Lessons From The Past: How mRNA Can Thrive In The Evolving ATMP Market
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
As I’ve prefaced in a handful of articles, there are many reasons we’re simultaneously living in “the best of times and the worst of times” in the ATMP space. To be sure, the financial landscape is improving day by day, and we continue to see more clinical advancements, positive data, and regulatory approvals. However, as we’ve been reminded from the beginning, getting our products into and through the clinic is only one part of the battle; getting a product through the clinic is far from demonstrative or instructive on the realities of the commercial market. And, as we’ve started to encounter lately, the commercial market has not exactly been kind to recent CGT launches.
This odd Dickensian “best of times, worst of times” dynamic was clearly reflected throughout a handful of presentations from the AGC Biologics CDMO Summit a few weeks ago in Milan. In my first recap from the CDMO Summit, I shared a few updates — predominantly positive — on the state of the financial sector undergirding CGT development today. However, we can’t overlook how a handful of less-than-rosy commercial launches have impacted funding dynamics and dimmed some (though certainly not all) hopes that the sector will, one day, affordably meet the needs of more patients and/or larger patient populations.
As more ATMPs approach or somersault onto the market, we’re increasingly challenged to shift our narratives from the “how” of our product’s therapeutic mechanisms/promises to the “why” and “when” of our therapies for governments, payers, physicians, and patients — especially in situations where there are already established standards of care.
As I’ve argued before, answering “why” and “when” it must be an mRNA therapeutic will be some of the most important questions we answer in the upcoming years as more products enter the clinic. Fortunately, as multiple presenters during the AGC CDMO Summit explained, there have been a few historical case studies of how the industries preceding us — namely the mAb and gene therapy space — did (or didn’t quite) do the due-diligence they should have to trigger meaningful societal change (e.g., improved prescribing practices and reimbursement reform). Not only do these case studies provide a few tactical pointers for those of us in the mRNA/RNA therapeutics space, I also think they can be particularly instructive in helping us craft/finetune mRNA’s value proposition.
“Beginning With The End In Mind” for mRNA Therapies: A Two-Pronged Approach
In the nascent stages of a new therapeutic modality market, it’s not unusual to lose sight of two important “long games:” Commercial manufacturing and policy. In the ATMP space, we’ve certainly become more invested in “beginning with the end in mind” as it relates to our manufacturing, thanks to the regulatory CMC hangups we encountered early on. (To be clear, we still have a long way to go…) However, now that we’re starting to see more commercial launches — and sluggish ones — it would make sense our conversations are starting to shift toward how to better prepare the commercial markets for our therapies. And, as Anthony Davies of Dark Horse Consulting shared at the CDMO Summit, the launch of Roctavian, an AAV5 gene therapy for Hemophilia A, offers us a rich assortment of cautionary tales we should hope to avoid with our own therapies. But there were two points Davies made that I thought were worth reiterating for those of us in mRNA space.
First, I was struck by patients’ concerns about Roctavian’s durability and the (current) inability to redose. In the mRNA space, we’re no stranger to patient reticence, thanks to the wealth of misinformation and conspiracy theories that proliferated during the pandemic. Of course, our reticence in the mRNA field is blossoming from an entirely different root than that of AAV; after all, unlike AAV, mRNA is transient and offers us the ability to redose.
It’s this point that I think is important to reemphasize here; though the concept of one and done has been shiny in years’ past, conversations from Advanced Therapies Week this past January provided some important reminders of the benefits chronically dosed products offer patients — especially given that appetites for risk can vary dramatically within a single patient population. Yes, we have a long way to go to improve the overall durability of our mRNA therapies to limit the amount of redosing necessary. But the ability to redose remains an important part of mRNA’s value proposition — particularly in a reimbursement landscape that has yet to figure out how to tackle the high costs of one-and-done therapies.
On the flip side of this, however, being a chronically dosed therapy — and one that has a potentially high price tag, as some of our mRNA therapies may require — comes with its own hurdles on the patient and the payer front. It’s important we not (at least initially) overestimate two factors: 1., Patients’ willingness to transition from a familiar/currently effective and reimbursed standard of care, and 2., payers’ willingness to put our mRNA therapies on one of the “earlier/lower” steps of a step therapy program — let alone to cover it at all.
Understanding our patient populations’ overall need/appetite for an alternative treatment, as well as their overall journey toward and relationship with current standards of care, will be critical to successfully communicating the “why and when” of an mRNA therapy to both patients and payers. Likewise, there is no one-size-fits-all approach for payers and/or provider practices, and as Davies reminded us, two to three claims for some of the marketed ATMPs today historically have caused serious cash flow problems for smaller payers and, in some cases, left provider practices hurting as they waited for reimbursement.
Secondly, as multiple speakers — but Davies in particular — emphasized throughout the CDMO Summit, we’re at a complicated time in the CGT space overall. Our cell and gene therapies (including some mRNA therapies) have the potential to make a meaningful impact in small patient populations — and to be sure, some already are, albeit in smaller segments of already small populations. But as Davies argued, the real turn-around for the ATMP space (i.e., our emergence from the Gartner Hype Cycle’s “trough of disillusionment”) will — as hard as it may be to read/hear — hinge upon a crisis. And that crisis will be “the arrival of a transformational drug addressing a large patient population that we are unable to afford because the drug costs too much to make.” In fact, we saw such dynamics in the biologics space with the arrival of the now-blockbuster Herceptin. Despite the game-changing clinical results of Herceptin upon approval, patient access to this life-saving drug was severely limited by manufacturing problems — a problem that Genentech “fixed” using “good, old-fashioned manufacturing sciences” (i.e., think stacking its process science department with 400-plus people), Davies added.
Once again, I see Davies’ history lesson/predictions illuminating where mRNA has a chance to excel (i.e., manufacturing efficiency/scalability to reach larger patient populations). But how revolutionary our mRNA therapies will be hinges upon how well we fight the good “process development fight” in these early days to achieve greater time/cost efficiencies in the future.
Given the current diversity of therapeutic approaches in the mRNA space, there will be no “one-size-fits-all” approach to commercialization for mRNA-based products — be it a CRISPR therapy, a cancer vaccine, or a protein replacement product. Each will undoubtedly have different pricing, administration, and reimbursement needs/considerations. But if we’ve learned anything from the ATMPs and mAbs that have come before us, it’s that understanding the clinical and economic environments into which we’re launching our drug products is king. And if we want our products to be the answer for as many patients as possible, we must put our best foot (or feet) forward from a production and COGS standpoint.