Several companies developing kallikrein inhibitors to treat DME

Multiple companies are developing kallikrein inhibitor therapies for various routes of delivery to provide an alternative treatment for patients with diabetic macular edema rather than the traditional treatment of anti-VEGF injections.

Approximately half of patients with DME are not optimal responders to anti-VEGF injections to treat their disease. Companies are developing treatments to improve efficacy and sustainability of therapy for patients who do not satisfactorily respond to anti-VEGF injections, OSN Retina/Vitreous Board Member Pravin U. Dugel, MD, said.

“There are a lot of opportunities out there because approximately half of the patients with our current treatments ultimately are not optimal responders. You have opportunities to develop better therapies in terms of efficacy because there are many patients with DME that require more than just anti-VEGF injections. You also have an opportunity to develop drugs that offer more in terms of sustainability,” Dugel said.

Pravin U. Dugel, MD
Pravin U. Dugel

Encouraging clinical data

Several kallikrein inhibitor therapies are currently in preclinical and clinical development stages. Oxurion recently released positive topline data from a phase 1 study of THR-149, a plasma kallikrein inhibitor for the treatment of DME.

“It’s a first-in-man study, only 12 patients, but I think what one looks for in these early phase studies are two things. You look for a good safety profile and a biological signal. With the caution that it was only 12 patients, I think both were seen. The safety profile was excellent, and there was a biological signal,” Dugel said.

The open-label, multicenter, nonrandomized trial evaluated a single intravitreal injection of THR-149 at three ascending dose levels in 12 previously treated patients with visual impairment due to center-involved DME, according to an Oxurion press release.

Clinical data showed the therapy was well-tolerated and safe. By day 14, patients experienced an average improvement in best corrected visual acuity of up to 7.5 letters. The average BCVA improvement at day 90 was 6.5 letters after a single injection of the therapy.

“The study showed that this drug candidate is safe and delivers a rapid and sustained improvement in BCVA. This clinical profile suggests that it could potentially become a new best-in-class VEGF-independent therapy for treatment of DME patients. It could be used to treat, especially but not exclusively, those patients that do not respond to anti-VEGF therapy,” Patrik De Haes, MD, CEO of Oxurion, told Ocular Surgery News.

Oxurion is currently preparing the initiation of a phase 2 study with multiple injections of THR-149 and anticipates the enrollment of the first patient in early 2020, he said.

Oral therapies in development

Verseon has developed multiple novel chemotypes of small-molecule plasma kallikrein inhibitors to treat DME. The candidates have single-digit nanomolar potency and hundredfold selectivity over other serine proteases, David Kita, Verseon founder and vice president of research and development, told OSN.

The company is planning to take its first candidate to clinical trials in 2020, he said.

“These drug candidates show good pharmacokinetics and bioavailability suitable for oral dosing as prodrugs. ... Verseon’s candidates have also demonstrated efficacy in multiple preclinical in vivo models, including human plasma kallikrein and VEGF injection models. These models mimic the two key aspects of DME in humans, retinal thickening and retinal vascular permeability,” he said.

Verseon’s oral plasma kallikrein inhibitors could give patients an alternative to treat their DME without eye injections, Kita said.

“These drug candidates may be suitable not just for treatment, but they could also help prevent the onset of DME in millions of diabetes patients at risk,” he said.

Phase 2 data by 2020

KalVista Pharmaceuticals has several therapies in clinical or preclinical stages. It is evaluating the possibility of an oral plasma kallikrein inhibitor to treat DME and completed a phase 1 clinical trial of KVD001, an intravitreal plasma kallikrein inhibitor, according to a company presentation.

The open-label, single ascending dose phase 1 trial included 14 patients with DME previously treated with anti-VEGF. Researchers found KVD001 was well-tolerated, and patients gained an average of slightly more than four letters of BCVA by day 84.

The phase 2 study includes 123 patients with center-involving DME previously treated with anti-VEGF therapies. The sham-controlled, double-masked clinical trial will evaluate two doses of KVD001, and efficacy endpoints include BCVA, central subfield thickness and Diabetic Retinopathy Severity Scale score.

“The KalVista product is also an anti-kallikrein, and the target is the same as the Oxurion NV THR-149. The phase 2 results are expected to be released by the end of the year or perhaps early next year. We’re all waiting on the results,” Dugel said. – by Robert Linnehan

Disclosures: De Haes reports he is the CEO of Oxurion. Dugel reports he is a member of the scientific advisory board for Oxurion. Kita reports he is the founder and vice president of Verseon.

