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SAT-LB12 Once-Weekly Somapacitan vs Daily Growth Hormone in Growth Hormone Deficiency: 2-Year Safety Results From Real 3, a Randomized Phase 2 Trial

ABSTRACT: Abstract Growth hormone (GH) replacement therapy currently requires daily injections. Somapacitan is a long-acting GH-derivative being developed for once-weekly (OW) use in children and adults with GH deficiency (GHD). A phase 2, multinational, randomized, open-label, controlled trial (ClinicalTrials.gov: NCT02616562) investigated the efficacy and safety of OW somapacitan compared with daily GH (Norditropin® FlexPro®). GH-treatment-naïve prepubertal children with GH deficiency received 0.04 (n=16), 0.08 (n=15) or 0.16 mg/kg/wk (n=14) subcutaneous (sc) OW somapacitan, or sc GH 0.034 mg/kg/day (0.24 mg/kg/wk; n=14) for 52 wks, followed by a 104-wk safety extension with all patients on somapacitan receiving 0.16 mg/kg/wk while GH dose was unaltered. Safety endpoints included frequency of adverse events (AEs), including injection-site reactions, and occurrence of anti-somapacitan/anti-human growth hormone (hGH) antibodies. The 52-wk efficacy and safety results have been reported. We report here safety results at 104 wks’ total treatment. Number of AEs (% of patients) was as follows: OW somapacitan 0.04/0.16 mg/kg/wk, 51 (75%); 0.08/0.16 mg/kg/wk, 89 (80%); 0.16/0.16 mg/kg/wk, 89 (100%); and for daily GH, 82 (100%). Nasopharyngitis, influenza, allergic rhinitis and gastroenteritis were the most common AEs across all treatment groups. Pyrexia was more common in the OW somapacitan 0.04/0.16 mg/kg/wk (43.8%) and 0.08/0.16 mg/kg/wk (26.7%) groups vs the higher-dose OW somapacitan and daily GH groups (7.1% each). Most AEs were mild to moderate and unlikely related to treatment. Ten serious AEs were reported in five (8.5%) children and unlikely related to treatment, except two AEs of moderate severity during the first 26 wks: generalized edema and vomiting in one child on 0.16 mg/kg/wk OW somapacitan, rated as probably related to treatment although she was also given intravenous antibiotics for suspected infection. Injection-site reactions were reported in the 0.04/0.16 mg/kg/wk (n=2) and 0.16/0.16 mg/kg/wk (n=1) OW somapacitan groups and in the daily GH group (n=1). Four children (0.04/0.16 mg/kg/wk) and one child (0.16/0.16 mg/kg/wk) had transient anti-somapacitan antibodies; one child (0.16/0.16 mg/kg/wk) had low-titer anti-somapacitan antibodies at two consecutive visits; in one child (daily GH group) with persistent low-titer anti-hGH antibodies, treatment was discontinued at wk 52. All antibodies were non-neutralizing. In conclusion, OW somapacitan was well tolerated at all doses, with no new safety or tolerability issues identified after up to 104 wks of treatment. The frequency, severity and type of AEs were similar in the OW somapacitan and daily GH treatment groups except for pyrexia, which was unlikely related to treatment and more frequently reported in the lowest dose somapacitan group.

SUBMITTER: Savendahl L

PROVIDER: S-EPMC7209577 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Project description:Daily growth hormone (GH) injections can be burdensome for patients and carers. Somapacitan is a long-acting, reversible albumin-binding GH derivative in development for once-weekly administration in patients with growth hormone deficiency (GHD). The objective of this study is to evaluate the efficacy, safety, and tolerability of once-weekly somapacitan vs once-daily GH. REAL 3 is a multicenter, randomized, controlled, double-blind (somapacitan doses), phase 2 study with a 26-week main and 26-week extension phase (NCT02616562). This study took place at 29 sites in 11 countries. Fifty-nine GH treatment-naive prepubertal children with GHD were randomly assigned; 58 completed the trial. Interventions comprised 3 somapacitan doses (0.04 [n = 16], 0.08 [n = 15], or 0.16 mg/kg/wk [n = 14]) and daily GH (0.034 mg/kg/d [n = 14]), administered subcutaneously. The primary end point was height velocity (HV) at week 26. Secondary efficacy end points included HV SD score (SDS) and insulin-like growth factor-I (IGF-I) SDS. At week 26, mean (SD) annualized HV for the somapacitan groups was 8.0 (2.0), 10.9 (1.9), and 12.9 (3.5) cm/year, respectively, vs 11.4 (3.3) cm/year for daily GH; estimated treatment difference (somapacitan 0.16 mg/kg/week-daily GH): 1.7 [95% CI -0.2 to 3.6] cm/year. HV was sustained at week 52, and significantly greater with somapacitan 0.16 mg/kg/week vs daily GH. Mean (SD) change from baseline in HV SDS at week 52 was 4.72 (2.79), 6.14 (3.36), and 8.60 (3.15) for the somapacitan groups, respectively, vs 7.41 (4.08) for daily GH. Model-derived mean (SD) IGF-I SDS for the somapacitan groups was -1.62 (0.86), -1.09 (0.78), and 0.31 (1.06), respectively, vs -0.40 (1.50) observed for daily GH. Safety and tolerability were consistent with the profile of daily GH. In children with GHD, once-weekly somapacitan 0.16 mg/kg/week provided the closest efficacy match with similar safety and tolerability to daily GH after 26 and 52 weeks of treatment. A short visual summary of our work is available (1).

