Faculty Bibliography

CONTEXT:Growth hormone deficiency (GHD) in children is currently treated with daily injections of GH, which can be burdensome for patients and their parents/guardians. Somapacitan is a GH derivative in development for once-weekly treatment of GHD. OBJECTIVE:This work aimed to assess the efficacy and safety of somapacitan, and associated disease/treatment burden, after 4 years of treatment and 1 year after switching to somapacitan from daily GH. METHODS:This long-term safety extension of a multicenter, controlled phase 2 trial (NCT02616562) took place at 29 sites in 11 countries. Patients were prepubertal, GH-naive children with GHD. Fifty patients completed 4 years of treatment. Patients in the pooled group received somapacitan (0.04, 0.08, 0.16 mg/kg/week) for 1 year, followed by the highest dose (0.16 mg/kg/week) for 3 years. Patients in the switched group received daily GH 0.034 mg/kg/day for 3 years, then somapacitan 0.16 mg/kg/week for 1 year. Main outcome measures were height velocity (HV), change from baseline in HV SD score (SDS), change from baseline in height SDS, disease burden, and treatment burden for patients and parents/guardians. RESULTS:Changes from baseline in HV and HV SDS were similar and as expected in both groups. Observer-reported outcomes showed that patients and parents/guardians seem to have experienced a reduced treatment burden when switching from daily GH to somapacitan. Most parents/guardians (81.8%) strongly/very strongly preferred somapacitan over daily GH. CONCLUSIONS:Somapacitan showed similar efficacy and safety in patients who continued somapacitan treatment and those who switched from daily GH to somapacitan. Once-weekly injections may lead to a reduced treatment burden relative to once-daily injections. A plain-language summary of this work is available.

After the isolation of pituitary growth hormone (GH) in 1957, this form of GH, always in limited supply, was the only drug available for the treatment of GH deficiency. In 1985, recombinant GH became available, and the modalities of GH therapies changed dramatically as the supply was unlimited. New indications for GH in pediatrics and adult medicine were developed. Treatment was daily. Now in 2021 long-acting GH (LAGH) became available the world over making GH therapy more patient-friendly and even showing slightly greater efficacy than daily GH therapy. We are now entering a new era of LAGH therapy for pediatric and adult use with new formulations of GH, which will predictably be the preferred form of GH therapy for years to come increasing adherence to GH therapy and possibly even efficacy, that is, better growth rate. The continued availability of new safety data will further solidify the use of LAGH in clinical medicine.

In 1957, Maurice Raben at Yale was able to isolate and purify growth hormone from cadaveric pituitary glands. Pituitary growth hormone was the only way to treat children with growth hormone (GH) deficiency, until 1985 when recombinant GH became available for daily subcutaneous injection. For many years, the pediatric endocrine community longed for a long-acting recombinant GH formulation that would decrease the inconvenience of daily injections. Several mechanisms were employed to develop a GH that is rapidly absorbed into the blood stream after subcutaneous injection, but provides slow removal from the circulatory system to potentially optimize patient adherence to GH therapy. Four long-acting growth hormones are currently available in the world, or are close to regulatory approval. They are: (1) Pegylated formulations, (2) Prodrug formulations which are converted into active drug, (3) Nonvalent transient albumin binding GH compounds and (4) GH fusion proteins where a protein si fused with GH. All four formulations have undergone detailed phase 3 studies and were found to show non-inferiority in these clinical studies. All four demonstrate a safety and tolerability profile that is comparable to that of daily somatropin with an excellent adherence profile.

