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CLINICAL TRIAL DOWNLOAD: Discussing New Data on a Bispecific Molecule for Neovascular AMD

A majority may have achieved 16-week dosing.

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The opportunities in the treatment of neovascular AMD include better short-term efficacy, greater durability, and sustained long-term benefits. Most investigators believe that these challenges will only be met with a combination drug strategy. Intuitively, it makes sense to combine a potent antipermeability drug with one that restores homeostasis. The ideal such drug is a bispecific agent that allows for dual inhibition with a single clearance rate. This is a very difficult product to make. Roche/Genentech have spent nearly a decade to produce faricimab (previously known as RG7716) using a proprietary crossmab technology. It is an elegant design with 2 fab arms (anti-VEGFA and anti-Ang2) and an optimized Fc portion that minimizes systemic exposure and inflammation. The BOULEVARD DME study showed encouraging results that have progressed to phase 3 studies. The AVENUE and STAIRWAY neovascular AMD studies were recently presented. Here we ask several leaders in retina for their impressions of the recent data.

Pravin U. Dugel, MD, is managing partner with Retinal Consultants of Arizona in Phoenix, Arizona. He reports consultancy to Roche/Genentech. Anat Loewenstein, MD, reports consultancy to Allergan, Bayer, Forsightlabs, Notal Vision, Novartis, and Roche. Carl D. Regillo, MD, FACS, reports research grant support from and consultancy to Genentech. Andrew Antoszyk, MD, reports consultancy to Roche/Genentech, Opthea, Clearside Biomedical, and JAEB.

Editor’s note: Companies mentioned in this column are given an opportunity to respond to comments if desired.

Anat Loewenstein, MD, Department of Ophthalmology, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel

The Roche/Genentech faricimab (RG7716) molecule represents an important technological step in developing a bispecific molecule, namely, a molecule with 2 targets, one of which is in an anti-VEGF A monoclonal antibody fragment (fab), and the other an anti-angiopoietin-2 (Ang2) fab. Anti-Ang2 binding to Tie2 actually facilitates anti-VEGF activity. Combatting these 2 targets in one molecule, which has only one clearance rate, makes sense to potentially enhance efficacy. Thus, we are dealing with a novel molecule with a unique “dual action” design that shows promise in maintaining vascular stability in retinal disease.

The results of the phase 2 clinical trials in the use of faricimab in neovascular AMD show that this novel dual-action molecule may have greater effectiveness than anti-VEGF monotherapy in neovascular AMD. However, overall results seem to be relatively similar to other anti-VEGF therapies with no overwhelming superiority for the dual-action design.

In the AVENUE study, faricimab had results at least as good the monotherapy ranibizumab arm, regardless of treatment regimen. The group treated with faricimab every 8 weeks had similar results to the group treated with monthly treatment with either ranibizumab or faricimab. In the STAIRWAY study, faricimab patients treated either every 12 weeks or 16 weeks demonstrated sustained vision outcomes comparable to ranibizumab given monthly.

The study included a small number of patients, making it unlikely the results would differentiate between the drugs, and even smaller possibility of detecting differences across the study arms compared with the control group (that by design had half the number of patients in each of the other groups).

In summary, there is a theoretical advantage to using this dual-molecule drug in retinal dis-ease. While the results for neovascular AMD in the phase II trials did not show any definitive advantage of such a molecule, the multiple arms with a relatively small number of patients in each arm makes it difficult to determine with certainty whether there are differences among the treatment arms.

Carl D. Regillo, MD, FACS, Wills Eye Hospital and Thomas Jefferson University, Philadelphia, Pennsylvania

The AVENUE and STAIRWAY studies were a pair of phase 2 clinical trials that assessed the efficacy, safety, and durability of intravitreal faricimab (RG7716) to treat neovascular AMD, with the former study focusing on efficacy compared to ranibizumab and the latter study exploring the potential durability of faricimab. The AVENUE study showed that faricimab had comparable efficacy to ranibizumab and was well tolerated, but did not show significantly better efficacy when both drugs were dosed monthly. The STAIRWAY study, however, showed that 65% of eyes in the faricimab arms did not have signs of disease activity as defined in the protocol at week 24, which is 12 weeks after 4 monthly loading doses. In addition, with further follow-up, the maintenance of visual gains in the faricimab arms dosed every 12 weeks and/or every 16 weeks out through week 52 was comparable to monthly ranibizumab injections over that time frame.

Lastly, faricimab dosed every 12 or 16 weeks after the loading period showed similar reductions in optical coherence tomography (OCT) central subfield thickness (CST) at week 52 to monthly ranibizumab. These data suggest that faricimab may be more durable than ranibizumab and the other currently available anti-VEGF agents for treating neovascular AMD. We look forward to larger prospective, controlled neovascular AMD studies with faricimab to definitively determine the exact long-term durability.

Andrew Antoszyk, MD, Charlotte Eye Ear Nose & Throat Associates, P.A., Charlotte, North Carolina

A recent presentation at the Retina Society in San Francisco by Dr. Pravin Dugel provided the first look at the faricimab (RG7716) phase 2 AVENUE results. Faricimab is a novel bispecific molecule designed to inhibit VEGF A and Ang2. AVENUE was a phase 2 trial to explore the safety and efficacy of faricimab in neovascular AMD. Patients (n=273) were randomized in a 3:2:2:2:3 fashion to ranibizumab 0.5 mg every 4 weeks; faricimab 1.5 mg every 4 weeks; faricimab 6 mg every 4 weeks; faricimab 6 mg every 4 weeks x 4, then every 8 weeks; and ranibizumab 0.5 mg every 4 weeks x 3 doses then faricimab 6 mg every 4 weeks, respectively. The primary endpoint was mean best corrected visual acuity (BCVA) at 36 weeks and ranged from 5.9 letters to 9.1 letters, the latter being achieved in the faricimab 6 mg every-4-week dosing arm. All treatment groups had a significant reduction in CST as measured by spectral-domain OCT.

Results of STAIRWAY, a phase 2 trial designed to explore the efficacy of extended dosing of faricimab for neovascular AMD in treatment-naïve patients were presented at AAO. The study enrolled 76 patients with neovascular AMD who were randomized to 1 of 3 treatment arms in a 2:2:1 fashion: faricimab 6 mg every 4 weeks x 4 doses then every 12 weeks; faricimab 6 mg every 4 weeks x 4 doses then every 16 weeks; and ranibizumab 0.5 mg every 4 weeks. The primary endpoint was mean BCVA at 40 weeks. The retreatment algorithm utilized to assess disease activity at 24 weeks included CST changes of 50 microns to 75 microns, BCVA loss of 5 to 10 plus letters, presence of new macular hemorrhage, and investigator opinion of significant disease activity. At week 24, 65% (n=36/55) of people treated with faricimab had no active disease. The initial visual gains were maintained through week 52 with every 12 and 16 week dosing regimens. Faricimab treated patients treated every 12 and 16 weeks gained 10.1 and 11.4 letters respectively, compared to 9.6 letters gained in eyes treated monthly with 0.5 mg ranibizumab. The extended dosing cohorts also had reductions in the CST similar to the monthly ranibizumab.

These results are very encouraging, suggesting that the novel bispecific molecule faricimab may yield equivalent visual acuity and OCT results to current anti-VEGF therapies yet with extended dosing frequencies in patients with neovascular AMD. Phase 3 trials are being planned to validate these findings. RP