Once-weekly Somapacitan is Effective and Well Tolerated in Adults with GH Deficiency: A Randomized Phase 3 Trial

Abstract

Context: Growth hormone (GH) replacement requires daily GH injections, which is burdensome for some adult patients with GH deficiency (AGHD).

Objective: To demonstrate efficacy and safety of somapacitan, a once-weekly reversible albumin-binding GH derivative, versus placebo in AGHD.

Design: Randomized, parallel-group, placebo-controlled (double-blind) and active-controlled (open-label) phase 3 trial, REAL 1 (NCT02229851).

Setting: Clinics in 17 countries.

Patients: Treatment-naïve patients with AGHD (n = 301 main study period, 272 extension period); 257 patients completed the trial.

Interventions: Patients were randomized 2:2:1 to once-weekly somapacitan, daily GH, or once-weekly placebo for 34 weeks (main period). During the 52-week extension period, patients continued treatment with somapacitan or daily GH.

Main outcome measures: Body composition measured using dual-energy x-ray absorptiometry (DXA). The primary endpoint was change in truncal fat percentage to week 34. Insulin-like growth factor 1 (IGF-I) standard deviation score (SDS) values were used to dose titrate.

Results: At 34 weeks, somapacitan significantly reduced truncal fat percentage (estimated difference: -1.53% [-2.68; -0.38]; P = 0.0090), demonstrating superiority compared with placebo, and it improved other body composition parameters (including visceral fat and lean body mass) and IGF-I SDS. At 86 weeks, improvements were maintained with both somapacitan and daily GH. Somapacitan was well tolerated, with similar adverse events (including injection-site reactions) compared with daily GH.

Conclusions: In AGHD patients, somapacitan administered once weekly demonstrated superiority over placebo, and the overall treatment effects and safety of somapacitan were in accordance with known effects and safety of GH replacement for up to 86 weeks of treatment. Somapacitan may provide an effective alternative to daily GH in AGHD. A short visual summary of our work is available (1).

Keywords: REAL 1; adult growth hormone deficiency; body composition; hypopituitarism; long-acting growth hormone; somapacitan.

Figure 1.

Trial design. *Numbers in the treatment boxes show patients exposed to treatment. One patient in the somapacitan group did not receive any treatment and was not included in any analyses. The grey box indicates the main period of the trial. Purple bars indicate titration periods and green bars, fixed-dose treatment periods. Time axis is not to scale. Abbreviations: AGHD, adult growth hormone deficiency

Figure 2.

Blood sampling for IGF-I in the main study period and dose titration of somapacitan, placebo, and daily GH. Arrows indicate timing of blood sampling, which was performed before administration of drug (weeks 0, 2, 4, 6, 8) or between planned doses (weeks 1, 3, 5, 7, 9, 16, 25, and 33). For the extension period, titration followed a similar pattern, with week 35 corresponding to week 0. Blood sampling also followed a similar pattern up to 53w4d (corresponding to 16w4d) and continued at 64w1d, 75w4d, and 86w4d. Time axis is not to scale. Abbreviations: d, days; GH, growth hormone; IGF-I, insulin-like growth factor-I; SDS, standard deviation scores; w, weeks.

Figure 3.

Patient disposition. *One patient in the somapacitan group was randomized but did not receive any trial drug (no reason was provided) and was therefore not included in any analyses. The shaded box represents the main period of the trial. Abbreviations: GH, growth hormone; soma, somapacitan

Figure 4.

Time course of IGF-I SDS according to titration adjustments for somapacitan. (a) Main period; (b) Extension period. Peak IGF-I samples (days 1–4) by titration (down, up, or none) from start dose to fixed dose of somapacitan for subjects entering the fixed-dose period. For visual purposes, trough IGF-I samples are not included. Data are observed mean (95% CI) (points and error bars) and the mean of individual predictions (solid lines). Dotted lines show target IGF-I SDS range. Abbreviations: IGF-I, insulin-like growth factor-I; SDS, standard deviation score.

Figure 5.

Adjusted changes from baseline in DXA-derived body composition measures during the main period (left hand graphs) and extension period (right hand graphs) (full analysis set). ETD values are shown for somapacitan minus placebo (main period) and for somapacitan/somapacitan minus daily GH/daily GH (extension period). For effects on fat mass, a reduction is desired. A negative ETD means the reduction appeared more pronounced with somapacitan than with the comparator. For effects on lean mass, an increase is desired. A positive ETD means the increase appeared more pronounced with somapacitan than with the comparator. Adjusted values are change from baseline estimates based on an analysis of covariance model (main period) or mixed model for repeated measurements (extension period) adjusted for baseline characteristics. The y-axes show the adjusted change from baseline at week 34 or week 86. Abbreviations: CI, confidence interval; DXA, dual-energy x-ray absorptiometry; ETD, estimated treatment difference; GH, growth hormone; soma, sompacitan.

Figure 6.

Empirical distribution (cumulative frequency) of IGF-I SDS values. Mean values at specific timepoints are shown in the tables below the figures. (a) Main period: distribution at week 34. Baseline values are also shown. IGF-I SDS increased in the somapacitan and daily GH groups but not in the placebo group. (b) Extension period: distribution at week 86. IGF-I SDS increased in all treatment groups. The black curve shows baseline values. Weeks 9 (main period) and 44 (extension period) mark the first visit after the end of the titration period. Full analysis set. n values show the number of patients contributing data (IGF-I values were not available for all patients at all visits). Abbreviations: GH, growth hormone; IGF-I, insulin-like growth factor-I; SDS, standard deviation score.

Figure 7.

Most frequent adverse events, occurring in ≥5% of patients in any treatment arm. (a) Main period. (b) Extension period. Abbreviations: %, Percentage of exposed subjects having the event; R, event rate per 100 patient-years at risk.

Figure 8.

Fasting plasma glucose by visit (safety analysis set). (a) Main period. (b) Main and extension periods. Observed data. Mean (filled symbols), median (center line), 25th and 75th percentiles (box), 5th and 95th percentiles (whiskers), individual outliers: nondiabetic at baseline (open circles), diabetic at baseline (crosses). Numbers of patients contributing to the data points appear in the bottom panel. Abbreviations: FPG, fasting plasma glucose.