Children with GHD are currently treated with daily subcutaneous growth hormone (GH) injections, which can be burdensome. Somapacitan is a long-acting GH derivative in development for once-weekly use in children with GHD. REAL 3 (NCT02616562) is a phase 2, multinational, randomised, open-label, controlled trial assessing efficacy and safety of somapacitan versus daily GH (NorditropinR). Prepubertal, GH-naive children with GHD received 0.04 (n=16), 0.08 (n=15) or 0.16 (n=14) mg/kg/week somapacitan, or 0.034 mg/kg/day daily GH for 1 year. In a 2-year safety extension, all patients on somapacitan (n=45) received 0.16 mg/kg/week; patients receiving daily GH remained on daily GH. In a 4-year safety extension, treatment switched to somapacitan 0.16 mg/kg/week in the daily GH group (daily GH/somapacitan, n=11) and remained unchanged in the somapacitan group (somapacitan/somapacitan, n=39). We present results from year 4, the first year of the 4-year safety extension. Data are mean (SD). Height velocity (HV) was 7.4 (1.6) cm/ year for somapacitan/somapacitan and 6.6 (1.6) cm/year for daily GH/somapacitan, versus 8.3 (1.7) and 7.6 (2.0) cm/year for somapacitan/ somapacitan and daily GH, respectively, at year 3. HV SD score (SDS) was 1.55 (1.70) and 0.88 (1.61) for daily GH/somapacitan; change in height SDS from baseline was 2.85 (1.25) and 2.28 (0.97); insulin-like growth factor-I SDS was 1.29 (1.23) and 0.94 (1.60) for somapacitan/somapacitan and daily GH/somapacitan, respectively. The Table shows overall scores of GHD-child treatment burden (CTB) and GHD-parent treatment burden (PTB), reported by parents/guardians. During year 4, 20 patients (51.3%) receiving somapacitan/ somapacitan experienced 84 adverse events (AEs), and eight patients (72.7%) receiving GH/somapacitan experienced 12 AEs. Most AEs were mild/moderate and unrelated to treatment. Height-related outcomes were similar between and as expected for both treatment arms. Somapacitan may lead to improvement in treatment burden versus daily GH. Somapacitan safety profile was consistent with previous reports

Turner syndrome is the most common sex chromosome abnormality in women. Infertility and short stature are the most striking findings seen in these patients. Unfortunately, many girls are still being diagnosed too late and therefore early diagnosis and treatment key. Turner syndrome affects many systems of the body; therefore, a comprehensive approach is key for therapeutic intervention.

Objectives Lonapegsomatropin (TransCon hGH) is a once-weekly prodrug of somatropin, recently approved by the US FDA for the treatment of pediatric growth hormone deficiency (GHD) due to inadequate secretion of endogenous GH in patients 1 year and older. Lonapegsomatropin demonstrated safety and efficacy in treatment-naive and -experienced children in the 52-week heiGHt Trial and 26-week fliGHt Trial, respectively. Safety and efficacy were evaluated for participants who enrolled in the ongoing open-label extension trial enliGHten. Methods Upon entry into enliGHten, all participants received lonapegsomatropin via vial/syringe, with subsequent switch to the TransCon hGH Auto-Injector when available. Results are reported at Week 130 of the extension trial (data snapshot date: September 01, 2021) Results A total of 298 participants (98% of parent trial enrollment) continued into enliGHten. At Week 130, 248 participants remained in the trial, and 36 participants had completed the study. The mean (standard deviation [SD]) height standard deviation score (SDS) at Week 130 was -0.64 (0.85) compared with enliGHten baseline value of -1.56 (0.88). Participants continued to approach the average parental height SDS mean (SD) of -0.39 (0.77). The annualized height velocity mean (SD) at Week 130 was 9.32 cm/year (0.45). Average IGF-1 SDS (SD) at Week 130 was 1.46 (1.18) compared with 0.52 (1.58) at enliGHten baseline. Of the 36 participants who have completed the study, 14 had reached bone age of >14 years (girls) or >16 years (boys), and 24 had completed the study based on investigator judgement that treatment for pediatric GHD was no longer necessary. For the 36 completers, the difference between mean (SD) height SDS at last visit and average parental height SDS was -0.05 (0.75), and 61.1% of these participants had met or exceeded the average parental height SDS. With continued lonapegsomatropin treatment, the AE profile remained consistent with what was observed in the parent trials, with no new safety signals. Conclusions Children and adolescents treated with lonapegsomatropin showed continued improvement of height SDS through their 3rd year of therapy while demonstrating a safety profile that remained consistent with prior parent trials

PURPOSE/OBJECTIVE:The objectives of the ongoing, Phase 3, open-label extension trial enliGHten are to assess the long-term safety and efficacy of weekly administered long-acting growth hormone (LAGH) lonapegsomatropin in children with growth hormone deficiency (GHD). METHODS:Eligible subjects completing a prior Phase 3 lonapegsomatropin parent trial (heiGHt or fliGHt) were invited to participate. All subjects were treated with lonapegsomatropin. Subjects in the US switched to the TransCon hGH Auto-Injector when available.​ Endpoints were long-term safety, annualized height velocity (AHV), pharmacodynamics (insulin-like growth factor-1 standard deviation score [IGF-1 SDS] values), and patient- and caregiver-reported assessments of convenience and tolerability. RESULTS:Lonapegsomatropin treatment during enliGHten was associated with continued improvements in height SDS through Week 104 in treatment-naïve subjects from the heiGHt trial (-2.89 to -1.37 for- the lonapegsomatropin group; -3.0 to -1.52 for the daily somatropin group). Height SDS also continued to improve among switch subjects from the fliGHt trial (-1.42 at fliGHt baseline to -0.69 at Week 78). After 104 weeks, the average bone age/chronological age ratio for each treatment group was 0.8 (0.1), showing only minimal advancement of bone age relative to chronological age with continued lonapegsomatropin treatment among heiGHt subjects. Fewer local tolerability reactions were reported with the TransCon hGH Auto-Injector compared with syringe/needle. CONCLUSIONS:Treatment with lonapegsomatropin continued to be safe and well-tolerated, with no new safety signals identified. Children treated with once-weekly lonapegsomatropin showed continued improvement of height SDS through the 2nd year of therapy without excess advancement of bone age.

