Amgen’s Response to the Institute for Clinical and Economic Review (ICER) Draft Report on Anabolic Therapies for Osteoporosis in Postmenopausal Women: Effectiveness and Value
Amgen appreciates the opportunity to comment on the ICER draft report “Anabolic Therapies for Osteoporosis in Postmenopausal Women: Effectiveness and Value.” Osteoporosis is an important disease that remains under-diagnosed and under-treated, and in which innovative therapies have an important impact on patients. Hence, it is critical that any assessment on this topic keeps patients at the center and uses appropriate methods and inputs.
Before sharing our comments on ICER’s draft report, we would like to acknowledge that Amgen no longer expects FDA approval of EVENITY (romosozumab) in 2017. Amgen and UCB recently announced that the romosozumab ARCH study met both primary endpoints and the key secondary endpoint. In ARCH, treatment with EVENITY for 12 months was followed by alendronate for at least 12 months. At 24 months, women in the EVENITY treatment group experienced statistically significant risk reductions of 50% in new vertebral fractures, 19% in non-vertebral fractures and 27% in clinical fractures, in addition to nominally significant reduction in hip fractures compared to alendronate alone. Overall, adverse events and serious adverse events were generally similar between treatment groups throughout the study. 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). (Appendix A). Amgen has agreed with the FDA that the ARCH data should be considered in the regulatory review prior to the initial marketing authorization. It is important that the regulatory agencies review the full evidence package of FRAME and ARCH before a value assessment is conducted. Amgen asks ICER to remove romosozumab completely from this assessment as we believe reaching conclusions around the value of new technologies based on incomplete information is contrary to basic medical research principles and can have unintended negative consequences for patients.
While we expect ICER to remove romosozumab, we have provided our comments on the draft report to help correct some of its major issues and deficiencies.
ICER’s osteoporosis assessment has serious methodological flaws that compromise its results, which inappropriately imply overall poor value of bone-forming agents. For example, ICER selected an inappropriate comparator for this assessment despite extensive feedback on this issue. ICER’s comparative clinical effectiveness is based on a literature review that does not include one of the comparators, zoledronic acid (ZA), in the search strategy (draft report tables A2-A4). Moreover, ICER’s base case cost-effectiveness model utilizes clinically unsound efficacy assumptions and data inputs, and does not reflect the uncertainty associated with efficacy estimates and their impact on the results and conclusions. Summarized below are the critical issues and recommendations, and how to address them based on an understanding of economic evaluation; clinical practice; the biology of osteoporosis; and of patients suffering its consequences.
Critical issues and recommendations:
- Comparing bone-forming agents to bisphosphonates is an inappropriate way to estimate the value of bone-forming agents. Despite early feedback from multiple stakeholders, ICER continues to base their value assessment of bone-forming agents (teriparatide, abaloparatide, and romosozumab) on a comparison to a bisphosphonate. ICER selected ZA as the comparator, with the rationale that this agent is used in patients at high risk for fracture. However, this comparison is fraught with limitations. Bisphosphonates, including ZA, are a different class of agents that slow bone loss rather than building new bone, and are generally used in a treatment context that differs from bone-forming agents. Recommendation: Value assessments should compare newer therapies to the most relevant comparator being used in the same context, with the same therapeutic objective in the same population. In this case, a comparison across bone-forming agents would be most appropriate.
- ICER’s assessment is based on clinically unfounded efficacy assumptions. (1). Available hip fracture data (e.g., romosozumab’s HR 0.54 vs. placebo at 12 months) are not used for any product due to some not having appropriate data (i.e., abaloparatide) and non-vertebral fracture data are used to model hip fractures for all products, (2). Time-dependent treatment effects are not considered despite existing evidence of the rapid onset of bone-forming agents (1-2 years), particularly romozosumab (1 year), in contrast to 3-5 years of ZA and bisphosphonates in general. Recommendation: (1). ICER should use existing hip fracture data and replace with non-vertebral fracture data only for those treatments lacking robust data (e.g., abaloparatide), (2). ICER should incorporate time-dependent efficacy data into the model to capture the rapid effect of bone-forming agents, particularly romosozumab.
