ISIS-GCGR on Path to Become Important Diabetes Drug

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.