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New Bone Drug: Amgen And UCB Announce Top-Line Phase 3 Data From Active-Comparator
Study Of EVENITY™ (Romosozumab) In Postmenopausal Women With Osteoporosis
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About EVENITY
EVENITY is an investigational bone-forming monoclonal antibody and is not approved by any regulatory authority for the treatment of osteoporosis. It is designed to work by inhibiting the activity of sclerostin and has a dual effect on bone, increasing bone formation and decreasing bone resorption. EVENITY is being studied for its potential to reduce the risk of fractures in an extensive global Phase 3 program. This program includes two large fracture trials comparing EVENITY to either placebo or active comparator in more than 10,000 postmenopausal women with osteoporosis. Amgen and UCB are co-developing EVENITY.
Bone-forming agents in non-responders to bisphosphonates [Romosozumab ]- Comment
Lancet Sept 30 2017 - -Juliet Compston
Department of Medicine, Cambridge Biomedical Campus,
Cambridge CB2 0SL, UK
Osteoporosis is a chronic disease requiring long-term treatment. Oral bisphosphonates, which act by inhibiting bone resorption, are most commonly prescribed but inadequate response, development of intolerance, or fear of long-term side-effects sometimes necessitate change to an alternative therapy.1 One option is to switch to teriparatide, a bone-forming agent, but enthusiasm for this strategy is tempered by the blunting of the bone mineral density (BMD) response to teriparatide seen in patients previously treated with antiresorptives.2, 3, 4
Romosozumab (AMG 785) is a monoclonal antibody that binds to and inhibits sclerostin, a negative regulator of bone formation. In addition to stimulating bone formation, it also inhibits bone resorption. Previous studies have shown that in postmenopausal women with low bone mass, treatment with romosozumab 210 mg subcutaneously for 12 months resulted in significantly greater increases in hip and spine BMD than did treatment with teriparatide, and in postmenopausal women with osteoporosis, treatment for 12 months with this dose of romosozumab significantly reduced vertebral and clinical fractures compared with placebo.5, 6 Romosozumab is awaiting regulatory approval in the USA, Canada, and Japan, although because of an imbalance in serious adverse cardiovascular events in the ARCH study a decision is not expected until 2018.7
Against this background, in a randomised open-label study in 436 postmenopausal women who were previously treated with oral bisphosphonates for a mean duration of 6⋅2 years, Bente Langdahl and colleagues8 compared the effect of transitioning to 12 months' treatment with teriparatide or romosozumab. Despite earlier bisphosphonate therapy, these women all had osteoporosis (BMD T score ≤-2⋅5) and a history of fracture after the age of 50 years. For the primary endpoint, percentage change from baseline in areal BMD by dual-energy x-ray absorptiometry at the total hip up to month 12, romosozumab was significantly superior to teriparatide (change +2⋅6% in the romosozumab group vs -0⋅6% in the teriparatide group; p<0⋅0001). Cortical hip volumetric BMD increased at 6 and 12 months in women treated with romosozumab, but decreased in those treated with teriparatide. Hip strength, estimated by finite element analysis, was significantly increased at both timepoints in the romosozumab group, whereas in women receiving teriparatide a significant decline was seen at 6 months and the mean value remained below baseline at 12 months. Adverse events, including fractures (reported as serious adverse events), were generally balanced between groups.
Comparison of the effects on hip BMD of transitioning to romosozumab or teriparatide is of particular interest in view of the decline in hip BMD previously reported in several studies of sequential exposure to bisphosphonates and teriparatide.2, 3, 4 The study by Langdahl and colleagues supports and extends this finding, providing additional information about changes in hip cortical and trabecular bone. Transition to teriparatide was accompanied by a decrease in cortical volumetric BMD and an increase in trabecular volumetric BMD; although there was little overall change in integral (cortical plus trabecular) volumetric BMD, bone strength estimated by finite element analysis decreased. By contrast, transition to romosozumab was associated with an increase in hip cortical and trabecular volumetric BMD, and in hip strength. These opposing effects of the two drugs on hip cortical bone might reflect differing mechanisms of action. The anabolic effects of teriparatide depend to a large extent on its pro-remodelling activity, and the decline in hip cortical BMD might be caused by increased cortical porosity and reduced mineralisation of newly formed bone.9, 10 By contrast, changes associated with romosozumab might be mediated more by modelling-based bone formation, accompanied by inhibition of bone resorption and hence suppression of bone remodelling.11 However, increases in bone density and strength resulting from prolonged therapy with teriparatide, which is approved for up to 2 years of treatment, cannot be excluded on the basis of this 12-month study.
