Up to 5 years of weekly somatrogon in children with growth hormone deficiency: final data from the global phase 3 study

Abstract

Purpose

This open-label extension (OLE) study aimed to evaluate the long-term efficacy and safety of once-weekly somatrogon in pediatric patients with growth hormone deficiency (GHD) following up to 5 years of somatrogon treatment.

Methods

Patients who had previously completed 12 months of treatment (somatrogon or somatropin) in a phase 3, randomized, active-controlled study (NCT02968004) were eligible to enroll into this OLE study; somatropin-treated patients were switched to somatrogon (0.66 mg/kg/week), and somatrogon-treated patients received somatrogon at their previous dose.

Results

A total of 212 patients entered the OLE. Mean annualized height velocity at the end of OLE Year 1 (Y1), Y2, Y3, and Y4 was 8.11, 7.91, 7.02, and 6.56 cm/year, respectively. Mean height SDS increased in each year of the OLE and approached 0 SDS by OLE Y4. Mean (SD) IGF-I SDS was positive and within the normal range throughout the OLE. The incidence of adverse events (AEs) was 53.8% to 72.3%, with most being mild to moderate. The incidence of serious AEs in each year was low (0-4.7%), and none were related to treatment. The most common treatment-related AEs were injection-site pain and injection-site erythema. The presence of antidrug antibodies did not appear to impact safety or efficacy outcomes.

Conclusion

Based on the final data from the largest cohort of somatrogon-treated patients to date, once-weekly somatrogon demonstrated sustained efficacy and an acceptable safety profile during the OLE period. Once-weekly somatrogon constitutes a valuable long-term alternative to once-daily somatropin, offering potentially improved adherence and treatment outcomes.

Growth hormone deficiency (GHD) in children is characterized by impaired growth and development, leading to short stature in adulthood. Recombinant human growth hormone (rhGH) has been established as a cornerstone treatment for children with GHD, promoting linear growth and accrual of lean body mass. Despite the efficacy of rhGH, the requirement for daily subcutaneous injections poses a considerable burden on pediatric patients and their caregivers (1). Adherence to daily rhGH injections is a challenge, with noncompliance leading to suboptimal growth outcomes and diminished adult height (2). The recent development of several long-acting growth hormone (LAGH) treatments (3) is expected to lead to improved adherence and treatment outcomes.

Somatrogon (MOD-4023) is a once-weekly LAGH currently approved in more than 60 countries for the treatment of children with GHD. Somatrogon comprises the amino acid sequence of hGH and 3 copies of the C-terminal peptide from the β-subunit of human chorionic gonadotropin. The fusion of C-terminal peptides to hGH prolongs the half-life of the hGH moiety (4), enabling somatrogon to be injected less frequently compared with daily rhGH treatments.

The efficacy and safety of somatrogon have been demonstrated in several clinical studies in pediatric patients with GHD (5-8). Three clinical studies, a phase 2 dose-finding study (8), a global phase 3 study (5), and a phase 3 study conducted only in Japan (6), consisted of a 12-month main study period, during which patients were randomized to receive either somatrogon administered once weekly or somatropin administered once daily. All 3 studies established the efficacy and safety of somatrogon over the short term (12 months) but given that children with GHD are likely to require treatment for several years until they reach their adult height, long-term data on the efficacy and safety of somatrogon treatment are needed. Upon completion of the main study period, patients in each of the 3 somatrogon studies were eligible to enter their study's open-label extension (OLE) period, where all patients received somatrogon once weekly irrespective of their initial assigned treatment. Data from the initial years of the OLE period of both the phase 2 (n = 48) (9) and Japanese phase 3 (n = 42) (10) studies showed that long-term treatment with once-weekly somatrogon (up to 5 years) was well tolerated and resulted in a sustained increase in height standard deviation score (SDS).

