The Totality of Evidence for SDZ-deno: A Biosimilar to Reference Denosumab.

Abstract

Purpose: Sandoz biosimilar denosumab (GP2411 [SDZ-deno]; Jubbonti/Wyost) is approved by the US FDA, EMA and Health Canada for all indications of reference denosumab (REF-deno; Prolia/Xgeva), a fully human IgG2κ monoclonal antibody that binds with high affinity and specificity to receptor activator of nuclear factor kappa-B ligand (RANKL). Denosumab blocks RANKL, preventing bone resorption and loss of bone density/architecture in conditions characterized by excessive bone loss such as osteoporosis in postmenopausal women and metastatic bone disease, among others.

Methods: This narrative review summarizes the totality of evidence (ToE) for SDZ-deno that supported its approval as Jubbonti/Wyost in the EU and US.

Findings: Analytical evaluation indicated that SDZ-deno has high purity and structural homology with REF-deno. SDZ-deno also demonstrated similar binding affinities, size and charge variants, and disulfide isoforms to REF-deno, and did not trigger clinically meaningful antibody-dependent cellular cytotoxicity. In clinical evaluation, SDZ-deno was similar to REF-deno in pharmacokinetics (PK) and pharmacodynamics (PD) in a 39-week Phase I study in 502 healthy male participants, and to REF-deno in a 72-week Phase III study in 527 postmenopausal women with osteoporosis. In both studies, the 90% and 95% confidence intervals (for PK and PD endpoints, respectively) of the geometric mean ratios for AUC_inf, C_max (and AUC_last in the Phase I study; PK endpoints), and area under the effect versus time curve of percent change from baseline in serum carboxy-terminal crosslinked telopeptide of type I collagen (PD endpoint), were fully contained within the prespecified equivalence margins (0.80, 1.25). The Phase III study also demonstrated SDZ-deno is similar in efficacy to REF-deno in postmenopausal women with osteoporosis, as the difference in percent change from baseline in lumbar spine bone mineral density at week 52 between REF-deno and SDZ-deno was fully contained within the prespecified equivalence margins (-1.45, 1.45). SDZ-deno was well tolerated in both studies. As the ToE has established biosimilarity of SDZ-deno and REF-deno, extrapolation to all indications is justified based on the common mechanism of action and the comparable PK, safety, and immunogenicity across all indications.

Implications: The ToE for SDZ-deno suggests it will be an effective biosimilar to REF-deno, and its lower unit price is anticipated to increase the number of appropriate patients who will benefit.