Project description:Abstract Somapacitan is a long-acting, reversible albumin-binding growth hormone (GH) derivative being developed for once-weekly dosing in adults and children with GH deficiency (GHD). The efficacy, safety and tolerability of somapacitan were compared with daily GH in children with GHD in a multicenter, randomized, controlled, double-blinded to dose, phase 2 trial (REAL 3, NCT02616562). Treatment-naïve, prepubertal children with GHD were randomized 1:1:1:1 to once-weekly sc somapacitan (0.04, 0.08 or 0.16 mg/kg/week [wk]) or daily sc GH (Norditropin®; 0.034 mg/kg/day) during the 26-wk main trial period and 26-wk extension. Efficacy of the 0.16 mg/kg/wk dose was similar to that of daily GH, judged by height standard deviation scores (SDS) and insulin-like growth factor-I SDS, and, at wk 52, height velocity was statistically significantly greater with somapacitan 0.16 mg/kg/wk vs daily GH. Safety and tolerability of somapacitan were consistent with the profile of daily GH. Here, we report the results of a pre-planned analysis of patient-reported outcomes (PROs) collected during REAL 3. This is, to our knowledge, the first report of a disease-specific PRO score from a randomized trial in GHD. PROs were investigated using the Growth Hormone Deficiency - Child Impact Measure observer-report (GHD-CIM ObsRO). This is a new, validated questionnaire, developed according to US FDA guidance, to assess the impact of GHD on physical functioning, and social and emotional wellbeing in children aged 4 to <13 years, to be completed by caregivers. Minimal important differences (MID) in scores were determined based on Patient and Clinician Global Impression of Severity. Changes from baseline to wk 52 in GHD-CIM ObsRO scores were compared between daily GH and each dose of somapacitan, and were analyzed using an analysis of covariance model. A total of 59 patients were randomized (somapacitan n=45; daily GH n=14); the full analysis set included 57 children (somapacitan: 0.04 mg/kg/wk n=14; 0.08 mg/kg/wk n=15; 0.16 mg/kg/wk n=14; daily GH n=14). Mean age was 5.9 years; 60% were male; 11 children were <4 years old at baseline. For the change from baseline in GHD-CIM ObsRO score, the estimated treatment differences (ETDs) between somapacitan 0.16 mg/kg/wk and daily GH at wk 52 exceeded the MID in favor of somapacitan for the emotional wellbeing (ETD -9.34; MID 7) and social wellbeing domains (ETD -10.12; MID 5), as well as total score (ETD -7.43; MID 5). The somapacitan 0.16 mg/kg/wk group showed a numerical improvement over daily GH across all GHD-CIM ObsRO domains and total score, although none of the ETDs reached statistical significance. At 52 wks, the difference in GHD-CIM ObsRO scores between somapacitan 0.16 mg/kg/wk and daily GH exceeded the MID for the total score, and for the emotional and social wellbeing domains, suggesting clinically relevant improvement for these parameters in favor of somapacitan in children with GHD.