The global phase 3 study contains the largest number of somatrogon-treated children with GHD, with 108 somatrogon-treated patients and 114 somatropin-treated patients completing the 12-month main study (5). A total of 212 of the 222 patients who completed the main study entered the OLE period, during which they all received once-weekly somatrogon. Results from the first 2 years of the OLE period were reported recently (manuscript submitted) and showed that somatrogon-treated children with GHD demonstrated a sustained improvement in linear growth following up to 3 years of somatrogon treatment, consistent with what was observed in the OLE period of the phase 2 (9) and Japanese phase 3 (10) studies. Here we report the final results from the full OLE period of the global phase 3 study, comprising data from the largest group of patients who received up to 5 years of somatrogon treatment, constituting an important contribution to the medical literature on LAGH treatments.

Methods

Study design and treatment

The phase 3 somatrogon study was an open-label, multicenter, randomized, active-controlled, parallel-group trial conducted at 83 sites across 21 countries (5). During the 12-month main study period, patients were randomized 1:1 to receive either somatrogon (0.66 mg/kg/week) administered subcutaneously once weekly or somatropin (0.034 mg/kg/day, equivalent to 0.24 mg/kg/week) administered subcutaneously once daily (5). Additional details on the methodology of the 12-month main study as well as the study results can be found in the publication by Deal et al (5).

Upon completing the 12-month main study period, patients were eligible to enroll in the OLE. Patients who completed 12 months of somatropin treatment in the main study period were switched to somatrogon at a dose of 0.66 mg/kg/week, whereas those who completed 12 months of somatrogon treatment continued with the same dosage. The somatrogon dose was adjusted every 3 months according to body weight, with mandatory dose reductions for safety reasons, such as adverse events (AEs) or 2 consecutive instances of IGF-I SDS >2 (IGF-I serum values). Specifically, patients with 1 instance of IGF-I SDS >2 are asked to return for another visit within 4 to 6 weeks. At the second visit, patients who still have IGF-I SDS >2 were recommended to have their somatrogon dose reduced by 15%. The somatrogon dose could also be reduced based on the physician's judgement after 1 instance of IGF-I SDS >2.

This study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice guidelines and was approved by the Institutional Review Board or Independent Ethics Committee of the participating institutions. Written informed consent was obtained from each patient's parents/legal guardians prior to study initiation.

Patients

For the full details of the inclusion and exclusion criteria, readers are directed to the main study publication by Deal et al (5). Eligible patients were prepubertal children aged ≥3 years, who were not yet 11 years for girls (10 years and 364 days) or not yet 12 years (11 years and 364 days) for boys, on the date of informed consent form signature, who had been diagnosed with GHD. Inclusion criteria included confirmation of GHD through 2 different GH provocation tests (peak plasma GH level ≤10 ng/mL), impaired height velocity (HV) (annualized HV below the 25th percentile for chronological age and sex [HV < −0.7 SDS], based on 2 height measurements at least 6 months apart but not exceeding 18 months before inclusion), baseline IGF-I level of at least 1 SD below the age- and sex-standardized mean IGF-I level (IGF-I SDS ≤−1), and no previous rhGH therapy. Exclusion criteria included a body mass index SDS <−2, the presence of anti-hGH antibodies at screening, psychosocial dwarfism, chromosomal abnormalities, type 1 or type 2 diabetes mellitus, being born small for gestational age, prior history of cancer, or receipt of radiation therapy or chemotherapy.

Study assessments

Efficacy

Key efficacy endpoints included HV, change in height SDS, IGF-I SDS, and IGF-binding protein 3 (IGFBP-3) SDS. Height was measured using a calibrated, wall-mounted stadiometer, with 3 independent readings recorded at each visit. Height SDS was derived from age and sex standards from the 2000 US Centers for Disease Control (CDC) growth charts (11). IGF-I and IGFBP-3 levels were measured in a central laboratory, with IGF-1 concentrations quantified using the IDS-iSYS chemiluminescence immunoassay (12). As previously described in Deal et al, bone age was evaluated by X-ray using the Greulich-Pyle method. Specifically, X-ray films of the left hand and wrist were sent to a qualified central reader who was blinded to the chronological age, study treatment, and the name of the patients.