In clinical practice, it is not uncommon to encounter patients who despite adequate adherence to medication apparently do not respond to oral bisphosphonates, with persistently low BMD or incident fracture during treatment. Some of these patients might respond to intravenous bisphosphonate therapy, but in others switching to a drug that stimulates bone formation is a reasonable approach. Although the effects on fracture risk have not been established, the results of the study by Langdahl and colleagues suggest that the greatest benefits for hip BMD and estimated strength are obtained with a drug such as romosozumab that stimulates bone formation and inhibits bone resorption. Use of sequential therapy in osteoporosis is the focus of much attention,12 and this study shows the potential for the use of drugs with different mechanisms of action as a strategy to improve outcomes in the management of osteoporosis. Since the duration of therapy with bone-forming agents is limited and bone loss follows treatment withdrawal, the subsequent use of interventions to maintain treatment benefits is an important area for future research.
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Amgen And UCB Announce Top-Line Phase 3 Data From Active-Comparator Study Of EVENITY™ (Romosozumab) In Postmenopausal Women With Osteoporosis
ARCH Study Met Primary and Key Secondary Endpoints by Reducing the Incidence of New Vertebral, Clinical and Non-Vertebral Fractures
Imbalance in Cardiovascular Events Observed as New Safety Signal
News provided by
Amgen
May 21, 2017, 18:01 ET
http://www.prnewswire.com/news-releases/amgen-and-ucb-announce-top-line-phase-3-data-from-active-comparator-study-of-evenity-romosozumab-in-postmenopausal-women-with-osteoporosis-300461160.html
THOUSAND OAKS, Calif. and BRUSSELS, May 21, 2017 /PRNewswire/ --Amgen (NASDAQ: AMGN) and UCB (Euronext Brussels: UCB) today announced that the EVENITY™* (romosozumab) ARCH study met both primary endpoints and the key secondary endpoint. At the primary analysis, treatment with EVENITY for 12 months followed by alendronate significantly reduced the incidence of new vertebral fractures through 24 months, clinical fractures (primary endpoints) and non-vertebral fractures (key secondary endpoint) in postmenopausal women with osteoporosis at high risk for fracture, compared to alendronate alone. An imbalance in positively adjudicated cardiovascular serious adverse events was observed as a new safety signal (2.5 percent EVENITY versus 1.9 percent alendronate at 12 months).
"The efficacy results from this study comparing EVENITY to an active control are robust. At the same time, the newly observed cardiovascular safety signal will have to be assessed as part of the overall benefit:risk profile for EVENITY," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "Together with UCB, we will engage with global regulators and medical experts in the field to conduct a thorough evaluation of these data."
EVENITY is an investigational bone-forming agent that rapidly increases bone formation and reduces bone resorption simultaneously, increases bone mineral density and reduces the risk of fracture. In this study, women received subcutaneous injection of EVENITY monthly for 12 months followed by oral alendronate weekly for at least 12 months. At 24 months, women in the EVENITY treatment group experienced a statistically significant 50 percent reduction in the relative risk of a new vertebral (spine) fracture compared to those receiving alendronate alone. Women in the EVENITY treatment group also experienced a statistically significant 27 percent reduction in the relative risk of clinical fracture (non-vertebral fracture and clinical vertebral fracture) at the primary analysis. Additionally, non-vertebral fractures were statistically significantly reduced by 19 percent in the EVENITY treatment group, including a nominally significant reduction in hip fractures.
"We are impressed with the statistically significant superior fracture risk reduction of EVENITY over alendronate, a current standard of care in osteoporosis. When we think that patients who have had a fracture are highly likely to suffer another one, the importance of post-fracture care cannot be emphasized enough," said Iris Loew-Friedrich, UCB's chief medical officer. "We are working on understanding the observed cardiovascular safety signal and will continue to discuss these results with global regulators and experts in the field."
Overall adverse events and serious adverse events were generally similar between the treatment groups throughout the study and also in the initial 12-month EVENITY treatment period. In the initial 12-month EVENITY treatment period, the three most commonly reported adverse events in both arms were nasopharyngitis, back pain and arthralgia. Injection site reactions were reported in 4.4 percent of patients in the EVENITY treatment group and 2.6 percent in the alendronate group during the initial 12-month period. Most injection site reactions were reported as mild in severity. During the open-label alendronate period, there were two positively adjudicated events of osteonecrosis of the jaw, one in a patient treated with EVENITY followed by alendronate and one treated with alendronate alone. There were six patients with positively adjudicated events of atypical femoral fracture during the open-label alendronate period (two patients treated with EVENITY followed by alendronate and four treated with alendronate alone). The patient incidence of positively adjudicated cardiovascular serious adverse events at 12 months was 2.5 percent in the EVENITY group compared to 1.9 percent in the alendronate group. No imbalance in cardiovascular serious adverse events was seen in the 7,180-patient placebo-controlled FRAME study.
