Post hoc subgroup analysis of Asian children with paediatric GHD from the global phase 3 efficacy and safety study of once-weekly somatrogon vs. once-daily somatropin

Introduction

Recombinant human growth hormone (rhGH) has a well-documented efficacy and safety profile for the treatment of children with GH deficiency (GHD) and has been shown to increase linear growth velocity, enabling these children to reach an acceptable adult height [1, 2]. Until recently, however, most rhGH formulations have required a once-daily injection. Although effective, daily injections can be challenging to maintain and can constitute a substantial burden for children and their caregivers [1, 3].

For children, daily GH injections can cause both physical pain (discomfort, pain and bruising at the injection site) and emotional pain (anxiety about the injection procedure, anger at interference with everyday activities and embarrassment about their condition among peers), all of which severely impact their quality of life [3]. Some studies have shown that long-term treatment adherence may be poor, particularly among children who begin GH therapy before they are 8 years old [3] and among teenagers [1]. As a result, rhGH doses are missed, leading to wastage of healthcare resources and suboptimal treatment outcomes, with affected children having a near-adult height below the mid-parental target height and the population mean [1]. Furthermore, parents/caregivers do not always appear to be aware that a high level of treatment adherence is required for optimal therapeutic response [3, 4]. Based on a discrete choice experiment, McNamara et al. (2020) [4] suggested that injection schedule was the most important patient factor affecting adherence to rhGH and, ultimately, clinical outcomes. Patients were reported to prefer a less frequent injection regimen for the treatment of paediatric GHD (pGHD). It has been suggested that GH treatments with a lower injection frequency may help to reduce the incidence of non-adherence and improve clinical outcomes [5].

Somatrogon is a long-acting rhGH (LAGH) consisting of the amino acid sequence of human GH and three copies of the carboxy-terminal peptide (CTP) of human chorionic gonadotropin. These CTPs extend the half-life of rhGH, allowing longer intervals between doses [6]. Somatrogon is currently approved in several countries as a once-weekly subcutaneous (SC) injection for paediatric patients with GHD. A pivotal global phase 3 study reported that once-weekly SC injections of somatrogon were non-inferior to once-daily injections of somatropin (Genotropin^®) for the treatment of pGHD, and that both treatments had a similar safety and tolerability profile [7].

The global phase 3 study was conducted in 21 countries and included patients from several different ethnicities. As race and ethnicity are known to impact exposure and therapeutic response to some drugs [8, 9], including GH [10], it is important to identify any variations in treatment efficacy and safety due to ethnicity. For instance, there is evidence to suggest that both short-term response and adult height are reduced in Japanese children receiving GH treatment compared with their Caucasian counterparts [10, 11]. The objectives of this post hoc subgroup analysis were to evaluate the efficacy and safety of once-weekly somatrogon compared with once-daily somatropin specifically in Asian patients from the global phase 3 study (excluding patients from Japan, who were part of a separate phase 3 study [12]) and to establish whether data from this subgroup were consistent with data from the full patient cohort in the global phase 3 study [7].

Materials and methods

The full methodology for the global phase 3 study (NCT02968004) is described in the publication by Deal et al. [7], and readers are directed to that publication for additional details and full inclusion and exclusion criteria. This study took place between April 2017 and August 2019, was approved by the independent Review Board or independent Ethics Committee of the participating institutions and followed the Declaration of Helsinki (as revised in 2013) and International Council for Harmonisation Guideline for Good Clinical Practice. Safety was reviewed regularly by an independent Data and Safety Monitoring Board. Informed consent was obtained from all individuals included in this study, or their legal guardians or wards.

Results

Efficacy

At month 12, the least squares (LS) mean estimate of annual HV (primary endpoint) using the ANCOVA model was 10.95 cm/year in the somatrogon group and 9.58 cm/year in the somatropin group (Figure 1), with missing data imputed. The treatment mean difference (somatrogon−somatropin) was 1.37 cm (95 % CI: −0.20, 2.94), which favoured somatrogon. The lower bound of the two-sided 95 % CI of the treatment difference was −0.20. The observed mean annualized HV at month 6 was numerically higher in the somatrogon group than in the somatropin group, with LS mean estimates of 11.23 cm/year and 8.31 cm/year, respectively. Mean HV was also numerically higher for somatrogon than for somatropin at all other post-baseline visits (Figure 1).

Figure 1:

Height velocity (cm/year) over time in a subgroup of Asian children with growth hormone deficiency who received either somatrogon (n=24) or somatropin (n=21) for 12 months.

Mean change in height SDS from baseline to 6 months was numerically higher in the somatrogon group compared with the somatropin group (0.65 vs. 0.39). The same trend was also seen for mean change in height SDS from baseline to 12 months (1.14 vs. 0.84) (Figure 2). The mean change in IGF-1 SDS from baseline was numerically higher in the somatrogon group compared with the somatropin group; this was observed at all post-baseline visits, including month 6 (2.13 vs. 0.92) and month 12 (2.64 vs. 0.99) (Figure 3).

Figure 2:

Height SDS over time in the subgroup of Asian children with growth hormone deficiency who received either somatrogon (n=24) or somatropin (n=21) for 12 months. SDS, standard deviation score.

Figure 3:

IGF-1 SDS over time in the subgroup of Asian children with growth hormone deficiency who received either somatrogon (n=24) or somatropin (n=21) for 12 months. IGF-1, insulin-like growth factor-1; SDS, standard deviation score.

