Results from a phase 3 trial suggested similar efficacy and safety of the denosumab biosimilar candidate Arylia (AryoGen Pharmed) to the reference product (Prolia) in postmenopausal osteoporosis.

In their paper published in Arthritis Research & Therapy, the authors highlighted the prevalence of osteoporosis, citing an estimate from the International Osteoporosis Foundation that approximately 30% of women and 20% of men over 50 years old will develop an osteoporosis-induced fracture in their lifetime.With the expected increase in osteoporosis due to an aging world population, they wrote, “developing drugs and preventive approaches are of great importance in managing osteoporosis and its consequences.”

Denosumab is an anti-resorptive agent that has been used to treat osteoporosis in postmenopausal women since its approval by the FDA in 2010. The monoclonal antibody blocks an interaction between receptor activator of nuclear factor kappa-B ligand (RANKL) and its receptor (RANK) on osteoclasts (bone-resorbing cells), leading to inhibition of osteoclast-mediated bone resorption.

The clinical trial was conducted across 12 centers in Iran, where patients received a 60 mg subcutaneous injection of the biosimilar or originator at months 0, 6, and 12 after enrolling, and were followed until month 18. The study included 190 postmenopausal women between the ages of 45 and 75 years with T-scores between -2.5 and -4 at the lumbar spine, total hip, or femoral neck, or who required medical treatment due to a high risk of fracture.

The primary endpoint was noninferiority of the biosimilar to the reference product for percentage change of bone mineral density (BMD) at 18 months at the lumbar spine, total hip, and femoral neck. Secondary endpoints included safety, incidence of new vertebral fractures, and bone turnover markers.

Bone Mineral Density Changes Not Significantly Different Between Groups

There were significant increases in BMD in both groups at the lumbar spine, total hip, and femoral neck. At 18 months, the percent changes in BMD were 5.91 (SD, 5.58) at the lumbar spine, 2.32 (SD, 5.24) at the total hip, and 1.91 (SD, 6.32) at the femoral neck in the biosimilar group, compared to 5.52 (SD, 5.59), 2.28 (SD, 5.52), and 1.50 (SD, 6.62) in the reference product group. The differences were not statistically significant at any of the 3 sites.

Furthermore, the results demonstrated noninferiority of Arylia compared to the reference product. The lower limits of the 2-sided 95% confidence intervals of the difference between groups in mean BMD change were greater than the predefined noninferiority margin of -1.78 at each site. The mean differences between groups and confidence intervals were 0.39 (95% CI, -1.34–2.11), 0.04 (95% CI, -1.61–1.69), and 0.41 (95% CI, -1.58–2.40) at the lumbar spine, total hip, and femoral neck, respectively.

The investigators also reported comparable results in safety, new vertebral fractures, and bone turnover markers. No new vertebral fractures occurred in either group. However, the authors added, “further studies with more prolonged periods and larger sample sizes are needed” to evaluate rare and long-term adverse events such as new fractures and osteonecrosis of the jaw.

Bone Turnover Markers “Followed a Similar Trend” in the 2 Groups

Bone turnover markers were assessed at months 0, 6, 12, and 18. According to the authors, bone formation markers bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and procollagen type 1 N-terminal pro-peptide (P1NP) decreased over the study duration. Likewise, bone resorption markers serum C-terminal telopeptide (CTX) and serum N-terminal telopeptide (NTX) decreased over the 18-month study.

Comparable Safety and Immunogenicity

Throughout the 18-month study, 135 adverse events (AEs) were reported in 78% of patients in the biosimilar group and 64% in the reference product group. The most common AEs were hypocalcemia and hypertension. There were no significant differences in AEs between the biosimilar and reference product groups. Thirteen serious AEs were reported (in 6% of patients in each group), all resulting in hospitalization. However, the investigators noted that all serious AEs were considered unrelated to treatment.

The authors mentioned that previous research suggested denosumab treatment is associated with increased risk of serious infections. In their study, they said, infections were comparable between groups, occurring in 5.3% of patients in the biosimilar group and 4.2% in the reference product group.

Anti-drug antibodies were detected in 1 patient at months 0 and 6. All other patient samples were negative for anti-denosumab antibodies.

The investigators concluded the denosumab biosimilar candidate Arylia was noninferior to the reference product for treating postmenopausal women with osteoporosis and had a comparable safety profile.