Can Innate Immune Agonists Help Deliver Hepatitis B Cure?

This episode, "Can Innate Immune Agonists Help Deliver Hepatitis B Cure?," features the panel examining a TLR9 agonist's early signals and where it might fit in future regimens.

Dr. Chung introduces another therapeutic class working through the innate immune response, a compound called cavrotolimod, and asks Dr. Gish to explain its mechanism along with how to interpret phase 1b results showing manageable adverse events but surface antigen clearance in only one patient.

Dr. Gish confirms this is a TLR9 receptor agonist and immune modulator, framing immune modulation as foundational to hepatitis B treatment and noting the field has moved through several generations of this approach. He describes the earliest generation as interferon, followed by TLR7 and TLR8 agonists that did not demonstrate meaningful immune modulation, viral control, or clearance. He sees TLR9 agonism as a stronger next step, grounded in solid underlying science, and expects it to ultimately function within a combination regimen, where direct-acting antiviral agents suppress the virus while immune modulation provides durable long-term control. He notes early hints that this kind of immune modulation may help deactivate cccDNA and potentially enhance its clearance, though its effect on integrated viral DNA remains uncertain. He characterizes the phase 1b safety signals as reasonable and views combination therapy as the logical next step in its development, then asks Dr. Chung for his own perspective.

Dr. Chung says he takes an optimistic view of innate immune agonists such as TLR9 or TLR7 compounds but, like Dr. Gish, sees them as adjunctive rather than sufficient on their own. He believes a rational combination approach that intentionally engages the innate immune response will be necessary, noting that bepirovirsen may already be doing this incidentally, and that these early signals support innate immune agonists having a role in a broader combination regimen.

Our next episode, "Therapeutic Vaccines and the Global Divide in E-Antigen Disease," turns to therapeutic vaccines designed to engage T-cell immunity directly.