A summary of my DD into Atherogenics (AGIX). This first post is background. Feel free to comment/rip.
Science – The primary drug (currently in a large Phiii of MACE for CAD which will report in Q1) is AGI-1067. It is based on Probucol which was pulled from the US market in the mid to 90’s due to lowering HDL and prolonging Qtc interval – but Probucol has been shown in a randomized trial to be about as efficacious in MACE as statins (I guess this plus Torc pretty clearly shows HDL isn’t everything). Some of the primary design criteria for AGI-1067 were to avoid the Qtc and yet to continue to act as an anti-inflammatory agent. The most thoroughly documented proposed method of action has been to turn down Redox Sensitive Inflammatory Gene Expression in endothelial cells (VCAM-1 etc) and in macrophages (TNF-α etc.).
Finished Trials:
1) Ph I’s showed that it is efficacious in slowing atherosclerosis in a variety of animal models despite having a varied effect on HDL and LDL (in some models it actually increased total cholesterol – but it still decreased atherosclerotic burden).
2) CART-I a dose ranging trial (6 weeks on medication) to treat restenosis and measure via IVUS measurements at week 2 and 6 months. On most measurements there was a clear benefit to lumen volume and total vessel volume in the higher two doses of AGI-1067 (and Probucol) vs placebo or the lowest dose of AGI-1067. There was also a secondary endpoint of IVUS measurement on a reference segment (not stented) with similar results to the stented version.
3) CART-II was intended to be another IVUS restenosis trial but with 12 months on medication and 3 different protocols vs placebo (450 people total). But it was changed in the middle of the trial to be about the non-stented sections. There is significant controversy here because the initial IVUS results were from the evaluation of the Montreal Heart Center (MHC) and showed stronger efficacy than later analysis by the CCF. (the CCF not only saw somewhat lesser benefit to AGI-1067, but also threw out half of the patients as unevaluatable – but despite this improved the p value in some cases because they lowered the measurement error). But even the CCF saw IVUS efficacy the same as, or better than, the REVERSAL trial of high dose Atorvastatin – and stat sig benefit vs SoC for both total atheroma volume and atheroma volume in most diseased 10mm. The paper for this trial is still not published although it has been 2+ years since the end of the trial. Other known results of this trial – significant efficacy on MPO (there is some evidence this is a stronger marker than CRP), no Qtc prolongation and lowered HDL.
4) ALPS – 250 patients not on statins randomized to either AGI-1067 or placebo to look at blood parameters related to LDL and HDL. Raised LDL very minorly, lowered HDL 4-6% although it might be somewhat transient. Increased CETP mass stat significantly. No effect on CRP.
Ongoing trials – only 1 that I know of for AGI-1067: ARISE. 6000+ patients with MI within previous year. Event triggered at about 1000 events. Events are Cardiovascular MACE. Trigger hit in August and company announced would finish analysis in early 2007. Note that in June it released blended event curve relative to IDEAL and PROVE-IT. See later post for analysis.
Partnership with AstraZeneca – development and regulatory milestones of up to $300M and additional sales milestones up to another $650M. Stepped royalties on sales (mid teens to mid thirties).
Moderately strong insider buying by Chief Medical Officer and two directors in the last 9 months (when ARISE took too long to end).
Will follow up over the next few days with a post on the blended result of ARISE, a positives post and a concerns post. Again, feel free to critique.
