|By Richard Mark Kirkner, Editor|
Oxurion is in the unique position of pursuing two candidates to treat exudative retinal disease on parallel tracks: the plasma kallikrein inhibitor THR-149 for diabetic macular edema that doesn’t respond to anti-VEGF therapy; and the small-molecule pan-RGD integrin antagonist THR-687, which the company says is a potential first-line treatment for DME.
The Phase II KALAHARI trial of THR-149 is currently recruiting, with a readout due later this year. Arshad Khanani, MD, MA, managing partner and director of clinical research and fellowship at Sierra Eye Associates in Reno, Nevada, and a clinical associate professor at the University of Nevada, answers questions about the trial. Dr. Khanani is a consultant to and receives research support from Oxurion.
Q: Please describe the mechanism of action of THR-149 in your own words.
A: THR-149 is a highly potent, subnanomolar reversible inhibitor of human plasma kallikrein (PKal). Plasma kallikrein is a serine protease, which has been implicated in many physiological and pathological processes. The plasma kallikrein kinin system (KKS) is activated during vascular injury. KKS activation leads to PKal activation, which triggers the release of the vasoactive peptide bradykinin.
Intraocular activation of the KKS has been shown to increase retinal vascular permeability and retinal thickening, and these responses are exacerbated in diabetic animals. PKal deficiency and pharmacological inhibition of PKal lowers bradykinin levels and reduces retinal edema.
Encouraging preclinical data have shown the potency and efficacy of bicyclic peptide inhibitors of PKal such as THR-149.1
Q: What’s the rationale for targeting DME in the Phase II KALAHARI trial?
A: The rationale for targeting DME is twofold. On the one hand, while both vascular endothelial growth factor and PKal levels are increased in the vitreous of DME patients, their levels don’t correlate. Some patients exhibit high levels of PKal but low to non-detectable levels of VEGF.2 These observations imply that additional mechanisms beside VEGF upregulation play a role in mediating DME, and that PKal and KKS may contribute to DME in a VEGF-independent manner.
On the other hand, a significant fraction (40 percent) of the patients treated with current standard-of-care treatments such as anti-VEGF drugs respond suboptimally. Therefore, it’s important to identify other targets, such as PKal, in DME. Anti-PKal therapy represents an attractive treatment option, in particular, for patients responding suboptimally to current standard-of-care treatment.
Preclinical and early clinical data strongly support the role of PKal in the development of DME.
Q: Please describe the design of the Phase IIa and IIb trials.
A: The Phase II study consists of two parts. Part A is a randomized, single masked, parallel group, dose-finding study including three injections of THR-149, one month apart in three dose levels (low dose 0.01 mg; medium dose 0.04 mg; and high dose 0.13 mg). Six patients will be randomized in each dose level and followed for six months. A safety monitoring committee will select the optimal dose for inclusion into the Part B of the study.
In part B, which is the randomized, double-masked, active-controlled phase of the study with two treatment arms, the selected dose of THR-149 will be compared to aflibercept in 104 patients in a 1:1 randomization ratio. Patients in each arm will receive three injections one month apart and will be followed for six months.
The Phase II study will evaluate THR-149 as a monotherapy in patients with persistent central involved DME despite prior treatment with anti-VEGF. The data of the Phase II study is expected to inform us on whether THR 149 can be the best second-line treatment for DME patients.
Q: Where would THR-149 potentially fit in the retina specialist’s toolbox?
A: Subject to data, I could envision THR-149 claiming its place as a monotherapy in patients with persistent central-involved DME despite prior treatment with anti-VEGF therapy. THR-149 definitely holds potential as a first-in-class, second-line treatment for DME.
Further down the road, I could even envision the use of THR-149 in combination with anti-VEGF for treatment-naïve patients.
Q: What else can you tell us about THR-149?
A: It’s important to look at new mechanisms of action beyond VEGF inhibition to treat our patients with DME. THR-149 fits in that category as it has a novel mechanism of action and has shown good safety and efficacy signals in the Phase I trial. I continue to be very excited about this program as an investigator and look forward to seeing the efficacy and safety results of THR-149 from the Phase II trial in the near future. RS
1. Teufel DP, Bennett G, Harrison H, et al. Stable and long-lasting, novel bicyclic peptide plasma kallikrein inhibitors for the treatment of diabetic macular edema. J Med Chem. 2018;61:2823-2836.
2. Kita T, Clermont AC, Murugesan N, et al. Plasma kallikrein-kinin system as a VEGF-independent mediator of diabetic macular edema. Diabetes. 2015;64:3588-3599.