RhuFab V2 trials show positive results in AMD

By Laszlo Dosa
In Fort Lauderdale

Clinical trials with the anti-angiogenesis agent rhuFab V2 (Lucentis™, Genentech) indicate that the drug reduces macular oedema and leakage from new blood vessels and provides meaningful improvements in vision in patients with neovascular age-related macular degeneration (AMD), according to researchers at the annual meeting of the Association for Research in Vision and Ophthalmology.

Philip J. Rosenfeld MD, PhD presented data from a phase I randomised trial conducted at the Bascom Palmer Eye Institute in Miami that looked at the safety, tolerability, and efficacy of dose escalation injections of rhuFab V2 in the eyes of patients with neovascular AMD. The trial was designed to determine if doses of rhuFab V2 greater than 500 micrograms could be administered without eliciting significant inflammation in the eye.

The protocol enrolled 29 patients into three dosing regimens. All patients were treated for a total of 16 weeks and followed for 20 weeks. Group 1 received escalating doses of RhuFab V2 from 300 µg to 1.0 mg every two weeks over six weeks, followed by 1.0 mg at weeks 8, 12 and 16. Group 2 received escalating doses from 300 µg to 2.0 mg every two weeks over 14 weeks, followed by a final 2 mg dose at week 16. Group 3 received escalating doses from 300 µg to 2 mg every four weeks over 16 weeks.

Every patient underwent early treatment diabetic retinopathy study (ETDRS) visual acuity testing, ophthalmologic examination, and adverse event assessment at each visit, with fundus photography, fluorescein angiography, optical coherence tomography, and pharmacokinetic evaluations at selected visits.

"All the patients responded anatomically to the use of rhuFab V2. Macular oedema resolved in all the patients, and most of the sub retinal fluid resolved as well. Vision was stable or improved in 93% of patients; 44% of patients experienced a three-line or greater visual improvement, using the ETDRS visual acuity chart, with each line representing five letters and three lines representing a doubling of the vision. So, for example, the patient who started with 20/50 vision would have achieved 20/25 vision, or the patient who started with 20/100 vision would have achieved 20/50 vision or better. So 44% of the patients experienced a three line or better visual improvement by day 140," Dr. Rosenfeld told EuroTimes.

He added that additional, larger randomised controlled investigations are needed to demonstrate whether this treatment effect is real and just how permanent this improvement really is.

Neovascular AMD
In a related presentation, Jeffrey S. Heier, MD, reported data on the six-month safety and biologic activity of multiple intravitreal rhuFab V2 injections for neovascular AMD. The open-label, controlled study included 64 subjects who were randomized to either rhuFab V2 or to "usual care." Two dose levels of rhuFab V2 were studied. Usual care subjects were observed in the case of minimally classic lesions or were offered verteporfin therapy in the case of predominantly classic lesions. Most usual care subjects crossed over to rhuFab V2 treatment for 12 weeks after the initial study period.

The mean age of the subjects was 77 years (range 59-91). In this Phase I/II trial, patients in the first of the two dose groups were injected with 300 micrograms of rhuFab V2 every 28 days, and those in the second with 500 micrograms every 28 days. Patients in both dose groups were given a total of four injections each. In the 500 microgram dose group, the first injection was kept at 300 micrograms in order to minimise inflammation.

The second phase of the protocol involved a second set of injections, which could be up to four injections. At Dr. Heier’s site a few subjects in the 300 microgram dose group did not continue to receive further injections because these patients appeared to have improved or stable vision after completing their fourth injection.

"We have seen few serious adverse events and through this stage of the study, and those have resolved with stable vision. The most common adverse effect we’ve seen is mild inflammation, which has been reversible and transient, and has not limited either treatment or outcome. With regard to biologic activity, we have seen that 44% of the patients treated for six months at our site improved by three or more lines in ETDRS visual acuity," Dr. Heier told EuroTimes

The study also showed that 94% of the patients were stable, having either gained letters or lost fewer than 15 letters of vision following treatment. Of the 16 patients who progressed at six months, only one lost more than 15 letters of acuity.
Dr. Heier is still looking at safety and efficacy of treatment in these patients. He says, patients receiving rhuFab V2 continues to demonstrate visual acuity improvement between the three-month and six month time points. The treatment appears to be well tolerated by patients and, at least to date, is indicating biologic activity in a very difficult disease.

"This work is showing promise that we may have a treatment in the future to help these patients who, to date, had very little hope," he added.

RhuFab V2 is an antibody fragment derived from a full-length antibody that was engineered to bind vascular endothelium growth factor (VEGF). It was further engineered to have an even higher affinity for VEGF than the original monoclonal antibody. It was "humanised" from a mouse monoclonal antibody whose amino acids have been changed so that it more closely resembles a human antibody with the goal of preventing any immunologic response once injected into a human.

Philip J. Rosenfeld, MD, PhD
Bascom Palmer Eye Institute
prosenfeld@med.miami.edu

Jeffrey S. Heier, MD
Ophthalmic Consultants of Boston
Tufts Medical School
JSHEIER@eyeboston.com

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