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Abstract Context Somapacitan is a long-acting GH derivative for treatment of GH deficiency (GHD). Objective Evaluate the efficacy and tolerability of somapacitan in children with GHD after 2 years of treatment and after the switch from daily GH. Design A randomized, multinational, open-labelled, controlled parallel group phase 3 trial, comprising a 52-week main phase and 3-year safety extension (NCT03811535). Setting Eighty-five sites across 20 countries. Patients A total of 200 treatment-naïve prepubertal patients were randomized and exposed; 194 completed the 2-year period. Interventions Patients were randomized 2:1 to somapacitan (0.16 mg/kg/wk) or daily GH (0.034 mg/kg/d) during the first year, after which all patients received somapacitan 0.16 mg/kg/wk. Main outcome measures Height velocity (HV; cm/year) at week 104. Additional assessments included HV SD score (SDS), height SDS, IGF-I SDS, and observer-reported outcomes. Results HV was sustained in both groups between 52 and 104 weeks. At week 104, mean (SD) for HV between weeks 52 and 104 was 8.4 (1.5) cm/year after continuous somapacitan treatment and 8.7 (1.8) cm/year after 1 year of somapacitan treatment following switch from daily GH. Secondary height-related endpoints also supported sustained growth. Mean IGF-I SDS during year 2 was similar between groups and within normal range (−2 to +2). Somapacitan was well tolerated, with no safety or tolerability issues identified. GH patient preference questionnaire results show that most patients and their caregivers (90%) who switched treatment at year 2 preferred once-weekly somapacitan over daily GH treatment. Conclusions Somapacitan in children with GHD showed sustained efficacy and tolerability for 2 years, and after switching from daily GH. Patients/caregivers switching from daily GH expressed a preference for somapacitan. Clinical Trial Registration NCT03811535

Growth hormone (GH) replacement therapy usually requires daily subcutaneous (s.c.) injections that can be burdensome for patients and their caregivers. Somapacitan, a long-acting reversible albumin-binding GH derivative, is in development for once-weekly s.c. administration in children with GH deficiency (GHD). REAL4 is a randomised, multi-national, open labelled, and active-controlled parallel group phase 3 trial, comprising a 52-week main phase and three-year extension period (NCT03811535). Two-hundred GH-treatment-naïve, prepubertal children with GHD (74.5% male) were randomly assigned in a 2: 1 ratio to receive 0.16 mg/kg/week s.c. somapacitan (n=132) or daily s.c. GH (0.034 mg/kg/day Norditropin®; n=68). The 52-week main trial results are presented here. The primary endpoint was annualized height velocity (HV) after 52 weeks of treatment. At week 52, the estimated mean HV was 11.2 cm/year for somapacitan compared to 11.7 cm/year for daily GH. The estimated treatment difference was -0.5 [95% CI -1.1 to 0.2] cm/year, confirming non-inferiority (non-inferiority threshold: -1.8 cm/year). Secondary height-related endpoints supported the primary endpoint. Insulin-like growth factor-I standard deviation score (IGF-I SDS) showed consistent increases for both somapacitan and daily GH over the 52 weeks, with change differences from baseline not statistically significant between treatment groups. At week 52, mean IGF-I SDS levels were similar between somapacitan (+0.28) and daily GH (+0.10) and within normal range (-2 to +2). Somapacitan was well tolerated, with no safety or local tolerability issues identified. There were no clinically relevant findings with respect to changes in glucose metabolism, no neutralizing anti-somapacitan or anti-GH antibodies were detected, and a low number of patients reported injection-site reactions, with similar proportions for somapacitan (5.3%) and daily GH (5.9%). In both treatment groups, 1.5% of patients reported injection site pain. Adherence was high for both treatments. The mean and median adherence for somapacitan treatment were 95.8% and 100%, respectively. The mean and median adherence for the daily GH group were 88.3% and 96.9%, respectively. In conclusion, once-weekly somapacitan has a similar efficacy and safety profile as daily GH with similar mean IGF-I levels in treatment-naïve children with GHD. Presentation: Sunday, June 12, 2022 1:06 p.m. - 1:11 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Disclosure: J. Blair: Advisory Board Member; Self; Novo Nordisk. Speaker; Self; Novo Nordisk, Ipsen. Other; Self; Novo Nordisk. B.S. Miller: Consulting