Tuesday, January 20, 2015

RG-101 for HCV: Give Me 8mg/kg

Last October, Regulus Therapeutics announced stunning data from an ongoing trial of anti-miR122 RG-101 for the treatment of HCV infection.  Accordingly, 6 out of 14 patients administered a single injection of 2mg/kg of the GalNAc-conjugated antisense oligonucleotide dropped to what the company referred to as ‘below the level of quantitation’ (BLOQ) by day 30 and remained there as of the update (day 57 for those treated first in the study).

*BLOQ is not the same as 'undetectable'.  It is 'undetectable' for x number of weeks that technically defines a cure.

2mg/kg data looking ever better

The more I look at the data (here for the corresponding dataset), the more intrigued I get.  For starters, the 2mg/kg was only the starting dose in the patient cohort.  Moreover, a patient that had been more recently treated and had reached only 29 day in late October seemed to be on his way to BLOQ.  In fact, after his titers had dropped to below ~1000 IU/ml, viral decline seemed to accelerate as if a threshold had been reached. 

Overall, it seemed that as long as you got below ~1000 IU/ml, the virus would not rebound (at least until day 57).  Accordingly, the 5 patients that rebounded got close (1000-10000 IU/ml), but never below the apparent threshold.  The lack of overlap between the individual knockdown curves also suggest that viral rebound is not the result of stochastic escape mutations, as is often the case in HCV, but simply due to diminishing drug concentrations.

This leaves two patients which as of the update were still slowly declining as if the threshold rule was counterbalanced by declining oligonucleotide concentrations in the liver after day 30.

In summary:

Everybody responded irrespective of genotype and starting viral titers, of these…
…6/14 BLOQ;
…3/14 undecided;
…5/14 nadir of 1000-10000 IU/ml, then rebound.

A one-shot cure?

In the current marketplace, comprising of ~12M untreated HCV patients in the top 7 pharmaceutical markets plus hundreds millions more in the rest of the world, HCV treatment success has less become a function of viral cure rates achieved in clinical trials, but more one of compliance with the pill regimens.  Therefore, a therapy which would shorten current treatment regimens (say to 4 instead of 8-12 weeks), or even involve just one or two subcutaneous administrations in the physician’s office as part of routine checkup visits, would have great pharmacoeconomic impact.

The company is currently crunching the numbers for the next higher, 4mg/kg cohort.  In general, with RNAi and antisense therapeutics, what you see with increased doses is a slight acceleration of gene knockdown (thereby shifting the knockdown curves down), and, likely of more importance in this case, extended duration of drug activity.

The latter is supported by animal, including non-human primate data that showed that liver concentrations of RG-101 increase linearly with dose from 1-10mg/kg.  This means that for the 3 undecided patients in the 2mg/kg cohort, a doubling of the drug concentration could have easily pushed them BLOQ.  

Alternatively, a second dose of 2mg/kg on day 29 would have achieved that as also supported by animal data showing that viral nadir drops further when a second dose is given (on the left is an example from the challenging chimeric mouse model).

I am less sure whether the other 5 patients would have gotten there with 4mg/kg, but would be much more sanguine about it with a dose of 8mg/kg.

A mistake not to escalate to 8mg/kg

Unfortunately, Regulus Therapeutics stated last year that based on biomarker data which measures the activity of human genes naturally regulated by miR-122, 4mg/kg would be the highest dose to be tested in HCV.  This is because the biomarker response seemed to have saturated already by 2-4mg/kg.  This despite of the fact that they had established in the same phase I study that 8mg/kg is also safe and well tolerated in non-infected healthy volunteers.

I clearly think that stopping at 4mg/kg is a mistake.  First, I highly doubt that at least in terms of duration of biomarker activity, they did not see improvements with higher doses (show me the data).  Second, it is wrong in my opinion to assume that drug saturation with regard to microRNA activity against endogenously expressed genes is a good reflection of microRNA activity in the context of viral replication.  In this case, the rationale is further in question because of the special way miR-122 acts in HCV replication (increases, not decreases activity).

Tempering expectations

As we await the 4mg/kg data and an update on the 2mg/kg cohort in ‘early February’ according to recent company guidance, I should caution that the above scenario suggesting a one-shot monotherapy cure is within reach is obviously an unbelievably exciting best-case scenario.  There is a lot which could make the market react adversely to the upcoming data.  This includes emerging side effects, and responses that could even be worse than the 2mg/kg data, e.g. if some patients do not respond at all or if the company is right in their biomarker assumptions which due to chance could make the 4mg/kg data look worse numerically. 

Therefore, my base case for market-neutral data is that all patients will have to respond, and that the extent of the response will be similar to that seen with the 2mg/kg dose.  But then again, I’m looking at the data and keep thinking to myself…’8mg/kg might be the one-shot cure that could transform HCV treatment’.  In any case, the company has little to lose from dose escalating to 8mg/kg.


Anonymous said...

Is there a precise date or period for data release?

Dirk Haussecker said...

'Early February' as per January guidance.

Anonymous said...

Great analysis of the curves Dirk. I never would have put as much thoughtt into what you are seeing. lesson learned?! There s probablly lots of time to still dose up to 8 if its really going to be a transformative therapy. Going to market with lower dose would mean fetching a higher price when going back to market at a higher dose. Looking forward to early Feb!!

Anonymous said...

The data may be so stellar as what Dirk alludes to, that the FDA may feel obligated to go straight to market with the product while trials are continued.

This reminds me of HIV and the HAART regime back in the nineties. MRK was centre stage then as well.

