AKST4290, an Oral Therapy for nAMD, Shows Promise in Phase 2a Studies

October 16, 2019

Michael Stewart, MD, of Mayo Clinic Jacksonville, discusses the results of 2 phase 2a studies examining the use of AKST4290 in treatment naive and refractory neovascular age-related macular degeneration.

A new era in the treatment of age-related macular degeneration could be on the horizon, as a potential oral therapy has shown the ability to be well tolerated and improve visual acuity.

AKST4290, a small molecule antagonist of human CCR3, was shown to improve vision in patients with treatment naive and refractory neovascular age-related macular degeneration(nAMD) in phase 2a and 2b studies presented at the American Academy of Ophthalmology (AAO) 2019 Annual Meeting in San Francisco.

To assess the safety and effectiveness of AKST4290, investigators enrolled cohorts of 30 treatment naive patients and 26 refractory nAMD patients from Poland and Hungary. Mean age of the treatment naive cohort was 73 years, 60% were women, had the disease for a mean of .28 years, and had a best-corrected visual acuity (BCVA) of 56.6 at baseline. Among patients in the refractory cohort, mean age was 76 years, 61.5% were female, mean duration of the disease was 1.9 years, and the mean BCVA was 52.7.

Patients received treatment over the course of 6 weeks and were directed to use the oral therapy twice daily. At the end of the studies, 29 patients were analyzed in the naive cohort and 25 remained in the refractory cohort. Upon analyses, which included information from a follow-up period period that lasted until day 71, investigators noted improvements in BCVA in both studies.

Among patients with refractory nAMD, investigators observed 72% of eyes experienced maintenance or improvement in BCVA at week 6 and mean improvement in the group was 2 letters. Furthermore, 32% experienced a gain of 0 to less than 5 letters, 40% gained 5 or more letters, and 8% experienced a gain of more than 10 letters.

In those included in the treatment naive cohort, the mean BCVA gain was 7 letters and 83% of eyes achieved maintenance or improvement in BCVA. Of those patients, 28% experienced a gain of 0 to less than 5 letters, 55% gained 5 or more letters, and 21% experienced a gain of more than 10 letters.

To learn more about the potential of this treatment and what it would mean for the patient burden incurred by anti-VEGF injections, lead investigator Michael Stewart, MD, of Mayo Clinic Jacksonville, sat down with us at AAO 2019 to lend his perspective and give insight on future trials.

MD Mag: Can you elaborate on the AKST4290 results presented at AAO 2019?

Stewart: Both of the trials that we'll discuss have been 2a—they were run parallel with each other. One was a treatment naïve that we've done with just over 2 dozen patients. Patients with newly diagnosed neovascular age-related macular degeneration treated with oral AKST4290 dosed twice daily for 6 weeks after which, patients were observed for an additional 4 weeks while off all therapy and in that trial patients improved by an average of 7 letters of visual acuity with a drop-off of almost 3 letters after the conclusion of therapy. Through the 4 week follow-up period, patients had no statistical change in central subfield thickness but they interestingly didn't have a significant decrease in retinal pigment epithelial detachment height. Patients tolerated the drug well, there were only minimal systemic side effects—none of which required cessation of therapy.

In the second trial, done in parallel, again with just over 2 dozen patients. This was done in patients who were previously treated with standard anti-VEGF therapy and were deemed to be incomplete responders—persistent fluid despite monthly therapy and visual acuity improvements of less than 5 letters. So, in these patients anywhere from 30 to 90 days after their last anti-VEGF injection. Patients were then begun on, again, twice-daily AKST4290 oral therapy, treated for 6 weeks, (and) followed for an additional four weeks after cessation of therapy. In these patients, the visual acuity improved by mean of 2 letters at the 6-week primary end point. Again, central sub field thickness changed minimally but, interestingly, after completion of therapy when patients were off all treatment the central subfield thickness increased significantly afterwards—suggesting the drug may have had an inhibitory effect on leakage while treatment was actually being administered. Once again, the drug was tolerated very well. No patients were forced to discontinue therapy throughout the trial.

MD Mag: How would an oral therapy impact the current state of nAMD?

Stewart: So, if this is substitute for anti-VEGF therapy, not a complete substitute but, if it's significantly lessens the burden of interventional injections or significantly expands the timeframe between injections or after initial therapy completely obliterates the need for therapy, then patients would not have to have injections into the eye with all the discomfort and risks that it engenders. They wouldn't have to come to a physician’s office anywhere near as often. Therefore, it wouldn't have to be a burden on others to bring them to the office and they wouldn't have to undergo all the anxiety, etc. that is related to intravitreal therapy.

So, what it does is it allows patients to be much more independent and lessens the necessary interaction with the physician's office thereby allowing the physicians to see other patients who are needful of diagnosis and treatment for this or any other number of diseases. Interestingly, the potential advantage to oral therapy is what it may do therapeutically to the other eye. Either in terms of treating both eyes simultaneously—potentially, this is to be investigated down the road as a inhibitory factor in the other eye or since it's an anti-inflammatory, even whatever effects it may have on the development of geographic atrophy. All these are questions to be answered in future studies.