Equivalence trial of proposed denosumab biosimilar GP2411 and reference denosumab in postmenopausal osteoporosis: the ROSALIA study.

Denosumab is a monoclonal antibody used to reduce risk of fractures in osteoporosis. ROSALIA was a multicenter, double-blind, randomized, integrated phase I/phase III study comparing the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and safety of proposed biosimilar denosumab GP2411 with reference denosumab (REF-DMAb) (Prolia®; Amgen). Postmenopausal women with osteoporosis were randomized 1:1 to 2 60-mg doses of GP2411 or REF-DMAb, one at study start and one at week 26. At week 52, the REF-DMAb group was re-randomized 1:1 to a third dose of REF-DMAb or switch to GP2411. The primary efficacy endpoint was percentage change from baseline (%CfB) in LS-BMD at week 52. Secondary efficacy endpoints were %CfB in LS-BMD, FN-BMD, and TH-BMD at weeks 26 and 78 (and week 52 for FN-BMD and TH-BMD). Primary PK and PD endpoints were the area under the serum concentration-time curve extrapolated to infinity and maximum drug serum concentration at week 26, and the area under the effect-time curve of the %CfB in serum CTX at week 26. Secondary PK and PD endpoints included drug serum concentrations and %CfB in serum CTX and P1NP during the study period. Similar efficacy was demonstrated at week 52, with 95% CIs of the difference in %CfB in LS-BMD between treatment groups fully contained within prespecified equivalence margins. Similarity in PK and PD was demonstrated at week 26. Immunogenicity was similar between groups and was not impacted by treatment switch. The rate of new vertebral fractures was comparable. Treatment-emergent adverse events were comparable between groups (63.6% [GP2411/GP2411]; 76.0% [REF-DMAb/REF-DMAb]; 76.6% [REF-DMAb/GP2411]). In conclusion, ROSALIA showed similar efficacy, PK and PD, and comparable safety and immunogenicity of GP2411 to REF-DMAb in postmenopausal osteoporosis.

Denosumab is a biologic treatment that stops bone breakdown. This clinical trial evaluated how similar GP2411 (a denosumab biosimilar in development) is compared with European-approved reference denosumab in women with post-menopausal osteoporosis. Biosimilars are highly similar to the original treatment ('reference denosumab') and may have a lower price. 263 patients were randomly assigned to receive GP2411 and 264 to reference denosumab. Treatment was given at the study beginning, at Week 26 and at Week 52. 124 patients were re-assigned at Week 52 to test the effect of changing from reference denosumab to GP2411. The study showed similarity in how the body interacts with the treatments, what effects the treatment has (both measured over 26 weeks), and bone mineral density (measured over 78 weeks). Antibody responses to GP2411 were detected in similar proportions of patients on each treatment. Reported adverse events were similar between treatments before Week 52, and from Week 52 to 78, and <5% of patients experienced serious adverse events. A change of treatment from reference denosumab to GP2411 did not affect outcomes. These results showed similarity between GP2411 and reference denosumab in this population. In future, GP2411 may enable more patients to benefit from denosumab.

Pharmacokinetics and pharmacodynamics of the proposed biosimilar denosumab GP2411 and reference denosumab in healthy males.

BACKGROUND: This Phase I study compared the pharmacokinetic (PK) and pharmacodynamic (PD) similarity of GP2411 proposed denosumab biosimilar to reference denosumab (a monoclonal antibody for specific pro-resorptive conditions). RESEARCH DESIGN AND METHODS: Healthy males (28-65 years, 50-90 kg) were randomized to a single sub-therapeutic subcutaneous injection of 35 mg GP2411, EU-Xgeva® or US-Xgeva®, and followed for 39 weeks. The primary endpoints were AUCinf, AUClast, and Cmax. RESULTS: Four hundred ninety-two participants completed treatment. The 90% confidence intervals (CIs) (AUCinf, AUClast, and Cmax) and 95% CI of the geometric mean ratios of AUEC of % change from baseline in serum CTX were fully contained within the prespecified equivalence margins (0.80, 1.25), demonstrating similarity. The occurrence of treatment-emergent adverse events (TEAEs) with GP2411, EU-Xgeva® and US-Xgeva® was similar (72.9%, 76.0%, and 71.0% of participants, respectively). Most were Grade 1 or 2, <30% were treatment-related, and there was only one TEAE-related study discontinuation. Rates of positive anti-drug antibodies (ADAs) were similar (57.8%, 64.9%, and 69.1% of participants respectively), but immunogenicity was only borderline detectable and of very low magnitude. Ninety-nine percent of positive ADAs were transient. CONCLUSION: GP2411 demonstrated similarity with EU-Xgeva® and US-Xgeva® in PK, PD, safety, and immunogenicity in this population. CLINICAL TRIAL REGISTRATION: EudraCT 2019-001651-39.

Denosumab is a biological treatment that inhibits bone degradation. It is very effective in conditions characterized by elevated bone degradation, such as osteoporosis in women who have gone through the menopause, and in the treatment of specific bone cancers. However, the cost of the original patented denosumab ('reference denosumab') treatment may result in fewer eligible patients receiving denosumab treatment. A biosimilar is highly similar to the original treatment but at a lower price, enabling more patients to benefit.GP2411 is being developed as a proposed biosimilar to denosumab. This Phase I clinical trial was the first clinical trial to compare GP2411 to the EU and US versions of the reference denosumab (EU-Xgeva® and US-Xgeva®). All three products were given at a dose of 35 mg to 502 healthy males. The dose was lower than the dose that would be used in clinical practice to provide a more sensitive evaluation of similarity. Healthy males were chosen because they have fewer hormonal fluctuations than females, and are considered the most appropriate population for detecting differences in pharmacological effects of denosumab.The results demonstrate that GP2411 proposed denosumab biosimilar is highly similar to the reference products in absorption, distribution, and elimination, and other outcomes, including bone turnover. The incidence of adverse events was also comparable, most adverse events were very mild, and GP2411 was not associated with a higher rate of immune reactions.These results support its continued development and GP2411 may, in future, enable more patients to benefit from denosumab treatment.

Efficacy of sodium valproate and haloperidol in the management of acute mania: a randomized open-label comparative study.

This study was carried out to compare the efficacy of intravenous sodium valproate with intramuscular haloperidol in patients with acute mania. A total of 30 patients meeting DSM-IV criteria for acute manic episodes were enrolled. They were randomly assigned to 2 groups of 15 patients each. Both groups were treated twice daily with haloperidol (10 mg, intramuscular) and sodium valproate (500 mg, intravenous). The patients were assessed on days 1, 5, 9, and 13. Improvement in symptoms was assessed by reduction in the Young Mania Rating Scale (YMRS). Outcome criterions for analysis were latency of response and remission; additional drugs were required for sedation. At the end of the 2-week study period, overall response rate in both the groups was similar (P > .1). In comparison to haloperidol group, patients treated with sodium valproate showed faster response, and on day 5, significant reduction in YMRS score was observed in the group treated with sodium valproate (P < .05). Total amount of lorazepam was less in patients treated with sodium valproate. Extrapyramidal symptom episodes were observed in 60% of patients treated with haloperidol. Sodium valproate in the treatment of acute mania is as efficacious as haloperidol but provides a faster response. It is safer compared to haloperidol.