Thoughts on Alnylam's HBV Program

by Robert Kruse

Most of the discussion in HBV siRNA therapies has centered around Arrowhead and Tekmira, since their programs are further advanced and seem to be the primary focus of investors for each company. Lagging behind is Alnylam, which has its own siRNA assets and program against HBV. I wanted to quickly review its HBV targeting strategy with comparisons to Arrowhead and Tekmira, and see if there are any potential advantages.

I listed below a brief summary of the three companies for anyone unfamiliar with their HBV portfolios.

Arrowhead: Currently using IV delivery, composed of two different siRNA molecules against HBV; recently published a generation that can be delivered subcutaneous and target the liver via GalNac.

Tekmira: Lipid nanoparticle based formulation, delivered IV. composed of three different siRNA molecules against HBV

Alynylam: Has both lipid nanoparticle technology delivered IV and GalNac conjugation and subcutaneous delivery strategies, will use two different siRNA molecules; proposed combination with PDL1 siRNA


What intrigues me about Alynylam is their intention to use siRNA against PD-L1 in order to remove the break on virus specific T cells in the liver. This is an added feature that Arrowhead and Tekmira lack in their programs (although Tekmira has begun a multi-pronged approach buying small molecule assets recently). It is well known that chronic viral infections induce exhaustion in CD8 T cell effectors, including in HBV. PD-L1 can be upregulated on hepatocytes in chronic infection, in addition to PD1 upregulation on T cells, leading to inhibition of virus T cell responses. Thus, the PD1 pathways has been proposed as a target to re-awaken the fight against infections, similar to how it is being targeted in cancer immunotherapy currently. A proof of principle for this siRNA PD-L1 therapy was already modeled against murine cytomegalovirus infection of the liver in mice. Furthermore, there has been a published report using the anti-PD1 antibodies as therapies for HBV and that it can enhance activity of T cells in mice. The HBV mouse model used for this purpose has limited direct applications for human anti-HBV immune modeling, however, and direct testing in chimpanzees or phase I trials in patients is needed to truly test the exhausted HBV specific T cell phenotype. The reports of leveraging the PD1 / PD-L1 pathway against viruses looks promising in summation though.

The downside of PD-L1 siRNA could be unlocked any inflammatory effects of T cells against the liver. Currently, anti-PD1 antibodies have well studied toxicities, but the specific targeting here to the liver could uncover potential new toxicities. For example, there could be auto-reactive T cells, held in check by PD-L1 hepatocyte expression, that are then activated by the siRNA. It's worrisome in such a vital organ that a large hepatotoxicity side effect could occur. I would imagine the FDA will be monitoring this closely going forward in any clinical trials. On this point, anti-PD1 antibodies have been used in early trials for HBV+ liver cancer patients, and so perhaps there is already some safety data on inhibiting this pathway in patients with HBV. Additionally, Bristol Meyers-Squibb is planning to test anti-PD-L1 antibodies in HBV infected patients. It remains to be seen whether an siRNA against PD-L1 is similarly safe.

Those concerns aside, the angle of combining HBV and immune targeting with siRNA is very enticing. If the REPLICor reports are to be believed, then a combined HBsAg knockdown and immune stimulation (IFN alpha in their trial) is required for sustained virology response and cure. Given that interferon is challenging for patients to take, an siRNA against PD-L1 could be a more specific and potent immune activator, with less systemic side effects. It seems more and more likely that siRNA against HBV will not be enough, and that other triggers might be needed in order to induce HBV cure. In this respect, Alnylam is ahead of the game having it built into its strategy already.