In a multinational randomized phase 3 trial, once-weekly somapacitan demonstrated superiority over placebo for treatment of patients with adult growth hormone (GH) deficiency, according to study results published in The Journal of Clinical Endocrinology & Metabolism.

Hormone replacement is a common component of care for patients with hypopituitarism, but its daily subcutaneous injections can be burdensome for some patients. This burden may result in reduced compliance or adherence or in an unwillingness on the part of physicians to add to their patients’ treatment burden. Long-acting alternatives to daily injections could reduce the burden of treatment and thus lower the barrier to therapy.

Somapacitan is a novel once-weekly reversible albumin-binding GH derivative, with a similar long-lasting mechanism as insulin detemir. Studies have shown once-weekly somapacitan to be well tolerated in healthy adults, but none have examined its efficacy in adult GH deficiency treatment.

To evaluate this, researchers randomly assigned 301 patients with adult GH deficiency at 92 sites in 17 countries in a 2:1:2 ratio to receive once-weekly somapacitan, once-weekly placebo, or daily GH for 34 weeks. Patients 23 to 79 years of age with a diagnosis of adult- (69.7%) or childhood-onset (30.3%) adult GH deficiency who were naive to GH treatment or had no exposure to GH therapy for ≥180 days prior to treatment assignment were included. This main period of 34 weeks was followed by an extension period to examine longer-term use.


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The main period was double blinded for the somapacitan and placebo cohorts but open label for daily GH use. Investigators and trial sites remained blinded throughout the entire trial. Dose titration occurred during the first 8 weeks of the main trial until a steady state insulinlike growth factor-1 (IGF-1) standard deviation score (SDS) of -0.5 to +1.75 was achieved. The remaining 26 weeks consisted of fixed-dose treatment.

The 52-week open-label extension period allowed for evaluation of efficacy and safety of somapacitan for up to 86 weeks of treatment. Patients who had been receiving somapacitan continued to do so (somapacitan/somapacitan group), those receiving placebo were switched to somapacitan (placebo/somapacitan group), and those receiving daily GH were randomly assigned 1:1 to continue with daily GH (daily GH/daily GH group) or to switch to somapacitan (daily GH/somapacitan group).

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At week 34, somapacitan reduced truncal fat percentage from baseline by 1.06% compared with a 0.47% increase for placebo (estimated treatment difference, -1.53%; 95% CI, -2.68 to -0.38; P =.009), demonstrating superiority over placebo. Compared with placebo, the somapacitan group also had decreased visceral fat and increased lean body mass and appendicular skeletal muscle mass at week 34.

Similar changes in visceral fat, total lean body mass, and appendicular skeletal muscle mass were observed in the somapacitan and daily GH groups at week 34. A less pronounced reduction in truncal fat percentage was observed with somapacitan treatment compared with daily GH treatment at week 34. No significant difference in body weight from baseline to week 34 was observed for the somapacitan (+1.40 kg) or placebo (+0.39 kg) groups, but was observed between somapacitan and daily GH (+0.27 kg; estimated treatment difference, 1.13 kg; 95% CI, 0.13-2.12) groups.

At week 86, there were no notable differences between the somapacitan and daily GH groups for percentage change in visceral fat, lean body mass, or appendicular skeletal muscle mass, and improvements in visceral fat and lean body mass were maintained. However, treatment effects on other body composition measures were less pronounced with somapacitan treatment vs daily GH therapy. For patients who switched from placebo to somapacitan in the extension period, improvements were observed in all body composition measures to a similar degree as with long-term daily GH treatment.

No significant differences in mean levels of corrected total bone mineral content or density from baseline to week 86 in the somapacitan and daily GH groups were observed, nor was there a significant difference in these levels between these 2 groups.

Two individuals had severe adverse events that were possibly related to trial products during the study period. One was a patient in the daily GH/no treatment group, who was also receiving testosterone and suffered a life-threatening hemoconcentration, but recovered with treatment. The other patient was in the daily GH/somapacitan group and was diagnosed with bladder transitional cell carcinoma in week 80, but went on to complete the trial.

One of the concerns about continuous exposure to GH is that it may result in negative effects on insulin sensitivity and glucose metabolism. In this trial, fasting plasma glucose and hemoglobin A1c values did not increase over 86 weeks, and there were no new cases of diabetes in patients treated with somapacitan. The limited negative effects paired with somapacitan’s potentially superior effects on visceral fat reduction vs placebo by week 34 of treatment suggest that somapacitan may provide an effective alternative to daily GH in adults with GH deficiency.

Some limitations of this study included the reliance on patient reporting for adherence to treatment as well as the open-label nature of the daily GH treatment group. In addition, some patients in the active drug groups had IGF-1 SDS values below -2 at the end of the titration period and so may not have received the full benefit of GH replacement. Finally, the less pronounced effect of somapacitan on truncal fat and body weight when compared with daily GH over the long term cannot be explained by a different response in IGF-1 SDS, as mean levels and distributions were similar.

Disclosure: This study was funded by Novo Nordisk, the manufacturer of somapacitan. All but one author on the study has received either employment, contract work, or funding from Novo Nordisk.

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Reference

Johannsson G, Gordon MB, Rasmussen MH, et al. Once-weekly somapacitan is effective and well tolerated in adults with GH deficiency: a randomized phase 3 trial [published online February 5, 2020]. J Clin Endocrinol Metab. doi:10.1210/clinem/dgaa049