NEW AMD TREATMENTS

The first evidence that intravitreal lampalizumab (Genentech/Roche) slows the progression of geographic atrophy appears to support the role of complement inhibition in the treatment of dry age-related macular degeneration (AMD). This is just the beginning, as lampalizumab and similar agents modulating the complement pathway enter clinical trials, said Zohar Yehoshua MD at the 14th EURETINA Congress in London.

“Today we have very good treatments for wet AMD and we can preserve vision, however many patients with AMD still have decreased vision due to the development of geographic atrophy. Ultimately, we would like to prevent AMD-related vision loss and that requires preservation or replacement of the photoreceptors, RPE, and choriocapillaris. Modulation of the immune system through complement inhibition is one of several strategies under investigation for achieving that goal,” said Dr Yehoshua, of Bascom Palmer Eye Institute, University of Miami, Florida, US.

Lampalizumab, an antigen binding fragment of a humanised monoclonal antibody against complement factor D (CFD), is a selective inhibitor of the alternative complement pathway. In the Phase II MAHALO trial, 129 patients with bilateral geographic atrophy were randomised to receive lampalizumab 10.0mg or sham monthly or every other month.

Results of the primary endpoint analysis that assessed mean change in geographic atrophy area from baseline to month 18 showed a 20.4 per cent treatment benefit for monthly lampalizumab. The benefit was observed by month six and maintained through 18 months. Monthly lampalizumab decreased the rate of geographic atrophy growth by 44 per cent among patients positive for complement factor inhibition (CFI), 57 per cent of the population, and by 54 per cent among those positive for CFI with vision of 20/50 to 20/100 at baseline.

Dr Yehoshua cautioned that the results from the biomarker analysis must be considered carefully because of the small sample size. He noted that it is unclear why the better seeing eyes among CFI positive patients might respond better.

Looking ahead to the possibility of positive results in the Phase 3 lampalizumab trials, one audience member questioned the ethics of a treatment involving bilateral intravitreal injections in patients with fairly good vision.

Other drugs in clinical development are targeting different effector molecules in the complement system. For example, POT-4 (Potentia/Alcon), a C3 inhibitor that inhibits all three major pathways of complement activation, is also administered intravitreally and will be entering into Phase 2 research.

Dr Yehoshua also discussed two monoclonal antibodies against C5 – intravitreal LFG316 (Novartis) and intravenous eculizumab (Soliris, Alexion). “There may be an advantage with agents targeting C5 because the proximal complement functions remain intact,” said Dr Yehoshua. Data from the Phase 2 COMPLETE study showed eculizumab did not significantly decrease the growth rate of geographic atrophy.

Zohar Yehoshua: zyehoshua@miami.edu