Aerpio Therapeutics: Focus on Tie2 Activation

Aerpio Therapeutics is focused on the development of novel therapeutics for vascular disorders, with a concentration on eye diseases. Joseph Gardner, CEO of Aerpio, provided an overview of the company’s approach to addressing retinal diseases through activation of Tie2, a tyrosine kinase receptor. “Tie2 is now widely published as being one of the most important regulators of vascular tone and vascular leak, and being able to activate Tie2 is critical to maintaining a stable vasculature,” said Gardner. “How you go about activating [Tie2] actually does make a difference, so we think our approach to activating it is going to be advantaged over the anti-Ang2 approaches that are being pursued by Roche and Regeneron.”

AKB-9778 is a small-molecule inhibitor that blocks an enzyme that acts as a negative regulator at the Tie2 receptor and is up-regulated in all of the retinopathies (wet AMD, DME, and RVO), thereby restoring Tie2 signaling and vascular integrity. This small molecule is dosed systemically via subcutaneous injection rather than via intravitreal injection, enabling patient self-administered bilateral treatment.

In the company’s TIME-2 Phase IIa clinical study, 144 subjects with decreased vision from DME were evaluated with ranibizumab (Lucentis) and/or AKB-9778, either as monotherapy or in combination, over three months. Combination treatment showed a statistically significant reduction in central subfield thickness (CST) versus ranibizumab monotherapy. Gardner noted that this is the first time in a randomized trial that Tie2 activation has been demonstrated to improve the activity of an anti-VEGF. There was a positive trend toward vision improvement, but greater numbers or longer duration may be required to reach statistical significance. Additional analysis of the diabetic retinopathy severity score (DRSS) in non-study fellow eyes suggests that AKB-9778 monotherapy has the potential to favorably impact bilateral DR severity in earlier-stage disease.


Joseph Gardner

Joseph Gardner

Joseph H. Gardner, Ph.D. In December of 2011 Joseph founded Aerpio Therapeutics, Inc. as a spin out from Akebia Therapeutics, Inc. As CEO of Aerpio, Dr. Gardner successfully closed two series A financings which are funding the lead Tie2 activator, AKB-9778, through human proof of concept studies in patients with diabetic macular edema (DME).