- ICER underestimates fracture costs and overall disease burden, including mortality. (1). Short and long-term fracture costs (the primary direct medical cost) are underestimated by ICER by using cost data from as far back as 2001 and 1989 respectively, (2). Fracture-related impact on death is inadequately captured. Recommendation: ICER should use up-to-date short and long-term cost estimates for fractures based on a systematic review of the literature. ICER should also account for the downstream disease burden of fractures in terms of their impact on mortality as inputs into their model, to better capture the value of preventing such catastrophic events for patients.
- ICER uses unrealistic base case assumptions that do not reflect clinical practice. (1). ICER assumes 100% persistence for ZA despite their acknowledgment of real world evidence indicating that up to 60% of US patients discontinue ZA after 1 injection, (2). The assumption of a rate of decline of the effect over 10-years post-ZA appears unsubstantiated as it is based on data on residual effects on the bone and not on long-term fracture protection data over 10 years. Recommendation: ICER should simulate real world estimates of persistence of each therapy over time and assume credible ranges for the decline of effect over time.
- ICER’s model is unstable as demonstrated by the extremely large volatility of its results. In ICER’s model, variation in one model input changes the results by millions of dollars per QALY. This is a sign of enormous uncertainty and lack of robustness of the model. However, ICER chose to focus the sensitivity analysis on factors with little impact on results such as utility (40% of ICER’s one-way sensitivity analysis) and reaches strong and definitive conclusions that seem disconnected from the underlying uncertainty. Recommendation: ICER should choose clinically sound base case assumptions and conduct a robust assessment of uncertainty around data inputs and assumptions, and utilize the results to appropriately inform conclusions of the assessment as per established good practice in economic evaluation.1
The above-mentioned issues are further detailed below:
1. Comparing bone-forming agents to bisphosphonates is an inappropriate way to estimate the value of bone-forming agents.
Bone-forming agents are viewed as a distinct class of therapy by the medical community.2-4 Although ICER correctly notes treatment recommendations of a T-score ≤ -2.5 or 10-year fracture risk based on FRAX (hip fracture risk of ≥ 3% or major osteoporosis-related fracture risk of ≥ 20%), patients who receive the bone-forming agent, teriparatide, tend to be at a much higher fracture risk relative to patients treated with antiresorptive agents.5,6 Real world evidence show that patients receiving teriparatide were significantly older, had more comorbidities and fracture-related hospitalizations and substantially higher baseline fracture rates.7-9 In these higher-risk patients, bone-forming agents can improve impaired bone mass and structure allowing for more rapid offset of fracture risk. Subsequent sequencing to antiresorptive agents may help maintain or augment gains in new bone and continue fracture reduction over the long-term. Prior fracture history, lower BMD, and other co-morbidities are features reflecting higher fracture risk. Amgen is conducting research that will further identify patients who are at high risk of a near-term fracture and can provide additional information on this.
ICER compares bone-forming agents to a bisphosphonate requiring making a comparison across different classes of agents, generally used in different treatment contexts, in different patients and over different timeframes. This indicates a lack of recognition of patients’ heterogeneity in their needs and preferences and it seems more a misleading price-centric comparison than one informing a relevant decision. Furthermore, ICER also compares active treatments to no treatment, which again represents an unrealistic scenario where bone-forming agents may be considered and yet does not compare bone-forming agents to each other, which would be a more useful exercise of value assessment.
Value assessments should compare therapies intended for use in a given population with the same therapeutic needs. In this case, a comparison across bone-forming agents would be most appropriate.
2. ICER’s assessment is based on clinically unfounded efficacy assumptions.
Product-Specific Hip Fracture Estimates
The ICER base case model uses nonvertebral fracture estimates in place of hip fracture estimates for all products evaluated. This could be considered appropriate in the case of abaloparatide since hip fracture estimates could not be accurately calculated given only two hip fractures were observed (both in the placebo arm) in the ACTIVE trial10. However, using nonvertebral data instead of hip fracture data for romosozumab is inappropriate as hip fractures are reported from the FRAME study: HR 0.54 (0.22 – 1.35) for romosozumab vs. placebo at 12 months and 0.50 (0.24 – 1.04) for romosozumab/denosumab vs. placebo/denosumab at 24 months.11
ICER only tests this flawed assumption in a sensitivity analysis resulting in almost double the estimated health benefit and a change in result for romosozumab from over $4 million dollars per QALY to less than $193,000 per QALY (draft report tables 16 and 24).
