Learning From Oligos: Delivery & Clinical Strategies For mRNA Therapeutics

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

Admittedly, as the editorial director of Advancing RNA, I have been quite remiss in my coverage of an equally important part of our industry: The oligonucleotide sector.

In all fairness, learning the nuances of one manufacturing paradigm and regulatory paradigm has been more than enough for my poet brain to handle. But given the overall growth and ongoing commercial success of the oligo space, it’s becoming more difficult to justify this distinct gap in my editorial coverage — “poetry brain” or otherwise.

Obviously, there are distinct differences between encoding and noncoding therapeutics from a manufacturing, regulatory, and functionality standpoint. However, as numerous of my past editorials have revealed, I’m a sucker for comparing different industry sectors and identifying learnings that can be carried across modalities. Considering that the noncoding half of our industry currently boasts more clinical, regulatory, and commercial maturity than the encoding sector, the oligo sector is in a great position to teach its cousin industry — the mRNA industry—some tricks of its therapeutic trade.

Fortunately, those of us who attended the Alliance for mRNA Medicines’ inaugural Ascent conference last fall had the opportunity to hear from Zdravka Medarova of TransCode Therapeutics on her experiences working in the oligo sector. Here, I summarize some of her learnings and/or suggestions for the encoding RNA field as we set out to develop mRNA therapeutics for oncology.

Delivery: It’s About The Destination AND The Journey

In our line of work, conversations about delivery are, broadly speaking, often limited to one central question: How are we going to get our drug product to the appropriate cellular “destination?”

Obviously, for our therapeutics to have an effect, they need to reach the appropriate organ/tissue in the body. But as Medarova reminded us, we can’t forget about the journey to the final destination, either. There’s a lot we need to consider and understand about how our therapeutics fare on their journey through the body.

When tackling oncology indications, for example, Medarova emphasized several important characteristics our oligos and our mRNA products must embody — starting with the duration of a drug’s circulation in the body.

“In the context of cancer, we don’t want the drug to be cleared too rapidly,” she explained. “The product needs to circulate long enough to exit the bloodstream and enter the target tissue.”

Now, if you’ve spent any time in the ATMP space and/or the oncology space, you’re likely familiar with the many reasons as to why the tumor microenvironment is a scary place for our drugs to (try to) visit. As Medarova clarified, tumors typically comprise a mosaic of different cell types (e.g., immune cells, fibroblasts, and endothelial cells). The complexity of this ecosystem raises many questions, but at a high-level, we need to definitively know two things: One, is the therapy in fact reaching and entering the cancerous cells; and two, once inside the cell, does the product escape the cell’s endosome? (Because why wouldn’t our therapies be hunted on this challenging journey, as well?)

Much of our targeting work today is done by identifying common antigens on the surface of cancer cells. In fact, as Medarova went on to add, it’s thanks to antigen targeting that we’ve had success delivering oligos to the liver using GalNAc.

“Part of the reason GalNAc was successful at delivering RNA to hepatocytes is because the target receptor for galNAc is abundantly expressed on that cell type,” she said. “For cancer, we don’t know of a receptor that is similarly overly expressed.”

Though the work we’re doing in the personalized immunotherapy space will undoubtedly help us learn more about the tumor-specific antigens across a variety of different cancers, Medarova posits that we may need to think more carefully about other mechanisms by which we can guarantee our products’ targeted delivery and entrance into cancerous cells.

“Perhaps we can strive to use some other delivery methods that are not dependent on the expression of a given antigen but rather depend on the metabolic activity of the tumor cell,” she offered.

For example, as she went on to explain, an approach she’s explored has been to rely on particles coated with a glucose polymer, seeing as cancer cells often have a sugar tooth and crave glucose to feed their growth.

Phase 1 is Cool But… Have You Heard of Phase 0?

I’ll be the first to admit that “Phase 0” sounds like the title of a particularly bad zombie apocalypse movie. (To be clear, it’s not.) And as Medarova also clarified, it may not necessarily always be the easiest or most feasible type of trial to carry out in the oncology space, either. However, we’re no strangers to the limitations of preclinical models in helping us predict our therapy’s clinical effect in humans. In Medarova’s experience, the Phase 0 trial has been a particularly important means of better understanding the PK distribution of a drug in the human body.

“I’m a strong proponent of spending the time to conduct a Phase 0 clinical trial rather than going straight into a Phase 1 clinical trial,” she explained. For one, “The path to FDA approval for a Phase Zero trial is much shorter.”

As she went on to explain, because the dosing regimen for a Phase 0 trial is so small, garnering the FDA’s OK for the Phase 0 trial did not require the same burden of proof a company would need for a Phase 1 trial. For example, to dose patients with a micro-dose of their lead candidate (i.e., 90 mcg), Medarova explained that the company needed to provide a toxicity study in one rodent species, as opposed to data from two species (rodent & nonrodent). Likewise, the overall CMC requirements were reduced, though she clarified that the radiolabeling of the product — which was essential for identifying the drug’s distribution — had to be done under GMP.

Carrying out a Phase 0 study can help “fill in the blanks” about a product’s delivery to a tissue of interest. However, she acknowledged that patient recruitment for such a trial can be (even more) challenging. Afterall, the purpose of a Phase 0 trial is not to administer a therapeutic (i.e., clinically meaningful) dose. As such, “You have to be very smart about how you’re going to recruit patients,” Medarova concluded.