Dante J. Pieramici, MD: Population Pharmacokinetics, Safety of Sozinibercept

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Data from PK profiles and safety analyses of intravitreal sozinibercept suggest the promise of the drug in combination with standard anti-VEGF agents for AMD and DME.

The pharmacokinetic profile of intravitreal sozinibercept (OPT-302) showed low systemic exposure and similar drug levels in the vitreous half-life to other anti-vascular endothelial growth factor-A (VEGF) agents in 3 trials, suggesting its promise as a combination therapy in patients with retinal vascular diseases.

The pooled analysis, presented at the American Society of Retina Specialists (ASRS) 41st Annual Meeting, similarly showed sozinibercept combination therapy had a favorable safety and tolerability profile, compared to standard-of-care anti-VEGF-A monotherapy.

“I think that if we get the same visual results, the better visual acuity with a combination approach that we saw in phase 2 clinical trials, I think that OPT-302 will have a big place in our market,” Dante J. Pieramici, MD, a partner at the California Retina Consultants, told HCPLive. “It will have the ability to actually improve vision over monotherapy and be something unique and it’ll add to our armamentarium that we can use to treat patients with age-related macular degeneration (AMD) and diabetic eye disease.”

Sozinibercept is a novel, first-in-class “trap” inhibitor protein blocking VEGF-C/D in patients with retinal vascular diseases. In combination with any VEGF-A inhibitor, sozinibercept completely blocks VEGFR-2 and VEGFR-3 signaling, inhibiting the pathways driving angiogenesis and vascular leakage.

In preclinical pharmacokinetic (PK) analysis, sozinibercept shows similar bioavailability and PK as compared to aflibercept. A large phase 2b clinical study with approximately 366 patients with nAMD reported superiority in best-corrected visual acuity (BCVA) gains with sozinibercept 2mg combination therapy with ranibizumab versus ranibizumab monotherapy.

An analysis of sozinibercept serum PK of completed studies may help interpret safety and efficacy results and inform dosing for phase 3 trials. In this analysis, investigators conducted a pooled data analysis of the phase 1/2a trial in wet AMD (sozinibercept ± ranibizumab), phase 1b/2a in DME (sozinibercept ± aflibercept), and the phase 2b trial in wet AMD (sozinibercept ± ranibizumab) to describe PK parameters and safety following intravitreal administration.

The trials administered sozinibercept via intravitreal injection every 4 weeks (Q4W) in the study eye at doses of 0.3 mg, 0.5 mg, 1 mg, or 3 mg for up to 3 - 6 months. Pooled data from a total of 1,853 intravitreal injections of sozinibercept were administered, including 1,130 intravitreal injections of 2.0 mg sozinibercept. PK samples in human serum were collected at pre-dose, then ≥1 to 168 hours post-dose, and analyzed by an ELISA assay.

Study data showed patients had an average age of 73 years and most had wet AMD. The pooled systemic serum PK data of the 2.0 mg showed a Cmax of ~20ng/mL, a Tmax of ~30 hours, and a T1/2 of ~7 days in the serum.

Investigators found no evidence to suggest that the PK of sozinibercept was altered by disease indication (wet AMD vs DME), age, renal impairment classification, or anti-VEGF-A co-therapy. In the serum PK analysis, the investigative team developed an eye model to determine the absorption half-life in the vitreous and found it was approximately 4.6 days (95% CI, 3.6 - 5.8).

The pooled safety analysis showed sozinibercept was well-tolerated across the entire dose range and comparable to monotherapy. Adverse events were identified as generally mild, unrelated to the study drug, and/or not significantly different than anti-VEGF-A monotherapy. There were no additional ocular safety events, inflammatory events, and/or systemic events comparing monotherapy to combination therapy in the trials.

For the phase 3 program, the ShORe trial is studying sozinibercept in combination with ranibizumab Q4W or Q8W versus monotherapy. The COAST trial is evaluating sozinibercept in combination with aflibercept Q4W or Q8W versus monotherapy. The trials are superiority studies with a primary outcome of visual acuity at 1 year.

“This really may be something for every patient,” Pieramici said. “It may also be something we use, particularly in patients that are harder to treat. But again, you know, this study is looking at naive patients with AMD. If we get better results with the combination approach, patients may elect for this going forward.”

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