Predicting the Outcome of Regulus HCV microRNA Therapeutics Study

Regulus Therapeutics is on track to reveal phase I results of its anti-HCV compound by the end of the year according to a presentation at last week's OTS.  Although the phase I study is largely a healthy volunteer dose-escalating safety study, it does involve a cohort of HCV patients to assess the viral knockdown kinetics following a single dose of anti-miR122 RG-101. 

MicroRNA-122 is a small RNA host factor that had been identified to play an important role in HCV replication.  As a therapeutic target it promises a low risk of viral resistance, pan-genotypic activity, and entirely novel mechanism of action making it suitable for combination therapy.

Based on the experience with an LNA-based competitor compound by Santaris/Roche (Janssen et al. NEJM 2013), I predict a 2 to 3 log viral knockdown, with a 3 log viral knockdown setting the scene for RG-101 as a single shot in a 4-week treatment regimen in combination with other oral direct-acting antiviral agents (DAAs).  If viral reductions were on the low end of my expectations, it may require 2 or 3 doses within 4 weeks for GalNAc, cET-enhanced RG-101 to facilitate such a short treatment period which is considered a necessary attribute of future treatment regimens in an increasingly competitive market.

Miravirsen comparison

Earlier studies by Regulus competitor Santaris/Roche largely form the basis for my predictions.  In particular, a phase II study of 5 weekly doses of miravirsen at 3, 5, and 7mg/kg yielded 1.2log (3mg/kg) and ~3log (5 and 7mg/kg) viral knockdowns.  Miravirsen is an LNA-based antisense compound whereas RG-101 involves the analogous high-affinity cET chemistry.  Conservatively, miravirsen has a slight (1-3x) potency advantage over RG-101 without the GalNAc conjugation when considering non-human primate and clinical AldoA and cholesterol results which reflect anti-miR122 activity.

However, the GalNAc conjugate in RG-101 is giving it a great 10-30x boost in potency, meaning that overall RG-101 should be 3-30x more potent than miravirsen.  It is because of this and considering that RG-101 is given at 2 and 4mg/kg in the phase I trial in HCV patients, that I arrive at a predicted 2-3 log HCV reduction in the phase I study.  This also makes the conservative assumption that 3log viral reductions is all that an anti-miR122 treatment strategy may achieve based on the apparent plateauing of miravirsen at 5mg/kg.  The 3 log prediction would require that a single shot of RG-101 can already achieve super-therapeutic tissue levels of the oligo.  This, however, cannot be assumed given that for non-ligand-targeted phosphorothioate antisense technology at least this would normally require a multi-dose loading schedule.

But isn’t RG-101 late to the HCV game?

It’s long been thought that it’s game over for RG-101 given the dynamics in the HCV markets.  In particular, the already approved and soon-to-be-approved all-oral DAAs which typically achieve cures in >90% of patients in 8-12 weeks in well-supervised clinical trial settings, would make newer agents like RG-101 seem outdated.  On the other hand, especially given cost pressures (~$100K per average treatment and ~4 million infected in the US alone), the uptake of the new treatments has been relatively slow with only 1-2% treated thus far (according to some of the analyst reports that I have read).  And even then, the sales have been spectacular: Sovaldi e.g. is on track to become the most successful drug launch ever being on track for more than $10 billion in sales in its first launch year!!!

It is the cost pressures (pricing per pill, not per cure) and improved adherence that make a shortened 4-week treatment period so desirable.  A single or two subcutaneous injections in the doctor’s office during routine check-ups where blood is taken anyway should add to compliance.  Holding the subcutaneous route of administration of RG-101 against the drug is therefore wrong in my opinion and the ‘all-oral’ notion, a misnomer really, has only been so attractive because the former subcutaneous standard of care, interferon, was so unpopular not because of the needle injections, but because of its side effects.

So place your bets.  I believe RG-101 has value and will not only be superior to the Santaris/Roche drug, but has pretty much caught up with it in development terms given that miravirsen has only been tested with a DAA (telaprevir) that is already long outdated.  As to the necessary Big Pharma/Biotech licensee, Johnson&Johnson tops my list.

Disclosure: Long RGLS as an RNA Therapeutics stock waiting to be re-discovered with an increasingly broad and clinical-stage pipeline and good financials.  The RG-101 results should only be the trigger for the re-discovery of this ~$300M market cap company.