A multicenter, randomized, rater-blinded, parallel-group, phase 3 study to compare the efficacy, safety, and immunogenicity of biosimilar RGB-10 and reference once-daily teriparatide in patients with osteoporosis

Recombinant human teriparatide (rhPTH [1–34]), produced in E. coli, is the 1–34 N-terminal active fragment of endogenous 84-amino acid human parathyroid hormone (PTH). Teriparatide exerts the same physiological actions on bone and kidney as PTH, including the elevation of serum calcium levels through indirect stimulation of bone resorption by enhancing the production of receptor activator of NF-κB ligand (RANKL) and inhibiting the expression of osteoprotegerin, promoting the re-absorption of calcium and excretion of phosphate from the renal tubule, and promoting 1,25-dihydroxyvitamin D production, which indirectly increases calcium absorption from the intestine [1‐4].

Effects of teriparatide on the skeleton differ depending on the pattern of systemic exposure: intermittent administration of teriparatide promotes bone formation, increases bone mineral density (BMD), and restores bone microarchitecture, resulting in fracture prevention, whereas continuous exposure to teriparatide promotes bone resorption over bone formation and results in a reduction in bone mass [3, 5]. Taking advantage of the bone formation effect resulting from intermittent administration, 20 μg once-daily injection of teriparatide has been approved for the treatment of osteoporosis in the USA, EU, and Japan, among other countries. Although multiple studies have demonstrated that teriparatide can increase BMD and prevent vertebral and non-vertebral fragility fractures [6‐9], its high cost as a biological medicinal product places a heavy burden on individual patients and on the healthcare systems.

A biosimilar is a biological medicine with high similarity to another biological medicine already approved by a Stringent Regulatory Authority (a so-called ‘reference medicine’) [10, 11]. Regulatory guidelines in the EU, USA, and Japan require similarity in terms of quality characteristics, biological activity, safety, and efficacy to be demonstrated between the biosimilar and the reference medicine in a comprehensive comparability exercise [12‐14]. Given their relatively low price compared with reference medicinal products, biosimilars represent a more affordable but equally efficacious and safe treatment option for patients and healthcare systems, thus increasing patients’ access to treatment.

RGB-10, manufactured by Gedeon Richter Plc., has been developed as a biosimilar to reference teriparatide, and its active ingredient has an amino acid sequence identical to that of teriparatide. RGB-10 also shows a high level of similarity to teriparatide with respect to quality characteristics, pharmacological effects, and toxicities (data on file). Furthermore, a comparative pharmacokinetic (PK) study sponsored by Gedeon Richter Plc. and conducted in healthy female volunteers in the United Kingdom (NCT02223416) demonstrated equivalence in terms of PK characteristics following administration of a single dose of RGB-10 or the reference teriparatide [15]. Based on these results, RGB-10 was approved by the European Medicines Agency (EMA) in 2017 [16] for the same indications as those stated in the EU label for reference teriparatide.

The objectives of the current phase 3 study were to evaluate equivalence in efficacy and compare safety between RGB-10 and reference teriparatide in patients with osteoporosis at high risk of fracture.

A total of 369 patients were screened, of which 250 were randomized to either RGB-10 or reference teriparatide treatment groups (n = 125 in each group). A total of 219 patients completed the 52-week treatment period. The most common reason for discontinuation in both groups was occurrence of AEs (RGB-10, n = 15; reference teriparatide, n = 11) (Fig. 1). The FAS included all 250 patients, and 32 of these patients were excluded from the PPS. No patients were excluded from the SS. The baseline demographics and characteristics of patients were balanced between the groups (Table 1); 96.4% (n = 241) of the randomized patients were female and the mean patient age (± SD) was 70.4 ± 6.4 years. Lumbar spine (L2–L4) BMD at baseline (mean ± SD) was 0.6275 ± 0.0752 g/cm². The percentage of patients with prior treatment with bisphosphonates was 4.4% (n = 11). Oral minodronate, risedronate, alendronate, and intravenous ibandronate were reported as prior treatment with bisphosphonates. All randomized patients were of Asian ethnicity.

This phase 3 study evaluated the similarity in efficacy and safety of RGB-10 and reference teriparatide administered to patients with osteoporosis at high risk of fracture for 52 weeks.

Although biosimilars to teriparatide, including RGB-10, have previously been reported in highly regulated regions [15, 19], to the best of our knowledge, this is the first phase 3 study of a biosimilar teriparatide with the primary objective of demonstrating therapeutic equivalence in terms of BMD assessed at 12 months. RGB-10 is the first biosimilar teriparatide to have been granted marketing authorization in the EU, and the first biosimilar to have been approved along the principles of the specifically tailored approach. In line with pertinent EMA guidelines, given the simple molecular structure and the well-established mechanism of action of teriparatide as well as the robust quality and non-clinical comparability data for RGB-10 and the European reference product, a comparative PK/PD study in healthy volunteers was considered sufficient for granting marketing authorization. A phase 3 study of another biosimilar teriparatide conducted in the USA evaluated the immunogenicity of the biosimilar and the reference formulations of teriparatide as its primary objective.

