Findings from a phase 2 randomized controlled trial (MAHALO) showed that an experimental intravitreal drug from Genentech (lampalizumab) offered moderate benefits in reducing progression of geographic atrophy. The new therapy could, however, provide significant anatomic benefits for carriers of complement factor I (CFI) risk allele.
Lampalizumab is human monoclonal antibody directed against complement factor D, a pivotal activator of the alternative complement pathway that has been implicated in the pathogenesis of AMD.
Study design
For this 18-month study, 129 patients were randomized to 1 of 3 groups: lampalizumab monthly (n=42), lampalizumab every other month (41), or sham injection (40).
The primary outcome measure was mean change in lesion area from baseline. Change in BVCA was evaluated as a secondary outcome measure and as an indicator of lampalizumab’s safety.
Outcomes
Using a prespecified significance level of P<0.2, MAHALO met its primary endpoint. The monthly lampalizumab group demonstrated a 20% reduction in lesion area progression compared with controls (P=0.117). According to the authors, the significance level was selected “given that this was a proof-of-concept, hypothesis-generating clinical study with smaller sample size designed to identify minimal treatment efficacy that would be investigated in confirmatory phase 3 studies.” There was no apparent treatment benefit observed in patients who were dosed with lampalizumab every other month.
Over the study period of 18 months, mean change in BCVA deteriorated in all 3 groups, dropping by 3.3 letters in the lampalizumab monthly group, 1.4 letters in the lampalizumab every other month group, and 4.9 letters in the sham group. The authors did not specify if the changes were significant.
Lampalizumab demonstrated an acceptable safety profile. Most ocular adverse events were associated with the injection procedure.
In a subgroup analysis, investigators noted a substantially greater treatment benefit among complement factor I (CFI) risk-allele carriers, a genetic mutation previously linked to an increased risk of developing AMD. The subgroup of monthly injection patients with CFI polymorphisms (approximately 57% of the cohort) demonstrated a 44% reduction in geographic atrophy area progression vs. sham (P=0.0037).
The subgroup findings suggest that the 20% reduction on lesion area observed in the entire monthly cohort was driven exclusively by the 44% reduction in the CFI carrier subgroup. These patients also demonstrated a dose-response to lampalizumab that was not apparent in patients lacking the mutation. Visual outcomes for CFI carriers were not discussed.
Limitations
Aside from the relatively small sample size, the 20% reduction in lesion size did not reach a significant value of P<0.05. The study was also not powered to detect differences in geographic atrophy area within the CFI subgroup, thus a larger study will be necessary.
Clinical significance
This is a very exciting study as dry AMD remains a significant unmet clinical need. The findings suggest modulation of the alternative complement pathway has the potential to be a safe and effective treatment for the advanced form of the disease, geographic atrophy.
Two phase 3 trials, SPECTRI and CHROMA, are currently underway to investigate the efficacy and safety of lampalizumab, with an estimated enrollment of 936 patients in each study. Topline results are expected later this year. If the findings are positive and significant, lampalizumab could represent a significant advance in the treatment of atrophic AMD.