ICER assumes an immediate, full effect of ZA, which over-estimates the value of ZA. Clinical trials have reported effects at time points that are not always aligned with each other; while cross-study comparisons require considering heterogeneity in patient populations studied, the time frame of efficacy assessments across studies should be reflected in ICER’s modeling. The clinical trial data ICER is considering, in combination with an understanding of the mechanism of action of each therapy, strongly suggest a faster effect attributable to bone-forming agents (1-2 years) and romosozumab in particular (1year) in contrast with a slower, more gradual effect with bisphosphonates such as ZA, particularly for non-vertebral fracture.10-13
It is also important to note that romosozumab is penalized in the ICER assessment for offering a 1 year treatment option, with rapid results (at 1 year), since it results in only 7 years of treatment for the sequence including romosozumab compared to 8 years for the sequences including teriparatide or abaloparatide (2 years treatment). This stems from the questionable assumption of a fixed 6 year sequenced treatment with ZA following each bone-forming agent, instead of a non-sequenced comparison or the use of the same total time frame across products (i.e. all treatment sequenced for X years).
ICER should use all relevant data available for each product and their specific time-dependent benefits without imposing artificially created rules that penalize specific products unnecessarily.
3. ICER underestimates fracture costs and overall disease burden, including mortality.
ICER’s model utilizes fracture and post fracture cost inputs from as far back as 2001 and 1989 respectively, with just an adjustment for inflation that could not possibly account for the changes in care and the use of new technology that has occurred in the last 25 years. This represents a gross underestimation of the financial burden of osteoporosis even when compared to estimates from 200714 with differences of up to $10,000 dollars per fracture, or about 50% of their cost, observed.
An equally concerning issue identified in ICER’s assessment is their reference of Tosteson et al 2007 in the claim that “excess mortality only occurred after hip fractures.” Tosteson does not make that claim.15 The article focuses on mortality associated with hip fractures, and states that vertebral and nonvertebral fractures were too difficult to identify from retrospective patient charts and were thus not considered. In a literature search, we identified multiple references providing evidence that mortality increases after other fracture types such as vertebral fracture.16-23
Underestimating the burden of osteoporosis does a disservice to patients and physicians by undervaluing the impact of fracture-related mortality and costs, and ultimately the value of the bone-forming agents that have demonstrated their efficacy in preventing fractures. The incomplete picture painted by ICER could perpetuate under treatment of an already undertreated patient group and disease in general with often quoted treatment rates of 20% or less24,25 even in high risk elderly post-fracture patients.
ICER should use up-to-date short and long-term cost estimates for fractures based on systematic literature review and appropriately account for the downstream disease burden of fractures in terms of their impact on mortality, as inputs into their model to better capture the value of preventing such catastrophic events for patients.
4. ICER uses unrealistic base case assumptions that do not reflect clinical practice.
ICER assumes 100% persistence for ZA.; however, recent peer-reviewed publications26,27 on real world use of osteoporosis therapies indicate 30-60% of US patients discontinue ZA after 1 injection. ICER’s report acknowledges the issue citing a 59% discontinuation of ZA by two years and 67% for teriparatide, and yet assumes 100% persistence, for six years in the case of ZA. Importantly, compromised persistence for ZA may be related to the high incidence of infusion reactions that occur with ZA.10-13 In addition, the assumption of an additional 10-years offset of effect for ZA is based on bone mineral density data of much shorter duration, which show only residual bone mineral density effects on the bone (not long-term fracture protection over 10 years). With the combined assumptions of 100% persistence and an additional 10-years offset effect for ZA, ICER’s assessment inappropriately overestimates the real-world benefit of ZA.
Finally, ICER focuses on the time on sequenced therapies (i.e., on ZA), which confounds the estimation of value of the bone-forming agents being assessed; time on ZA accounts for 80% of the total treatment period in ICER’s assessment.
ICER should simulate real world estimates of persistence of each therapy over time, credible offset effect duration and not focus excessively the attention of the assessment on the time post bone-forming agents to better reflect current clinical reality and assess their value.
5. ICER’s model is unstable as demonstrated by the extremely large volatility of its results.
Variations of one single input in ICER’s model cause changes on results by millions of dollars per QALY. In the case illustrated above (issue #2), when the use of non-vertebral fracture rates to model hip fractures is reversed, the results are approximately 15 times or $4M/QALY better for romosozumab. However, ICER does not make an appropriate use of probabilistic sensitivity analyses to examine the joint uncertainty in parameters thus putting too much emphasis on point estimates that are greatly uncertain. This results in overly strong conclusions disconnected from the high uncertainty around key parameters and assumptions made.
