Regulus Therapeutics RG-101 Continues to Have Potential in HCV Treatment Landscape

Having attended the International Liver Congress last week in Vienna, Austria, it has become clear to me that HCV is not going away soon.  Even in the US where progress towards its ‘eradication’ may be considered most advanced with about 1/5 of the known patient population treated last year alone (~250k), it will be an uphill battle to identify, treat, and pay for the millions more infected. Worse still, it is not enough to simply cure the existing pool of HCV patients, but also stop the cycle of re-infection (largely the result of injection drug use).

Treatment cost is one challenge and the current drug rationing approach leads to the counterproductive warehousing phenomenon where current medical intervention is focused on the patients with more advanced liver disease.  This is not only the hardest-to-treat population, but also allows the liver health of the previously less sick patients to deteriorate.  This obviously makes little sense also from a pharmaco-economical perspective when getting rid of HCV early on has now been shown over and over again to dramatically reduce HCV-related cirrhosis and liver cancer.

Another problem is the fractured treatment landscape that exists for the various patient populations (split up according to fibrosis/cirrhosis stage, genotype, co-morbidities, the rapidly growing concerns around drug-drug interactions, available/accessible meds etc) making it difficult for even the learned gastroenterologist to keep up with the latest developments and putting HCV treatment practically out-of-reach for the general practicioner.  

12-24 weeks remains the standard drug treatment duration with docs worrying about shorter treatment regimens being sub-optimal.  A triple regimen by Gilead after 4 weeks of treatment merely achieved a 27% SVR12 which in the DAA world is practically synonymous with a cure.  The best shot at shortening treatment duration may therefore come from Achillion with 6 week of DAAs achieving high cure rates in 'easy' patient populations.

While interferon is on the way out, it could make an at least transient comeback for the hard-to-treat genotype 3 where, in addition to cirrhosis, cure rates with the all-oral DAAs low (60-80%).

To sum it up, the liver community has expressed multiple times at ILC2015 that a short-acting pangenotypic regimen is an important goal in the development of new medications for HCV.   And if they paid attention at the oral late-breaker on Saturday, RG-101 is poised to play a critical role in filling this unmet treatment goal due to its long duration of antiviral activity following administration, regardless of genotype.

RG-101 update: more relapses, but thesis intact

The clinical investigators of Regulus Therapeutics presented a 20 week update on the phase I study in genotype 1, 3, and 4 patients with good to moderate liver health.  28 patients received study drug RG-101, 4 placebo.

At the primary endpoint on week 8 (reported in earlyFebruary), slightly more than half (15/28) of patients treated with RG-101 were below the level of quantitation (BLOQ).  According to the company, most of them were not only BLOQ, but undetectable (by sensitive PCR) at that.  This is a remarkable feat given that the GalNAc-conjugated phosphorothioate antisense molecule had been only given once.

According to the latest update, half of those patients eventually relapsed (7-8 depending on whether you count the patient that was lost to follow-up), most of them shortly after week 8.  Although the relapsers are slightly disappointing as in the short-acting DAA world undetectable virus for 8 (or better 12, SVR12) weeks following cessation of treatment is more or less equivalent to a full-blown cure.

Of course, the prognostic rules for a long-acting agent like RG-101 with a slower onset of antiviral knockdown ought to be different.  The notion that the viral rebounds were simply due to waning drug levels in the liver (and not due to viral escape mutations!), was supported by the biomarker analysis in the healthy volunteer part of the phase I study, also presented at ILC2015, where the trough in viral knockdown (~day 28) more or less coincided with maximal total cholesterol lowering as a predicted by miR-122 biology.

Of note, there was no apparent benefit of increasing the dose from 2 to 4mg/kg which was consistent with preclinical evidence that showed a declining liver/kidney drug ratio at 4mg/kg and maximal cholesterol lowering at 2mg/kg in humans.  This indicates that ASGPR receptor binding becomes saturated when too much GalNAc antisense is given at once.  The increased drug liver concentration at higher concentrations observed in earlier preclinical studies probably indicate uptake in non-productive compartments of the liver, including Kupffer and sinusoidal endothelial cells.

  

The hope is that with a second dose of RG-101 28 days after the first shot, maximal viral suppression can be maintained for at least another 4 weeks to stave off any viral comeback as seen in the single-dose study.  This is supported by both the healthy volunteer part of the study and the chimeric PXB mouse experiments presented which showed that such a second dose not only maintained drug potency, but in fact led to a step-up in efficacy.  I am therefore optimistic that with 2 doses of RG-101 monotherapy alone ~50% cure rates can be achieved in patient populations similar to that in the phase I study.

This, however, is not even the goal.  The ultimate goal would be to establish a simple pan-genotypic 4-week treatment regimen.  Accordingly, the combination of RG-101 with a DAA(s) (sandwich regimen) can be expected to result in a very, very deep viral knockdown by week 4.  At this point, a second shot of RG-101 would be administered to give the immune system another 6 weeks or so to finish off the virus.  I believe a very realistic scenario, and depending on which patient populations you are looking at a very compelling alternative to current HCV medications and those in development. 

PS: Open questions

Unfortunately, given that cholesterol lowering was still close to maximal at week 8, it would have been comforting to show a mutation analysis from the clinical study to confirm that viral relapse was not explained by the virus successfully developing resistance against RG-101.  This is such an obvious question that one wonders why Regulus did not present the data (yet). 

Another question mark around the current data set is why Regulus is not disclosing the differential effect of RG-101 on good and bad cholesterol and instead is reporting total cholesterol lowering.  The study investigator said that they are still analyzing the data from the multi-dose healthy volunteer study  (months after completing dosing???) and are planning to publish those.  I am mildly optimistic that this could unexpectedly bring to the fore the cardiovascular potential of miR-122 targeting, although in this case (à mostly chronic treatments) the liver cancer concern around miR-122 inhibition may be more valid than it is for the 2-shot HCV treatment goal.