ALK4290 and Potential of Oral Therapies for Neovascular AMD

An oral treatment for neovascular age-related macular degeneration for patients who have not responded well to standard anti-VEGF therapies may soon be on the horizon. 



Results of an open-label phase 2a study examining the use of AKST4290 (ALK4290), a C-C chemokine receptor type 3 (CCR3) antagonist, for 6 weeks in patients with nAMD refractory to anti-VEGF therapy was presented at the 2019 American Society of Retina Specialist Annual Meeting. 



Presented by Michael Stewart, MD, the study returned positive results for what could become the first oral nAMD treatment. To determine the efficacy and safety profile of AKST4290, investigators conducted a study in Hungary and Poland where patients were given 400 mg tablets of ALK4290 twice daily by mouth for 6 weeks. 



To be included, patients had to be at least 50 years old and have active, refractory nAMD. Patients must have received at least 3 consecutive anti-VEGF injections with their last injection taking place between 30 and 90 days prior to the screening visit. Additionally, patients needed to have persistent sub retinal or intraretinal fluid, and absence of improvement of best-corrected visual acuity.

Endpoints for the study included safety and tolerability, early treatment diabetic retinopathy study (ETDRS) BCVA assessment, and morphological measurements with the spectral domain optical coherence tomography fundus and photography/fluorescein angiography. Investigators noted that additional exploratory biomarker analyses were performed.

A total of 25 patients completed the study, which included an additional 2 weeks of follow-up following dosing. The mean age of participants was 76 years and, at baseline, subjects had a man BCVA of 53.4 letters and a mean disease duration of 1.9 years.

Upon analyses, investigators found that the mean BCVA was +2 when compared to baseline. Investigators noted that 72% of subjects either improved or maintained their vision, 40% had a 5 letter gain, and 8% had a 10 letter gain. 



Of the patients who gained 5 letters, the mean change in BCVA was +7.7 letters. No adverse events led to discontinuation of ALK4290. 


After his presentation at ASRS 2019, Stewart sat down with MD Magazine to discuss the implications of the phase 2a study.





MD Mag: What were the results of the phase 2a study examining ALK4290 (AKST4290)?

Stewart: So, what we're reporting on today is the results of treatment with AKST 4290 in patients with treatment-resistant neovascular age-related macular degeneration. The current standard of care is intravitreal anti-VEGF for patients with choroidal neovascularization due to neovascular AMD and though most patients respond well to therapy there is a significant minority of patients who don't do well either morphologically or functionally. So, an additional therapy that is either incremental to or in place of anti-VEGF therapy in this difficult to treat patients would be advantageous.

So, this was a phase 2a trial formed in Hungary and Poland on patients who had treatment-resistant neovascular AMD. 26 patients were enrolled in the trial and 24 patients were to completion. Entrance criteria was standard for neovascular AMD trials but patients were required to receive at least 3 anti-VEGF injections and the last one had to be between 30 and 90 days prior to the screening visit. So patients that were enrolled in the trial were typical of patients with neovascular AMD in terms of their demographics.

What we found with the results was with 6 weeks of AKST4290 monotherapy, the mean best corrected visual acuity was at +2 letters and 72% of patients had stable or improved visual acuity by the 6-week endpoint. We found that central subfield thickness of the macula did not change significantly over the 6-week period but, interestingly, after treatment was stopped, over the 4-week follow-up period central subfield thickness increased significantly — suggesting that withdrawal of therapy actually worsened the disease.

Secondly, the retinal field epithelial detachment height did not change significantly during the trial, which actually was a little bit different because in the 2a trial treatment-naïve patients pigment epithelial detachment height decreased significantly while on therapy. Patients tolerated the drug well, there were very few systemic or ocular adverse events and no patients discontinued the trial because of serious adverse events.

So, what we found with this molecule is that we found that in patients with treatment-naïve disease in a previous 2a trial is that visual acuity improved by 7 letters, which is actually quite impressive at 6 weeks and that was with monotherapy. In that trial, 83% of patients improved or had stable visual acuity and 21% improved by at least 3 lines. In the study today, inpatients who failed anti-VEGF therapy we found an improvement of 2 letters at 6 weeks with monotherapy. Again, a reasonable signal for therapeutic effect that deserves further evaluation.

So what we're looking at now down the road is trying to further develop this molecule for use as monotherapy or potentially as a supplemental therapy to anti-VEGF therapy and the advantages are oral therapy as opposed to intravitreal injections. So, the patients can be treated at home, decrease the needs for visits to the office, decrease the backlog of patients that are clogging up the retinal physicians’ offices, and to decrease the current reliance on regular repeated anti-VEGF therapy. So, this may be, if it works well, the first oral therapy for age-related macular degeneration.