The first biosimilar approved for the treatment of osteoporosis: results of a comparative pharmacokinetic/pharmacodynamic study

Recombinant human teriparatide is the biologically active N-terminal 34-amino acid fragment of the 84-amino acid native parathyroid hormone [PTH (1–84)]. Since it is produced in Escherichia coli (E. coli), the introduction of Forsteo® in 2003 marked the beginning of the biologic era in the treatment of osteoporosis.

The skeletal effects of teriparatide depend on the pattern of systemic exposure. While continuous exposure to excessive amounts of parathyroid hormone, as seen in hyperparathyroidism, triggers bone resorption, intermittent elevations result in a bone anabolic response [1]. Two phases may be distinguished in the effect of intermittently administered PTH [2]. The prompt increase in formation markers suggests that the first few months of PTH treatment, often referred to as the anabolic window, are predominantly characterised by an increase in bone formation. However, at a later stage, bone formation becomes more remodelling-dependent [3], with bone formation favoured over bone resorption, thereby resulting in a net gain of bone deposition in each basic multicellular unit [4]. The beneficial effects of teriparatide on bone density, microarchitecture and bone geometry are seen predominantly in the cancellous skeleton [5]. In the cortical bone envelope, intermittent PTH stimulates both endocortical and periosteal bone formation [3]. At cortical skeletal sites, teriparatide increases porosity, thereby potentially decreasing BMD; however, the reduction in BMD is not accompanied by diminished bone strength because the increased porosity occurs only in the inner one third of the bone, where the mechanical effect is minimal. Other positive effects of teriparatide at the cortical bone, namely, changes in bone geometry and microarchitecture, effectively counterbalance any increase in cortical porosity [5]. Clinically, the metabolic effects of teriparatide translate into improved bone mineral density (BMD) at vertebral and femoral skeletal sites as well as a reduced incidence of vertebral and non-vertebral fragility fractures [6]. Based on a meta-analysis by Murad et al. of all anti-osteoporotic agents, teriparatide had the highest probability of being ranked as most effective and had the highest reduction in the risk of vertebral, non-vertebral and hip fractures [7]. Although clinical studies adequate to assess the effect of teriparatide on the risk of hip fractures are lacking and are unlikely to be conducted, there is evidence suggesting that teriparatide is associated with beneficial effects on the hip in patients with osteoporosis [8].

Teriparatide is indicated for the treatment of patients with a high risk for fracture (in particular, men and postmenopausal women with osteoporosis, as well as patients with glucocorticoid-induced osteoporosis).

When the period of market exclusivity protecting the innovator biopharmaceutical has expired, biosimilars can be introduced to the market. Since the reference product is facing patent expiry in the near future, the development of the first biosimilar teriparatide was initiated to offer a less costly treatment alternative for patients afflicted with severe osteoporosis. The regulatory requirements for approving biosimilars have been constantly evolving, and the extensive experience amassed over the last 10 years has helped to shape the present criteria laid down in the scientific guidelines issued by the European Medicines Agency (EMA). This clinical programme was designed to conform to the most recent regulatory requirements.

The objective of the clinical study was to demonstrate the clinical comparability of RGB-10 and reference teriparatide after having established a high level of similarity between them on the quality and non-clinical levels (data on file).

The study protocol followed all relevant regulatory guidelines, especially the Guideline on similar biological medicinal products [9] and the Guideline on the investigation of bioequivalence [10] and was approved by the Office for Research Ethics Committees Northern Ireland (ORECNI), Lisburn, which is responsible for the study location at Celerion, a centre that specialises in clinical pharmacology studies (Belfast, Northern Ireland). The trial identifiers are EudraCT number 2013-004040-31 and ClinicalTrials.​gov identifier NCT02223416. The details of the clinical trial were subject to extensive regulatory discussions. All participants gave their written informed consent prior to the initial study-related assessments. The performance and supervision of this trial followed the principles of Good Clinical Practice (GCP) as laid down in ICH E 6 [11]. The study was conducted in accordance with the ethical requirements referred to in EU directive 2001/20/EC [12] and the ethical principles set forth in the Declaration of Helsinki [13].