Correcting the above-mentioned additional issues results in romosozumab being cost-effective according to generally accepted willingness-to-pay thresholds.
Amgen, in collaboration with external experts, have replicated ICER’s cost-effectiveness model, despite the scarcity of details provided, and also created a de-novo model based on published models. The former was used to estimate the extent of the impact of the assumptions and data input choices made by ICER in the results, which helped confirm the issues illustrated above. The latter was used to simulate relevant comparisons using clinically relevant inputs and assumptions and demonstrates that romosozumab would provide good value for patients, healthcare systems and society as a whole, and will be subject of upcoming publications.
The correction of the flaws in the ICER assessment is strongly recommended to ensure an appropriate valuation of bone-forming agents for osteoporosis in postmenopausal women in need of rapid bone formation. To provide full transparency, ICER should make their model more transparent and accessible.
Amgen urges ICER to address the above-noted critical flaws that compromise its draft report for osteoporosis. A more credible value assessment will align its methods, inputs and assumptions with health economic good research practices, with clinical guidelines and real-world clinical practice, based on an understanding of the biology of osteoporosis and patient considerations.
In addition, ICER should remove romosozumab completely from this assessment given that additional data will be included in the FDA submission and market approval is no longer expected in 2017.
- Caro JJ, Briggs AH, Siebert U, Kuntz KM, Force I-SMGRPT. Modeling good research practices--overview: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force--1. Value Health. 2012;15(6):796-803.
- Baron R, Hesse E. Update on bone anabolics in osteoporosis treatment: rationale, current status, and perspectives. J Clin Endocrinol Metab. 2012;97(2):311-325.
- Gennari L, Rotatori S, Bianciardi S, Nuti R, Merlotti D. Treatment needs and current options for postmenopausal osteoporosis. Expert Opin Pharmacother. 2016;17(8):1141-1152.
- Herrero S, Pico Y. Treatments for post-menopausal osteoporotic women, what's new? How can we manage long-term treatment? Eur J Pharmacol. 2016;779:8-21.
- Aspray TJ. Fragility fracture: recent developments in risk assessment. Ther Adv Musculoskelet Dis. 2015;7(1):17-25.
- Cosman F, de Beur SJ, LeBoff MS, et al. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2014;25(10):2359-2381.
- Cheng LI, Durden E, Limone B, et al. Persistance and compliance with osteroporosis therapies among women in a commercially insured population in the United States. J Manag Care Spec Pharm. 2015;21(9):824-833, 833a.
- Yusuf A, Feudjo Tepie M, Kalouche -K, L., et al. Effectiveness of bone therapies in routine clinical practice: Two retrospective database analyses using US MarketScan and Medicare. Poster presented at 2016 World Congress On Osteoporosis, Osteoarthritis And Musculoskeletal Diseases, Malaga, Spain, April 14-17, 2016.
- Boytsov N, Yu M, Sugihara T, Swindle R. Defining the teriparatide patient: Osteoporosis sequence of care and healthcare resources. Am J Pharm Benefits. 2015;7:16-23.
- Miller PD, Hattersley G, Riis BJ, et al. Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women With osteoporosis: A randomized clinical trial. Jama. 2016;316(7):722-733.
- Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N Engl J Med. 2016;375(16):1532-1543.
- Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356(18):1809-1822.
- Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344(19):1434-1441.
- Bonafede M, Shi N, Viswanathan HN, Yurgin N. Osteoporosis-related fracture costs among female commercially insured and medicare patients. Value in Health. 2011;14:A125.
- Tosteson AN, Gottlieb DJ, Radley DC, Fisher ES, Melton LJ, 3rd. Excess mortality following hip fracture: the role of underlying health status. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2007;18(11):1463-1472.
- Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA, Center JR. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. Jama. 2009;301(5):513-521.
- Center JR, Nguyen TV, Schneider D, Sambrook PN, Eisman JA. Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet. 1999;353(9156):878-882.
- Cooper C, Atkinson EJ, Jacobsen SJ, O'Fallon WM, Melton LJ, 3rd. Population-based study of survival after osteoporotic fractures. American journal of epidemiology. 1993;137(9):1001-1005.
