Mark R. Barakat, MD, and Michael Singer, MD

Today I have the pleasure of interviewing my good friend, Dr. Mark Barakat, at Retina Macula Institute of Arizona.

Dr. Barakat, you recently presented some interesting new data at the Angiogenesis meeting on a molecule from Kodiak called KSI-501. Can you please describe the molecule, the study, and the results?

We know that anti-VEGF agents are fantastic at controlling exudative retinal diseases, but there is still room for improvement. One of the pathways that we are looking at for this improvement is the IL-6 pathway. IL-6 is a pro-inflammatory cytokine that has been implicated in multiple retinal diseases and associated with poor anti-VEGF treatment response. It stimulates the effect of angiogenesis and it is involved in inflammation, as well as the breakdown of the blood-retinal barriers.

KSI-501 is a bispecific that has VEGF trap and anti-IL-6 antibodies, with the capacity to bind 1 VEGF and 2 IL-6 molecules. By combining this bispecific fusion protein—KSI-101 in its unconjugated state—with a high molecular weight biopolymer, we get KSI-501 as a biopolymer conjugate designed for increased molecular size and ocular half-life.

We know from preclinical data that, if you introduce vascular and RPE cells (key components of the inner and outer blood-retinal barriers) to exogenous VEGF and IL-6, they experience loss of tight junctions, mimicking the breakdown of the blood-retinal barriers. In turn, when treated with either an anti-VEGF or an anti-IL-6 agent, they normalize somewhat, but they normalize the most if they are introduced to KSI-501, which blocks both.

The KSI-501 phase 1 trial was a multiple ascending dose study of 4 doses in patients with diabetic macular edema (DME). There were 16 patients in the trial: 7 were treatment-naïve and 9 were previously treated. The trial was conducted at 5 sites with 3 to 5 patients in each dose group. Patients received 3 monthly intravitreal treatments and were followed for approximately 24 weeks.

Patients were the typical subjects you would expect to see in a DME trial: Their A1C was 12 or lower, their BCVA was between 25 and 70 letters, and their central subfield thickness (CST) had to be greater than or equal to 320 μm. We saw a response in BCVA and CST in both treatment-naïve and previously treated patients. Two-line gainers were between 66% and 71% in both the previously treated and treatment-naïve cohorts, and three-line gainers were between 22% and 43%. These data point to a biologic signal of potential BCVA vision improvements with this agent.

Ultimately, this was a phase 1 trial in which we prioritized safety as well as the biologic signals, and KSI-501 was well tolerated. One patient had mild intraocular inflammation with their first administration, which resolved with topical treatment and did not recur with re-treatment of KSI-501 on subsequent visits. No patients had retinal vasculitis, occlusive issues, or hypotony.

Tell me about OCT.

I do not have that breakdown in great detail yet, but I can tell you that the treatment-naïve patients had an approximately 100-μm improvement after their first treatment, which was sustained during the course of the trial. The previously treated population had improvement approaching 50 μm with treatment, which lasted for another 4 to 8 weeks. More data on that is forthcoming.

Was there an AMD portion of the study as well, or just DME?

There was no AMD portion, although that is certainly one of the disease states that is being considered going forward.

Tell us about next steps.

The next step in development is to bring forward KSI-501 as an antibody-bio-conjugate for retinal vascular diseases. There will also be KSI-101, a first-in-class bispecific anti-VEGF, anti-IL-6 without the conjugation to the biopolymer. KSI-101 will be put forward for macular edema secondary to inflammation.

KSI-501 can offer durability, which is something we look for in the clinic for high-burden retinal diseases. The unconjugated protein with KSI-101 offers a higher molar dose, which might be of more benefit in instances where patients may not need longer durability, but perhaps a bit more potency.

It is creating a stronger effect. This is exciting data.

Absolutely. I think we have been spoiled by the efficacy of anti-VEGF, and it is time that we start adding other mechanisms of action. We are starting down that path with anti-ANG-2, and hopefully we can add anti-IL-6.

I am always grateful to get a chance to talk to you, and our readers appreciate hearing this new data. Hopefully we will have the opportunity to use KSI-501 in clinical trials and ultimately add it to our arsenal.

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