Amgen and UCB's Romosozumab (Evenity) Granted Clinical Trial Approval in China for High-Risk Postmenopausal Osteoporosis

Text | Zhang Hongli

The official website of the Center for Drug Evaluation (CDE) under China’s National Medical Products Administration indicates that the clinical trial application for romosozumab injection, a novel monoclonal antibody targeting sclerostin developed by Amgen/UCB, has received implicit approval. The specific indication is for the treatment of osteoporosis in postmenopausal women at high risk of fracture.

The World’s First Approved Anti-Sclerostin Monoclonal Antibody

Osteoporosis is a disease caused by a decline in bone density and quality. It weakens and brittles bones, significantly increasing the risk of fractures. Bone loss is a silent, progressive process, so there are usually no symptoms before the first fracture occurs. Statistics show that globally, one in three women and one in five men are at risk of osteoporotic fractures. There is still considerable room for improvement in the treatment and management of osteoporosis, particularly in the post-fracture setting.

Romosozumab is a monoclonal antibody targeting sclerostin, jointly developed by Amgen and UCB. It inhibits the activity of sclerostin, thereby simultaneously accelerating bone formation and reducing bone resorption, and is developed for the treatment of osteoporosis in both men and women. Sclerostin is a secreted glycoprotein. In vivo studies have demonstrated that sclerostin is specifically expressed in osteocytes and inhibits bone formation by osteoblasts. Antagonizing sclerostin can alleviate the symptoms of osteoporosis, providing new insights and approaches for the clinical treatment of osteoporosis and other related conditions.

In January 2019, romosozumab received the world’s first marketing approval in Japan for reducing fracture risk and increasing bone mineral density in postmenopausal women and men with osteoporosis at high risk of fracture. In the same month, Amgen and UCB announced that romosozumab had received strong support (18:1) from the U.S. FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC). The U.S. FDA subsequently granted formal marketing approval for romosozumab, marketed under the brand name Evenity, for the treatment of osteoporosis in postmenopausal women at high risk of fracture.^®Romosozumab also became the first anti-sclerostin monoclonal antibody drug approved for marketing globally.

The FDA approval was based on data from two pivotal Phase 3 trials of romosozumab (FRAME and ARCH). FRAME (NCT01575834) was a multicenter, international, randomized, double-blind, placebo-controlled, parallel-group study conducted in 7,180 postmenopausal women with osteoporosis. The results demonstrated that, compared with the control group, Evenity reduced the risk of new vertebral fractures by 73% (p<0.001) after 12 months of treatment, and by 75% (p<0.001) after 24 months of treatment.

The ARCH trial (NCT01631214) was a randomized, double-blind, alendronate-controlled study conducted in 4,093 postmenopausal women with osteoporosis who had a history of fracture and were at high risk for fracture. The treatment regimen consisted of 12 months of Evenity (210 mg) followed by at least 12 months of alendronate (70 mg). The results demonstrated that, compared with alendronate monotherapy, the Evenity-based regimen reduced the risk of new vertebral fractures by 48% after 24 months of treatment (p<0.001).

Currently, Evenity is approved in South Korea for the treatment of osteoporosis in postmenopausal women and men at high risk of fracture, and in Canada for the treatment of osteoporosis in postmenopausal women at high risk of fracture.

Cardiovascular Risk Is a "Hard Endpoint"

In fact, the regulatory review process for romosozumab in the United States lasted approximately two years and nine months. In July 2016, Amgen and UCB initially submitted a marketing application for romosozumab to the FDA, based on clinical data from the FRAME trial. One year later (in July 2017), the FDA issued a Complete Response Letter requesting the submission of additional recent clinical trial data. In July 2018, Amgen and UCB submitted their second marketing application for romosozumab to the FDA.

Furthermore, the FDA-approved labeling for Evenity restricts its indication to postmenopausal women at high risk for fracture and recommends limiting treatment duration to 12 months. The labeling also includes a Boxed Warning indicating that the drug may increase the risk of myocardial infarction (heart attack), stroke, and cardiovascular death. The FDA has also required postmarketing studies to evaluate the cardiovascular safety of Evenity in postmenopausal women with osteoporosis, including a 5-year observational feasibility study, which may be followed by a comparative safety study.

The cardiovascular risk of romosozumab, a significant “Achilles’ heel,” was clearly evident in the ARCH study. Compared with the alendronate group, the Evenity group exhibited a 30% increase in cardiovascular risk, as reflected by the incidence of composite cardiovascular endpoint events: 2.5% in the Evenity group versus 1.9% in the alendronate group.

Thus, although the regulatory review pathway in the United States was fraught with challenges, romosozumab ultimately gained approval; in contrast, the European Union outright rejected it. On June 27, 2019, Amgen and UCB announced that they had received notification that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) had issued a negative opinion, recommending against the approval of romosozumab for the treatment of severe osteoporosis. The primary reason for the refusal was concern over an increased risk of serious cardiac or circulatory events (such as myocardial infarction or stroke) in patients receiving romosozumab.

Development Progress of Other Major Anti-Sclerostin Antibodies

In addition to romosozumab, Eli Lilly’s LY2541546 and Mereo BioPharma’s setrusumab are in clinical development and represent two noteworthy candidates currently in clinical trials. There are relatively few domestic companies developing similar antibodies; Hengrui Medicine’s SHR-1222 is in Phase I clinical trials and stands as a leading anti-sclerostin antibody candidate in China.

References:

1. CDE Official Website

2. 18:1 Strong Support: Innovative New Osteoporosis Drug Expected to Gain Approval (Source: WuXi AppTec)

3. A Tortuous Review Path! Evenity Finally Approved in the U.S. (Source: CPhI Pharmaceutical Online)

4. EU Rejects Approval of New Osteoporosis Drug Evenity Due to Significant Cardiovascular Risks (Source: PharmCube)