Santaris reported yesterday intriguing antiviral HCV efficacy results from an ongoing phase IIa study of miravirsen, Santaris’ LNA-based antisense inhibitor of microRNA-122 (miR-122), miravirsen, an important host factor in HCV replication. Full interim results will be presented in a late-breaking oral session at the upcoming AASLD, The Liver Meeting.
The phase IIa study investigates 3, 5, and 7mg/kg of miravirsen, given weekly to treatment-naïve HCV patients subcutaneously for 29 days. According to the abstract, with the study now in the 3rd and last dose cohort, patients in the second, 5mg/kg cohort showed very encouraging mean reductions in viral plasma RNA levels from baseline of up to 2.5logs when miravirsen was given as a single agent compared to placebo control. 5 of the 9 miravirsen subjects had reductions of more than 2 logs (>100-fold) with viral RNA in one patient becoming undetectable 10 weeks after the dose. Although the cohorts were relatively small, 9:3 drug:placebo, almost all efficacy measurements reached statistical significance.
What was interesting is that the decline in viral titers was quite prolonged, with the biggest viral reductions being observed after treatment had finished. While having prolonged drug activity per se is positive, the gradual decline is not optimal as it increases the chance of selecting for escape mutants, a major issue in HCV treatment in general and reason why the industry is busy developing new HCV treatment options to be added to the arsenal. In fact, a recent study out of
Irrespective of the viral escape issue, slow clinical responses may also make it somewhat more difficult to integrate miravirsen into the newly emerging treatment paradigms, one aim of which is the reduction of treatment times. Here, RNAi Therapeutics would have an obvious advantage over miravirsen by acting much more rapidly than phosphorothioate antisense oligos which rely on tissue enrichment over time. This is also supported by the data that were recently reported by SomaGenics in collaboration with Tekmira and Roche.
On the safety front, the abstract noted the absence of drug-related serious adverse events. It did, however, note that among the supposed biomarker signals for anti-122 efficacy was an elevation of alkaline phosphatase (ALP) levels. ALP elevations are normally considered a marker of liver injury similar to ALT/AST, so I am not really sure how why this is not considered a safety signal. We will therefore have to for the conference presentation to learn more about the safety profile of miravirsen.
Overall, with the demonstration of antiviral activity and reductions in cholesterol levels which further support functional inhibition of miR-122, the abstract marks an important milestone in the development of microRNA Therapeutics: The first unambiguous demonstration of MicroRNA Therapeutic activity in Man.
Roche AASLD RNAi Therapeutics abstracts: HCV and LNP
Roche will present at the AASLD meeting on two RNAi Therapeutics studies. Both studies involve LNP01, which I assume involves ‘lipidoid’ LNP delivery chemistry. In one study, Roche and their academic collaborators targeted a host factor believed to be involved in the development of HCV drug resistance, especially to the interferons which are at the risk of becoming replaced and, unsurprisingly, Roche would like to revive that franchise. The abstract, together with the recent SomaGenics/Tekmira revelations, further demonstrates that Roche had been quite interested in RNAi Therapeutics for HCV. It also makes me think that maybe Novartis has not picked HCV as a target under Alnylam IP which would e.g. allow Tekmira to step into the void- well, if it saw any reason to do so, maybe out of strategic considerations.
The other abstract concerned potential innate immune stimulation elicited by LNPs. Consistent with what had already been known or suspected, TLR7/8 are the major innate immune receptors and cause of LNP hepatotoxicity, and this can be alleviated by simple 2’-O-methylation as demonstrated before by Tekmira before. What was particularly nice though in this particular study was that with the use of TLR3 knockout mice, TLR3 can now essentially be excluded as a significant tox factor for LNP delivery.