The osteoporosis drug market has evolved markedly since the introduction of the bisphosphonates in 1995. Developed to help prevent bone loss and the complications of bone fracture, and to increase bone mass overall, the market grew to include the selective estrogen receptor modulators in the 2000s, and then biologics in 2010.
Amgen’s denosumab (Prolia®), a RANKL monoclonal antibody, is indicated for the treatment of osteoporosis in postmenopausal women. At Amgen’s November 2020 investor conference, the company stated that its net US sales of Prolia reached $478 million for the third quarter of 2020 (or an annualized figure of about $1.9 billion). Global third-quarter sales were $701 million, which was an increase of 11% from the third quarter of 2019. Sales of Prolia are expected to increase significantly until 2025, when biosimilar competition may arrive in the US.
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. Amgen cited third-quarter net sales of Xgeva separately, with a total of $363 million, or annualized sales of more than $1.4 billion.
It is an open question as to whether a biosimilar manufacturer will seek the indications of both Prolia and Xgeva; the principal patents for both products expire in 2022 in the EU, and in 2025 in the US. According to Drug Patent Watch, Amgen holds more than 100 patents on denosumab; some of these have already expired.
The Likely Denosumab Biosimilar Competition: The Outlook in 2021
A couple of biosimilar makers who are active in the US market and prospective foreign manufacturers have embarked on denosumab development programs. The furthest along seems to be Samsung Bioepis and its partner Biogen.
Samsung Bioepis/Biogen. This prolific South Korean biosimilar maker announced December 14, 2020 that its phase 3 trial for SB16 had begun recruitment. The study is a double-blind, randomized design that will enroll 432 women with postmenopausal osteoporosis, and will compare efficacy, safety, and other outcomes of SB16 with US-licensed Prolia. The study aims to be completed in full by March 2023 (primary completion date September 2022).
Of interest, Samsung Bioepis started their phase 3 trial soon after beginning its phase 1 investigation (which began in October 2020 and is scheduled for completion in August 2021). The latter will test the agents pharmacokinetics and pharmacodynamics in healthy volunteers. Therefore, one may wonder if Samsung Bioepis is taking a considerable risk in initiating the more expensive, late-stage trial. On the other hand, Samsung may simply be extremely confident of its preclinical physiochemical analysis results and wants to gear up for 2022 EU regulatory submission. Based on the phase 3 trial end date, and assuming a successful result, 351(k) filing with the Food and Drug Administration could occur as early as Q2 2023.
Celltrion. Celltrion also has a long history of biosimilar development, and in November 2020, it initiated a phase 1 pilot study of its agent CT-P41. The phase 1 test will comprise 30 healthy volunteers and conclude in April 2021.
Other Potential US Competitors
Four companies from China and one from Taiwan have begun clinical trials of their denosumab biosimilars. It is unclear whether any of the companies listed below intend to seek US Food and Drug Administration approval. If they do, these manufacturers will likely need to acquire a partner for commercialization. Another company, Neuclone, which we profiled in 2020, is in the preclinical development for its denosumab biosimilar.
Qilu Pharmaceutical. A phase 1 study of this company’s denosumab biosimilar, QL1206, was completed in October 2020 with 144 healthy volunteers. A phase 3 trial was reported to have begun in November 2019 and been completed in July 2021 in 216 patients with postmenopausal osteoporosis.
Another interesting aspect of Qilu Pharmaceutical’s efforts is that it reported a phase 3 trial testing QL1206 against Xgeva’s indications. This double-blind study of 700 patients with bone metastases from solid tumors is due to complete in June 2022, with preliminary results available in March 2021.
Shanghai Biomabs Pharmaceutical Co, Ltd. Shanghai Biomabs Pharmaceutical began its phase 3 trial of CMAB807 this month. The study includes 278 Chinese participants, and is scheduled to be completed in June 2023. A phase 1 investigation of CMSB807 wrapped up in June 2020.
Kunming Pharmaceuticals, Inc. This company’s denosumab biosimilar, MV088, is in the midst of a phase 1 trial, the estimated completion date of which is October 18, 2021.
Shanghai Henlius Biotech. A phase 1 investigation of HLX14 appears to have just gotten underway, and the final completion date is listed as August 2021. In this very small trial (24 healthy volunteers), the pharmacokinetics and safety of the biosimilar will be compared with EU-licensed Prolia.
JHL Biotech. This Taiwan-based company announced a three-arm, phase 1 trial of JHL1266 in healthy Australian subjects in May 2020. This study is not listed on http://www.clinicaltrials.gov and thus could not be verified. No further information was available.