- Ensrud KE, Thompson DE, Cauley JA, et al. Prevalent vertebral deformities predict mortality and hospitalization in older women with low bone mass. Fracture Intervention Trial Research Group. J Am Geriatr Soc. 2000;48(3):241-249.
- Hasserius R, Karlsson MK, Jonsson B, Redlund-Johnell I, Johnell O. Long-term morbidity and mortality after a clinically diagnosed vertebral fracture in the elderly--a 12- and 22-year follow-up of 257 patients. Calcif Tissue Int. 2005;76(4):235-242.
- Hasserius R, Karlsson MK, Nilsson BE, Redlund-Johnell I, Johnell O, European Vertebral Osteoporosis S. Prevalent vertebral deformities predict increased mortality and increased fracture rate in both men and women: a 10-year population-based study of 598 individuals from the Swedish cohort in the European Vertebral Osteoporosis Study. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2003;14(1):61-68.
- Johnell O, Kanis JA, Oden A, et al. Mortality after osteoporotic fractures. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2004;15(1):38-42.
- Kado DM, Browner WS, Palermo L, Nevitt MC, Genant HK, Cummings SR. Vertebral fractures and mortality in older women: a prospective study. Study of Osteoporotic Fractures Research Group. Archives of internal medicine. 1999;159(11):1215-1220.
- Solomon DH, Brown EM, Chandler D, et al. Patterns of treatment among a cohort of older low-income adults starting new medications for osteoporosis. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2014;25(9):2255-2262.
- Yusuf AA, Matlon TJ, Grauer A, Barron R, Chandler D, Peng Y. Utilization of osteoporosis medication after a fragility fracture among elderly Medicare beneficiaries. Arch Osteoporos. 2016;11(1):31.
- Curtis JR, Yun H, Matthews R, Saag KG, Delzell E. Adherence with intravenous zoledronate and intravenous ibandronate in the United States Medicare population. Arthritis Care Res (Hoboken). 2012;64(7):1054-1060.
- Durden E, Pinto L, Lopez-Gonzalez L, Juneau P, Barron R. Two-year persistence and compliance with osteoporosis therapies among postmenopausal women in a commercially insured population in the United States. Arch Osteoporos. 2017;12(1):22.
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
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.
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 treatment is 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.
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.
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
Amgen Forward-Looking Statements
This news release contains forward-looking statements that are based on the current expectations and beliefs of Amgen. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements, including estimates of revenues, operating margins, capital expenditures, cash, other financial metrics, expected legal, arbitration, political, regulatory or clinical results or practices, customer and prescriber patterns or practices, reimbursement activities and outcomes and other such estimates and results. Forward-looking statements involve significant risks and uncertainties, including those discussed below and more fully described in the Securities and Exchange Commission reports filed by Amgen, including its most recent annual report on Form 10-K and any subsequent periodic reports on Form 10-Q and Form 8-K. Unless otherwise noted, Amgen is providing this information as of the date of this news release and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.
No forward-looking statement can be guaranteed and actual results may differ materially from those Amgen projects. Discovery or identification of new product candidates or development of new indications for existing products cannot be guaranteed and movement from concept to product is uncertain; consequently, there can be no guarantee that any particular product candidate or development of a new indication for an existing product will be successful and become a commercial product. Further, preclinical results do not guarantee safe and effective performance of product candidates in humans. The complexity of the human body cannot be perfectly, or sometimes, even adequately modeled by computer or cell culture systems or animal models. The length of time that it takes for Amgen to complete clinical trials and obtain regulatory approval for product marketing has in the past varied and Amgen expects similar variability in the future. Even when clinical trials are successful, regulatory authorities may question the sufficiency for approval of the trial endpoints Amgen has selected. Amgen develops product candidates internally and through licensing collaborations, partnerships and joint ventures. Product candidates that are derived from relationships may be subject to disputes between the parties or may prove to be not as effective or as safe as Amgen may have believed at the time of entering into such relationship. Also, Amgen or others could identify safety, side effects or manufacturing problems with its products after they are on the market.