Safety

Safety endpoints included treatment-emergent AEs and serious AEs (SAEs), dose reductions and treatment discontinuation due to AEs, dose reductions due to 2 consecutive instances of IGF-I SDS >2, and the incidence of antidrug antibodies (ADAs) to somatrogon. Serial serum samples were collected to identify antisomatrogon ADAs, which were characterized (including neutralizing properties) using qualitative, validated methods as described by Zelinska et al (8). In the OLE period, IGF-I was to be measured at Day 4 (−1) postdose, as samples at this time point have been shown to provide an accurate estimate of mean IGF-I levels over the dosing interval (13). Adverse events were coded using the Medical Dictionary for Regulatory Activities v22.0, with intensity or severity characterized as mild, moderate, or severe.

Statistical analyses

Statistical analyses were descriptive, with no formal hypothesis testing performed. Post hoc analyses were performed to stratify growth outcomes according to peak GH level at baseline (≤3 ng/mL, >3 to ≤7 ng/mL, and >7 to <10 ng/mL; all patients enrolled in the study had peak GH levels <10 ng/mL at baseline) and age (>3 to ≤7 years and >7 years). Efficacy and safety endpoints were summarized according to ADA status (positive for ADAs vs negative for ADAs). The baseline values from the main study baseline were used when change in baseline was calculated for an efficacy parameter. The mean height deficit at each visit in the OLE was calculated as the average of all individual differences between each patient's height SDS at each visit and their mid-parental height SDS, where each patient, maternal and paternal height SDS was calculated using CDC age- and sex-specific reference values. While safety data are reported up to the end of OLE Y5, efficacy data are reported up to the end of OLE Y4, due to efficacy data only being available for a small number of patients in OLE Y5.

Results

Patients

A total of 228 patients were randomized, and 224 received at least 1 dose of study drug in the 12-month main study period; 4 patients did not receive study drug. Of the 222 patients who completed the 12-month main study period, 212 (104 patients originally randomized to somatrogon and 108 to somatropin) entered the OLE. At the end of OLE Year 1 (Y1), 11 patients discontinued from the study, and 24 patients from India were considered to have completed the study so their participation in the study was concluded at this time point (per protocol, patients in India completed only 12 months of OLE treatment). The number of patients who entered OLE Y2, Y3, and Y4 were 177, 170, and 162, respectively. In OLE Y4, 81 patients discontinued from the study. The main reasons for study discontinuation were sponsor discontinuation of the study (n = 48; per protocol, due to somatrogon becoming commercially available) and local crisis (n = 19; due to the military conflict in Ukraine). Two patients completed somatrogon treatment during the study, having attained near adult height during the OLE period; a patient was considered to have achieved their near adult height if their HV for the preceding 6 months was <1 cm/year. As reported by Stawerska et al (manuscript submitted), at the start of the OLE period (OLE baseline) most patients were male (male: 70.8%; female: 29.2%) and White (76.4%), and the mean (SD) age was 8.8 (2.5) years. At the end of the main study period, 91.5% of patients (females: 56/62; males: 138/150; total: 194/212) were at Tanner Stage I (Table S1) (14). By the end of OLE Y4, the percentage of patients at Tanner Stage I had decreased to 42.6% (females: 3/14; males: 20/40; total: 23/54) whereas the proportion of patients at Tanner Stages IV and V had increased to 37.0% (Stage IV females: 4/14, males: 6/40; Stage V females: 3/14, males: 7/40).

Efficacy

Mean HV at OLE baseline (start of the OLE period after the end of the 12-month main study) was 10.27 cm/year for patients originally randomized to somatrogon and 9.72 cm/year for patients originally randomized to somatropin. Mean (SD) HV at the end of OLE Y1, Y2, Y3, and Y4 was 8.11 (1.84), 7.91 (1.84), 7.02 (1.75), and 6.56 (1.91) cm/year (Fig. 1A), respectively. At OLE baseline, mean HV SDS was 4.41 and 4.14 for patients originally randomized to somatrogon and somatropin, respectively. Mean (SD) HV SDS decreased gradually with each year of the OLE (as expected following the initial period of catch-up growth) but remained higher than HV SDS prior to treatment (HV < −0.7 SDS was required for inclusion in the study), with values of 2.10 (1.83), 1.63 (1.52), 1.07 (1.24), and 0.92 (0.87) at OLE Y1, Y2, Y3, and Y4, respectively (Fig. 1B).

Figure 1.