Fee; Self; Abbvie, Bristol-Myers Squibb, Novo Nordisk, Pfizer, Inc., EMD Serono, Endo Pharmaceuticals. Grant Recipient; Self; Alexion Pharmaceuticals, Inc., Abbvie, Amgen Inc, Novo Nordisk, Pfizer, Inc. M. Hojby: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. A.K. Maniatis: Research Investigator; Self; Novo Nordisk, Pfizer, Inc. J. Mori: Advisory Board Member; Self; Novo Nordisk. Speaker; Self; Novo Nordisk, Pfizer, Inc. V. Boettcher: Advisory Board Member; Self; Merck. Speaker; Self; Novo Nordisk, Merck. Other; Self; Ferring Pharmaceuticals, Lilly USA, LLC, Merck, Novo Nordisk. H. Kim: None. R. Beck Bang: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. L. De Fries Jensen: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. M. Polak: Advisory Board Member; Self; Ipsen, Novo Nordisk, Pfizer, Inc. Grant Recipient; Self; Ipsen, Novo Nordisk, Pfizer, Inc., Sandoz, Sanofi, Merck. Speaker; Self; Novo Nordisk, Ipsen. R. Horikawa: Advisory Board Member; Self; Novo Nordisk, Pfizer, Inc. Grant Recipient; Self; Sandoz. Speaker; Self; Novo Nordisk, Pfizer, Inc. Growth hormone (GH) replacement therapy in children requires daily subcutaneous (s.c.) injections. Although beneficial to growth and other health related outcomes, daily injections can be burdensome for patients and their caregivers. This is acutely apparent in pediatric patients, such as children with GH deficiency (GHD), where both the child and parent/caregiver’s lifestyle are affected. Indeed, concerns have been raised that this burden is linked to lower adherence rates for daily GH treatment and a subsequent reduction in the efficacy of treatment. Somapacitan is a long-acting reversible albumin-binding human GH derivative in development for once-weekly s.c. administration in children with GHD. REAL4 is an ongoing multi-national, randomized, open labelled phase 3 trial consisting of a 52-week main phase and three-year extension period (NCT03811535). During the main phase, results showed that once-weekly s.c. somapacitan (0.16 mg/kg/week) has a similar efficacy and safety profile compared to daily GH (0.034 mg/kg/day Norditropin®) treatment (non-inferiority confirmed). Following the main phase, patients who had been taking daily GH (n=68) switched to once-weekly s.c. somapacitan. After 4 weeks (week 56), the parents/caregivers of these patients were asked to complete a patient preference questionnaire. Results from this questionnaire are presented here. The first question asked was: Which treatment do you prefer? Responses showed 45/50 (90%) preferred once-weekly somapacitan, 5/50 (10%) had no preference, and no respondents preferred daily GH treatment. Of the 45 respondents who preferred the somapacitan treatment regime, 38 (84.4%) ‘very strongly’ or ‘strongly’ preferred it, while 7 (15.6%) had a not very strong preference. Among the reasons respondents preferred somapacitan were: number of times needing to do injections (27/45; 60%); less worried about remembering to do injections (21/45; 46.7%); and child less worried about getting injections and child less annoyed about getting injections (both 15/45; 33.3%), as well as others. Finally, when asked which treatment they would be most adherent to, most (35/45; 77.8%) answered that they would be more adherent to once-weekly somapacitan compared to the daily GH treatment regime. In conclusion, these results indicate that once-weekly somapacitan treatment is preferred by parents/caregivers with a child that has switched from daily GH. The main reason for this preference being a reduction in the number of injections needed. Notably, these respondents believe they will be more adherent to GH replacement therapy with once-weekly somapacitan. Presentation: Saturday, June 17, 2023

Disclosure: B.S. Miller: Consulting Fee; Self; Abbvie, Bristol-Myers Squibb, Novo Nordisk, Pfizer, Inc., EMD Serono, Endo Pharmaceuticals. Grant Recipient; Self; Alexion Pharmaceuticals, Inc., Abbvie, Amgen Inc, Novo Nordisk, Pfizer, Inc. J. Blair: Advisory Board Member; Self; Novo Nordisk. Speaker; Self; Novo Nordisk, Ipsen. Other; Self; Novo Nordisk. M. Hojby: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. A.K. Maniatis: Research Investigator; Self; Novo Nordisk, Pfizer, Inc. J. Mori: Advisory Board Member; Self; Novo Nordisk. Speaker; Self; Novo Nordisk, Pfizer, Inc. V. Boettcher: Advisory Board Member; Self; Merck. Speaker; Self; Novo Nordisk, Merck. Other; Self; Ferring Pharmaceuticals, Lilly USA, LLC, Merck, Novo Nordisk. H. Kim: None. R. Beck Bang: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. M. Polak: Advisory Board Member; Self; Ipsen, Novo