The RNA Ties That Bind: 3 Takeaways From The OPT Congress
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
Two years and some months ago, I started covering the RNA sector here on Advancing RNA. However, those of you who have been regular readers will know that there is a slight mistruth to this statement; I spent the first two years delving into the nuances of the “new(ish) nucleic acid on the block” — mRNA and its next-gen siblings — while leaving the noncoding sector largely overlooked (but still fabulous). But those of you who know me should also know that I will never shy away from a challenge, and I obviously couldn’t stay away from the oligo sector forever.
Fast forward to this past month (mid-March): I got the chance to attend the OPT Congress in Boston, at which I spent most of my time “haunting” the oligo CMC and manufacturing track. Throughout the two days, I was met with several fantastic discussions on the challenges of implementing novel manufacturing paradigms (i.e., enzymatic ligation); the difficulties of obtaining global regulatory approval for oligos; and the steps towards establishing process control strategies.
On the surface, there are some big differences between the mRNA and ASO/siRNA worlds — the manufacturing and regulatory paradigms being the most noticeable/significant. But what struck me as I sat through each presentation was how familiar everything felt. Though the oligo space boasts a more mature commercial landscape than mRNA and certain ATMPs, it’s not immune to many of the same CMC and commercial challenges/questions impacting mRNA/ATMP products.
Here, I unpack three takeaways I had from the OPT Congress, each of which I’d argue are indicative of the interconnectedness across the genetic medicines field.
“Why RNA?” Remains a Question, Even Post-Commercialization
Over the past few years, I’ve written articles emphasizing how important it will be for the mRNA field to answer the question, “Why mRNA?”— an answer which continues to be held at bay until more of our therapeutic products are in the clinic providing us with much-needed clinical efficacy data.
Meanwhile, the oligo space has been holding strong at upwards of 20 approved siRNA and ASO products. We understand more clearly (to some extent) their regulatory journey and what they have to offer clinically. In turn, we could argue that we know the answer of “Why RNA?” in the context of an oligo therapeutic — a point that was nicely substantiated by Sebastian Trousil, Co-Founder & COO of City Therapeutics:
“Look at the antibody field where we now look at differentiation of the clinical data and not necessarily how the molecule was created or which company it came from. Even though those latter aspects are important, we still always come back to the clinical data of the molecule today in the oligo field. In some ways, I think that's exciting because it shows that some of the oligo modalities are really maturing in that sense.”
But the oligo space in its clinical maturity also nicely demonstrates that the “Why RNA?” question will live on and continue to evolve long after we cross the commercialization finish line. Afterall, as drug developers, we are only capable of answering the clinical half of the question, “Why RNA?” Physicians and patients (and yes, don’t forget the payers!) will also be key in answering this question. In fact, if there’s one other marker of maturity in the RNA space I’d call out, it’s going to be our ability to view our RNA therapies in the context of a much broader toolbox the way physicians/patients/payers will be approaching our products: As one option (hopefully) amongst many. As Sepp-Lorenzino nicely articulated:
“There isn’t a single modality that's going to override the whole therapeutic space. We're increasing the number of options. So, think of a toolbox — a therapeutic toolbox — that will enable the physician and the patient to decide which modality is going to be the most appropriate for a particular genetic disease driver and which will also offer them the flexibility to choose whether they want a chronic therapy or a ‘one and done’ option, and/or perhaps a route of administration that will be less intrusive than others.”
Approved Oligo Products ≠ Easy Analytical Development
Overall, the OPT Congress was a great reminder that, regardless of how many molecules may be on the market, analytical development remains complicated. This is exceptionally true in the oligo space, which is striving to find its CMC identity while facing a general lack of oligo-specific guidance. (In many cases today, we’re relying a lot on the “spirit” of certain guidances/guidelines to carry us across the finish-line.) The difficulties we still face became quite clear during a preconference short course on the successful late-stage regulatory submission for a complex oligo, during which analytical development received a great deal of attention.
Throughout the presentation, both speakers — consultants Mike Webb and Chris Oswald — emphasized the importance of staying on our toes analytically, so to speak, especially if we are striving to rely on platform methods. As consultant Mike Webb explained, there are a lot of factors that complicate our analytical development — whether it be the complexity/heterogeneity of the molecule itself; closely related impurities; the current lack of standards; and/or future innovations in analytical technologies that may boast greater sensitivity/resolution. In fact, the growth of the market not only gives us more clarity on the structure/function/clinical benefits of our oligos, but it also opens the door for greater analytical technology innovations.
“Once we get more oligos out on the market, I fully anticipate that there's going to be some technological advances,” said Webb. “So, you want to be prepared for those. How is that going to affect your molecule? Are you going to get better resolution? Do you need to come back and revisit some of your process characterization based on different sensitivities?”
Though we may have a leg up on the small molecule sector in terms of the amount of platform data for oligos we do have today, Oswald reminded us that our data — especially around process related impurities — is only as good as the analytical method itself. This is exceptionally important for companies approaching the finish line with one molecule that are looking to rely on a platform method for another earlier-stage product.
“The number that you're presenting is only as good as the analytical technique,” he said. “So just remember that if you're going to be presenting a number to the regulators, make sure that you're confident in that number and that it's resolving the impurities.”
Regulatory Scientific Alignment Remains A Challenge
Scientific alignment across regulatory agencies has always been a big topic of conversation in every pharma sector I’ve covered — be it biosimilars, CGTs, or mRNA therapies. As such, it was hardly a surprise to learn that getting an oligo approved by different regulatory agencies is not always a straightforward effort. In fact, as Stephanie Nelson of Ionis Pharmaceuticals emphasized in her presentation, “The queries that we received on drug substance manufacturing, as well as specs, can be challenging to address, sometimes requiring detailed justifications in the responses, provision of additional data, and updated CTD sections.”
For example, the company had to update its MAA filing for Europe to incorporate more information to justify the use of galNAc as a starting material — including more information on the process understanding and impurities of the galNAc conjugate. The company also supplied more information around drug product stability (i.e., additional data demonstrating 18-month vs. 12-month stability and a longer shelf life of 36 months vs. 30 months); and added an EU-based secondary packaging and labeling and release testing site.
As Nelson went on to offer, leveraging previous regulatory approvals is a helpful strategy for resolving issues that can arise with other regulatory agencies. Likewise, Nelson emphasized the role that platform data/prior knowledge can and did play in easing the regulatory submission and justification process. However, as we’ve seen before across the ATMP space, the concept of “platform” remains controversial across regulators. Though the US, Canada, and TGA didn’t bat an eye, so to speak, at the concept of “platforming,” the EMA once more emphasized that “platform technology” is not part of the EU legal framework.
“They asked us to present comprehensive justification for the approach with a clear definition of what constitutes a platform in terms of structure, synthesis, and control,” Nelson qualified. “They asked us to present information on all the batches that we had included and considered as ‘platform’ batches, and they asked us to expand the discussion in P2 to include more detailed info.”
Switzerland was also not keen on the concept of platforming for drug substance characterization and setting specs, articulating that it was “too early” to apply such a concept, asking Ionis to “clearly describe differences and similarities between the ASOs… used as part of our platform data.”
If there was one clear-cut takeaway we can glean from this example moving forward, it’s that the use of the term “prior knowledge” is a much safer bet when working with global regulators.