In the 2½ years since we last updated the denosumab biosimilar pipeline, several new manufacturing/commercialization partners have emerged on the horizon, and the first 351(k) application has been filed with the Food and Drug Administration (FDA). As importantly, denosumab, along with ustekinumab, appears to be one of the most hotly contested biosimilar categories for the near-term pipeline.
Amgen’s denosumab (Prolia®), a RANKL monoclonal antibody, is indicated for the treatment of osteoporosis in postmenopausal women. At Amgen’s first-quarter 2023 earnings conference, the company stated that US sales of Prolia reached $623 million (or an annualized estimate of $2.49 billion). This represents a 9% increase from the same quarter in 2022.
Amgen’s Xgeva® is the same compound as Prolia, but Amgen branded it separately for its different dosage schedules and indications. Xgeva is specifically indicated for (1) the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors and (2) the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. US sales of Xgeva were $384 million (or an annualized estimate of $1.54 billion), a 7% increase from Q1 2022. This implies overall estimated US revenues of approximately $4 billion for denosumab.
Prolia is injected by a healthcare provider every 6 months. Because the medication is not intended for self-injection, it is generally covered under the medical benefit. An inherent benefit to this is to optimize adherence and have patients visit the office every 6 months for evaluation and follow-up. However, there is an opportunity for health plans and insurers to disseminate via specialty pharmacies, which would threaten providers’ buy-and-bill reimbursement. In fact, data provided to BR&R by IQVIA indicates that 14% of Prolia prescriptions are covered by the pharmacy benefit, compared with only 3% of Xgeva prescriptions. The Figure, also based on the IQVIA data analysis, shows where Prolia fits in the current osteoporosis market, at about 17%, behind alendronate, the market leader.
Furthermore, the medication can be administered at home by visiting nursing staff; in this case, it could also be covered under the pharmacy benefit. However, Xgeva would remain firmly covered as a medical benefit drug, given as an ancillary therapy in patients receiving cancer chemotherapy.
The principal patent in the US is estimated to expire in February 2025.
The Likely Denosumab Biosimilar Competition: The Outlook in July 2023
| Biosimilar Developer | Name | Stage/Status |
| Alvotech | AVT03 | Phase 3 study to be completed November 2024 |
| Biocon | Bmab1000 | Phase 3 study to be completed June 20, 2024 |
| Celltrion | CT-P41 | Phase 3 study to be completed March 2023 |
| Eden Biologics | EB1001 | Phase 1 study underway |
| Fresenius Kabi | FKS518 | Phase 3 study to conclude July 26, 2023 |
| Gedeon Richter | RGB-14-P | Phase 3 study to conclude November 15, 2023 |
| Intas | INTP23 | Phase 3 study to conclude November 2024 |
| Samsung Bioepis | SB16 | Phase 3 study completed Dec 2022 |
| Sandoz | GP2411 | FDA BLA filing Feb 6, 2023 for both indications |
| Shanghai Biomabs Pharma | CMAB807 | Phase 3 study to be completed November 1, 2023 (not likely to be marketed in the US) |
| Shanghai Henlius/Organon | HLX14 | Phase 3 study to be completed April 30, 2024 |
| Teva | TVB-009 | Phase 3 study completed June 2023 |
The denosumab biosimilar pipeline today is very different than the one cited in 2021. Whereas partners Samsung Bioepis and Biogen were considered the front runner then, Sandoz is certainly in the lead today. The number of potential competitors has been significantly expanded, with European and Southeast Asian manufacturers dominant. A few players new to the US biosimilar market also appear, such as Gedeon Richter and Intas. Keep in mind, this pipeline analysis is based mostly on potential players who have undertaken Phase 3 trials of their investigational products. It may be possible in the future that a biosimilar maker obtains FDA approval with only Phase 1 or 2 evidence.
Sandoz. As reported earlier this year, Sandoz filed the first US biologic licensing application for a denosumab biosimilar February 6. It is seeking approval for both Prolia and Xgeva biosimilars (clinical trials were conducted for the osteoporosis indication). Based on the filing date, it could receive an FDA decision as early as late 2023, though the launch would be expected no earlier than February 2025.
Samsung Bioepis/Biogen. Samsung Bioepis completed its Phase 3 trial of SB16 late last year, and it is possible that the 351(k) submission could be filed later this year.
Celltrion. Celltrion, which was also cited in the 2021 review, was scheduled to complete its Phase 3 trial of CT-P41 in March 2023 (this was not confirmed), which could also result in a biosimilar application in late 2023 or early 2024.
Teva. The Phase 3 trial of TVB-009 was completed in June 2023, which may mean a 351(k) application filed in the second or third quarter of 2024 (and thus an FDA decision in the first or second quarter of 2025).
Fresenius Kabi. FKS518’s Phase 3 trial should conclude at the end of this month, which would put it on a track similar to that of Teva for filing and potential approval.
Gedeon Richter. A late-stage trial is set to conclude in November 2023. Hikma Pharmaceuticals, which has a limited US footprint, signed a contract with Gedeon Richter to commercialize its biosimilar agent RGB-14-P should FDA approval be obtained (perhaps in late 2024 or 2025).
Other Potential US Denosumab Competitors Completing Studies in 2024
Assuming FDA approvals and licensing agreements are not signed with the reference manufacturer, each of the drug makers above should be preparing for launch just around the February 2025 patent expiration date.
Another group of prospective denosumab biosimilar manufacturers should be wrapping up their late-stage trials in 2024, and they include Alvotech (AVT03), Biocon (Bmab1000), partners Shanghai Henlius and Organon (HLX14), and Intas (INTP23). Unless their individual developmental consultations with the FDA determine that Phase 3 trials are no longer necessary for this drug category, they will be at a distinct disadvantage with later market entries.
