Month: 17 Nov 2017
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New geographic atrophy drug for AMD fails to meet primary endpoint in age-related macular degeneration
A new antibody drug (lampalizumab) targeting geographic atrophy in age related macular degeneration has missed its primary endpoint in two pivotal Phase III studies comprising >1,800 patients. The drug, sponsored by Genentech (Roche), was designed to target a key molecular component in the complement pathway, understood to be a critical pathway leading to the accumulation of drusen in patients with dry AMD. Despite the failure of the drug, several other complement pathway experimental therapies are likely to continue in development due to their therapeutic potential in a disease of high unmet need.
The two Phase III clinical trials, known as “Spectri” (975 patients) and “Chroma” (906 patients), were assessing the administration of 10mg lampalizumab against complement factor D, known to be a rate-limiting enzyme involved in the activation and amplification of the complement pathway. The primary outcome measure had sought to reduce the progression of geographic atrophy at 48 weeks compared with a sham control. While detailed data was not available, the sponsor of the studies stated, “lampalizumab did not reduce mean change in GA lesion area compared to sham treatment at one year (48 weeks). The safety profile was in line with previous lampalizumab trials. Based on the totality of data from Chroma and Spectri, Genentech will not pursue approval from the U.S. Food and Drug Administration (FDA) for lampalizumab in geographic atrophy.” The result clearly represents a disappointment in the field however, a number of companies and clinical investigators believe all may not be lost.
Interest in targeting the complement pathway arose in the mid 2000s when several genome wide association studies (GWAS) indicated a potential role in complement cascade activation. Drusen, a significant risk factor for developing AMD is comprised of “complement” – serum proteins which mediate one of the more important immune system’s antibody-mediated disposal mechanisms, a process known as “complement fixation”. This observation led researchers to the suggestion that drusen is the product of a localised inflammatory response and a series of research publications beginning in 2005 showed convincing links between mutations in complement factor genes and the occurrence of age related macular degeneration. A major breakthrough in 2005 identified the factor H gene (known as CFH or HF1) located on human chromosome 1q32 as a major risk factor for AMD. Since then several follow up studies have confirmed the finding in addition to identifying further variants and further genes conferring risk or protection in the development of AMD. Between 46% and 71% of symptomatic variance among twins has being explained by genetic factors. Several genomic wide association studies (GWAS), and follow up meta-analyses, have logged multiple genetic variants in over 20 different genes, each demonstrating an association with AMD risk. Common variants in the CFH gene account for the disease in some families but fail to explain patterns of disease in other families with multiple affected members. However, not all investigators agree on the pharmacological significance of the genetic data. In a November 2017 Nature Biotechnology article, Prof. Jayakrishna Ambati, at the University of Virginia School of Medicine in Charlottesville, stated that, “complement activation is neither necessary nor sufficient for the pathophysiology of the disease,” in addition to claiming that continued development of complement based therapies is “misguided by an over-reliance on and infatuation with statistical genetics, which has proved a false therapeutic compass in the past.” Regardless of the debate on biological significance, the complement cascade comprises multiple targets and a number of independent investigators and commercial sponsors believe that the continued pursuit of therapeutic strategies in this area is justified by existing experimental and clinical results. Investigators will now pick through the detailed data of prior trial results to determine what if anything might improve outcomes, potentially focusing on earlier treatment or combining approaches that target more than one component in the complement cascade.Back to previous