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Joseph Gardner: Well, first, I want to thank Emmett and the organizing committee for inviting us this year to talk about our approach to activating Tie-2, which is similar to the mechanism that Regeneron has going after and Roche is going after with their anti-ANG-2 approach. So thank you David for introducing the topic of Tie-2. Tie-2 is now widely published as being one of the most important regulators of vascular tone and vascular leak. And being able to activate Tie-2 is critical to maintaining a stable vasculature. So it is a transmembrane receptor. It has to be dimerized and phosphorylated to be active. And how you go about activating it actually does make a difference. So we think our approach for activating is going to be advantaged over the anti-ANG2 approaches that are being pursued by Roche and Regeneron. So what Roche and Regeneron have ignored, and what we’ve leveraged, is there’s actually another negative regulator on the Tie-2 receptor, and that negative regulator is a phosphotase enzyme called VETPT. The phosphotase actually dephosphorylates the active receptor and inactivates Tie-2. And the phosphatase is also up-regulated in all the retinopathies, including wet AMD, DME, and RVO, just like ANG-2. So both factors are conspiring to turn Tie-2 off, which helps contribute to the pathologic state. So what we’ve done at Aerpio is we’ve developed a small molecule inhibitor of the phosphatase. And when you inhibit the inhibitor, you remove the brake and you activate Tie-2. So we know that our small molecule can activate Tie-2 in cells; it activates Tie-2 in animals, and it activates – well, it appears to have a clinical effect in the phase 2 trial I’ll show you in a moment. And the other important advantage is we can dose a small molecule systemically, and we can treat both eyes. So this is not an intravitreal injection. This would be the first patient self-administered drug to treat DME or wet AMD. Now why is the mechanism important, and why is our approach different? So this is a western blot showing activated or phosphorylated Tie-2 in the black blobs on the bottom. And each column represents what was in the lane. So if you look at the 2 yellow lanes, 2 and 3, there you have a high concentration of ANG-1 plus our phosphatase inhibitor 9778, and you get this super activation of Tie-2. However, even in the absence of ANG-1 our 9778 molecule can still activate Tie-2. And what was more interesting to us is lanes 4 and 5, where you have high concentrations of angiopoietin-2, and obviously in lane 4 you get no activation. But we can actually activate Tie-2 in the presence of high concentrations of ANG-2. Now I want to go back to lane 1 here and comment that OK, not having ANG-2 around, or removing it, is not necessarily going to be sufficient to get activated Tie-2. So it’s very unclear to us that the anti-ANG-2 approach is going to be as powerful as our approach based on this data and much additional preclinical data we have in animals as well. So it’s a very exciting as a drug developer to take a new mechanism, and in this case a new way to manipulate the mechanism into humans for the first time. And so last year we ran a well-controlled trial called the Time 2 study. This has now been published. Unlike Theranos and other companies, we actually publish our data in peer reviewed journals, and we are very transparent. And so we ran this randomized trial. The top bar is the monotherapy of 9778, with sham injections of Lucentis. The middle therapy is the combination arm, and that is monthly injections of Lucentis with daily subcutaneous injections of 9778 for 3 months. And the bottom arm is a contemporaneously randomized Luncentis control. Now we did this trial for 3 months because at the time we only had 3 months of tox data, and we powered the trial to see changes in anatomy. We did not really expect to get changes in vision in 3 months. We were hoping for that, but we were really expecting the changes in anatomy. So this is the primary result. This is the change in central subfield thickness, and as you can see, the monotherapy top line really didn’t do anything. Lucentis is the blue line, and it did pretty much what Lucentis normally does. And the combination arm in the orange line on the bottom gave a statistically significant improvement over Lucentis at months 2 and months 3. Now, whenever you see data like this, or whenever I see data like this, I always ask myself is that statistical significance real or is it driven by just 2 or 3 patients. So another thing we do to be transparent is we actually show the individual patient data. So this is a rank ordering of all the patients in the combination group and in the Lucentis group from the worst responders on the left to the best responders on the right. And you can see all the orange bars are the patients that had a significantly better decrease in retinal thickness versus Lucentis alone. So this is the first time in a randomized trial activation of Tie-2 has been demonstrated to improve the activity of an anti-VEGF. So we were very excited and encouraged by this. We did see a trend in visual acuity, shown here. That trend was – we barely moved the mean up to 6.3 letters. However, we did get a trend in improvement on 2 line gainers and 3 line gainers, and we’re very confident that if we run these trials out to 6 months or a year, we will be able to separate vision versus Lucentis or Eylea alone. Now the other thing we incorporated in the study was an analysis of the diabetic retinopathy severity score. And here we studied both the study eye and the fellow eye. In the study eye, we analyzed them based on the treatment groups, but for the fellow eye analysis, we analyzed them based on pooling the 2 arms that were treated with 9778 because in the fellow eye they didn’t get intravitreal injections. And we compared that to the placebo control. And what was very interesting to us is here the monotherapy actually worked as well as Lucentis. We got about a 10% increase in the two step improvers at 3 months, which is pretty similar to what Lucentis did in Rise and Ride. And what was interesting or more interesting to us is we got a fellow eye result as well, where the monotherapy improved the 2 step improvers in the fellow eye as well. So this demonstrates that our monotherapy may be useful for treating diabetic retinopathy, and we can move into earlier stage disease as we are going to focus on the combination therapy for DME, and then ultimately go after AMD as well. Real quickly, the safety profile was exquisitely clean. This will get presented later this week as ASRS, so I’m not going to go into this in the interest of time. So I just want to summarize that the Time 2 trial provides proof of concept that a combination therapy can actually improve an anti-VEGF. We also believe that we have an interesting signal and DR as well. So we do plan to move forward as combination therapy with an anti-VEGF for the treatment of DME, and we are going to move forward for the treatment of DR as well. So with that, in the interest of time, I will stop and thank you again for your attention, and thanks again for the invitation to speak.