I recently had the pleasure of returning to my hometown of San Diego for the 49th annual Macula Society meeting. One of the anticipated highlights was the opportunity to hear about the latest tyrosine kinase inhibitor, OTX-TKI (Ocular Therapeutix), which had just announced the topline results of its Phase III SOL-1 trial in subjects with wet age-related macular degeneration.

Many of us have been looking forward to the promise of 6+ month durability with TKIs. SOL-1 was designed as a superiority trial to show that it’s better than aflibercept 2 mg. At first glance, the primary endpoint results seemed good with the proportion of subjects losing <15 ETDRS letters from baseline at week 36 being 74.1 percent in the OTX-TKI arm versus 55.8 percent in the aflibercept 2 mg arm (p=0.0006). However, in contemplating the study design and discussing with others, it’s really concerning from an ethical standpoint.

Patients in SOL-1 were selected based on their response to aflibercept. After receiving two monthly loading doses, they had to achieve a best-corrected visual acuity of 20/20 or gain at least 10 ETDRS letters along with a central subfield thickness of 350 µm or less. By design, the study clearly selected the best responders. They were then randomized to the OTX-TKI arm versus aflibercept arm and received that drug on day one. Subjects could only receive rescue aflibercept through week 52 if they lost 15 ETDRS letters or had new vision-threatening macular hemorrhage. Such rescue criteria seem egregious since we know that patients with wet AMD who lose vision, for example due to loss to follow-up, will typically not recover it even after treatment is restarted.1 During the presentation, no details were given about the 25.9 percent of subjects in the OTX-TKI arm or the 44.2 percent in the aflibercept arm who required rescue therapy by week 36. How many recovered vision back to their optimal level?

During the session, the speakers seemed to indicate that the trial design was not only endorsed by the Food and Drug Administration, but that it, in fact, was demanded. When we entered medical school and took the Hippocratic Oath, the first principle was to do no harm. While I wasn’t privy to the conversations with the FDA, I would argue that it would be imperative to educate them and explain that such a study design doesn’t meet that basic tenet. I hope that future studies will use rescue criteria that most of us would consider reasonable and minimizes the risk of permanent vision loss for our patients. RS

 

REFERENCE

1. Soares RR, Mellen P, Garrigan H, Obeid A, Wibbelsman TD, Borkar D, Ho AC, Hsu J. Outcomes of eyes lost to follow-up with neovascular age-related macular degeneration receiving intravitreal anti-vascular endothelial growth factor. Ophthalmol Retina 2020;4:2:134-140.