Kodiak Sciences reported 12-week data from its phase 1a single ascending dose clinical study of KSI-301, an investigational anti-VEGF antibody biopolymer conjugate, in nine patients with severe diabetic macular edema.
After a single dose, eight of nine patients responded to KSI-301, as assessed by improvement from baseline in vision, anatomy, or both. Rapid improvements were observed as early as 1 week after the injection. The treatment effect increased through 4 weeks resulting in a median best corrected visual acuity (BCVA) improvement of 12.5 eye chart letters and median central retinal thickness on optical coherence tomography (OCT) improvement of 120 microns, pooled across all three dose levels.
Among the responders to KSI-301, all had sustained improvements from baseline (vision, retinal anatomy, or both) at the 12-week last visit. At 12 weeks after the single dose, a median BCVA improvement of 9 eye chart letters (almost two lines of vision) and median OCT improvement of 121 microns were observed, pooled across all three dose levels. The single non-responder subject had previously failed to respond through a regimen of Lucentis and Eylea treatments.
Through the 12-week last visit, single doses of KSI-301 demonstrated no dose-limiting toxicities, no drug-related adverse events, and no signs of intraocular inflammation. As previously reported, the highest dose tested, 5 mg, has been selected for advancement into pivotal studies.
In a previously-published phase 1 single-dose study with 4 mg aflibercept –twice the marketed dose of Eylea– in five patients with DME, 6 weeks after the single injection, four of the five patients showed improvement in BCVA (median improvement of 3 letters) and four of the five showed improvement in OCT (median improvement of 74 microns). At four weeks after the single injection, the median improvement in OCT was 49 microns and the median improvement in BCVA was 9 letters.
“We are very encouraged by the depth and durability of treatment responses. This study of KSI-301 was designed as a first-in-human, single-dose safety study and has exceeded our expectations from the standpoints of bioactivity and durability. DME can be a challenging retinal disease to treat due to high intraocular VEGF levels and concurrent retinal vascular inflammation. For example, the approved dosing regimen for Eylea in DME commences with five monthly loading doses. In our Phase 1a study, we observed compelling responses after only a single dose,” Jason Ehrlich, MD, PhD, Kodiak’s Chief Medical Officer and Chief Development Officer, said in a company news release. “We continue to believe KSI-301 has the potential to be a leading next-generation anti-VEGF therapy that addresses the heavy treatment burden and suboptimal real-world outcomes of current medicines. We are fully committed to the continued rapid clinical development of KSI-301 and will evaluate its potential broadly in the treatment of patients with retinal vascular diseases. Our phase 1b multiple-dose study is now recruiting patients with neovascular (wet) age-related macular degeneration, DME, and macular edema due to retinal vein occlusion. Given the results of the phase 1a study, we are excited about the potential for important durability signals to emerge in phase 1b.”
“These 12-week data also increase our confidence in the potential durability advantage of KSI-301 in wet AMD which is a more localized retinal disease with typically lower levels of VEGF compared to DME,” said Victor Perlroth, MD, Kodiak’s Chief Executive Officer. “For this reason, we have enhanced our wet AMD pivotal phase 2 study design to include evaluation of 20-week along with 16-week and 12-week dosing intervals in comparison to Eylea on its 8-week labeled regimen. We believe that, if successful, a regimen which provides nearly all patients with a 12-week or better treatment interval would be unique and industry-leading. We remain on track for this study to begin enrollment in the second quarter of 2019.”
“Furthermore, the bioactivity and durability profile of the treatment responses seen so far, as well as the observed safety profile, support the evaluation of KSI-301 in earlier forms of diabetic eye disease such as non-proliferative diabetic retinopathy,” said Dr. Perlroth. “Treating the right NPDR patients with an infrequent dose regimen and before vision loss occurs could have a tremendous public health impact. We look forward to sharing more about our strategy for earlier diabetic retinopathy over the course of the coming year.”
“In addition to the early-onset responses observed in some patients (as reported earlier), we were also pleased to see that initial treatment responses in some patients continued to increase in magnitude through the 12-week last visit, suggesting that KSI-301 may be affecting the disease in a way that we have not seen with currently available anti-VEGF agents,” said Diana Do, MD, Professor of Ophthalmology at Stanford University School of Medicine and Chair of the Kodiak clinical advisory board. “The science underlying KSI-301’s design and Kodiak’s ABC Platform is intriguing, and I look forward to presenting the data at the upcoming ophthalmology Angiogenesis meeting in Miami on February 9, 2019.”