Safety and effectiveness of replacement with biosimilar growth hormone in adults with growth hormone deficiency: results from an international, post-marketing surveillance study (PATRO Adults)

Purpose To evaluate safety and effectiveness of biosimilar recombinant human growth hormone (rhGH; Omnitrope®) in adults with growth hormone deficiency (GHD), using data from the PATRO Adults study. Methods PATRO Adults was a post-marketing surveillance study conducted in hospitals and specialized endocrinology units across Europe. The primary objective was to assess the safety of rhGH in adults treated in routine clinical practice. All adverse events (AEs) were monitored and recorded for the complete duration of Omnitrope® treatment. Effectiveness was evaluated as a secondary objective. Results As of January 2020, 1447 patients (50.9% male) had been enrolled from 82 centers in 9 European countries. Most patients had adult-onset GHD (n = 1179; 81.5%); 721 (49.8%) were rhGH-naïve at study entry. Overall, 1056 patients (73.0%) reported adverse events (AEs; n = 5397 events); the majority were mild-to-moderate in intensity. Treatment-related AEs were reported in 117 patients (8.1%; n = 189 events); the most commonly reported (MedDRA preferred terms) were arthralgia (n = 19), myalgia (n = 16), headache (n = 14), and edema peripheral (n = 10). In total, 495 patients (34.2%) had serious AEs (SAEs; n = 1131 events); these were considered treatment-related in 28 patients (1.9%; n = 35 events). Mean (standard deviation) IGF-I SDS increased from – 2.34 (1.47) at baseline to – 0.23 (1.65) at 12 months, and remained relatively stable thereafter (up to 3 years). Body mass index remained stable between baseline and 3 years. Conclusion Data from PATRO Adults indicate biosimilar rhGH (Omnitrope®) is not associated with any unexpected safety signals, and is effective in adults with GHD treated in real-world clinical practice.


Introduction
GH deficiency (GHD) in adults is a well-recognized condition amongst adult endocrinologists [1]. Growth hormone (GH) is frequently the first hormone to be affected in hypothalamic-pituitary disorders, however deficiency can remain unrecognized by other specialists, which could lead to delays in referral for treatment. Adults with severe GHD may be eligible for GH replacement therapy, the main goals of which are to reverse the metabolic, functional, and psychological abnormalities associated with adult GHD [2][3][4]. Treatment of GHD in adults with recombinant human GH (rhGH) has proven to be effective for improving body composition, exercise capacity, skeletal integrity, blood lipid profile, and overall quality of life (QoL) [3,[5][6][7]. Clinical practice guidelines suggest that the risks associated with rhGH therapy are low [3]. However, extended clinical studies are required to confirm the long-term safety of rhGH therapy in routine clinical practice, particularly with regard to the potential diabetogenic and oncogenic risk.
Omnitrope ® (somatropin) is a biosimilar rhGH approved by the European Medicines Agency in 2006, with approval granted on the basis that it matches the reference medicine (Genotropin ® , Pfizer) in terms of safety, efficacy, and quality. PATRO Adults is an observational, multicenter, longitudinal study of Omnitrope ® , conducted in hospitals and specialized endocrinology clinics across Europe. The primary objective was to assess the safety of rhGH in adults treated in routine clinical practice. Effectiveness was evaluated as a secondary endpoint [8]. Here, we present safety and effectiveness data from a snapshot analysis carried out in January 2020.

Methods
The design of the study has been reported previously [8]. Eligible patients were male or female adults who were receiving Omnitrope ® treatment and who had provided informed consent. Patients who received treatment with another rhGH medicine before starting Omnitrope ® therapy were also eligible for inclusion.
All adverse events (AEs) were monitored and recorded for the complete duration of Omnitrope ® treatment. Particular emphasis was placed on: long-term safety; reoccurrence or de novo onset of malignancies; the incidence of hyperglycemia; and the development of glucose intolerance or diabetes. The relationship between AEs and Omnitrope ® treatment was independently evaluated by investigator and sponsor assessment, and classified according to the worse case. Laboratory assessments and vital signs were requested to be documented at least once a year, according to routine clinical practice. Effectiveness assessments included analysis of IGF-I levels, anthropometric measures and lipids.

Data collection/analysis and study populations
Patient data were entered into an electronic case report form (eCRF) at each routine visit. eCRFs were reviewed by data management and on-site monitoring was performed by a contract research organization. Standard descriptive statistics (mean, standard deviation, and frequency) were used to describe continuous parameters (e.g. age, height, weight) and categorical parameters (e.g. gender); median and range were used to describe parameters (e.g. treatment duration) that are not normally distributed.
The safety population consisted of all patients documented within the eCRF at the time of the analysis cut-off date (January 31, 2020). Patients for whom neither a visit date nor a start date of Omnitrope ® treatment had been documented were not included. The effectiveness population was a subset of the safety set and consisted of all patients with a documented baseline visit (start of Omnitrope ® treatment) and at least one documented visit under Omnitrope ® treatment with the corresponding dates.
Further characteristics of enrolled patients are shown in Table 1

Adverse events
A summary of reported AEs is shown in Table 2. Overall, 1056 patients (73.0%) reported AEs (n = 5397 events), the majority of which were considered to be mild or moderate in intensity. AEs considered to be related to treatment were reported in 117 patients (8.1%; n = 189 events). The most commonly reported treatment-related AEs (MedDRA preferred terms) were: arthralgia (n = 19), myalgia (n = 16), headache (n = 14), and edema peripheral (n = 10).
Overall, 39 events of confirmed diabetes mellitus (Med-DRA high-level term: Diabetes [including subgroups]) were reported in 37 patients; 32 events (in 30 patients) were newly diagnosed, and 7 events (in 7 patients) were worsening or A total of 69 events of malignancies were reported in 60 patients. These events were documented under the SOC 'Neoplasms benign, malignant, and unspecified' and classified via medical review as being malignant. Sixty events (in 51 patients) were newly diagnosed; the most common (by MedDRA preferred term) were basal cell carcinoma (13 events in 12 patients), prostate cancer (9 events in 9 patients), malignant melanoma (5 events in 5 patients), and breast cancer (3 events in 3 patients).

