This morning, Regulus Therapeutics greeted us with amazing results
from a phase I study of RG-101, an anti-microRNA 122 oligo for the treatment of HCV
infection. The results show that in the
exploratory HCV-infected patient subgroup, a single
dose of 2mg/kg of RG-101 resulted in a mean
viral load reduction of 4.1log on day 29. All responded with viral declines, with 6 and 3 of the 14 patients with viral levels below the level of
quantitation on days 29 and 57, respectively.
These results even
exceed my own wildest imaginations (as discussed here yesterday) and I’m amazed
how much this virus, in all patients, seems to have come to rely on this host-derived microRNA
for replication and/or genome stabilization.
It is not clear whether increasing the dose to 4mg/kg, the pre-planned upper dose
in the HCV-infected cohort for which dosing is ongoing will bring any additional benefit given that the
biomarker data (host genes targeted by miR-122) from the healthy volunteers
showed a plateau already at 2mg/kg, indicating the power of this GalNAc
chemistry approach. My guess is that the main benefit from a higher dose would be a decrease in response variability.
Interestingly, IL-28 status, frequently a predictor of
treatment success, did not influence the results, nor did HCV genotype seem to
have an impact (small numbers). This further supports that RG-101 could fill some
of the more attractive opportunities in the current HCV market.
Regarding safety, mild and transient injection site
reactions seemed most significant with no serious adverse events in the entire study, including the healthy volunteer cohorts (up to 8mg/kg). This is also consistent with data for Alnylam’sALN-TTRsc which uses a similar GalNAc chemistry and where multiple doses up to 10mg/kg had been tolerated, with injection site reactions, especially at 10mg/kg, being the
main safety finding.
So what’s it all
worth? The results position RG-101
to facilitate a 4-week HCV dosing regimen (compared to typically 8-12 weeks currently), potentially in combination with a
single direct-acting antiviral such as Olysio by Johnson&Johnson. One or two injections maximum. Great compliance, potentially pan-genotypic,
ideal for the busy practicing physician who does not have the time nor inclination to know the
ins and outs of each DAA.
In dollar terms, I’d like to think that with this drug profile,
this overlooked compound and company are worth as much as what Merck recently paid for HCV drug developer Idenix: $3.85B. The market valuation of Regulus
before the news: $300M. Needlessly to say that I'm long the stock.
PS: GSK once had rights to a precursor compound of RG-101
which it did not exercise. Importantly,
at the time, Regulus’ anti-miR122 compound was not GalNAc-enabled. This would have necessitated much more
frequent dosing and higher dosages and resulted in less potent and more protracted viral
declines, i.e. something that would not have been competitive in the current HCV marketplace. But as often the case with
Big Pharma and cutting-edge technology, today’s data clearly shows them
wrong. It has to be said though that GSK
more or less got out of HCV which also would have explained GSK’s decision RE
anti-miR122.