Project description:Abstract Background: Growth hormone deficiency (GHD) requires long-term daily injections with GH replacement therapy and is associated with considerable treatment burden. Somapacitan is a long-acting GH derivative being developed for once-weekly dosing in adults and children with GHD. A well-established protraction method, successfully used to extend the half-life of insulin and glucagon-like peptide (GLP)-1, has been applied in developing somapacitan: an albumin-binding moiety (1.3 kDa) is attached to a single amino acid substitution in the GH molecule (22 kDa). Objective: To evaluate the efficacy, safety, and tolerability of three once-weekly somapacitan doses, compared with Norditropin®, a daily GH. Methods: This multicenter, open-label, randomized, controlled phase 2 study (ClinicalTrials.gov: NCT02616562) was double-blind with regard to dose levels of somapacitan, and height assessors were blinded to treatment. GH-treatment-naïve prepubertal children with GHD were randomized to somapacitan (N=45) or Norditropin® (N=14). Patients received 0.04 (n=16), 0.08 (n=15) or 0.16 mg/kg/wk (n=14) subcutaneous (sc) somapacitan once weekly, or sc Norditropin® 0.034 mg/kg/day (0.24 mg/kg/wk; n=14). Patients completed 6 months of treatment as follows: somapacitan 0.04 (n=14), 0.08 (n=15) and 0.16 (n=14) mg/kg/wk, and Norditropin® 0.034 mg/kg/day (n=13). Results: At 6 months, mean (SD) annualized height velocity (HV, cm/year) for the three somapacitan doses was 8.0 (2.0), 10.9 (1.9) and 12.9 (3.5), respectively. HV for the 0.08 and 0.16 mg/kg/wk doses did not differ significantly from HV with Norditropin® (11.4 [3.3]). Insulin-like growth factor (IGF)-I increased dose-dependently: change from baseline in IGF-I standard deviation score (SDS) was 1.08, 2.15 and 3.21 for the somapacitan groups, respectively, when measured at peak of the IGF-I profile over the dosing interval, and 2.03 for Norditropin®. Modeling yielded IGF-I SDS average over the dosing interval for the somapacitan 0.16 mg/kg/wk group that was similar to observed values for Norditropin®. Adverse events were mild-to-moderate and most were evaluated as unrelated to treatment by the investigator. One patient had persistent anti-hGH antibodies of low titer and three patients had a single positive measurement of anti-somapacitan antibodies of low titer. All antibody positive samples were negative for in vitro neutralizing antibodies. There were no clinically relevant changes from baseline to Week 26 in any treatment group in mean HbA1c, fasting glucose or insulin. Tolerability was consistent with known properties of GH. Conclusion: In children with GHD, the efficacy, safety and tolerability of once-weekly somapacitan was similar to that of daily Norditropin®. Results from this phase 2 trial provide support for the initiation of a phase 3 trial of somapacitan in children with GHD.

Project description:Abstract Treatment of persistent short stature in children born small for gestational age (SGA) requires daily growth hormone (GH) injections that can be burdensome for patients and caregivers. Once-weekly somapacitan is a long-acting GH currently in phase 3 development for replacement therapy in children with GH deficiency. We report the 26-week results of the first phase 2, multinational, randomized, open-label, controlled, dose-finding trial (NCT03878446) investigating the efficacy and safety of somapacitan as treatment for short stature in children born SGA compared with daily GH (Norditropin®, Novo Nordisk A/S). A total of 62 (35.5% female) GH-treatment-naïve, prepubertal children received 0.16, 0.20 or 0.24 mg/kg/week subcutaneous (s.c.) somapacitan, or 0.035 or 0.067 mg/kg/day s.c. daily GH for 26 weeks (main phase). All children are subsequently included in an extension to this trial. The primary outcome was annualized height velocity (HV). At week 26, the estimated mean HV was: 8.9, 11.0 and 11.3 cm/year for 0.16 mg/kg/week (n=12), 0.20 mg/kg/week (n=13) and 0.24 mg/kg/week (n=12) somapacitan, respectively, versus 10.3 and 11.9 cm/year for 0.035 mg/kg/day (n=12) and 0.067 mg/kg/day (n=13) daily GH, respectively. A dose-dependent response in the estimated mean HV was observed with both somapacitan and daily GH. The effect of somapacitan on HV was not statistically significantly different compared with daily GH. A similar pattern was observed for change from baseline in height standard deviation score (SDS) and change from baseline in HV SDS. Consistent dose-dependent increases were observed in insulin-like growth factor-I (IGF-I) SDS with both somapacitan and daily GH. Exposure-response modeling of somapacitan exposure versus HV and IGF-I SDS vs. HV indicated an exposure-dependent increase in HV for both these parameters. Somapacitan was well tolerated at all doses investigated, with no safety or local tolerability issues identified. There were no clinically relevant findings with respect to glucose metabolism, and no detection of anti-drug antibodies in any of the dose groups. In conclusion, all investigated doses of weekly somapacitan were efficacious and well tolerated throughout the study period. Based on the totality of data on improvements in height-based parameters combined with exposure-response analyses, a somapacitan dose of 0.24 mg/kg/week appears as the most efficacious dose, providing similar efficacy, safety and tolerability to daily GH 0.067 mg/kg/day after 26 weeks of treatment. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:51 p.m. - 12:56 p.m.