(A) Height velocity, (B) height velocity SDS, (C) height SDS, and (D) change in height SDS at month 12 of each year. Mean values shown, with error bars representing standard deviation. ^aNumber of patients for whom data are available. Abbreviations: OLE, open-label extension; SDS, standard deviation score; Y, year.

Mean height SDS continued to increase every year throughout the OLE, approaching 0 SDS by the end of OLE Y4 (Fig. 1C), indicating the efficacy of somatrogon was sustained over the 4 years of the OLE. At OLE baseline, mean (SD) height SDS was −2.00 (1.07) for somatrogon-treated patients and −1.94 (1.13) for somatropin-treated patients. Mean height SDS was highest at the end of OLE Y4, with a mean (SD) value of −0.46 (0.87) (Fig. 1C). Similarly, the cumulative change in height SDS continued to increase each year and was greatest at the end of OLE Y4, with a mean (SD) value of 2.01 (0.75) (Fig. 1D).

An analysis of height deficit SDS (difference between patient height SDS at last visit and mid-parental height SDS) showed that the absolute height deficit decreased throughout the OLE (Fig. 2). By OLE Y4, there was very little difference between the mean patient height SDS at last visit and the mean mid-parental height SDS (Fig. 2), indicating that a large proportion of patients had met (or exceeded) their mid-parental height.

Figure 2.

Height deficit SDS (calculated as the difference between patient height SDS and mid-parental height SDS). Mean values shown, with error bars representing standard deviation. ^aNumber of patients for whom data are available.

Abbreviations: OLE, open-label extension; SDS, standard deviation score; Y, year.

At the main study baseline, mean IGF-I SDS was −1.98 and −1.74 in patients originally randomized to somatrogon and somatropin, respectively. Mean IGF-I SDS was positive at the end of each year of the OLE and remained within the normal range (−2.0 to +2.0 SDS). Mean (SD) IGF-I SDS was 1.21 (1.23) at the end of OLE Y1 and 1.59 (1.08) at the end of OLE Y4 (Fig. 3A). During the OLE, mean (SD) change in IGF-I SDS from the main study baseline ranged from 2.96 (1.20) at the end of OLE Y1 to 3.20 (1.06) at the end of OLE Y4 (Fig. 3B). Mean IGFBP-3 SDS values had a similar pattern to that observed for IGF-I SDS in the OLE (Fig. S1) (14). During the OLE, mean change in bone maturation (bone age divided by chronological age) ranged from 0.71 (OLE baseline) to 0.91 (end of OLE Y4). Mean bone maturation did not exceed 1.0 at any time point, indicating that bone age did not advance disproportionally beyond chronological age during the course of the OLE.

Figure 3.

(A) IGF-I SDS and (B) change in IGF-I SDS at month 12 of each year. Mean values shown, with error bars representing standard deviation. ^aNumber of patients for whom data are available. Abbreviations: IGF-I, insulin-like growth factor I; OLE, open-label extension; SDS, standard deviation score; Y, year.

Efficacy stratified according to peak GH level and age

The subgroup with peak GH ≤3 ng/mL appeared to have numerically higher mean HV, HV SDS, and change in height SDS compared with the other 2 subgroups (>3 to ≤7 ng/mL, and >7 to <10 ng/mL); this trend was observed in each year of the OLE (Fig. S2A-C) (14). The 2 age subgroups (>3 to ≤7 years and >7 years) had similar mean HV throughout the OLE (Fig. S3A) (14). The younger subgroup (aged >3 to ≤7 years) appeared to have numerically higher HV SDS and change in height SDS compared with the older subgroup in OLE Y1 to Y4 (Fig. S3B and S3C) (14). Following stratification by peak GH and age, the absolute height deficit for each subgroup decreased throughout the OLE, consistent with the full patient group (Fig. S4A and S4B) (14). By OLE Y3 and Y4, the absolute height deficit for each subgroup was close to zero, indicative of catch-up growth that enabled patients to achieve or exceed their mid-parental height. At OLE baseline and OLE Y1, the absolute height deficit appeared to be highest in the ≤3 ng/mL peak GH subgroup and lowest in the >7 to <10 ng/mL subgroup (Fig. S4A) (14). In OLE Y2 and OLE Y3, the absolute height deficit in the ≤3 ng/mL peak GH subgroup appeared to decrease more rapidly compared with the other 2 subgroups. In terms of age, the younger subgroup (aged >3 to ≤7 years) appeared to have a smaller absolute height deficit than the older subgroup (aged >7 years) up to OLE Y3 (Fig. S4B) (14).