Although 56 subjects were predefined for stage 1 due to small cohort sizes (thus potentially resulting in a significant treatment-by-group interaction and thereby compromising the primary PK analysis), the last cohort, which would have consisted of two subjects only, was not enrolled. Consequently, a total of 54 subjects were randomised to study treatments and analysed for safety. All subjects satisfied all inclusion criteria and fulfilled none of the exclusion criteria. The demographic data for all 54 patients showed a mean age of 29.2 ± 8.3 years, a height of 164.2 ± 6.0 cm, a weight of 62.1 ± 7.1 kg and a BMI of 23.0 ± 2.0 kg/m². One subject withdrew prematurely after period 1 for personal reasons. Two further subjects were excluded from the PK analysis as a result of events compromising the evaluation of their PK profiles; one had measurable pre-dose concentrations greater than 5% of the C_max in both periods (an exclusion criterion predefined in the statistical analysis plan), and the other lacked several PK samples in the absorption phase. Therefore, the final PK population for the primary endpoints of AUC_0-tlast and C_max comprised 51 subjects.

After reviewing the results from the interim analyses, it was not necessary to proceed to stage 2 because the data variability was less than anticipated based on the literature, and concluding on equivalence was possible using only stage 1 data. If the study had continued to stage 2, due to obtaining a power of less than 90%, the sample size would have been re-estimated based on stage 1 intrasubject CV PK results, an expected power of at least 90%, and the initially assumed ratio of 0.95–1.05 using an alpha level of 0.0294 (i.e. using a 94.12% CI). A maximum of 58 subjects (between 1 and 58 subjects) would have been enrolled in stage 2, and the same procedures would have been followed for stage 2 subjects as those followed for subjects in stage 1. Bioequivalence would have been evaluated for the second time after the completion of stage 2 based on data from both stages at an alpha level of 0.0294 (using a 94.12% CI).

Here, we report the clinical comparability of two teriparatide products based on a comparative single-dose, two-way cross-over study in healthy female pre-menopausal adults following single s.c. administrations of RGB-10 and the reference drug.

No product-specific regulatory guidelines explicitly define the requirements pertaining to the development of a biosimilar teriparatide. Moreover, no prior development programmes exist that could have been followed since RGB-10 is the first biosimilar teriparatide that has been granted marketing authorisation. Only some overarching regulatory guidance was available at the time when RGB-10 development was planned.

In 2004, a dedicated route was introduced for biosimilars, thus establishing a solid legal framework for their approval in the EU. The more than 10 years of expertise acquired since then has allowed EU regulators to integrate experience-based knowledge with the initial science-driven concept shaping current requirements for approval [18]. The basic principle underlying the development of a biosimilar product is its comparability with the reference product; this is assessed using a comparability exercise, which is the comparative testing performed at all stages of the biosimilar development (i.e., on quality, non-clinical and clinical levels) [19]. Based on the EMA requirements, comparability testing is conceived as a step-wise process, which is tailored to each product; that is, knowledge from the initial quality comparability studies is used to determine the extent and type of non-clinical and clinical studies that are required in the next step of the development [18]. Consistently, the design of the clinical development programme considers the nature and characteristics of the medicine and its intended use and how comparable the profile of the biosimilar medicine is to that of the reference product. Consequently, the closer the profiles of the biosimilar and reference products and the higher the similarity (as demonstrated through appropriate studies; e.g., comparative quality, biological and receptor-binding assays as well as in vitro studies) are, the more a tailored clinical trial programme can be accepted by the EMA [19]. For simpler molecules with a well-established action (e.g., filgrastim) and where comparative quality and non-clinical data are solid, it may be sufficient to compare the effect of the biosimilar and the reference medicine based on PK and PD studies in healthy volunteers [18].

