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VANCOUVER -- A dual-target monoclonal antibody outperformed anti-VEGF therapy in patients with diabetic macular edema (DME), according to data reported here.

Among patients with no prior anti-VEGF therapy, the bispecific antibody RG7716 led to a 13.9-letter improvement in best-corrected visual acuity (BCVA) at 24 weeks, compared with 10.3 letters with intravitreal ranibizumab (Lucentis). A lower dose of RG7716 led to a BCVA gain of 11.7 letters. In the subgroup of patients previously treated with anti-VEGF agents, the higher dose of RG7716 also outperformed ranibizumab.

Targeting VEGF-A and angiopoietin-2 (Ang-2), the bispecific antibody led to ≥10-letter improvement in BCVA in substantially more patients than did ranibizumab, irrespective of anti-VEGF treatment history, Rishi P. Singh, MD, of the Cleveland Clinic, reported at the annual meeting.

"RG7716 treatment resulted in clinically meaningful and statistically significant visual acuity gains versus anti-VEGF monotherapy in treatment-naive patients meeting the primary endpoint. More patients treated with RG7716 achieved a two-step or more improvement in the DRSS [Diabetic Retinopathy Severity Scale]. In previously treated patients, data on 10- and 15-letter gainers and CST [central subfield thickness] reduction supported the primary outcome.

"RG7716 showed potential for extended durability with a higher proportion of patients maintaining disease stability after the last dose. RG7716 was well tolerated and showed no new or unexpected safety signals."

Laboratory studies that Ang-2 is upregulated in the retina in the setting of diabetes and increases vascular permeability. Ang-2 interacts synergistically with VEGF to induce and drive vascular permeability and inflammation associated with diabetic retinopathy.

Singh reported findings from the randomized, phase II trial, comparing two doses of RG7716 and ranibizumab in 229 patients with central-involving diabetic macular edema (DME), CST ≥325 µM, and BCVA 20/40 to 20/320. The study population included 61 patients previously treated with anti-VEGF agents.

Patients in each group received intravitreal injections of assigned therapy every 4 weeks through week 20, and the primary endpoint was improvement in mean BCVA at 24 weeks in patients with no prior exposure to anti-VEGF therapy. The 3.6-letter difference between the higher dose of RG7716 and ranibizumab achieved statistical significance (P=0.03). In the subgroup of patients with prior anti-VEGF therapy, the higher dose of RG7716 resulted in a mean gain in BCVA of 9.6 letters versus 8.3 letters with ranibizumab.

The proportion of anti-VEGF-treated patients who had at least a 10-letter gain in BCVA was 70.5% and 61.2% with the higher and lower doses of RG7716 versus 57.1% with ranibizumab. Among patients with no prior anti-VEGF treatment, the rates were 65.2% with the higher dose of RG7716 and 42.9% with ranibizumab. The bispecific antibody led to greater reductions in CST in patients with or without prior anti-VEGF treatment.

Three times as many patients treated with the higher dose of RG7716 had at least a two-step decrease in DRSS compared with ranibizumab (39% versus 12%), including 88% versus 25% in the subgroup of patients with severe retinopathy at baseline (DRSS ≥53). Fewer patients in the RG7716 groups had ≥5-letter loss in BCVA from 24 to 36 weeks of follow-up, suggesting better durability versus ranibizumab, said Singh.

Targeting Oxidative Stress and Inflammation with Risuteganib

A second study suggested an integrin inhibitor called risuteganib could complement anti-VEGF agents in the treatment of DME.

About half of patients respond well to anti-VEGF therapy and the rest do not, suggesting that inflammation or other factors might play a greater role in the disease process in those patients, said Peter Kaiser, MD, also of the Cleveland Clinic.

Risuteganib targets oxidative stress and inflammation. The current study involved 80 patients with DME, randomized 1:2:2 to five doses of bevacizumab (Avastin) alone administered 4 weeks apart; a single injection of bevacizumab followed by three doses of risuteganib administered at weeks 1, 4, and 8; or bevacizumab and risuteganib given together on weeks 1, 4, and 8. The primary endpoint was change in BCVA at 20 weeks.

The trial met the primary endpoint of noninferiority for risuteganib versus bevacizumab monotherapy (6.2 versus 6.9 letters). However, subgroup analysis showed that patients with no prior anti-VEGF therapy responded better to bevacizumab (9.3 versus 4.1 letters), whereas patients who had not responded to prior anti-VEGF therapy did better with risuteganib (7.5 versus 5.2 letters).

The results also showed that patients derived particular benefit from risuteganib when the drug was preceded by the single dose of bevacizumab, a 40% improvement in BCVA, as compared with a previous evaluation of risuteganib monotherapy, Kaiser reported. That treatment strategy will be evaluated in a phase III trial.

"The idea is to 'drain the sink [of VEGF]' with bevacizumab and then 'turn off the faucet [for inflammation and VEGF]' with risuteganib, which seems to be associated with a better outcome," he explained.