Multiple companies are developing kallikrein inhibitor therapies for various routes of delivery to provide an alternative treatment for patients with diabetic macular edema rather than the traditional treatment of anti-VEGF injections.

Approximately half of patients with DME are not optimal responders to anti-VEGF injections to treat their disease. Companies are developing treatments to improve efficacy and sustainability of therapy for patients who do not satisfactorily respond to anti-VEGF injections, OSN Retina/Vitreous Board Member Pravin U. Dugel, MD, said.

“There are a lot of opportunities out there because approximately half of the patients with our current treatments ultimately are not optimal responders. You have opportunities to develop better therapies in terms of efficacy because there are many patients with DME that require more than just anti-VEGF injections. You also have an opportunity to develop drugs that offer more in terms of sustainability,” Dugel said.

Pravin U. Dugel, MD
Pravin U. Dugel

Encouraging clinical data

Several kallikrein inhibitor therapies are currently in preclinical and clinical development stages. Oxurion recently released positive topline data from a phase 1 study of THR-149, a plasma kallikrein inhibitor for the treatment of DME.

“It’s a first-in-man study, only 12 patients, but I think what one looks for in these early phase studies are two things. You look for a good safety profile and a biological signal. With the caution that it was only 12 patients, I think both were seen. The safety profile was excellent, and there was a biological signal,” Dugel said.

The open-label, multicenter, nonrandomized trial evaluated a single intravitreal injection of THR-149 at three ascending dose levels in 12 previously treated patients with visual impairment due to center-involved DME, according to an Oxurion press release.

Clinical data showed the therapy was well-tolerated and safe. By day 14, patients experienced an average improvement in best corrected visual acuity of up to 7.5 letters. The average BCVA improvement at day 90 was 6.5 letters after a single injection of the therapy.

“The study showed that this drug candidate is safe and delivers a rapid and sustained improvement in BCVA. This clinical profile suggests that it could potentially become a new best-in-class VEGF-independent therapy for treatment of DME patients. It could be used to treat, especially but not exclusively, those patients that do not respond to anti-VEGF therapy,” Patrik De Haes, MD, CEO of Oxurion, told Ocular Surgery News.

Oxurion is currently preparing the initiation of a phase 2 study with multiple injections of THR-149 and anticipates the enrollment of the first patient in early 2020, he said.

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Oral therapies in development

Verseon has developed multiple novel chemotypes of small-molecule plasma kallikrein inhibitors to treat DME. The candidates have single-digit nanomolar potency and hundredfold selectivity over other serine proteases, David Kita, Verseon founder and vice president of research and development, told OSN.

The company is planning to take its first candidate to clinical trials in 2020, he said.

“These drug candidates show good pharmacokinetics and bioavailability suitable for oral dosing as prodrugs. ... Verseon’s candidates have also demonstrated efficacy in multiple preclinical in vivo models, including human plasma kallikrein and VEGF injection models. These models mimic the two key aspects of DME in humans, retinal thickening and retinal vascular permeability,” he said.

Verseon’s oral plasma kallikrein inhibitors could give patients an alternative to treat their DME without eye injections, Kita said.

“These drug candidates may be suitable not just for treatment, but they could also help prevent the onset of DME in millions of diabetes patients at risk,” he said.

Phase 2 data by 2020

KalVista Pharmaceuticals has several therapies in clinical or preclinical stages. It is evaluating the possibility of an oral plasma kallikrein inhibitor to treat DME and completed a phase 1 clinical trial of KVD001, an intravitreal plasma kallikrein inhibitor, according to a company presentation.

The open-label, single ascending dose phase 1 trial included 14 patients with DME previously treated with anti-VEGF. Researchers found KVD001 was well-tolerated, and patients gained an average of slightly more than four letters of BCVA by day 84.

The phase 2 study includes 123 patients with center-involving DME previously treated with anti-VEGF therapies. The sham-controlled, double-masked clinical trial will evaluate two doses of KVD001, and efficacy endpoints include BCVA, central subfield thickness and Diabetic Retinopathy Severity Scale score.

“The KalVista product is also an anti-kallikrein, and the target is the same as the Oxurion NV THR-149. The phase 2 results are expected to be released by the end of the year or perhaps early next year. We’re all waiting on the results,” Dugel said. – by Robert Linnehan

Disclosures: De Haes reports he is the CEO of Oxurion. Dugel reports he is a member of the scientific advisory board for Oxurion. Kita reports he is the founder and vice president of Verseon.