Simply Good: Regulus Therapeutics’ MicroRNA Inhibitor for HCV

Last year’s European Liver Meeting in London (EASL) was all about progress made in the treatment of HCV.  In addition to the expected buoyant mood among participants, questions were asked about a) affordability and even more so, b) the complexity of the treatment landscape. 

We have heard a lot about certain pricing pressures in the HCV space recently.  Although more and more observers are now calling an annualized $14-18B market in the US and Europe alone over the next 10 years one not worth pursuing, I happen to disagree, especially if you are talking about an $800M market cap company like Regulus Therapeutics (unlike $90-150B for Gilead and Abbvie) and the continued unmet need in this market.

Practicing physicians want simplicity

Part of the unmet need is the noted complexity of the treatment landscape.  These days, which drug and for how long you take it depends on a number of factors such as your HCV genotype and liver fibrosis score.  Based on  today’s data, RG-101, a microRNA inhibitor developed by Regulus Therapeutics may change this and simplify the life of the busy practicing physician.

Add to this the fact that some subpopulations, e.g. genotype III (~12% of the 3-4 million US HCV population) have standard of care cure rates (12 week daily Harvoni plus much-hated ribavirin) of just over 80% in clinical trials, not counting those who either do not get their prescriptions filled, nor the ~5% that get them filled, but then do not adhere to daily pill regimens. Real life, not clinical studies.

RG-101 potency paves the way for simplified regimen

Accordingly, mean viral load reductions of 4.8log were achieved following a single (!) subcutaneous administration of 4mg/kg (4.1log for 2mg/kg), making RG-101 the single most potent HCV drug ever tested.  Moreover, every subject responded, regardless of genotype and fibrosis score. 

Almost as impressive, for the 2mg/kg single dose cohort where day 84 (SVR12) data is now available, 4 out of the 14 given RG-101 were undetectable for the virus and could well turn out to be cured from just a single dose of drug.  In the same cohort, two were below the level of quantitation (BLOQ) on day 57, but rebounded thereafter.  This is hardly surprising given that liver concentrations at that time are predicted to be around 6% of the starting dose.      

Importantly, such a rebound is not the same as treatment failure due to the development of viral drug resistance.  A previous mutation analysis by miR-122 competitor Santaris (Ottosen et al. 2015) which has been developing a less potent anti-miR122 drug has shown that in Man (unlike in prolonged tissue culture experiments), no drug-resistant escape mutant to a miR-122 inhibitor is generated.  Such a high barrier to resistance can be expected from targeting a host factor rather than acting as a direct antiviral.

In cases of viral rebound, a simple second shot on day 28 or a higher dose of say 8mg/kg as I have been whining about for weeks now* would have kept the virus in check, if not eradicated it.

* Parenthetically, today’s data showed that I was right that there would likely be a further dose response from 2mg/kg to 4mg/kg with particular benefit with longer duration (see diverging curves particularly after day 22), also because in preclinical animal data, the liver concentrations increase linearly between 1mg/kg to 10mg/kg.  This is why I am surprised the company Is not talking more about the potential of 8mg/kg even though that dose was found to be safe in the healthy volunteer part of the study.

A sandwich regimen for all

The current data thus support that RG-101 could be the foundation for a universal HCV treatment regimen that looks something like that:

When a patient walks into the doc’s office to discuss his HCV treatment options, the doc convinces him that he should get treated and offers to give him the first shot of RG-101 at that visit that sits in his fridge.  This would take into account that some patients first say ‘yes’ to treatment, but then don’t get their prescriptions filled.  The doc then writes a prescription for 28 days of a potent oral DAA pill such as Harvoni and instructs him to start the pills any time within the next 14 days and asks him to come back after a month.

On that second visit, the patient will receive his second dose of RG-101, just to make sure and torch the earth for for the virus another 30+ days.  He then tells the patient to finish his pack of pills and come back in 6 months to confirm that he got rid of HCV.

Sounds simple enough to me.

MicroRNAs as Therapeutic Targets

MicroRNAs are another class of endogenous cellular small RNAs that like siRNA in RNAi down-regulate target genes. Unlike siRNAs in mammalian cells, these mostly recognise their targets by incomplete base-pair complementarity. Consequently, each of the maybe 1000 microRNAs in humans has the potential to regulate a large number of target genes, with some estimates pegging that number upwards of 100. Together, these microRNAs regulate genes involved in almost all aspects of a cell’s life and some of them have been found to be involved in the pathogenesis of many diseases such as cancer and neurodegenerative conditions. It is therefore hoped that the targeting of microRNAs by antisense techniques or their over-expression in the form of siRNA-based microRNA mimics can be exploited for therapeutic purposes.

When the underlying cause or contributing factor (e.g. viral microRNAs) for a disease is a microRNA, then targeting it should stand a good chance in being an effective treatment as long as loss-of-function of that microRNA in the target cells does not have other undesirable side-effects. It appears to be, however, much more complicated when the idea is to target a microRNA as the regulator of a complex phenotype. One example of this approach is targeting microRNA-122, a highly expressed microRNA in the liver, for treating hypercholesterolemia. Down-regulation of this microRNA has been achieved in the liver in rodents and was shown to result in lower cholesterol levels. It needs to be questioned, however, if this approach is viable for chronic treatment given the importance of microRNAs in general for cell viability and the fact that microRNA-122 in particular makes up about 70% of liver microRNAs. It is interesting to note that targeting microRNAs as modulators of complex phenotypes versus RNAi Therapeutics approaches are derived from quite contrary drug development philosophies. The one philosophy (RNAi Therapeutics) holds that the best treatment with the least side-effect focuses on as few causative genes as possible. The other philosophy, however, proposes that single-gene targeting will only be successful in few instances and the best drugs are those that affect multiple targets. As such many of the small molecule inhibitors on the market today are now known to be actually much less specific than intended and their off-target effects contribute to the therapeutic outcome.

Four investing purposes, four companies that stand to benefit from the development of microRNA-based therapeutics come to mind: Alnylam (ticker: Alny), ISIS (ticker: Isis), Rosetta Genomics (ticker: Rosg), and Asuragen (privately held). Although many more microRNAs exist, Alnylam’s co-founder Tuschl identified the first 120 microRNAs in humans, and these are therefore likely to be amongst the most important in human biology. Alnylam partnered these microRNAs with ISIS Pharmaceuticals which owns many of the fundamental antisense patents required for the targeting of microRNAs. In addition to developing similar microRNA-based therapeutics, Rosetta and Asuragen (a privately-held company that was spun off from Ambion when it was acquired by ABI) are two companies that both expect to generate early revenues through the development of microRNA-based diagnostics, e.g. for the classification of cancers. In addition to their own discovered and characterised microRNAs, they will therefore have to pursue a prudent licensing policy to secure their freedom to operate.

While it is already obvious that microRNAs are extremely important for human gene regulation, much more work remains to be done to confidently identify suitable targets. Fortunately, much of this work is already being undertaken due to the immense interest in microRNAs in biology. In the meantime, let-7 in cancer and microRNA-122 for the treatment of HCV and hypercholesterolemia may lead the way in showing the promise of microRNA-based therapeutics.