Anonymous said...

Dirk, if you are so taken with the idea of RG-101 pushing towards a 'one shot cure' for HCV your stated position on Benitec is beginning to look more ridiculous by the second - given their potential to offer an entire platform technology for one shot cures across multiple orphan diseases.

Do you have anything but ridicule to offer in relation to what Benitec is progressing with TT-034? The data will eventually prove this beyond reasonable doubt...but many are getting kinda curious about your one-sided position...

Can you provide any concrete evidence to justify your extremely one-sided view re: Benitec's potential to become a major force with their one shot ddRNAi approach...or is it simply a case of sour grapes on your part?

William Joletti said...

I thought it would be obvious that the reason for lower doses is:
A/ it already shows efficacy.
B/ it has proven to be carcinogenic and has side effects which are dangerous.

Dirk Haussecker said...

'B/ it has proven to be carcinogenic and has side effects which are dangerous.'

That statement is true as it relates to the poor mice which have to live their entire lives without miR-122. In all other settings so far, including in probably now hundreds of humans, no such evidence has been gathered. Remember that 8mg/kg has already been apparently safely administered in this very trial. Plus, the expectation is that RG-101 will be dosed no more than 2 times, be it in monotherapy and/or combination therapy.

Dirk Haussecker said...

RE Benitec. Show me a real, serious biotech company and I will take it seriously. I wonder whether the $30M will be largely spent on IP lawyers, management suit and Directors as before, or whether there will be a real drive towards R&D. I doubt the latter and would like to be proven otherwise. But with all the dithering, much of the value they regained in 2009 has by now been wasted.

For gene therapy knockdown approaches more and more of the music has moved towards genome editing. It's not there isn't enormous ddRNAi potential, but little of it has been translated into the clinic in years past. Lack of leadership.

Dirk Haussecker said...

And the obvious distinction between RGLS and Benitec in HCV is: why would anyone want to be treated with a gene therapy that permanently leaves you extra DNA even after you've been cured, when there is a one-shot non gene therapy-alternative?

William Joletti said...

Thank you for that Dirk, I will be taking what you say on board. It was frustrating not knowing why people were dissing them.

And thanks for the extra words on RGLS safety profile.

Anonymous said...

Wouldn't this extra DNA act as an immunity or resistance to the HepC virus and stop any reinfection?

Anonymous said...

Dirk, in fairness to Benitec your previous issue with them was that they didn't have a lab. Now they do. They are now in the clinic, also.

PfizerSloth said...

Deutsche Bank gives a $30 rating to RGLS just as Mr. X sells down on option conversion and just as data release is about to occur.

The knee jerk reaction is he knows something about the data and it is not good.

I am very reluctant to believe such a sophisticated man would behave in such a blatantly crass manner.

Assuming data is good, if anything is to happen that brings the price down it will be a capital reconstruction of some sort. Or a full blown short attack as witnessed in ARWR.

My money is on the latter. Until PFE shines their light on the path to be taken status quo will remain.

But Mr. X's other company BIIB put on a full 10% in a single day. Or to put that in to context, BIIB increased in value by over $8bn in a single day.

As for PFE, they will be in attendance at the BIO CEO and Investor Conference and the second to last event belongs to PFE and the CEO/Chairman.

No doubt RGLS data will be on his mind.

Anonymous said...

Interesting. I don't understand why the buck stops at RGLS. They aren't the only ones with a one shot cure for HCV. Benitec has its own program.

From what I can gather, all the heavy lifting has been done by the Chinese and Australians in tandem with the Germans. Dirk, do you know about this?

Hence the prominence of the TPP and trans-Atlantic FTA talks.

The logic goes, no TPP agreement means the Chinese won't allow it. Which means the Germans won't allow it and that means no trans-Atlantic FTA either.

It will be interesting to see what Pfizer do.

If, as PfizerSloth suggests, they wish to lead the way, then I will remember the stories of how the Americans "took" Berlin at the end of WWII and liberated all those poor Jews from certain death.

Anonymous said...

Is RGLS IP proprietary to RGLS?

Anonymous said...

Dirk has not denied owning shares of benitec.

Anonymous said...

Interesting. . . this post cannot be sincere . . . . . . ALL OTHER THERAPIES ALLOW RE-INFECTION. . . and would require repeat of therapy. Will insurance pay for a second round of harvoni? . . . or anything else. . . and while we're on the subject, what are the RE-INFECTION rates around the world? ddrnai - no reinfection = Cure and "vaccine" effect. Most people hated cars and cell phones too. . . until they loved them.

By Dirk Haussecker. All rights reserved.

Disclaimer: This blog is not intended for distribution to or use by any person or entity who is a citizen or resident of, or located in any locality, state, country or other jurisdiction where such distribution, publication, availability or use would be contrary to law or regulation or which would subject the author or any of his collaborators and contributors to any registration or licensing requirement within such jurisdiction. This blog expresses only my opinions, they may be flawed and are for entertainment purposes only. Opinions expressed are a direct result of information which may or may not be accurate, and I do not assume any responsibility for material errors or to provide updates should circumstances change. Opinions expressed in this blog may have been disseminated before to others. This blog should not be taken as investment, legal or tax advice. The investments referred to herein may not be suitable for you. Investments particularly in the field of RNAi Therapeutics and biotechnology carry a high risk of total loss. You, the reader must make your own investment decisions in consultation with your professional advisors in light of your specific circumstances. I reserve the right to buy, sell, or short any security including those that may or may not be discussed on my blog.