Regulatory submissions for EVENITY based on the FRAME study results are currently under review with the U.S. Food and Drug Administration (FDA), Health Canada and the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. Amgen has agreed with the FDA that the ARCH data should be considered in the regulatory review prior to the initial marketing authorization, and as a result the Company does not expect approval of EVENITY in the U.S. to occur in 2017. Engagement with PMDA and Health Canada will occur as part of the ongoing review process. The preparation for the European regulatory submission will continue as planned. Further analysis of the Phase 3 ARCH study data is ongoing and will be submitted to a future medical conference and for publication.
About EVENITY
EVENITY is an investigational bone-forming monoclonal antibody and is not approved by any regulatory authority for the treatment of osteoporosis. It is designed to work by inhibiting the activity of sclerostin and has a dual effect on bone, increasing bone formation and decreasing bone resorption. EVENITY is being studied for its potential to reduce the risk of fractures in an extensive global Phase 3 program. This program includes two large fracture trials comparing EVENITY to either placebo or active comparator in more than 10,000 postmenopausal women with osteoporosis. Amgen and UCB are co-developing EVENITY.
About the ARCH study
ARCH (Active-contRolled FraCture Study in Postmenopausal Women with Osteoporosis at High Risk of Fracture) is a Phase 3 multicenter, international, randomized, double-blind, alendronate-controlled study of EVENITY in postmenopausal women with osteoporosis at high risk for fracture based on previous fracture history. The study evaluated 12 months of EVENITY treatment followed by at least 12 months of alendronate treatment, compared with alendronate treatment alone. The purpose of this study was to determine if EVENITY treatmentis effective in reducing the incidence of clinical fracture (non-vertebral fracture and clinical vertebral fracture) and new vertebral fracture. The incidence of clinical fracture was event-driven and the primary analysis occurred when 330 fractures occurred or the last patient was on the study for 24 months, whichever was later.
Patients (4,093) were randomized 1:1 to receive either 210 mg EVENITY subcutaneously every month or 70 mg alendronate orally every week for the duration of the 12-month double-blind alendronate-controlled study period. After the double-blind active-comparator study period, patients received alendronate while remaining blinded to their initial treatment assignment.
About the FRAME study
FRAME (FRActure study in postmenopausal woMen with ostEoporosis) is a multicenter, international, randomized, double-blind, placebo-controlled, parallel-group study in postmenopausal women with osteoporosis, defined as low bone mineral density at the total hip or femoral neck. The study evaluated the effectiveness of EVENITY treatment, compared with placebo, in reducing the risk of new vertebral fractures through 12 months. The study also further evaluated if EVENITY treatment for 12 months followed by denosumab treatment for 12 months, compared with placebo followed by denosumab treatment, was effective in reducing the risk of new vertebral fractures through 24 months. In addition, clinical fracture (a composite endpoint which encompasses all symptomatic fractures, both non-vertebral and painful vertebral fractures) risk reduction, non-vertebral fracture (fractures outside of the spine, excluding sites that are not considered osteoporotic, fractures due to high trauma or pathologic fractures) risk reduction and other endpoints were assessed at 12 and 24 months.
7,180 patients were randomized 1:1 to receive either 210 mg EVENITY subcutaneous (SC) monthly (QM) or placebo SC QM for the 12-month double-blind study period. After the placebo-controlled study period, patients entered the open-label phase where all patients received 60 mg denosumab SC every six months (Q6M) for 12 months, while remaining blinded to initial treatment. An additional 12 month extension period of open-label 60 mg denosumab SC Q6M is currently ongoing.
About the Amgen and UCB Collaboration
Since 2004, Amgen and UCB have been working together under a collaboration and license agreement to research, develop and market antibody products targeting the protein sclerostin. As part of this agreement, the two companies continue to collaborate on the development of EVENITY for the treatment of osteoporosis. This gene-to-drug project demonstrates how Amgen and UCB are joining forces to translate a genetic discovery into a new medicine, turning conceptual science into a reality.
About Amgen
Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.
Amgen focuses on areas of high unmet medical need and leverages its expertise to strive for solutions that improve health outcomes and dramatically improve people's lives. A biotechnology pioneer since 1980, Amgen has grown to be one of the world's leading independent biotechnology companies, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.
For more information, visit www.amgen.comand follow us on www.twitter.com/amgen.
About UCB
UCB, Brussels, Belgium (www.ucb.com) is a global biopharmaceutical company focused on the discovery and development of innovative medicines and solutions to transform the lives of people living with severe diseases of the immune system or of the central nervous system. With more than 7 500 people in approximately 40 countries, the company generated revenue of € 4.2 billion in 2016. UCB is listed on Euronext Brussels (symbol: UCB). Follow us on Twitter: @UCB_news
SOURCE Amgen
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