Immunogenicity Profile of Lonapegsomatropin During Long-Term Treatment in Children With Growth Hormone Deficiency.
Lonapegsomatropin shows low immunogenicity in children with GHD, with transient antibody responses primarily occurring in the first year of treatment.
Where it sits
this study against the rest of the hgh (somatropin) corpusSummary and findings
The study assessed the immunogenicity of lonapegsomatropin in 298 children with growth hormone deficiency (GHD) over a treatment period of up to six years. The findings indicated low rates of anti-drug antibodies (ADAs) against lonapegsomatropin, somatropin, and mPEG. No neutralizing antibodies were detected.
Abstract
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<sup>®</sup> 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.
Background
This paper addresses the immunogenicity of lonapegsomatropin, a prodrug of somatropin, in children with GHD. Immunogenicity is a critical aspect of biological therapeutics, as antibodies can impact safety and efficacy. Prior studies have shown varying immunogenicity profiles for different growth hormone therapies, making this assessment relevant for long-term treatment considerations.
Methods
The study utilized a comprehensive immunogenicity assessment involving four dedicated immunoassays in a cohort of 298 children with GHD. Lonapegsomatropin was administered once weekly for up to six years. The primary outcome measure was the detection of anti-drug antibodies (ADAs) against lonapegsomatropin, released somatropin, and mPEG.
Results
The primary endpoint revealed that 4.7% of children developed anti-lonapegsomatropin antibodies, 5.4% developed anti-somatropin antibodies, and 0.7% developed anti-mPEG antibodies. ADA responses were low titer and transient, primarily occurring within the first year of treatment. No neutralizing antibodies were detected.
Interpretation
The findings suggest that lonapegsomatropin has a low immunogenicity profile, consistent with somatropin. While the statistical significance of the findings is clear, the clinical significance of low titer antibodies remains uncertain. Limitations include the lack of long-term follow-up data and potential confounding factors related to the study design.
Key findings
- 4.7% of treated children developed anti-lonapegsomatropin antibodies.
- 5.4% of treated children developed anti-somatropin antibodies.
- 0.7% of treated children developed anti-mPEG antibodies.
- ADA responses were low titer and primarily observed within the first year of treatment.
- No neutralizing antibodies were detected.
Limitations
- No long-term effects beyond six years reported.
- Small n=298 for immunogenicity assessment.
- No clinical significance of low titer antibodies discussed.
- Single-site study may limit generalizability.