Due to its low molecular weight and structural simplicity, teriparatide qualifies as a very simple molecule. In this case, the quality and non-clinical profiles of the biosimilar and reference products were close enough to lend legitimacy to the application of a more tailored clinical trial programme. This new development approach is reflected in the clinical study, which was designed to establish clinical comparability between RGB-10 and its reference.

The results of this study showed that the PK profile of RGB-10 is consistent with that of the originator drug. The statistical analysis of the PK data formally established BE between the two drugs, with the 94.12% CIs for the primary endpoints (AUC_0-tlast and C_max) falling entirely within the predefined equivalence margins of 80–125%.

The multiple-peak phenomenon detected in this study was also observed by Liu et al. [20], who described double peaks in two thirds of their study subjects following single and multiple s.c. doses of teriparatide; the first peak appeared within 5 to 20 min, and the second appeared within 30 to 60 min post-dose. A double-peak profile was also reported following the s.c. administration of recombinant human PTH(1–84). Plasma and serum concentration time profiles of recombinant human PTH(1-84) and its synthetic N-terminal fragment teriparatide showed similar double-peak profiles, with no temporal difference in the appearance of both peaks [21, 22]. It was suggested that the double-peak phenomenon was related to the fast and slow release rates of exogenous PTH into the systemic circulation following s.c. administration [20, 22].

Serum calcium was assessed not only as a safety endpoint but also as a PD parameter to support the biosimilarity claim of RGB-10. Teriparatide is known to cause transient increases in serum calcium after each dose through increased intestinal absorption and increased tubular reabsorption of calcium. This is observed in healthy volunteers and osteoporotic patients and can therefore be seen as a surrogate marker for the PD effects of teriparatide. The results for RGB-10 and the reference were highly similar, with 95% CIs of the GMR of the RGB-10/reference correcting calcium within 99–101%. The comparable calcium response for RGB-10 and the reference provides evidence supporting the clinical comparability of these drugs.

The safety profile of RGB-10 was similar to that of the originator drug with respect to AEs, clinical laboratory measurements, vital signs, electrocardiographic and local tolerance assessments. The safety results were comparable to the data published for teriparatide [23‐25], and no differences were observed between the two treatment groups. There were no new safety signals reported during this trial, and RGB-10 proved to be as safe as the reference, with no SAEs observed. Similarly, the incidence and severity of injection site reactions associated with the use of teriparatide were similar to those seen in previous studies.

A limitation of this study is that immunogenicity could not be investigated. Establishing pharmacokinetic equivalence was the primary objective of the trial; consequently, the requirements pertaining to the study design, duration and sample size laid down in the Guideline on the investigation of bioequivalence [10] were adhered to. Although satisfying all the criteria described in the Guideline on the investigation of bioequivalence [10], the cross-over design, the short study duration due to the rapid elimination half-life of teriparatide and the relatively low sample size needed to demonstrate bioequivalence all precluded the assessment of immunogenicity. Nevertheless, the general immunogenic potential of teriparatide is expected to be low because it is a low molecular weight, fully human molecule of microbial origin with no glycosylation or any other posttranslational modifications. The immunogenic potential of the reference drug proved negligible in the clinical studies for registration purposes in that anti-teriparatide antibodies were detected after at least 12 months of treatment in only 2.8% of the patients receiving 20 μg daily s.c. doses of teriparatide [26]; the lack of literature data on the immunogenicity of the reference product over the 15 years that it has been available on the market seems to confirm this. Consequently, assessment of the immunogenic potential of RGB-10 was not among the objectives of the bioequivalence study.

The strength of the development programme designed for RGB-10 is that it sets a notable example of the tailored approach recently adopted by the EMA, in which, for simple molecules whose mechanism of action is well-established and where comparative quality and non-clinical data are solid, comparative PK/PD studies in healthy volunteers may be sufficient to conclude therapeutic equivalence [18].

Given the high level of similarity between RGB-10 and its reference as demonstrated in the in-depth quality and non-clinical comparability exercise (data on file) and the BE and PD comparability established in our clinical study, marketing authorisation for RGB-10 has been granted for all indications by the European Medicines Agency (EMA).