Project description:Abstract Somapacitan is a long-acting, reversible albumin-binding human growth hormone (GH) derivative based on a proven protraction technology. The objective of this trial was to evaluate the safety, efficacy and treatment satisfaction of once-weekly somapacitan compared with daily GH (Norditropin®) over 52 weeks in Japanese patients with adult GH deficiency (AGHD). This was a phase 3, multicenter, randomized, open-label, parallel-group, active-controlled trial (NCT03075644). Patients previously treated with human GH were randomized 1:3 to either daily GH or somapacitan, respectively, to undergo 20 weeks of dose titration and 32 weeks of fixed-dose treatment. The primary endpoint was the incidence of adverse events (AEs) from baseline to week 53. Secondary endpoints included change from baseline in visceral, subcutaneous and total adipose tissue (VAT, SAT and TAT, respectively) assessed with computerized tomography scans; change from baseline in treatment satisfaction evaluated using Treatment Satisfaction Questionnaire for Medication (TSQM-9) scores; and occurrence of anti-somapacitan antibodies. In total, 62 patients were randomized (16 to the daily GH and 46 to the somapacitan treatment arm), of which 60 completed the trial. Baseline characteristics for daily GH vs somapacitan groups, respectively, were: 43.8% vs 47.8% female, 87.5% vs 80.4% adult-onset GH deficiency, mean (SD) age 49.3 (11.5) vs 54.1 (12.1) years, weight 67.9 (12.0) vs 69.4 (22.7) kg, body mass index 24.8 (3.7) vs 26.4 (6.7) kg/m2, and GH dose at screening 0.29 (0.14) vs 0.31 (0.17) mg. Rate of AEs per 100 patient-years was similar between treatment arms (309.8 for daily GH, 312.7 for once-weekly somapacitan); most AEs were mild (97.9% and 93.1%, respectively) and none were severe. Four AEs in the somapacitan arm were serious; all were considered unlikely related to treatment. No anti-somapacitan antibodies were detected during treatment. Mean insulin-like growth factor-I standard deviation score (IGF-I SDS) at baseline was maintained with both treatments. The majority of the patients had IGF-I SDS values below +2. No significant differences in VAT, SAT and TAT were seen in both treatment groups after 52 weeks (estimated difference, somapacitan – daily GH [95% CI]): –1.74 [–18.13; 14.66], –11.53 [–35.54; 12.48], and –12.85 [–47.31; 21.62] cm2, respectively. TSQM-9 scores were not significantly different between treatments, but showed a tendency in favor of somapacitan (estimated difference [95% CI]): 4.87 [–3.46; 13.20] for effectiveness, 6.79 [–1.04; 14.61] for convenience, and 6.88 [–1.08; 14.85] for overall satisfaction. No new safety concerns were identified. Improvements in body composition were similar in the GH and somapacitan cohorts. The safety and tolerability of somapacitan in Japanese patients with AGHD were consistent with results from the global phase 3 trial (REAL 1).

Project description:NNC0195-0092 is a reversible, albumin-binding GH derivative, developed for once-weekly administration.The objective of the study was to evaluate safety, local tolerability, pharmacodynamics, and pharmacokinetics of multiple, once-weekly doses of NNC0195-0092, compared with daily GH.This was a phase 1, randomized, open-label, active-controlled, multiple-dose, dose-escalation trial.Thirty-four GH-treated adult subjects (male, n = 25) with GH deficiency participated in the study.Subjects were sequentially assigned into four cohorts of eight subjects, randomized within each cohort (3:1) to once-weekly NNC0195-0092 (n = 6) for 4 weeks (0.02, 0.04, 0.08, and 0.12 mg/kg) or daily injections of Norditropin NordiFlex (n = 2) for 4 weeks with a dose replicating the pretrial dose of somatropin. A safety assessment was performed prior to initiating treatment at the next dose level of NNC0195-0092. Daily GH treatment was discontinued 14 days before the trial start. Blood samples were drawn for assessment of safety, pharmacokinetics, pharmacodynamics (IGF-1 and IGF-binding protein-3) profiles, and immunogenicity studies.Numbers of adverse events were similar at the dose levels of 0.02, 0.04, and 0.08 mg/kg NNC0195-0092 vs daily injections of Norditropin NordiFlex, whereas the number of adverse events was greater at the highest dose level of NNC0195-0092 (0.12 mg/kg). NNC0195-0092 (area under the curve[0-168h]) and peak plasma concentration) increased in a dose-dependent manner, and a dose-dependent increase in IGF-1 levels was observed. IGF-1 profiles were elevated for at least 1 week, and for the 0.02-mg/kg and 0.04-mg/kg NNC0195-0092 doses, the observed IGF-1 levels were similar to the levels for the active control group.Four once-weekly doses of NNC0195-0092 (dose range 0.02-0.12 mg/kg) administered to adult patients with GH deficiency were well tolerated, and IGF-1 profiles were consistent with a once-weekly treatment profile. No clinically significant safety and tolerability signals causally related to NNC0195-0092 were identified, nor were any immunogenicity concerns revealed.

Dataset Information

SAT-LB12 Once-Weekly Somapacitan vs Daily Growth Hormone in Growth Hormone Deficiency: 2-Year Safety Results From Real 3, a Randomized Phase 2 Trial

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