Safety

In OLE Y1, 71.7% of patients reported AEs (total of 1077 AEs reported), and this incidence was similar in OLE Y2 (72.3%) and OLE Y3 (71.2%), (Table 1). The incidence of AEs appeared to be lower in OLE Y4 (54.3%) and OLE Y5 (53.8%) compared with the first 3 years of the OLE (Table 1). Most AEs were mild or moderate in severity. The incidence of severe AEs and SAEs remained low during the OLE period and appeared to largely decrease after OLE Y1 (Table 1). Severe AEs were reported by 12/212 patients (5.7%) in OLE Y1, 5/177 patients (2.8%) in OLE Y2, and 2/170 patients (1.2%) in OLE Y3 (Table 1); no severe AEs were reported in OLE Y4 or Y5. Serious AEs were reported by 10/212 patients (4.7%) in OLE Y1, 1/177 patients (0.6%) in OLE Y2, 1/170 patients (0.6%) in OLE Y3, and 3/162 (1.9%) patients in OLE Y4; none were considered related to treatment. No SAEs were reported in OLE Y5. The most frequently reported treatment-related AEs were injection-site pain and injection-site erythema. The incidence of injection-site pain was 25.9% (55/212), 19.8% (35/177), 14.1% (24/170), 9.9% (16/162), and 17.3% (9/52) in OLE Y1, Y2, Y3, Y4, and Y5, respectively. Throughout the OLE, most instances of injection-site pain were mild or moderate in severity.

Table 1.

AEs (all causalities)

n (%)	OLE Y1			OLE Y2	OLE Y3	OLE Y4	OLE Y5
	Originally randomized to somatrogon (n = 104)	Originally randomized to somatropin (n = 108)	Total (N = 212)	Total (n = 177)	Total (n = 170)	Total (n = 162)	Total (n = 52)
No. of AEs	446	631	1077	500	516	437	87
Patients with AEs	69 (66.3)	83 (76.9)	152 (71.7)	128 (72.3)	121 (71.2)	88 (54.3)	28 (53.8)
Patients with SAEsa	6 (5.8)	4 (3.7)	10 (4.7)	1 (0.6)	1 (0.6)	3 (1.9)	0 (0)
Patients with severe AEs	5 (4.8)	7 (6.5)	12 (5.7)	5 (2.8)	2 (1.2)	0 (0)	0 (0)
Patients discontinued from the study due to AEsb,c	1 (1.0)	6 (5.6)	7 (3.3)	2 (1.1)	0 (0)	0 (0)	0 (0)
Patients discontinued study drug due to AE and continued studyd	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Patients with dose reduced or temporary discontinuation due to AE	4 (3.8)	4 (3.7)	8 (3.8)	2 (1.1)	4 (2.4)	4 (2.5)	0 (0)

Abbreviations: AE, adverse event; OLE, open-label extension; SAE, serious adverse event; SD, standard deviation; SDS, standard deviation score.

^a Serious AEs were lymphadenitis (n = 1), adrenal insufficiency (n = 1), abdominal pain (n = 1), noninfective sialoadenitis (n = 1), appendicitis (n = 4), diverticulitis (n = 1), peritonitis (n = 1), pharyngitis streptococcal (n = 1), pneumonia (n = 1), tonsillitis (n = 1), adenoidal hypertrophy (n = 1), urticaria (n = 1), Kawasaki disease (n = 1), delayed puberty (n = 1), croup infectious (n = 1), and scrotal varicose veins (n = 1).

^b Patients with an AE record that indicates the AE caused the patient to discontinue from the study.

^c AEs leading to study discontinuation occurred only in OLE Y1 and Y2, and they were lysinuric protein intolerance (n = 1), injection-site erythema (n = 2), injection-site pain (n = 3), injection-site pruritus (n = 1), chronic recurrent multifocal osteomyelitis (n = 1), anxiety (n = 1), and irritability (n = 1).

