Phase II Data from Genentech’s BOULEVARD Study: Dual VEGF-A + Ang-2 Suppression with RG7716 for Diabetic Macular Edema

Nitish Mehta, MD
Ophthalmology Resident
New York University

Yasha Modi, MD
Assistant Professor of Ophthalmology
New York University

Many companies are working to fill unmet needs in the treatment of diabetic macular edema and neovascular AMD. Novel therapeutics may provide a more efficacious or durable treatment effect, a feature especially attractive in cases refractory to the current standard of care.

Data from the Phase II BOULEVARD study investigating RG7716, Genentech’s bispecific anti-vascular endothelial growth factor (VEGF)/anti-Angiopoietin-2 (Ang-2) antibody was presented at the 15th Annual Angiogenesis, Exudation, and Degeneration, a symposium hosted by Bascom Palmer Eye Institute.

Angiogenesis 2018

Dual VEGF-A/Ang-2 Suppression

The BOULEVARD study was designed to assess Genentech’s uniquely designed antibody, RG7716. One antigen binding fragment (Fab) of the fully humanized RG7716 inactivates the tyrosine kinase receptor Tie2’s partial agonist, Ang-2.

Consistent Tie2 activation is necessary for the maintenance of a quiescent, stable vasculature. In pro-angiogenic states, Ang2 is upregulated and outcompetes the normal activating agonist of Tie2, angiopoietin-1 (Ang-1). Ang-2 cannot phosphorylate Tie2; thus, a destabilized vasculature that is more susceptible to VEGF results.

The other Fab arm of RG7716 inactivates VEGF-A. In addition, inactivating mutations in the fragment crystallizable region (Fc region) were designed to increase the systemic, but not ocular clearance, of the molecule.

RG7716 Phase I Neovascular AMD Study

Genentech hopes this construct will provide safe and synergistic control of vascular permeability and inflammation in disease states. RG7716’s Phase I study on twenty-four patients with refractory neovascular AMD demonstrated a median visual acuity improvement of 7 letters in a single ascending-dose group that received 0.5, 1.5, 3, and 6mg doses of RG7716, and 7.5 letters in a multiple ascending-dose group that received three monthly treatments of 3 and 6mg doses, with no unexpected adverse events or dose-limiting toxicities in either arm. 

RG7716 Phase II DME Study: BOULEVARD

The 229-patient Phase II BOULEVARD study compared the safety and efficacy of 20-weeks of monthly intravitreal injections of 1.5 and 6mg of RG7716 to 0.3mg of ranibizumab in a prospective, randomized, double-masked fashion conducted at over 90 sites in the United States in patients with diabetic macular edema.


These patients were then observed for 16 more weeks for a total study period of 36 weeks. The study met its primary endpoint by demonstrating a significant improvement in best corrected visual acuity (BCVA) at week 24 for RG7716 versus ranibizumab in treatment-naïve patients, albeit only for the 6mg dose (an adjusted mean difference of +3.6 letters, p=0.03, 80% CI 1.53-5.61).

Adjusted mean improvement with 6 mg of RG7716, 3mg of RG7716, and 0.3mg ranibizumab was 13.9, 11.7, and 10.3 letter from baseline, respectively. Both RG7716 arms achieved a higher proportion of patients gaining more than one line of visual acuity, a greater reduction of central retinal thickness, and a greater two-step improvement of diabetic retinopathy severity compared to ranibizumab.

No new safety signals were observed. Genentech will use these results to discuss Phase III trials with the FDA.

Is Dual Suppression the Next Holy Grail?

 What meaningful advantages this new treatment may have over the standard of care is yet to be seen. The increased efficacy shown against ranibizumab was modest. It will perhaps be more interesting to see if the increased durability seen at week 24 in the BOULEVARD study was maintained at later time periods, as decreased treatment burden may be equally as important of a clinical trial endpoint as visual acuity gain.

Ophthotech’s inability to prove Fovista as more efficacious than standard of care in Phase III clinical trials after demonstrating modestly positive results in a Phase II trial may prove to be a word of warning.

In addition to BOULEVARD, Genentech is also evaluating RG7716 in the Phase II AVENUE and STAIRWAY studies for neovascular AMD.