Amgen's results may be affected by its ability to successfully market both new and existing products domestically and internationally, clinical and regulatory developments involving current and future products, sales growth of recently launched products, competition from other products including biosimilars, difficulties or delays in manufacturing its products and global economic conditions. In addition, sales of Amgen's products are affected by pricing pressure, political and public scrutiny and reimbursement policies imposed by third-party payers, including governments, private insurance plans and managed care providers and may be affected by regulatory, clinical and guideline developments and domestic and international trends toward managed care and healthcare cost containment. Furthermore, Amgen's research, testing, pricing, marketing and other operations are subject to extensive regulation by domestic and foreign government regulatory authorities. Amgen or others could identify safety, side effects or manufacturing problems with its products after they are on the market. Amgen's business may be impacted by government investigations, litigation and product liability claims. In addition, Amgen's business may be impacted by the adoption of new tax legislation or exposure to additional tax liabilities. If Amgen fails to meet the compliance obligations in the corporate integrity agreement between it and the U.S. government, Amgen could become subject to significant sanctions. Further, while Amgen routinely obtains patents for its products and technology, the protection offered by its patents and patent applications may be challenged, invalidated or circumvented by its competitors, or Amgen may fail to prevail in present and future intellectual property litigation. Amgen performs a substantial amount of its commercial manufacturing activities at a few key manufacturing facilities and also depends on third parties for a portion of its manufacturing activities, and limits on supply may constrain sales of certain of its current products and product candidate development. In addition, Amgen competes with other companies with respect to many of its marketed products as well as for the discovery and development of new products. Further, some raw materials, medical devices and component parts for Amgen's products are supplied by sole third-party suppliers. Certain of Amgen's distributors, customers and payers have substantial purchasing leverage in their dealings with Amgen. The discovery of significant problems with a product similar to one of Amge's products that implicate an entire class of products could have a material adverse effect on sales of the affected products and on its business and results of operations. Amgen's efforts to acquire other companies or products and to integrate the operations of companies Amgen has acquired may not be successful. Amgen may not be able to access the capital and credit markets on terms that are favorable to it, or at all. Amgen is increasingly dependent on information technology systems, infrastructure and data security. Amgen's stock price may be volatile and may be affected by a number of events. Amgen's business performance could affect or limit the ability of the Amgen Board of Directors to declare a dividend or its ability to pay a dividend or repurchase its common stock.
The scientific information discussed in this news release related to Amgen's product candidates is preliminary and investigative. Such product candidates are not approved by the U.S. Food and Drug Administration, and no conclusions can or should be drawn regarding the safety or effectiveness of the product candidates.
UCB Forward-Looking Statements
This press release contains forward-looking statements based on current plans, estimates and beliefs of management. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements, including estimates of revenues, operating margins, capital expenditures, cash, other financial information, expected legal, political, regulatory or clinical results and other such estimates and results. By their nature, such forward-looking statements are not guarantees of future performance and are subject to risks, uncertainties and assumptions which could cause actual results to differ materially from those that may be implied by such forward-looking statements contained in this press release. Important factors that could result in such differences include: changes in general economic, business and competitive conditions, the inability to obtain necessary regulatory approvals or to obtain them on acceptable terms, costs associated with research and development, changes in the prospects for products in the pipeline or under development by UCB, effects of future judicial decisions or governmental investigations, product liability claims, challenges to patent protection for products or product candidates, changes in laws or regulations, exchange rate fluctuations, changes or uncertainties in tax laws or the administration of such laws and hiring and retention of its employees. UCB is providing this information as of the date of this press release and expressly disclaims any duty to update any information contained in this press release, either to confirm the actual results or to report a change in its expectations.
There is no guarantee that new product candidates in the pipeline will progress to product approval or that new indications for existing products will be developed and approved. Products or potential products which are the subject of partnerships, joint ventures or licensing collaborations may be subject to differences between the partners. Also, UCB or others could discover safety, side effects or manufacturing problems with its products after they are marketed.
Moreover, sales may be impacted by international and domestic trends toward managed care and health care cost containment and the reimbursement policies imposed by third-party payers as well as legislation affecting biopharmaceutical pricing and reimbursement.
CONTACT: Amgen, Thousand Oaks
Trish Hawkins, 805-447-5631 (media)
Kristen Neese, 805-313-8267 (media)
Arvind Sood, 805-447-1060 (investors)
CONTACT: UCB, Brussels
France Nivelle, Global Communications, UCB
T +32.2.559.9178, firstname.lastname@example.org
Laurent Schots, Media Relations, UCB
Antje Witte, Investor Relations, UCB
T +32.2.559.94.14, email@example.com
Isabelle Ghellynck, Investor Relations, UCB