At this year’s
ADA diabetes meeting, ISIS presented the full dataset for ISIS-GCGR for the treatment of
advanced diabetes patients having failed oral options and who are on the way to taking
insulin. After having presented top-line
data a few weeks earlier claiming more than 2 percentage point reductions (on top of
metformin) in HbA1c, enthusiasm around the results was limited given concerns
about liver enzyme elevations that were not much further characterized and ISIS' history of being parsimonious when it comes to sharing safety data.
Data
indicate that good risk:reward will be found
A placebo-adjusted
1 percentage reduction of HbA1c reduction, the gold standard for measuring glucose
control, is generally considered to be quite meaningful. HbA1c stands for glycated hemoglobin and essentially integrates blood sugar levels over time.
In type II diabetes, blood sugar is elevated either due to insufficient insulin-mediated uptake of sugar (glucose) into liver, muscle, and
adipose tissue and/or due to excessive release of glucose from the liver stores
due to the action of glucagon.
Due to the
time-dependent nature of hemoglobin glycosylation, it takes at least 2-3 months for HbA1c to
reflect the full impact of an antidiabetic medication on blood glucose
levels. Because it takes another 1-1.5 month for a PS-based ASO like ISIS-GCGR to promote full target knockdown and in the
case of GCGR work its way downstream biologically, it will be about 4-5 months
before the full extent of HbA1c lowering will be seen with ISIS-GCGR.
This is
borne out by the HbA1c curves (slide 37) which appeared to be still declining after the 3
months of dosing in the study. Importantly, coincident with plateauing fasting plasma
glucose levels, a more proximate measure of the drug effect, liver
enzyme elevations, markers of liver injury, plateaued after ~1.5 months.
This not
only further supports that the liver enzyme elevations, the main safety concern with ISIS-GCGR, were due to on-target
pharmacology rather than a flaw of the ASO platform, it also suggests that
HbA1c lowering on the order of 1.5 percentage points or greater can be achieved without
triggering liver safety concerns.
At the 200mg
dose where more than 2 percentage points reductions were reported, liver enzyme
elevations as measured by ALT were 2.7 times the upper limit of normal (ULN). Although the variability of these ALT
elevations was remarkably small, consistent with on-target toxicity, a 2.7 ULN
is a non-starter for a drug in this population when in the drug world instances
of 3x ULN are often a show stopper.
At the 100mg
dose things become much more tolerable with 1.6 times ALT elevations and little
variability all the while 1.35 percentage reductions in HbA1c were
achieved. I therefore expect more than
1.5 percentage reductions in HbA1c following more prolonged dosing without a
further increase in liver enzyme levels.
Additional dosing optimizations and potentially drug combinations will
be the subject of future phase II studies.
Best-in-class
profile
Merck and
Eli Lilly have also been developing GCGR inhibitors, but using small molecules to
inhibit the proteins instead of oligonucleotides to inhibit glucagon receptor synthesis. Apparently, these drugs have not only seen
liver enzyme elevations in humans, again consistent with the on-target toxicity
hypothesis of the ALT elevations, but more importantly cardiovascular safety signals such as increases
in blood pressure. Whereas Merck seems
to have given up on further development of MK-0893, clinicaltrials.gov shows that development is
ongoing for LY2409021, including a safety-related study to characterize its effect on blood pressure.
In data presented at the 2011 ADA meeting, MK-0893 achieved HbA1c reductions of ‘0.6 to 1.5 percentage points’ in a 12-week study, with 0.8 and 0.5
drops observed in the metformin and placebo control groups, respectively. As presented at the 2011 European diabetes meeting, an up to
1 percentage point reduction was achieved with the Lilly drug LY2409021 in a study of shorter duration. I am not sure whether
results from longer studies are known, but it is probably a good assumption
that the reductions will fall in a range similar to the Merck drug.
In sum,
the ISIS drug is at least as potent, if not more potent (à
on top of metformin) as the small molecule competitors, but without the
additional safety issues, particularly the blood pressure increases. In addition, being an oligonucleotide, it
should be much easier to combine them with other antidiabetic medications. On the competitive downside, the small molecule
inhibitors are orally available, whereas ISIS-GCGR is administered
subcutaneously.
Given the
central importance of glucagon signaling in glucose homeostasis, a GCGR
inhibitor will have its place in the enormous and fractured diabetes market.
2 comments:
if kynamro wasnt suitable for a broad population, hard to believe anything else they have will be. best of luck with an outcomes study.
With Kynamro there was very little benefit (target knockdown) and only risk left. With all others after that you see much more on-target efficacy at least. So it shifts the equation into larger patient populations. But of course, with ISIS, I will count my safety chickens only after I have seen the briefing docs.
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