Abstract
Daily recombinant human GH (rhGH) is currently approved for use in children and adults with GH deficiency (GHD) in many countries with relatively few side-effects. Nevertheless, daily injections can be painful and distressing for some patients, often resulting in non-adherence and reduction of treatment outcomes. This has prompted the development of numerous long-acting GH (LAGH) analogs that allow for decreased injection frequency, ranging from weekly, bi-weekly to monthly. These LAGH analogs are attractive as they may theoretically offer increased patient acceptance, tolerability, and therapeutic flexibility. Conversely, there may also be pitfalls to these LAGH analogs, including an unphysiological GH profile and differing molecular structures that pose potential clinical issues in terms of dose initiation, therapeutic monitoring, incidence and duration of side-effects, and long-term safety. Furthermore, fluctuations of peak and trough serum GH and IGF-I levels and variations in therapeutic efficacy may depend on the technology used to prolong GH action. Previous studies of some LAGH analogs have demonstrated non-inferiority compared to daily rhGH in terms of increased growth velocity and improved body composition in children and adults with GHD, respectively, with no significant unanticipated adverse events. Currently, two LAGH analogs are marketed in Asia, one recently approved in the United States, another previously approved but not marketed in Europe, and several others proceeding through various stages of clinical development. Nevertheless, several practical questions still remain, including possible differences in dose initiation between naïve and switch-over patients, methodology of dose adjustment/s, timing of measuring serum IGF-I levels, safety, durability of efficacy and cost-effectiveness. Long-term surveillance of safety and efficacy of LAGH analogs are needed to answer these important questions.
Highlights
The long-term safety and efficacy of daily recombinant human growth hormone therapy in children with GH deficiency (GHD) are well-studied [1,2,3]
The major usefulness of long-acting GH (LAGH) analogs when compared with current recombinant human growth hormone (rhGH) formulations is that the former requires significantly lesser number of injections compared to the latter
Pitfalls of LAGH analogs include whether there are pathophysiological long-term implications of prolonged supra-physiologic elevations of serum GH and IGF-I levels, differences in tissue distribution and tissue sensitivity to modified GH molecules, development of anti-drug antibodies, and differences in the side-effect profile compared with daily rhGH injections
Summary
The long-term safety and efficacy of daily recombinant human growth hormone (rhGH) therapy in children with GH deficiency (GHD) are well-studied [1,2,3]. Further dose-finding clinical studies in various age groups were performed [30,31,32] and interestingly, these studies found that adults are inherently more sensitive to the effects of rhGH than children in terms of serum IGF-I generation and rate of side-effects [33], and that males are more responsive to rhGH therapy than females [34, 35] These and other data have resulted in the approval for rhGH replacement in children and adults with GHD by the United States Food and Drug Administration (FDA) and European Medicines Agency in 1985 and 1996, respectively, and translated into several published consensus guidelines for the management of children [2] and adults with GHD [36, 37]. Several other LAGH analogs have since been developed and additional studies performed to assess longitudinal growth velocity in children and changes in body composition in adults as primary endpoints [16, 19, 21, 22, 72]
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