CONTEXT/BACKGROUND:Current GH therapy requires daily injections, which can be burdensome. Somapacitan is a long-acting GH derivative in development for treatment of GH deficiency (GHD). OBJECTIVE:Evaluate the efficacy, safety, and tolerability of once-weekly somapacitan after 3 years of treatment. DESIGN/METHODS:A multicenter, randomized, controlled, phase 2 study comparing somapacitan and once-daily GH for 156 weeks (NCT02616562). SETTING/METHODS:Twenty-nine sites in 11 countries. PATIENTS/METHODS:Fifty-nine children with GHD randomized (1:1:1:1) and exposed to treatment. Fifty-three children completed the 3-year period. INTERVENTIONS/METHODS:Patients received somapacitan (0.04 [n=14], 0.08 [n=15] or 0.16 [n=14] mg/kg/week) or daily GH (n=14) (0.034 mg/kg/day, equivalent to 0.238 mg/kg/week) subcutaneously during the first year, after which all patients on somapacitan received 0.16 mg/kg/week. MAIN OUTCOME MEASURES/METHODS:Height velocity (HV) at year 3; changes from baseline in height standard deviation score (HSDS), HVSDS and IGF-I SDS. RESULTS:The estimated treatment difference (95% CI) in HV for somapacitan 0.16/0.16 mg/kg/week versus daily GH at year 3 was 0.8 cm/year (-0.4; 2.1). Change in HVSDS from baseline to year 3 was comparable between somapacitan 0.16/0.16 mg/kg/week, the pooled somapacitan groups, and daily GH. A gradual increase in HSDS from baseline was observed for all groups. At year 3, mean HSDS was similar for the pooled somapacitan groups and daily GH. Change from baseline to year 3 in mean IGF-I SDS was similar across treatments. CONCLUSIONS:Once-weekly somapacitan in children with GHD showed sustained efficacy over 3 years in all assessed height-based outcomes with similar safety and tolerability to daily GH.

INTRODUCTION/BACKGROUND:The phase 3 fliGHt Trial evaluated the safety and tolerability of once-weekly lonapegsomatropin, a long-acting prodrug, in children with growth hormone deficiency (GHD) who switched from daily somatropin therapy to lonapegsomatropin. METHODS:This multicenter, open-label, 26-week phase 3 trial took place at 28 sites across 4 countries (Australia, Canada, New Zealand, and the USA). The trial enrolled 146 children with GHD, 143 of which were previously treated with daily somatropin. All subjects received once-weekly lonapegsomatropin 0.24 mg human growth hormone/kg/week. The primary outcome measure was safety and tolerability of lonapegsomatropin over 26 weeks. Secondary outcome measures assessed annualized height velocity (AHV), height standard deviation score (SDS), and IGF-1 SDS at 26 weeks. RESULTS:Subjects had a mean prior daily somatropin dose of 0.29 mg/kg/week. Treatment-emergent adverse events (AEs) reported were similar to the published AE profile of daily somatropin therapies. After switching to lonapegsomatropin, the least-squares mean (LSM) AHV was 8.7 cm/year (95% CI: 8.2, 9.2) at Week 26 and LSM height SDS changed from baseline to Week 26 of +0.25 (95% CI: 0.21, 0.29). Among switch subjects, the LSM for average IGF-1 SDS was sustained at Weeks 13 and 26, representing an approximate 0.7 increase from baseline (prior to switching from daily somatropin therapy). Patient-reported outcomes indicated a preference for weekly lonapegsomatropin among both children and their parents. CONCLUSIONS:Lonapegsomatropin treatment outcomes were as expected across a range of ages and treatment experiences. Switching to lonapegsomatropin resulted in a similar AE profile to daily somatropin therapy.