^d Patients who have an AE record that indicates action taken with study treatment was drug withdrawn, but the AE did not cause the patient to be discontinued from the study.

In OLE Y1 and OLE Y2, 7/212 (3.3%) patients in OLE Y1 and 2/177 (1.1%) patients discontinued from the study due to AEs (Table 1). Of the 9 patients who discontinued from the study during the OLE due to AEs, 5 were deemed to have treatment-related AEs. There were no discontinuations due to AEs in OLE Y3 to Y5. The most common AEs that led to study discontinuation were injection-site pain (n = 3) and injection-site erythema (n = 2). No deaths were reported during the study. More than one-third of patients had dose reductions due to elevated IGF-I levels (includes patients with IGF-I SDS >2 on 2 consecutive assessments and those who had dose reductions based on clinical judgement after 1 assessment of IGF-I SDS >2) in each year of the OLE, with the incidence ranging from 35.4% (OLE Y1) to 43.8% (OLE Y4) (Table S2) (14). Patients who had dose reductions were stratified according to their peak GH level at baseline, and the subgroup with the largest proportion of patients in each year was the >3 to ≤7 ng/mL subgroup (Table S2) (14).

Immunogenicity

Overall, 74.5% of patients tested positive for antisomatrogon ADAs during the OLE period, with an incidence of 65.6% in OLE Y1, 55.4% in OLE Y2, 61.2% in OLE Y3, and 53.7% in OLE Y4. The proportion of patients who tested positive for ADAs specific for hGH ranged from 49.5% (OLE Y1) to 24.1% (OLE Y3). During the OLE, none of the patients tested positive for neutralizing antibodies (NAbs) to somatrogon and there were 5 occurrences of patients testing positive for NAbs to hGH. Patients who initially tested positive for NAbs tested negative for NAbs at all subsequent time points during the OLE. One patient who tested positive for ADAs during the OLE also tested positive for antisomatrogon NAbs at Month 12; this patient experienced a loss of somatrogon efficacy during the OLE and was subsequently confirmed to have a homozygous whole gene deletion of the GH1 gene. A total of 13 patients who discontinued somatrogon treatment during the OLE and tested positive for ADAs at their last assessment of the study provided blood samples after study discontinuation. Analyses of these poststudy blood samples showed that ADAs were either no longer detectable or had substantially decreased titers.

Efficacy and safety were evaluated according to ADA status and treatment received during the main study, as shown in Fig. S5 and Table S3 (14). At all time points during the OLE, HV was similar between patients who tested positive for ADAs and those who tested negative for ADAs (Fig. S5A) (14). Height SDS also showed a similar trend in OLE Y1 to Y3; in OLE Y4, patients originally randomized to somatrogon who were negative for ADAs appeared to have lower height SDS than the other subgroups (Fig. S5B) (14) though it should be noted that this subgroup contains far fewer patients (n = 3) than the other subgroups. The incidence of AEs and SAEs was similar between patients who tested positive for ADAs and those who tested negative for ADAs, at all time points during the OLE (Table S3) (14). Overall, the efficacy and safety of somatrogon during the OLE period did not appear to be affected by the presence of ADAs, but it should be noted that at each time point the number of patients who tested positive for ADAs was much higher than those who tested negative for ADAs.

Discussion

In this publication, we present the final clinical data from the largest cohort of somatrogon-treated patients to date, which demonstrate the long-term efficacy and safety of once-weekly somatrogon for the treatment of pediatric patients with GHD. Somatrogon efficacy was maintained for up to 5 years, with mean HV in each year persistently elevated compared with pretreatment baseline and mean height SDS increasing as the OLE progressed. During the OLE period, somatrogon was also well tolerated, and no new safety signals were observed. These data highlight the potential of once-weekly somatrogon as a viable long-term treatment for pediatric patients with GHD, helping to address the treatment burden associated with daily somatropin.