Discussion

Treatment effects are not necessarily homogeneous across patient populations, so subgroup analyses of large studies are key to establishing whether conclusions drawn from the overall study can be applied across the various subgroups within the study [8]. Ethnicity and race, in particular, can influence response to drugs [8, 9]. It was therefore of interest to characterize any potential differences in somatrogon treatment response due to race. To that end, we performed a post hoc subgroup analysis of once-weekly somatrogon vs. once-daily somatropin in pre-pubertal Asian children with GHD to explore the effect of race on somatrogon efficacy and safety. To our knowledge, this is the first subgroup analysis focused specifically on Asian children receiving a LAGH treatment as part of a global, randomized, controlled clinical trial.

In this subgroup of 45 Asian children, the LS mean estimate of annual HV after 12 months (primary endpoint) was 10.95 cm/year for somatrogon and 9.58 cm/year for somatropin, which was consistent with findings for the full population of the phase 3 study (224 participants; 10.1 cm/year for somatrogon vs. 9.78 cm/year for somatropin). The mean treatment difference (somatrogon–somatropin) for this subgroup was +1.37 cm/year in favour of somatrogon, and the lower bound of the two-sided 95 % CI was −0.20, which was similar to that of the overall study population (−0.24) [7]. Other efficacy outcomes for somatrogon-treated children in this Asian subgroup (HV at 6 months, HV SDS and IGF-1 SDS) were also similar (or numerically higher) to those for somatropin-treated children, consistent with data from the full population of the phase 3 study [7]. Overall, mean annual HV, change in height SDS, and change in IGF-1 SDS were numerically higher in somatrogon-treated Asian children compared with somatropin-treated Asian children at all post-baseline visits. This finding is unlikely to be specific to Asian children as this trend was also observed in the full study cohort. For the Asian subgroup, the ANCOVA of the difference in mean HV confirmed that somatrogon and somatropin had similar efficacy but the study did not have statistical power to establish non-inferiority in any subgroups. Therefore, while we have no evidence to confirm that somatrogon has better efficacy in Asian children, our data suggest that its efficacy may be at least comparable and non-inferior to somatotropin.

In a recent phase 3 study (NCT03874013) of Japanese children with GHD (n=44), once-weekly somatrogon (0.25 mg/kg/week for 2 weeks, 0.48 mg/kg/week for 2 weeks and after the first 4 weeks, patients received somatrogon at 0.66 mg/kg/week for the remainder of the study) was found to be comparable to once-daily somatropin (0.025 mg/kg/day, equivalent to 0.175 mg/kg/week) in terms of annual HV [12]. At month 12, the LS mean estimate for annual HV was 9.65 cm/year (somatrogon) vs. 7.87 cm/year (somatropin). The treatment mean difference in HV was +1.79 cm/year (95 % CI: 0.97–2.61) in favour of somatrogon [12], and this was similar to the treatment difference reported in this Asian subgroup (+1.38 cm/year).

In the Asian subgroup, once-weekly somatrogon had similar safety and tolerability profiles compared with once-daily somatropin, consistent with the findings from the full study population. Furthermore, this analysis did not identify any new safety concerns specific to this subgroup. Most of the children experienced ≥1 AE during the study (somatrogon, 83 %; somatropin, 76 %), most being mild or moderate in severity. The incidence of serious AEs was low in both treatment groups. The frequency of AEs in this subgroup was similar to the frequency of AEs in the full study population (somatrogon, 87 %; somatropin, 84 %) [7] and in the Japanese phase 3 study (somatrogon, 100 %; somatropin, 86 %) [12].

The most common all-cause TEAEs (≥5 %) reported in this Asian subgroup, irrespective of treatment group, were injection site pain, nasopharyngitis, anaemia, influenza and oropharyngeal pain. The incidence of injection site pain AEs (pain score ≥4) was higher in the somatrogon group (33 %) than in the somatropin group (5 %). A similar trend was observed for the full study cohort and for the Japanese somatrogon study [7, 12]. As described by Deal et al. [7], differences between the two treatment groups in the way injection site pain AEs were recorded may have contributed to the differences in the incidence of injection site pain observed. The incidence of children who tested positive for ADAs was higher in the somatrogon group compared with the somatropin group. This trend was also observed in the full study cohort and phase 3 study of Japanese children [7, 12]. In both studies, the presence of ADAs did not have an effect on the efficacy or safety of the somatrogon treatment.

One of the key strengths of this subgroup analysis is the fact that Asian participants in this subgroup were drawn from several different countries, which extends the generalizability of the findings. Although the number of children was well balanced between the treatment groups, the relatively small number of children overall (within this subgroup) is a limitation of this analysis. However, the efficacy and safety data reported for this subgroup are similar to those reported for the phase 3 somatrogon study in Japan [12].

Pain, discomfort, fear of injections, lack of confidence in administering injections and interruptions to everyday activities are some of the factors provided by children and their parents/caregivers to explain lack of adherence to daily rhGH injections [4]. As a result, a significant proportion of children waste healthcare resources and fail to achieve their target adult height. Development of LAGH formulations requiring fewer injections, such as once-weekly somatrogon, will potentially improve healthcare resource utilization and have a positive impact on adherence in the Asian patient population, which is critical for optimal therapeutic response.

Conclusions

This post hoc analysis of data from Asian children enrolled in the somatrogon global phase 3 study confirmed that efficacy and safety data from this subgroup were consistent with those of the overall population of the phase 3 study that demonstrated that once-weekly somatrogon is non-inferior to once-daily somatropin [7]. No new safety concerns were identified in this Asian subgroup. The reduction in the number of injections required with somatrogon may enhance adherence to treatment and subsequently contribute to improved healthcare resource utilization and efficacy outcomes in Asian patients.