Effectiveness
Data for effectiveness parameters are presented for patients who were rhGH-naïve on study entry. Mean (SD) IGF-I SDS increased from -2.34 (1.47) at baseline to -0.23 (1.65) at 12 months, and remained relatively stable thereafter (up to 36 months; Fig. 1). After 6 months, lean body mass increased by approximately 6% compared with baseline; the increase after 3 years was approximately 4% (Fig. 2a). Total fat mass also improved within the first year of treatment, decreasing by approximately 9% at 12 months, before returning to baseline levels at 36 months (Fig. 2b). BMI remained stable between baseline and 3 years (Fig. 2c).
Lipid profile improved over time with rhGH treatment. This is exemplified by the decrease in mean (SD) TC/HDL ratio over time, from 4.49 (1.42) at baseline to 4.28 (1.45) after 3 years (Fig. 3).

Discussion
The PATRO Adults post-marketing surveillance study will provide data on the long-term safety and effectiveness of Omnitrope ® treatment in adult patients with GHD in a reallife clinical setting. Based on the current analysis, there have so far been no unexpected safety signals, and treatment is effective (in rhGH-naïve patients).
AEs reported in the current analysis included 32 cases of new-onset diabetes mellitus (in 30 patients) and 7 cases of worsening of pre-existing diabetes mellitus. A previous evaluation of data from PATRO Adults (data cut-off July 2018) examined the impact of rhGH on glucose metabolism and onset of diabetes mellitus [9]. No signals of an increased risk of diabetes mellitus and glucose metabolism disorders were reported, consistent with the experience with other rhGH treatments [10][11][12]. A review of data from largescale registry studies of GH replacement therapy suggested that the incidence of diabetes mellitus may only be slightly increased in patients with pre-existing risk factors for diabetes mellitus, and not as a result of rhGH therapy [13].
The current analysis also includes 69 reports of malignancy events (in 60 patients). The occurrence of on-study malignancies in PATRO Adults has been reported previously (based on data from July 2018) [14]. While the data did not in general support a carcinogenic effect of rhGH in adults with GHD, an increased risk of second new malignancies in patients with previous cancer could not be excluded. Again, this is consistent with previous data reported for rhGH medicines in this setting [13,15]. A number of benefits of rhGH therapy in adult GHD have been previously reported, including improvements in body composition, exercise capacity, skeletal integrity, blood lipid profile, and QoL [3,16]. The data presented here suggest modest improvements in body composition and blood lipid profile with Omnitrope ® treatment (albeit data are included only for patients who were rhGH-naïve on study entry), consistent with previous reports.
It should be highlighted that the PATRO Adults study has several limitations, some of which are common to all observational studies. These include a potential for selection bias due to the inclusion of selected clinics and enrollment of patients from only these clinics. Also, as study data is collected according to routine clinical practice, there is no regular visit schedule, information bias is a possibility (as a result of incorrect or inexact recording), and different techniques may be used to measure the same parameter. Furthermore, there may be under-reporting of AEs because of the extended time periods between patient visits in the study (6-12 months) and restricted consultation time during visits. The relatively small sample size/data sets for some parameters is also a potential limitation and may hinder the interpretation of certain data. Another drawback is the possibility of missing out on useful information due to the set-up of the eCRF. For example, in the present study, the option to select 'other' as a reason for study discontinuation resulted in loss of potentially useful data for 150 participants. In the future, avoiding use of general data entry options such as 'other' may improve the quality of data collected from such observational studies.

Conclusion
In summary, data so far from PATRO Adults indicate biosimilar rhGH (Omnitrope ® ) is not associated with any unexpected safety signals, and is effective in adults with GHD treated in real-world clinical practice. However, continued follow-up of adult GHD patients during rhGH therapy and after treatment termination is necessary, to ensure long-term safety.
Acknowledgements The authors thank Yu-Ming Shen (Sandoz/Hexal AG) for providing statistical support. The authors thank all patients and investigators who participated in the PATRO Adults study. Medical writing support was provided by Tony Reardon of Aura, a division of Spirit Medical Communications Group Ltd, supported by Sandoz/ Hexal AG.
Author contributions All authors contributed to data interpretation, writing and review of the manuscript, and approved the final version of the manuscript for publication.

Funding
The PATRO Adults study is funded by Sandoz/Hexal AG. Medical writing support was funded by Sandoz/Hexal AG.

Data availability
The datasets generated during and/or analyzed during the current study are not publicly available as the study is still ongoing, but are available from the corresponding author on reasonable request.

Declarations
Conflict of interest CH has acted as an investigator for Sandoz, Pfizer, and NovoNordisk; has received lecture fees from Sandoz, Pfizer, and NovoNordisk; and is a member of the global steering committee for the PATRO Adults study. RDM has received research funding from San-

Time (months) TC/HDL (mean ± SD)
Consent for publication As part of the informed consent process, all patients provided written consent for the publication of data collected in the study.
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