The growth outcomes observed in the last 2 years of the OLE period are consistent with what has previously been reported for the main study period (5) and the first 2 years of the OLE period (manuscript submitted). Sustained growth continued to be demonstrated even in the last year of this study, with height SDS increasing from −0.71 in OLE Y3 to −0.46 in OLE Y4. It is notable that even at OLE Y4, mean HV SDS was still substantially higher than HV SDS prior to treatment (HV < −0.7 SDS for inclusion into the study). Further, the fact that 2 patients completed the present study having achieved near adult height following somatrogon treatment emphasizes the suitability of somatrogon as a long-term GH treatment that enables patients to achieve their genetic height potential. The growth outcomes observed over the entire study period were also consistent with the 5-year data from the phase 2 somatrogon study (9) and the 4-year data from the Japanese phase 3 somatrogon study (10). The efficacy findings from the main study period are also consistent with 2 recently published, small-scale, real-world studies comparing once-weekly somatrogon with once-daily somatropin in children with GHD (15, 16).

During the OLE period, once-weekly somatrogon was generally well tolerated in children with GHD. The incidence of AEs ranged from 53.8% to 72.3%, with the majority of AEs being mild to moderate in severity. The incidence of SAEs was low, with none considered related to treatment. The safety profile for somatrogon in this study was consistent with the somatrogon phase 2 study, which also reported the majority of AEs as being mild or moderate in severity and most AEs as unrelated to the study treatment (9). The incidence of AEs in this study was higher than the incidence reported in each year of the OLE of the phase 2 study, which ranged from 39.5% to 60% (9). Given that the present study had the largest population of somatrogon-treated patients to date, and was substantially larger than other somatrogon studies, it was reassuring to note that no new safety signals were observed for the duration of the OLE period. The AEs observed were also largely consistent with those observed for daily somatropin treatment in real-world clinical practice (17). During the OLE period, some patients reported IGF-I SDS >2 at 2 consecutive assessments, consistent with what was observed for somatrogon-treated patients in the main study period (5). To avoid prolonged elevations of IGF-I in somatrogon-treated patients in this study, patients with elevated IGF-I levels (>2 SDS at 2 consecutive assessments or based on clinical judgement after 1 assessment of >2 SDS) were to have their somatrogon dose reduced by 15% per protocol. While some studies suggest a potential association between elevated IGF-I levels and certain cancers in adults (18, 19), there is currently little evidence that transient elevations in IGF-I (>2 SDS) are associated with increased AEs in children with GHD treated with daily GH therapy (20). Further studies are required to assess whether short-term elevations in IGF-I levels pose any long-term safety risks in GH-treated children. In the present study, mean IGF-I levels in somatrogon-treated patients were in the normal range and therefore, aggregate risk of somatrogon treatment is not expected to result in long-term sequelae. These findings underscore the importance of IGF-I monitoring in patients receiving somatrogon treatment as part of routine clinical care.

Although a significant proportion of patients in this study developed ADAs, NAbs were rarely observed and mostly transient in nature. Testing ADA-positive for somatrogon did not have a discernable influence on safety outcomes as measured by the incidence of treatment-emergent AEs, SAEs, or AEs leading to discontinuation. Overall, there were no notable differences in efficacy and safety between patients who were ADA-positive compared with those who were ADA-negative (Fig. S5 and Table S3) (14), consistent with what has been reported in other somatrogon studies (9, 10). Although ADAs did not seem to affect treatment outcomes, these findings should be interpreted with caution given the disparities in the number of patients who tested positive for ADAs vs those who tested negative; this is especially true for patients originally randomized to somatrogon who tested negative for ADAs, which constituted a much smaller group (n < 15) at all time points.

Because it is generally observed that patients on daily rhGH with the most severe GH deficiency respond better than those with moderate GH deficiency (21-23), we conducted a post hoc analysis of growth outcomes stratified by peak GH level at baseline. The ≤3 ng/mL subgroup appeared to have higher HV SDS and change in height SDS when compared with the >3 to ≤7 ng/mL and >7 to <10 ng/mL subgroups; the >3 to ≤7 ng/mL and >7 to <10 ng/mL subgroups had similar growth outcomes. Donbaloglu et al (21) reported that children with idiopathic GHD who had a peak GH <3 µg/L had higher HV SDS and change in height SDS than patients with higher peak GH, following 1 year of rhGH treatment. This observation has also been noted for a different LAGH preparation; Backeljauw et al (24) reported that children with GHD who had peak GH ≤3 µg/L had greater HV and change in height SDS than patients with higher peak GH, following treatment with the LAGH somapacitan. These observations confirm that somatrogon has an efficacy profile similar to that of daily GH and other LAGH treatments. Further, the fact that children with the most severe form of GHD are likely to have the best response to treatment highlights the value of stratifying patients with GHD to ensure optimal analysis/comparison of efficacy.

