We also had a solid investor group who said this combined idea is compelling and that they would invest and bring in new investors, raise a lot, and build a bigger, better company.

We did the merger a year and a half ago. We raised $80 million for the Series A round for the new company. We had a great group of investors led by OrbiMed, one of the most well-known biotech investors. Then we brought in MPM Capital, Vida Ventures, Osage University Partners, and two investment groups—Colt Ventures and the Hunt Technology Ventures from Dallas, based on the connection with Dallas and UT Southwestern.

At that point, we had the whole story because we had the mRNAs, the lead programs, all the expertise for formulating and nebulizing LNPs for delivery directly into the lung. We now had our own internal world-class, world-leading LNP delivery platform. Importantly, the path into and through the clinic for these diseases is fairly well defined and consistent with our disease expertise. In addition to all of those things, we’ve also added complete gene correction using CRISPR to our toolbox. It’s gone from these two small companies trying to do some pretty targeted things to a company with many capabilities and an expansive vision.

We just raised another $80 million in our Series B round. That was a pretty good vision because we were able to raise even more investment from our previous group and, ultimately, bring in new high-profile investors like Pfizer Ventures, Sanofi Ventures, and EcoR1—a very well-known large biotech investment group.

GEN Edge: Was the delivery method that ReCode chose—LNPs—a founding idea for the company?

Lockhart: We decided early on that we didn’t want to deliver these things using viral vectors. We didn’t want to do that because we were keenly aware of some of the limitations of virus-based delivery. We chose the LNPs because they are a purely chemical approach. The components can be made with well-defined scalable chemistry. There are no peptide components, no viruses, and nothing that requires a bioreactor.

Over the last year and a half, we’ve made a lot of progress. We showed that certain things were possible. We did experiments in human cells, mice, dogs, and non-human primates. We’ve shown that these LNPs can be delivered not only directly into the blood, but they can also be nebulized and delivered directly into the airways if that’s relevant, as it is for diseases like CF and primary ciliary dyskinesia, where the target cells are the epithelial cells that line the conducting airways. It makes a lot of sense to deliver the mRNAs directly there. We did all of that, showed it was possible, and further optimized everything, which is great.

Alnylam opened this door; they had the first FDA-approved siRNA drug wrapped up in an LNP and delivered into the blood to get to the liver, where it’s needed for the amyloidosis disease they are going after. That experience certainly made people more comfortable with the idea of using LNPs as delivery agents.

GEN Edge: Was ReCode affected by the LNP-based mRNA vaccines for SARS-CoV-2?

Lockhart: With COVID, a billion-plus people have now been injected with at least one dose of an LNP-based vaccine. So, there’s even more reason to believe that LNPs can be used successfully and that they can go into the human body and be appropriately safe and well-tolerated.

Another thing that happened more recently was with Intellia. In the New England Journal of Medicine [in summer 2020], they showed that they have the first experimental [in vivo] drug ever, that I’m aware of, for doing CRISPR-based gene editing in patients. They only treated six patients. It wasn’t in the U.S.; it was in the U.K. and New Zealand, which are still sophisticated regulators, and they got the package approved to move forward in the clinic. They got the therapy into patients and showed that their LNP-formulated CRISPR components could be delivered into the body and do what they wanted them to do. So, along with the COVID mRNA vaccines and the siRNA drug from Alnylam, there are now multiple important examples of using LNPs to deliver different types of genetic medicines, not small molecules or proteins, but usually nucleic acids in some form or another.

When we were recently raising money and talking to people about doing mRNA drugs and gene correction using LNPs for delivery, they were more inclined to say it makes sense, instead of saying that’s too exotic or that it’s never going to work there. That we’re on the cutting edge, and on the right part at that edge.

In terms of Pfizer, those conversations were some of the most enjoyable pitches I’ve ever made because they already knew all the important things when we talked to them. We didn’t have to fill them in about LNPs or mRNAs. We could just say, look at the wonderful work we’ve done with mRNAs and LNPs, and what will be possible in the near future. Those pitches were fun because Pfizer had already gotten over significant hurdles regarding those types of therapies and delivery vehicles. They knew what the rest of the world could and couldn’t do.

GEN Edge: Is ReCode planning on creating the capabilities to manufacture these mRNA-based LNPs in-house?

Lockhart: Our vision of the company is a big one, involving multiple parts. One is we are developing new therapies—we’re not just a technology or platform company. We have what we believe is a really important LNP delivery platform that can do all the things I described. We are using that to build new therapies for people that need them. Part of us raising the $80 million is because of the capabilities of our unique and powerful delivery platform. We expect a significant amount of partnering and business development activity in our future to go after other diseases beyond CF and PCD.

But we’re not limiting ourselves to delivery to the lungs. We also want to develop our platform further to do other things like delivering specifically to the heart, kidney, muscle and brain. There’s a huge world of important things to do with our delivery platform that would be very important medically. Our goal beyond creating drugs is to develop the LNP platform even further. We intend then to use the power of the platform to build our pipeline of new therapies ourselves and also in partnership with other people.

Another part of our use-of-proceeds story is to build internal manufacturing capabilities. We’re confident that we can do that because we already make the needed parts. We make the mRNAs ourselves and do the chemistry on the LNPs. We buy the components that are available commercially, like cholesterol. And then we make the novel components of our LNPs, the ones that are not  commercially available. Then we scale everything up, make the payloads, design and produce the mRNAs, and do the final formulation of the LNPs that get delivered into the bodies of animals and eventually into patients’ bodies.

Currently, we make the materials on the research scale. Soon we’ll be moving into formal IND-enabling studies for the FDA, and there, the materials have to be made under Good Laboratory Practices (GLP). Initially, we’ll be working with contract research organizations (CROs) while in parallel, we build our own pilot-scale plant to do all of the manufacturing under GLP ourselves. This will set us up to build full-scale Good Manufacturing Practices (GMP) capabilities, to support everything we do from preclinical studies, clinical trials, partnering activities, and even launch and commercialization of new drugs.

GEN Edge: How does ReCode design and develop mRNA-based drugs?

Lockhart: Even back to the early stages of the company, we did a very rational job choosing the diseases to go after first. There’s minimal target risk. There’s no ambiguity about what causes CFor what mutations and genes cause primary ciliary dyskinesia and other genetic respiratory diseases. The inborn errors and the deficiencies that cause these diseases are clear. The biological functions that you have to correct is clear, and whether you’ve fixed it or not is generally very clear too.

Nobody’s been able to fix a lot of these problems. That’s why we’re developing these new drugs for people who really need them. I also like that we’re going after problems where protein therapy or small molecule therapy wasn’t a good way to fix them. But with the new types of genetic medicines, whether mRNA or gene correction, the solution to the problem is clear, and we can address these diseases in new ways that were not previously possible.

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