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CLINICAL TRIAL DOWNLOAD: Safety Data on KSI-301 Antibody Biopolymer Conjugate for Retinal Disease

Retina specialists discuss phase 1b data for a drug with potential for quarterly or longer administration.

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Carl C. Awh, MD Tennessee Retina, Nashville, Tennessee

Safe and effective treatment delivered via quarterly intravitreal injections would represent a tremendous improvement over the current standard of care for neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), and retinal vein occlusion (RVO). Could KSI-301 (Kodiak Sciences) provide this benefit? The preliminary outcomes of treatment in the phase 1b study of KSI-301 presented by Pravin Dugel, MD, at the 2019 American Society of Retina Specialists (ASRS) Annual Meeting are certainly tantalizing. No significant adverse outcomes were coupled with impressive positive effects on OCT thickness and vision. It’s a long road from phase 1 to a successful phase 3 outcome, but the glimpse provided by Dr. Dugel is intriguing and exciting.

Diana V. Do, MD Byers Eye Institute, Stanford University, Palo Alto, California

KSI-301 is a promising intravitreal VEGF inhibitor built with antibody biopolymer conjugates (ABC), a new class of molecules consisting of an antibody stably linked to an optically clear, high molecular weight phosphorylcholine biopolymer. KSI-301 is designed to have high retinal tissue bioavailability, high binding affinity and anti-VEGF potency, extended intraocular half-life, and rapid systemic clearance. In a phase 1a study in DME, KSI-301 met its primary endpoint and demonstrated safety with no ocular inflammation. In addition, KSI-301 demonstrated durable bioactivity after a single injection. A phase 1b study (NCT03790852) is ongoing, with 77 subjects enrolled as of July 24, 2019. To date, ocular safety of KSI-301 has been encouraging, with no reports of intraocular inflammation and no drug-related adverse events after 190 doses given. At the ASRS 2019 Annual Meeting, initial efficacy results were presented for the first 35 patients who reached 12 weeks of follow-up. Rapid, high-magnitude responses were observed in all cohorts. The median improvement in BCVA score was +8 letters in neovascular AMD (n=17, baseline 66 letters), +9.5 letters in DME (n=8, baseline 69.5 letters) and +26.5 letters in RVO (n=10, baseline 52.5 letters). The median improvement in OCT CST was -72 microns in neovascular AMD (baseline 380 microns), -197 microns in DME (baseline 491) and -209 microns in RVO (baseline 513). KSI-301 represents an exciting new technology with the potential to solve the real-world effectiveness problem. A phase 2 clinical trial in neovascular AMD, called DAZZLE (NCT04049266) will start in fall 2019.

Peter Kertes, MD Sunnybrook Health Sciences Center and University of Toronto, Toronto, Ontario

Among the many different strategies, devices, and agents that are being investigated to decrease treatment frequency in neovascular AMD, DME, and RVO, the Kodiak anti-VEGF ABC is certainly among the most innovative and exciting. This large optically clear molecule’s potential to act as a reservoir in which truly any drug or combination of drugs available now and in the future can be embedded, delivered by simple intravitreal injection make it a likely winner. Such a strategy would all but eliminate the fear of catastrophic vision loss that many of us have as we step our patients out to ever longer intervals in our treat-and-extend regimens. For the promising early outcomes in the small group of patients presented at ASRS, I wonder why the company and the investigators felt the need to still dose patients monthly for their first 3 injections. It is a large molecule and I worry that the added viscosity that I would anticipate would make it difficult to inject through a small-gauge needle.

Jason Ehrlich, MD, PhD Chief Medical Officer and Chief Development Officer, Kodiak Sciences Inc.

As Drs. Awh and Kertes allude to, one of the biggest challenges in the field of retinal therapeutics is the inadequate durability of our existing medications. The need for frequent injection of anti-VEGF therapy is a tremendous burden on both physicians and patients, and — even more importantly — may lead to diminished outcomes for patients. Additionally, there are some diseases, like nonproliferative diabetic retinopathy, for which anti-VEGF therapy is highly efficacious but where the chronicity of the disease means frequent intravitreal injections are not likely to be acceptable to patients.

Kodiak’s ABC technology is a new scientific approach for intravitreal drugs. The technology was developed in house at Kodiak and merges the fields of antibody-based and chemistry-based therapies. ABC medicines are designed to maintain potent and effective drug levels in ocular tissues for longer than existing agents. The first ABC medicine to enter the clinic is KSI-301, an anti-VEGF ABC. We were pleased with the promising efficacy and safety data presented at ASRS. Across all 3 disease areas under study in the multiple-dose phase 1b study, strong improvements were observed in vision and retinal anatomy, along with encouraging signs of disease modification. Additionally, more than 200 injections with KSI-301 have been given to date with no intraocular inflammation or ocular serious adverse events reported; these safety data are important as they further support our conviction in both KSI-301 and the broader ABC platform.

Dr. Kertes raises 2 important questions: first, are 3 initial monthly doses necessary? From an efficacy perspective, this is an important question in the field. There may be a theoretical benefit to “loading” the eye with more drug, in terms of maximizing early outcomes and needing fewer or less-frequent maintenance doses later. Ultimately, this can only be answered through a randomized study, and we hope to study that question in the future. For Kodiak’s phase 1b study, an additional key goal is understanding the safety of multiple, sequential doses of KSI-301, and the 3 monthly initiating doses are important there. As to injectability, KSI-301 in the phase 1b study is injected using a 30-gauge needle.

In Kodiak’s upcoming phase 2 DAZZLE study, we will compare KSI-301 against aflibercept in patients with treatment-na├»ve wet AMD. All patients randomized to KSI-301 will receive it on an every-12-week or longer interval after the initiating doses. As Dr. Awh notes, treatment delivered quarterly would be a great improvement to the current standard of care, and we are excited about the potential for KSI-301 to meet or even exceed this high bar. RP