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.
10 comments:
Dodgy CEO unfortunately makes this investor unhopeful of straightforward science or aboveboard handling of the data. A Venn diagram of his interests and my interests has very little overlap.
What is the significance of the pic?
I mean the first one. The second one carries the oblique reference of Bacon, Lettuce and Tomato and their HCV trials, doesn't it?
Dirk, has humor. Who would've guessed.
Are you receiving any consultant fees from ISIS or Regulus?
What percentage of total shares outstanding does the CEO hold?
Cornholed again
The CEO has 3705 direct and around 80000 indirect shares left as of 5 days ago. Selling nearly $8 million worth of stock in the last 3 months doesn't exactly inspire confidence.
No response from Dirk on the consulting fees
Hint hint
The fees from ISIS and Regulus are likely more for bullish articles and less for bearish
I doubt the CEO has left because of his trading. Usually, if there is any sensible governance in a company, an individual has to obtain approval from one of the various committees set up to oversee such things.
Perhaps there is something he knows which we do not.
If that is the case then there must be a pox on ALNY and ISIS as well.
How confident is Dirk with his never sell bigger than Apple ISIS stock now.
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