AKB-9778 (Aerpio) is a small-molecule, vascular endothelial protein tyrosine phosphatase (VE-PTP) inhibitor that has shown promise as a potential therapy for diabetic macular edema (DME).

Peter A. Campochiaro, MD, professor of ophthalmology and neuroscience at Johns Hopkins Wilmer Eye Institute, has a long-standing interest in the role of the Tie-2 pathway in retinal diseases. His preclinical studies have shown the potential benefits of AKB-9778 in targeting Tie-2. He also helped design and conduct the TIME-1 Phase IB/IIA and TIME-2 Phase IIB studies.1 TIME-2 results will be presented at the American Academy of Ophthalmology meeting  in November. Here, Dr Campochiaro lends insight into the TIME-1 trial.

The mechanism of action in his words:
AKB-9778 is a small-molecule antagonist for a phosphatase, VE-PTP, that normally keeps Tie-2 in the dephosphorylated, inactive state. Tie-2 is an endothelial-cell-specific receptor that, when phosphorylated, promotes quiescence and unresponsiveness to stimuli that cause endothelial-cell proliferation and/or leakiness. By antagonizing VE-PTP, which suppresses Tie-2, AKB-9778 activates Tie-2 and promotes quiescence.

How AKB-9778 and anti-VEGF differ:
Vascular endothelial growth factor (VEGF) is an important stimulator of vessel leakiness and neovascularization, and injections of VEGF-neutralizing proteins provide benefit in neovascular age-related macular degeneration, DME and macular edema due to retinal vein occlusion. Some patients obtain maximal benefit (elimination of all intraretinal and subretinal fluid) and some have considerable persistent fluid and reduced vision. These patients either have such high VEGF levels that it is not possible to neutralize them or other contributing factors. Activation of Tie-2 makes endothelial cells less responsive to VEGF and other pro-permeability/proangiogenic factors.

How that influences the additive effect of AKB-9778:
VEGF antagonists compete with VEGF to try to prevent binding to endogenous receptors to stimulate them. So if the VEGF levels are particularly high, then the antagonists are less effective because they basically compete. It’s in an equilibrium.  


Under normal conditions, Tie-2 activity is maintained by the binding of the activating ligand angiopoietin-1 (Ang1) or by oligomerization of the Tie-2 receptor. In diseased states, the negative regulators of Tie-2, Ang2 and vascular endothelial-protein tyrosine phosphatase (VE-PTP) are upregulated.  (Courtesy of Aerpio Therapeutics.).

AKB-9778 makes endothelial cells less responsive, so it requires more VEGF stimulation to have the stimulatory effect. Together, they work differently to reduce VEGF receptor signaling. Also, since AKB-9778 reduces endothelial-cell responsiveness to other factors besides VEGF, it addresses both issues that may make anti-VEGF agents suboptimal in some patients.  

What the open-label, dose-escalation Phase IB/IIA clinical trial revealed:
The dose-ranging study started with a 5-mg subcutaneous injection b.i.d. With that dose, there were no adverse effects and no effect on DME. With the second dose, 15 mg b.i.d., four out of six patients showed a substantial reduction in foveal thickness with some improvement in vision. In an uncontrolled trial, one cannot be certain that the effects are due to the agent and not simply to chance, but these were pretty substantial effects, so it appears that they were drug-related.

The next dose was 30 mg b.i.d. Two patients had a dramatic reduction in edema, which was less than in the 15-mg cohort. Both the 15-mg and 30-mg b.i.d. cohorts showed a mild reduction in mean systolic blood pressure, an on-target effect, because Tie-2 stimulates endothelial nitric oxide (NO) synthase, increasing NO and causing vasodilation.

One patient had a vasovagal episode consisting of slowed pulse, reduced blood pressure, dizziness and nausea. This might have been initiated by a greater-than-usual reduction in blood pressure, so a dose between 15 and 30 mg b.i.d., 22.5 mg b.i.d., was tested. In the 22.5-mg cohort, two patients had large reductions in edema and others had mild or no reduction. One patient had a vasovagal episode.

Several patients showed reduction in edema and improvement in vision, but not all showed a response. Therefore, it was felt that treatment with AKB-9778 alone might be sufficient in some patients with DME, but for most it may need to be combined with an anti-VEGF agent.   

These results helped to inform the design of the Phase II trial in which patients were randomized into three arms: AKB-9778 15 mg b.i.d., ranibizumab 0.5 mg (Lucentis, Genentech) intravitreous every four weeks or a combination of both. Phase IIB results will be presented at the American Academy of Ophthalmology meeting in November.

The most significant finding of the trial:
This is an agent that can be given systemically—it’s given subcutaneously—and it was shown to be quite safe. It causes a small reduction in systolic blood pressure, which is a desirable thing in most patients, but at doses above 15 mg b.i.d. it caused a vasovagal episode in two patients after the first injection, which is something that will be monitored closely in future trials.

A major advantage is that patients can self-administer the drug, which may help to reduce clinic visits. A potential advantage is that stimulation of Tie-2 in other vascular beds, particularly those of the kidney, may be beneficial in diabetics.

Big questions the Phase IIB trial should answer:

1) Are there enough patients who have an optimal response to AKB-9778 alone to consider monotherapy as a possibility? The heterogeneity seen in the Phase I trial suggested that this is unlikely but it is important to test this in a larger group of patients.

2) Does the combination of AKB-9778 and  ranibizumab have a greater effect on the reduction of DME than ranibizumab alone?

3) Are vasovagal effects a problem in patients treated with AKB-9778 15 mg b.i.d., as was seen in occasional patients treated with higher doses, and, if so, are there good strategies to manage them?

Big question the Phase IIB trial won’t answer:
Is 15 mg b.i.d. the optimal dose of AKB-9778?  RS


References
1. Campochiaro PA, Sophi R, Tolentin M. Treatment of diabetic macular edema with an inhibitor of vascular endothelial-protein tyrosine phosphatase that activates Tie-2. Ophthalmology. 2015;122:545-554.