One need look no further than the past few months and Ophthotech’s shocking failure with its anti-PDGF/anti-VEGF combination to see evidence that encouraging early-stage trials of investigational drugs do not easily translate into success in phase 3. With this sobering thought in mind, Genentech’s top drug researchers were cautiously optimistic as they discussed three promising current company investigational initiatives that involve potential next-generation treatments for retinal diseases.
In late March, Retinal Physician sat down for a wide-ranging chat with Anthony P. Adamis, MD, Genentech’s Global Head of Ophthalmology, Immunology, Infectious Disease and Metabolism, Clinical Science, and Jason Ehrlich, MD, PhD, Global Head, Clinical Ophthalmology. The interview focused primarily on three areas: the progress of the company’s effort to deliver Lucentis (ranibizumab) in a sustained-release format; the potential of the bispecific anti-VEGF/Ang2 inhibitor RG7716, now in 3 phase 2 clinical trials, and the move into phase 3 trials for lampalizumab, a complement inhibitor with neuroprotective qualities aimed at combating geographic atrophy.
 
Sustained Release: Ranibizumab Refillable Port Delivery System
This sustained-release format for delivering a steady and appropriate dose of Lucentis is now in the phase 2, 220-patient LADDER study following a small phase 1 study that established proof-of-concept for the system.
The refillable implant with a drug reservoir lasting 4 to 6 months offers the promise of a greatly reduced treatment burden for both physicians and patients. Currently, most patients being given Lucentis require an intravitreal injection every 4 to 6 weeks.
“We also see the implant as reducing the possibility of undertreatment, which has been identified in studies as a major reason for differences in real-world visual outcomes compared to those achieved in highly structured clinical trials,” says Dr. Ehrlich.
One hint that Genentech sees strong long-term potential in sustained-release is that it recently purchased ForSight Vision4, the maker of the refillable implant.
“The technology of the implant is simple but elegant,” says Dr. Ehrlich. “We see it as a platform for not only delivering Lucentis, but also other ocular drugs.”
 
RG7716 Ang2 Inhibiting/Anti-VEGF Bispecific
Developed using its patented CrossMab technology that allows one antibody molecule to bind two different targets, Roche/Genentech’s RG7716 bispecific Ang2 inhibitor/anti-VEGF biologic is already in 3 phase 2 clinical studies. Roche/Genentech is now employing RG7716 in a 75-patient extended-dosing study for wet AMD called STAIRWAY. RG7716, which has attracted great interest in the retina community, is already being studied in the phase 2 BOULEVARD and AVENUE trials for DME and wet AMD, respectively.
Asked whether a small but encouraging phase 1 study in the US helped “move the needle” in terms of building confidence in the future potential of RG7716, Dr. Ehrlich said “it showed safety (that’s the goal for phase 1) and moved the needle for us to move into phase 2 studies, which will establish proof of concept for the mechanism.”
 
Lampalizumab for Geographic Atrophy
Now in two fully recruited, 936-patient pivotal phase 3 trials (CHROMA and SPECTRI), lampalizumab is the furthest advanced of the company’s 3 investigational initiatives and is directed at the unmet medical need in geographic atrophy.
Much of the hope for lampalizumab stems from human genetics identifying the complement pathway and the promising phase 2 MAHALO study, in which all patients were genotyped and those with the specific CFI genetic biomarker on average were better responders to the drug than those without the biomarker.
“MAHALO contained some interesting findings regarding genetic factors and subsets of patients but it was a smaller study and the findings have to be confirmed in the large-scale phase 3 studies,” said Dr. Adamis.
 
Strong Progress in Retinal Research
Asked to assess the progress in retinal research over the past decade, Dr. Adamis said “it’s right up there compared to any other medical specialty.” He noted that the pace of research into potential therapies has advanced rapidly, with many new therapeutic targets, new companies, increased funding, and newly emerging areas of research such as gene therapy, gene editing, and neuroprotection.
“Five years from now, I think anti-VEGF will still be at the core of treating retinal disease, but we should also have longer-acting options and some anti-VEGF/Plus combinations that we can use. The move to more personalized treatment is a positive development — the right drug and the right dose for each patient — but today we still only have one major category of drugs (anti-VEGF) for retinal vascular diseases, so we need to see a greater range of approved therapies to get to a more personalized approach.”