The key strengths of this study are that it included the largest cohort of somatrogon-treated patients to date and documented a continuation of an acceptable safety profile for up to 5 years of somatrogon treatment. Another strength was the inclusion of a diverse population, with patients recruited from more than 20 countries. In addition, this study did not require that patients have a height deficiency to be enrolled, which enabled inclusion of children who have GHD but are yet to exhibit a severe height deficit. However, the single-arm design of the OLE and lack of statistical comparisons of efficacy and safety endpoints were limitations. Large, real-world studies are necessary to validate the clinical trial findings regarding efficacy, safety, and adherence.

In conclusion, somatrogon treatment in children with GHD led to sustained improvement in linear growth over 5 years, with an acceptable safety profile. Further, a recent clinical study of patients with GHD and their caregivers demonstrated that weekly somatrogon had a lower treatment burden and was associated with a more favorable treatment experienced compared with daily somatropin (25). Thus, once-weekly administration of somatrogon presents a promising alternative to daily somatropin, potentially enhancing long-term treatment adherence and growth outcomes in prepubertal children with GHD.

Funding

This study was sponsored by OPKO Health, which is a co-development partner with Pfizer.

Disclosures

R.S.: Research investigator: OPKO, REAL8, REAL9, LUM-201-01, 02 and 04, TCH306, EP00-401, EP00-402; Research support: Pfizer, Sandoz, NovoNordisk, Ascendis. J.C.: Employee: OPKO. R.W., M.P.W., D.L.T., and C.T.T.: Employees and stock owners: Pfizer. J.F.C.: Employee at the time of the study: Pfizer; stock owner: Pfizer. M.P.: Advisory board: AstraZeneca, Dompe, Eli Lilly, Insulet, Pfizer, Novo Nordisk, Sanofi, DreaMed Diabetes, Medtronic, embecta, Mannkind, Tandem; Consulting fee: Qulab Medical, Pfizer, DreaMed Diabetes, ProventionBio; Grant recipient (Institute headed by MP): Dompe, Novo Nordisk, Medtronic Diabetes, Eli Lilly, Sanofi, DreaMed Diabetes, OPKO, AstraZeneca, Pfizer, NG Solutions ProventionBio, Lumos, Gwave, Omega Galil; Research investigator: NIH Flair study (via Health Partners), BreakthroughT1D, Helmsley Trust; Stock owner: DreaMed Diabetes, NG Solutions. J.S.: Consultant: Azurity, BioMarin; Speaker: Pfizer. C.L.D.: Advisory board: Pfizer, LEVO Therapeutics, Neurocrine Bioscience, Worldwide Clinical Trials, Ipsen; Consulting fee: Pfizer, OPKO; Research investigator: Pfizer, OPKO, LEVO Therapeutics, Neurocrine Bioscience, Worldwide Clinical Trials, Ipsen; Speaker: Pfizer, OPKO, LEVO Therapeutics, Neurocrine Bioscience, Worldwide Clinical Trials, Ipsen; Other: Ad hoc consultant: LEVO Therapeutics, Acadia Pharmaceuticals, Neurocrine Bioscience, Worldwide Clinical Trials, Ipsen, Tolmar, POXEL SA, Inversago Pharma, Lumos Pharma. L.A.S.: Advisory board: Novo Nordisk, Pfizer, Endo, BioMarin, Ascendis; Consulting fee: OPKO, Pfizer; Research investigator: Novo Nordisk, Ascendis, Biomarin; Speaker: Pfizer

Data availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request. Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual deidentified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

Clinical trial information

ClinicalTrials.gov: NCT02968004.