Is This The Hardest Question Facing mRNA Therapeutics Makers?
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
“We can do anything we set our mind to.”
“Reach for the stars.”
“Think bigger.”
There are a lot of inspirational statements we can apply to the work we do in pharma. It’s thanks to peoples’ adherence to such motivational wisdom that we even have the medicines we do today — including the mRNA COVID vaccines. I continue to see this ambitious mindset embraced in the ever-evolving mRNA space. In fact, I once heard someone make the quite powerful argument that we shouldn’t be afraid to shatter current business models with our mRNA products’ successes. Whether that be developing better vaccines more efficiently with mRNA technology, making in vivo cell therapies a reality, offering a competitive, redosable alternative to current viral vector-based CGTs, or encoding antibodies in vivo, we are positively buoyant with opportunity today.
But I’ve also started to hear some equally important reminders to keep our eyes on the practicalities of the commercial market awaiting us/our products at the “other end.” Though these early days of our industry should be dedicated to “reaching for the stars” scientifically, it’s also equally important that we diligently assess how our potential products could go on to be received by our patient populations and compete within the broader biologics space. As I’ve been reminded on a few different occasions, there is a difficult truth we may need to wrap our brains around in certain situations: Just because we can make an mRNA therapy for an indication, doesn’t necessary mean we should — or that the patient population will necessarily want it or be able to access it.
There have been a few market examples and conversations over the past year that emphasize the importance of this practical “mantra” for our space. In past articles, I’ve argued that we should pay attention to the lessons learned from other ATMP products — and Roctavian (an AAV gene therapy in hemophilia A) is a timely example. Just this month, the company announced it would be revising its commercial strategy, after having previously admitted that “a motivated patient, a supportive payer, and a treatment site with a physician who is willing and able to use the product” have been three hard-to-secure factors in an indication with multiple well-established standards of care.
Likewise, as young a space as we may be, the mRNA vaccine sector already has a great case study of the commercial challenges in launching a novel technology against one existing (albeit still quite young) “standard of care.” Moderna’s launch of its RSV vaccine earlier this year was rightfully met with great celebration, especially given its comparable efficacy profile in clinical trials to GSK and Pfizer’s vaccines. However, as recently as the end of June, the vaccine’s 18-month durability/efficacy slipped below that of its non-RNA competitors.
To be fair, GSK’s vaccine is hardly a commercially mature standard of care, having only been approved a year prior to both Moderna’s and Pfizer’s vaccines. As we are still very early in assessing mRNA’s clinical profile, Moderna’s (albeit less rosy) RSV experience still gives us some much-needed data points on the possibilities and (current) clinical limitations of mRNA when up against existing vaccine/therapeutic technologies — mRNA’s more efficient cell-free manufacturing paradigm aside.
However, what these commercial examples both go to show is that uptake of a therapy can be an infuriatingly nuanced exercise — one that is informed by the (often misaligned and unpredictable) motivations of more stakeholders than we can count. But it’s important we keep these commercial complexities in mind as we weigh the indications and opportunities in which our mRNA products will truly have an opportunity to shine and make a difference. The success of certain mRNA therapies (and/or our ability to shatter current business models) will require the perfect marriage between CMC efficiencies/advantages and significant clinical improvement — particularly if we’re striving to compete in areas with current standards of care.
I often find myself returning to what one speaker said during an mRNA-focused panel from the last Alliance for Regenerative Medicines Meeting on the Mesa. As we weigh certain applications of mRNA, for example, in vivo antibody replacement, it’s important we recognize that “the value of mRNA needs to be significantly higher both from a clinical development perspective and from a CMC standpoint” to enable “wholesale changes” in treatment and manufacturing paradigms, the speaker explained.
“The use case must really be stellar, where you’re conferring an advantage in the clinical development setting. It’s not just developing another mAb against PD1 for the sake of developing it, but can you improve the therapeutic index? Can you improve the safety profile? From a translational perspective, though mRNA is easier to potentially scale, companies have invested billions in protein manufacturing architecture, and it’s a clear path to enabling approval. Outside of COVID, if there’s no clarity to that regulatory approval pathway, I don’t think companies will invest in the wholesale changes required to pursue some of these applications for mRNA.”
I’ll be the first to acknowledge it’s hard to know the true limits of mRNA/RNA technology today as we’re working to rapidly improve our drug cargos and delivery vehicles to make our products incrementally better. Identifying our space’s CMC and clinical potential will not happen overnight. Likewise, many of us with therapeutic dreams have yet to move beyond animal models — a reality which, as I described in a recent article, leaves much to be desired in predicting human clinical responses. Which is why, as I see it, one of biggest challenges facing the industry in the years ahead will not only be figuring out what an mRNA therapeutic is clinically, but it will be asking — let alone answering — the question of why and when it should/must be an mRNA therapeutic.