Nordisk, Pfizer, Inc. Grant Recipient; Self; Ipsen, Novo Nordisk, Pfizer, Inc., Sandoz, Merck, Sanofi. Speaker; Self; Novo Nordisk, Ipsen. R. Horikawa: Advisory Board Member; Self; Novo Nordisk, Pfizer, Inc. Grant Recipient; Self; Sandoz. Speaker; Self; Novo Nordisk, Pfizer, Inc. Growth hormone (GH) has a short half-life that necessitates daily subcutaneous (s.c.) injections for replacement therapy in children with GH deficiency (GHD). Although essential to achieve desired clinical outcomes, daily injections are often burdensome for both patients and their caregivers. Somapacitan (Novo Nordisk A/S) is a long-acting reversible albumin-binding human GH derivative in development for once-weekly s.c. administration in children with GHD, with the aim to overcome the treatment burden of daily injections. REAL4 is an ongoing multi-national, randomized, open labelled phase 3 trial consisting of a 52-week main phase followed by a single-group three-year extension period (NCT03811535). During the main phase, 132 patients received once-weekly 0.16 mg/kg/week somapacitan and 68 received daily GH (0.034 mg/kg/day Norditropin®, Novo Nordisk). After 52-weeks of treatment, patients in the daily GH group were switched to 0.16 mg/kg/week somapacitan (switch group) while patients receiving somapacitan continued treatment (soma/soma group). 104-week results are presented here. One hundred and ninety-four patients (67 and 127 for switch and soma/soma groups, respectively) completed 104 weeks of treatment. A small, numerical difference was observed at week 52 for mean height velocity (HV) between treatments and this minor difference was sustained from week 52 to 104 (8.7 vs. 8.4 cm/year for the switch and soma/soma groups, respectively). Underlying growth characteristics in year 1 persisted in year 2 for both groups, including when switching to somapacitan, indicating the treatment arm per se did not influence any difference in growth, but rather the baseline characteristics for each group was the cause of the difference. Other height-related endpoints supported these findings, for example a continuous trend towards increased Height SDS was observed in both groups (change from baseline to week 104 of 1.97 and 1.75 for the switch and soma/soma groups, respectively). Pharmacokinetic/pharmacodynamic modelling suggests similar mean average IGF-I SDS levels over the weekly dosing interval within normal range (-2 to +2 SDS) for both groups (0.754 and 0.725 for the switch and soma/soma groups, respectively) in year 2. Somapacitan was well tolerated, with no safety or local tolerability issues identified. There were no clinically relevant findings with respect to changes in glucose metabolism and no neutralizing anti-somapacitan antibodies detected. A low proportion of children reported injection-site reactions in the second year (2.9% and 2.3% in the switch and soma/soma groups, respectively) with no injection site pain reported in either group. In conclusion, once-weekly somapacitan showed sustained efficacy over 2 years and after one year following switch from daily GH treatment with a safety and tolerability profile similar to the well-known profile for daily GH. Presentation: Saturday, June 17, 2023

Insulin icodec (icodec) is a once-weekly basal insulin in development. This post hoc analysis used data from the NCT03951805 trial to investigate CGM-derived time in, above, below range (TIR, TAR, TBR) and glycemic variability measured as coefficient of variation (CV%). Insulin-naïve patients with T2D (N=205) received insulin glargine U100 (IGlar U100; pre-breakfast SMBG target 80-130 mg/dL, adjusted ±4U/day), icodec titration A (80- 130 mg/dL, ±21U/week), B (80-130 mg/dL, ±28U/week; most relevant comparator to IGlar U100), or C (70-108 mg/dL, ±28U/week). Treatments were titrated weekly. TIR (70-180 mg/dL), TAR (>180 mg/dL), TBR (<70 and <54 mg/dL) and CV% were calculated during the 2-week screening and the 16-week treatment periods using double-blinded Dexcom G6 CGM data. During the trial, across arms, TIR increased to >70% from weeks 7 and 8, TAR decreased to <25% from weeks 11 and 12, TBR and TBR remained below the recommended targets (<4% and <1). At weeks 15 and 16, proportion of patients achieving >70% TIR and TBR <4% were 63.3% for titration A, 80.0% for B, 66.0% for C and 64.0% for IGlar U100. CV% increased slightly over time but remained <36% in all arms. TIR increased during the trial across treatments, and similar or numerically higher proportion of patients achieved >70% TIR and TBR <4% with icodecvs. IGlar U100 at weeks 15 and 16