Immunogenicity Profile of Lonapegsomatropin During Long-Term Treatment in Children With Growth Hormone Deficiency.

Monitoring and evaluation of immunogenicity is important for biological therapeutics due to the potential impact of antibodies on safety and efficacy. A comprehensive immunogenicity assessment was conducted to support clinical development of lonapegsomatropin, a prodrug of somatropin, administered once weekly. Lonapegsomatropin is approved in the United States for pediatric and adult growth hormone deficiency (GHD), and in other countries for pediatric GHD. Lonapegsomatropin consists of somatropin, an inert methoxy polyethylene glycol carrier (mPEG), and a proprietary TransCon® linker that transiently binds somatropin to the carrier. Four dedicated immunoassays were developed, validated, and applied in a risk-based tiered approach to rigorously assess the immunogenicity of lonapegsomatropin in children with GHD. Samples collected from 298 children with GHD treated with lonapegsomatropin for up to six years were analyzed for anti-drug antibodies (ADAs) against lonapegsomatropin (intact prodrug), released somatropin, and mPEG. Treatment-emergent anti-lonapegsomatropin, anti-somatropin, and anti-mPEG binding antibodies were detected in 4.7%, 5.4%, and 0.7% of treated children, respectively. ADA responses were low titer, transiently detected, and primarily observed within the first year of treatment, and no neutralizing antibodies were detected. These findings support the long-term low immunogenicity of lonapegsomatropin in children with GHD, consistent with somatropin. Importantly, the multi-assay tiered strategy applied here was robust and reproducible, enabling sensitive detection of ADAs against the intact prodrug, mPEG, and released somatropin across trials, and demonstrated its clinical applicability for evaluating a complex long-acting growth hormone like lonapegsomatropin.