Episode 1: Retinal Physician Editor in Chief Diana Do, MD, interviews Dean Eliott, MD, professor of ophthalmology at Harvard Medical School, about TH103 (Kalaris Therapeutics), a pipeline drug to treat exudative and neovascular retinal conditions, including nAMD.
This editorially independent content is sponsored by Kalaris Therapeutics.
What follows is a lightly edited transcript of the conversation.
Diana V. Do, MD: Hi, welcome to Retinal Physician. I’m Diana V. Do, MD. Today I'm joined by one of the great retina leaders, Dean Eliott, MD, a professor of ophthalmology at Harvard Medical School. Dean, there's some exciting new technology now for neovascular age-related macular degeneration (nAMD). And one of the new drugs in clinical development was invented by Napoleone Ferrara, MD, who developed ranibizumab (Lucentis; Genentech) and added so much knowledge on how to treat vascular diseases.
This new agent, TH103 (Kalaris Therapeutics), targets both VEGF and heparan sulfate proteoglycans (HSPGs). Tell us a little bit about this new innovation.
Dean Eliott, MD: So the idea behind the molecule first got me excited, but we're pretty good at anti-VEGF drugs, right? We have great drugs, they have great efficacy, incredible safety, but the durability is not so great. And TH103 offers an opportunity to increase the durability. We'll find out if that's true when more clinical trial work is done.
Basically, you have an anti-VEGF portion, and you also have something that enables the drug to bind to naturally occurring tissue. And that tissue is within the retina, so potentially keeping the drug around longer as a reservoir and improving the durability.
Dr. Do: That's very exciting. And now we actually have some first-in-human clinical trial data. Can you share with us what you saw in the phase 1 study?
Dr. Eliott: The phase 1 study was pretty exciting. There were 17 patients with treatment-naïve nAMD, and they received a single ascending dose of TH103. What was most interesting was that at the 6-month endpoint—remember, they only had 1 injection—about one-third of patients didn't need any rescue. In addition, the patients had remarkable efficacy: at 1 week, the OCTs were considerably improved; at 1 month, they stayed really nice.
So we have potent anti-VEGF activity and we have some suggestion of durability. Obviously, this is phase 1, the numbers are small, and there's no control group. But nevertheless, the data is very encouraging.
Dr. Do: That's amazing if 1 single intravitreal injection truly can be this durable. You mentioned the technology—it binds to intraocular tissue to do this. And is the molar dose also playing a role? Is it a higher molar dose of a VEGF inhibitor as well?
Dr. Eliott: So there are ways to improve durability. One is to just inject a lot of anti-VEGF drug. That's not really what this is doing. Basically, you have something similar to aflibercept in that you have VEGF receptor 1 domain 2, which is very high affinity for VEGF. But instead of VEGF receptor 2 domain 3, which is on aflibercept, you have VEGF receptor 1 domain 3, and that binds to heparan sulfate proteoglycans.
So what are those things? So they're called HSPGs. They're heavily glycosylated proteins. They're in tissues. They're on cell surfaces and in the extracellular matrix. So if you inject the drug intraocularly, presumably the drug based on the VEGF receptor 1 domain 3 binds to the HSPG in the tissue. It keeps the drug around longer and the drug is still able to bind VEGF through the other domain.
Dr. Do: When this new technology is introduced into the human eye as an intravitreal injection, are there any safety concerns?
Dr. Eliott: With every drug, there are safety concerns. We have remarkable safety with the existing drug, so it's a high bar. There were some safety issues in the phase 1 clinical trial. Two patients at the 2.5 mg dose had some pretty mild inflammation that was controlled with steroids. That was in the first batch of drug. As you know, this is pretty common in drug development that early batches have inflammation. It's thought to be due to host cell proteins.
The company then refined the manufacturing process for batch number 2. Six patients were treated at the 2.5 mg dose and didn't have any inflammation. However, 1 patient at the 5 mg dose—the highest dose, because there was a dose escalation—they did have some transient mild inflammation. Once again, it was controlled with steroids.
There was another patient that had a 1.5 mg dose, but actually was on the third monthly injection. It was a different study because it wasn't just the single ascending dose. This patient had multiple doses. That patient also had some mild inflammation. So there's still some issues. They're being ironed out and I'm pretty confident that with additional host cell protein reduction through further manufacturing optimization that the drug can be more purified, as is very common in drug development.
Dr. Do: What are the next steps? Are you going to embark on a phase 2 clinical trial now or go straight to a phase 3?
Dr. Eliott: They are already enrolling a Phase 1b/2, where they'll have more patients and patients receive a 4-loading-dose regimen followed for up to 9 months and are retreated if needed. And we'll find out about the efficacy, safety, and durability. These are small numbers so far; we can't really conclude much, but the preliminary data is extremely encouraging. We have a great rationale as to why this might offer the advantages that I specified, particularly with durability. It's a brilliant idea by Napoleone Ferrara, no doubt. He always comes up with the brilliant ideas. So it's really exciting.
Dr. Do: This is such important information and it's exciting to see you as part of this innovation. We'll look forward to more data on TH103. Thank you, Dr. Eliott.
Dr. Eliott: Thank you, Dr. Do.