In the present study, equivalence in efficacy between RGB-10 and reference teriparatide was established: the between-group difference of the primary efficacy endpoint of percent change from baseline to 52 weeks in lumbar spine (L2–L4) BMD was − 0.65%, and its two-sided 95% CI (− 2.17% to 0.87%) was within the pre-specified equivalence margin of ± 2.8%. Furthermore, the percent change from baseline to 52 weeks in lumbar spine (L2–L4) (RGB-10, 8.94%; reference teriparatide, 9.65%) was similar to that reported in a phase 3 study of reference teriparatide in Japan (reference teriparatide, 9.82%) that we used as a reference in planning the design of this study and that had a similar patient population to that of our study [7].

In patients who completed 52 weeks of treatment with RGB-10 or teriparatide, the percent changes in lumbar spine (L2–L4) BMD from baseline to 52 weeks were 9.97 ± 5.82% and 10.46 ± 5.90%, respectively, which were similar to that in the reference phase 3 study (10.04 ± 5.23%) [7]. These changes in patients who completed the study were numerically larger than the results of the primary efficacy endpoint, where missing data were imputed with LOCF, suggesting that completion of 52 weeks of treatment was an important determining factor of the effect of teriparatide on BMD. Considering the low long-term adherence and persistence of teriparatide treatment, a general feature of osteoporosis medications [20], these results support the previously reported importance of intervention aimed at maintaining patient adherence and persistence to teriparatide [21‐24].

Lumbar spine BMD was measured primarily from L2 to L4 in the present study, as in the reference phase 3 study [7]. The trend in lumbar spine (L1–L4) BMD change in this study was similar to that of lumbar spine (L2–L4). In addition, the two-sided 95% CI of between-group difference in the percent change to 52 weeks in lumbar spine (L1–L4) BMD (− 2.05% to 0.93%) was also within ± 2.8%. These results strongly support the equivalence in efficacy between the two groups. The results for other efficacy endpoints (BMD change in femoral neck and total hip, serum P1NP change, and fracture incidence) were also similar between the two groups, which further supported the comparable efficacy of RGB-10 to reference teriparatide.

The safety profiles of RGB-10 and reference teriparatide were comparable. No clinically significant differences were observed between RGB-10 and reference teriparatide in terms of the type, incidence, severity, and seriousness of AEs. The incidence of AEs leading to study discontinuation was numerically higher in the RGB-10 group than in the reference teriparatide group. However, this higher incidence was considered to be of no clinical significance because the majority of AEs leading to study discontinuation in the RGB-10 group were events observed with the use of reference teriparatide in clinical trials and post-marketing exposure (Online Resource 3) [1]; there was no high incidence of any AEs leading to study discontinuation in the RGB-10 group; and most of the AEs leading to study discontinuation were mild to moderate in severity. The numerically higher incidence of injection site bruising in the RGB-10 group was considered to be an accidental finding because the severity, outcome, and onset time of injection site bruising were similar between the groups; the formulation of RGB-10 is the same as that of reference teriparatide; and the irritant potential of both drugs was considered to be similar based on findings in a repeat-dose toxicity study in rats (data on file). The difference in injection device was unlikely to have contributed to the higher incidence of injection site bruising in the RGB-10 group because both devices were comparable in terms of injection procedure and dose accuracy, and the same type of needle was used for both groups.

Regarding immunogenicity, the incidence of anti-teriparatide antibodies was comparably low, with antibodies detected in no patients in the RGB-10 group and in two patients in the reference teriparatide group, none of which tested positive for neutralizing activity. This finding was consistent with that of a previously reported study on reference teriparatide, where 2.8% of the patients receiving 20 μg daily teriparatide were positive for anti-teriparatide antibodies [1, 6], although the duration of the treatment in our study slightly differed from that described in the previous report (up to 52 weeks vs 18 months [mean]). Consequently, the immunogenic potential of RGB-10 was considered not to exceed that of the reference teriparatide

Although this study was conducted in a rater-blinded manner, patients were also largely unaware of their own assigned treatment group. To minimize potential bias, the name of the injection device was masked, and although patients knew that the injection devices for the two investigational drugs differed in appearance, they were not informed of their treatment group. Moreover, the blinding status of patients was considered unlikely to affect the efficacy data because BMD is an objective value, and raters, including the central assessment facility, remained blinded. This was also applicable to the safety data as the investigators involved in safety assessments were blinded. We therefore consider that any potential bias caused by the unblinding of patients was sufficiently minimized so as not to have substantially affected the efficacy and safety data in the present study.

A strength of the present study is that the patient population was similar to that found in clinical settings in Japan as the inclusion criteria were determined according to clinical guidelines, including Japanese guidelines for the prevention and treatment of osteoporosis [18].

The present study had some limitations. First, because the patients participating in the study were all of Asian ethnicity, the effects of RGB-10 in patients of other ethnic origins were unknown. However, because teriparatide meets most of the criteria for being less likely to be sensitive to intrinsic and extrinsic ethnic factors, similar efficacy and safety are expected in other populations [25]. Second, because this study was not designed to compare the effect of teriparatide on the reduction of fractures between the groups, the limited duration and the number of subjects did not allow for statistical assessment of the incidence of fractures. However, given that BMD is a widely accepted surrogate marker for fractures, accounting for up to a 30–41% reduction in the risk of vertebral fractures in the case of teriparatide treatment, and in view of the highly comparable changes in BMD in the RGB-10 and reference teriparatide groups observed in our study, the two compounds are expected to be therapeutically equivalent in terms of their effect on reducing the risk of fragility fractures [26].

In conclusion, the results of our study established therapeutic equivalence and comparable safety, including immunogenicity, between RGB-10 and the reference teriparatide, further substantiating the claim of biosimilarity.