Monday, February 9, 2015

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.


Anonymous said...

4weeks daa is not interesting (more new daa combinations likely shorter time).hope they try 2 or 1 week daa

Dirk Haussecker said...

4-week regimens for all or certain subgroups?

Anonymous said...

Now what happens if Benitec's TT-034 proves efficacious? I wonder what that result would do the the Regulus share price? It's a one shot treatment and the trial is getting close to therapeutic dosing levels. I guess we will just have to wait and see.

Anonymous said...

What's Benitec?

Anonymous said...

This is Benitec

Pete Carroll said...

I thought it was a good play call ?

Bill Belichick said...

Pete - You Blow - fire yourself

PfizerSloth said...

Dirk, do you give much credibility to this opinion?

Even if you don't have an opinion I am sure Mr. X does. Might be why we have not seen any move from PFE or BMY yet.

PfizerSloth said...

Trade officials from around the world are potentially just months away from completing what would be the largest free-trade deal in history, but the completion of that deal is reportedly struggling to get past an issue related to the regulation of biologics.

Biologics and Data Exclusivity

At issue is what is known as "data exclusivity," the period of time during which other products cannot be approved using the data generated by an innovator company. The term is also known as "regulatory data protection" in some parts of the world.

- See more at:

It looks to me like this is the reason why the market doesn't really react the way it should to great data like that from RGLS and ARWR.

PfizerSloth said...

Pfizer to move this week in establishing itself as a biotech player.

Are you hearing this story Dirk?

Anonymous said...

Mr. X a seller of RGLS...again. Mr. M a buyer of ALNY.

Is there something we should know?

Anonymous said...

RGLS set to lower the pps while simultaneously raising the market cap?

Use PIPE to establish pps and source capital. Use stock to buy up rivals and their IP etc.

ALNY to benefit.

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