Mapping The LNP Frontier: The Quest For Better LNPs
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
When I was in middle school, I had to make a globe for a school project. Now, before you visualize something remotely advanced, please note: This globe was constructed out of a single sheet of computer paper with all the continents printed on it (colored & labeled by yours truly) and a straw. This incredibly chintzy, not quite circular globe hung from the ceiling light in my childhood bedroom for years until recently when my mom gave it back to me. It is now sitting on top of a bookshelf in my living room. Little did I know that one day I’d be looking at that globe of the world and thinking about LNPs — all thanks to my recent conversation with Axelyf Co-Founder & CEO Örn Almarsson.
This is not to say that the current generation of LNPs on which we’re working are akin to an 8-year-old’s school project. As we’ve discussed on this site and in recent panel discussions, the past few years have been particularly dynamic for LNP development; it’s impossible to scroll through the LinkedIn newsfeed without coming across publications showcasing sophisticated new techniques for formulating, analyzing, and/or manufacturing LNPs. In fact, as Almarsson pointed out, it’s thanks to the growth in analytical techniques that we can get a much more sophisticated understanding of all the components decorating the surface of LNPs much like the continents, islands, and oceans decorate the globe.
Having previously served as the head of delivery sciences for Moderna pre-pandemic, Almarsson was part of the RNA-LNP delivery journey long before it was scientifically en vogue. That’s why I was excited to sit down with him to discuss the latest and greatest advancements in the RNA-LNP space. Here, we take stock of the developments he’s been watching in the passive and active delivery spaces. However, seeing as Almarsson is also a CEO, his observations move beyond the purely scientific, emphasizing the importance of having a solid commercial strategy underlying all the hard work we’re doing scientifically.
“We’re doing difficult work,” he said. “So, we might as well work on the hardest things that will also be the most societally impactful.”
From 2013 to Today: A Look At The LNP Journey
It’s hard to imagine a time when mRNA and LNPs weren’t household names. In fact, they often go together in my mind like peanut butter and jelly. Much like this timeless combination of flavors, it turns out that mRNA and LNPs have at least always been in each other’s orbits.
Back in 2013 when Almarsson joined Moderna, we were only at the start of thinking about mRNA delivery. Of course, it was widely acknowledged that mRNA required a delivery vehicle to survive in the body. There were a wide variety of options being explored to drive mRNA into cells — whether it be polymers or lipids or forces like electroporation. However, “When we ranked how well things worked in terms of delivery potency and tolerability for patients, LNPs were always coming in at the top,” Almarsson said — a fortuitous development that jived well with his background in small-molecule development and drug delivery. At the time, industry expertise deployed to mRNA was predominantly large-molecule oriented. As we now know, success in this industry demands expertise in both the small and large molecule worlds.
We’ve obviously come a long way from 2013. But to Almarsson, “We still have a long way to go with targeting RNA technologies and making these medicines more commercially viable. We’re still just at the beginning.”
This is why, throughout our conversation, Almarsson emphasized the importance of stepping back to evaluate what success — both scientifically and commercially — can and should look like for launching an mRNA-LNP-based product.
There are several ways we can interrogate our scientific progress to date. On the one hand, as he explained, we’ve gotten much better at analyzing our LNPs — referring me to two papers that recently caught his eye demonstrating our increased understanding of the surface and heterogeneity of our mRNA-LNPs. [“Study on molecular orientation & stratification in RNA-lipid nanoparticles by cryogenic orbitrap secondary ion mass spectrometry”, and “Single-particle multiparametric microscopy reveals structural size, and payload heterogeneity in mRNA-loaded LNPs”]
However, the characterization of our molecules is only one piece of the equation; there are still a number of questions around the impact of the in vivo environment on the LNP, as well.
For passive delivery, for example, “We’re asking, ‘How does the body modify this particle so that it can become targeted and/or reach the necessary cell type in vivo without the addition of active targeting moieties?” he explained. Though we may understand our LNPs physically (i.e., lipid ratios), we still need much more sophisticated analysis on what happens in vivo to continue to improve performance. “We don’t yet understand what is happening on the LNP’s journey to and into the destination cell type,” he added, giving credence to our industry’s long-held endosomal escape challenge, as well as lipid shedding and other factors involved in mRNA cargo release.
While we may have only just begun to scratch the surface of passive delivery, we’ve also started exploring how to make our LNPs even more complicated via targeted delivery strategies. We’ve already seen this strategy pay dividends (literally) with the high-profile acquisition of Capstan for its B-cell depletion and T-cell targeting capabilities. But to Almarsson, the active delivery “explosion” is yet to happen because there remains a diversity of untapped targets, particularly in the autoimmune and oncology realms today. Though CAR-T therapies are wondrous in many ways, it’s no secret that a majority of the ex vivo products and many in the first wave of in vivo products are targeting T cells and B cells and are limited to liquid tumors. However, there remains a whole cast of cellular “characters” to explore further, whether it be macrophages, monocytes, and/or dendritic cells. “We’ve started to address these different players in the cellular makeup of us,” he clarified, “but it’s really just the beginning.”
Stealth Delivery: Engineering LNPs to “Leave No Trace”
Regardless of whether we’re working on passive or active delivery strategies, there is one overarching development goal we do have: To increase the potency of our products without giving ground on tolerability, so we can ultimately reduce dose sizes and increase therapeutic margins. Almarsson used the metaphor of a delivery service to depict the challenge before us. In the therapeutic realm, we need our products to be the exact opposite of the Amazon delivery that rings the doorbell, leaves the package on the porch, and sends text messages/emails alerting about the delivery.
“Our products need to be small and stealthy,” he qualified. “They need to be like the delivery service that comes in your house undetected, unpacks the package quietly, sets the goods up properly, and then leaves, making sure the packaging disappears as well.”
Of course, part of being small and stealthy means having a product that is potent enough to maintain a favorable safety and tolerability profile, while using fewer particles. We’ve learned from both the AAV space and our still nascent LNP space that high doses can trigger the immune system. However, we’ve also seen that delivering the same higher dose over a longer period of time often gets around complement activation, suggesting that particle count in a given time frame plays a key role in a product’s tolerability profile.
“I go through this argument to emphasize that, if we can improve the potency and not give ground on the tolerability, we’re going to be dosing less and potentially solving for the sensitivities that exist in different patients,” he said. “Not to mention having lower doses is also good for reducing COGS, and we’re still struggling here today.”
The Commercial Reality: Meeting Payers & Physicians Where They Are
While we’re still very much in the early days of understanding our products biologically and therapeutically, I also greatly appreciated Almarsson’s necessary reminder that we not forget about the commercial realities that will one day be facing our mRNA-LNP products. Ensuring we’re picking the right indications has become an oft-professed best practice over the past few years. However, a successful commercial product goes far beyond good science and meeting unmet patient needs; it also means meeting physicians and payers where they are, as well.
Almarsson recounted a great example from his early years at Merck of what can happen when good science is not enough to guarantee the success of a therapy — observing first-hand Merck´s launch (the now hair-loss drug) finasteride into its original indication: Benign prostrate hypoplasia. Not only did payers prefer reimbursing the standard of care — a surgery — but urologists also benefited financially from the surgeries, a factor making them reticent to transition to a therapy.
“You can work on something that’s incredibly elegant, but if the treaters don’t want to use it and the payers don’t want to pay for it, you’ve created nothing useful yet,” he concluded. “You have to pick things that are important to do that are not being done well or have not yet been possible.”