ARCH CV Signal Scuppers Blockbuster Hopes For Amgen/UCB's Evenity
Executive Summary
New Phase III data for the novel osteoporosis therapy romosozumab are set to delay its approval, reduce its commercial potential and open the market to rivals.
A cardiovascular safety signal has overshadowed positive efficacy data for Amgen Inc./UCB SA's first-in-class osteoporosis therapy Evenity (romosozumab) in the 4,000-patient Phase III ARCH study, and is expected to push back its US approval by at least a year and reduce its blockbuster potential.
The setback follows the failure of Merck & Co. Inc.'s odanacatib last year on a stroke risk and leaves major rival Radius Health Inc.'s newly approved Tymlos (abaloparatide) with a clearer run of the novel anabolic osteoporosis drugs market. (Also see "Radius Prices Osteoporosis 'Blockbuster' Tymlos To Compete, Grow Market" - Scrip, 1 May, 2017.)
Evenity, a monoclonal antibody against sclerostin (see box), is already under review in the US, Canada and Japan, based largely on the results of the FRAME study reported in 2016 but the companies readily admit that approval is now unlikely to come this year (its current PDFUA target date is 19 July). Amgen had already agreed with the FDA that the ARCH data should be considered in the regulatory review prior to the initial marketing authorization.
Analysts at Leerink believe it is prudent to expect a full data review and re-submission to take at least three months, and then to trigger a new regulatory review cycle, delaying approval until mid-2018, or later. They have reduced their odds of eventual approval to 50:50, somewhat lower than analysts at Credit Suisse who now reckon the drug has an 80% chance of success, down from 100%.
A planned EU filing in the second half of this year remains unaffected, however.
How does it work?
Evenity is a novel humanized monoclonal antibody therapy targeting the osteocyte produced protein sclerostin, which inhibits bone formation in osteoblastic cells. As such, Evenity has an anabolic effect and is being developed as a treatment for postmenopausal women with osteoporosis. Sclerostin is a key part of the negative feedback loop that acts to control the activity of osteoblastic cells.
It is hypothesized that by inhibiting the activity of sclerostin as opposed to the activity of osteoclasts or osteoblasts directly, Evenity acts to uncouple the bone formation and bone resorption processes. This prevents the rebound increase in osteoclastic bone resorption that can be seen when parathyroid or parathyroid hormone-related peptides are used. This has been illustrated in both animal and human studies.
The ARCH data do at least provide reassurance over Evenity's efficacy profile – after the 7,810-patient FRAME fell short in this respect – by hitting both primary endpoints and a key secondary endpoint in a more advanced population. FRAME missed its secondary endpoint of reductions in non-vertebral fractures.
In ARCH, Evenity therapy for 12 months followed by alendronate significantly reduced the incidence of new vertebral fractures through 24 months (50% relative risk reduction), clinical fractures (27% relative risk reduction), the two primary endpoints, as well as non-vertebral fractures (a key secondary endpoint) in postmenopausal women with osteoporosis at high risk for fracture, compared with alendronate alone.
But the top-line ARCH results revealed an unexpected 2.5% incidence of serious cardiovascular adverse events with the investigational product, compared with 1.9% in the comparator arm testing alendronate.
This signal was not seen in FRAME but was in another smaller study in 245 men, called BRIDGE. Data from this trial presented at the ACR meeting in November showed that the patient incidence of positively adjudicated cardiovascular serious adverse events was 4.9% percent in the romosozumab group and 2.5% in the placebo group, although for cardiovascular death, the incidence was just 0.6% in the romosozumab group and 1.2% in the placebo group.
Theoretical Risks
Overall. the CV side-effect data seem to lend some weight to concerns stemming from a theoretical risk of vascular calcification with the product, which it is suggested could accelerate atherosclerosis. In a pessimistic case, the companies may need to conduct further studies to address this uncertatiny.
However, analysts at Credit Suisse are downplaying the risk. "Sclerostin is expressed in the vasculature and is a master regulator in mineralization, but there is no conclusive evidence of its role in the vasculature. We looked through the literature and it seems fairly inconclusive that inhibiting sclerostin leads to CV events in normal patients."
And analysts at Deutsche Bank point out that physicians' dismay at the odanacatib loss could work in Evenity's favor at the regulators. Merck & Co's decision to terminate odanacatib because of a 36% increased stroke risk in the Phase III LOFT disappointed some physicians when the full data were presented at the ASBMR meeting because the absolute numbers were small and there is significant need for novel treatments, they note.
"As a result, we believe regulators are likely to be amenable to a restricted approval that would likely lead to Evenity being approved but with a Black box warning for cardiovascular risk," the analysts said. "Unfortunately, this is likely to negatively limit the drug's commercial potential, particularly given that cardiovascular outcome trials are unlikely to be feasible and the highest risk osteoporosis patients are also likely to be those most at risk of cardiovascular events."
All in all, sales forecasts for the product have tumbled. Before the ARCH update, consensus forecasts had Amgen’s romosozumab revenue growing to $446m by 2020, and then to $975mm by 2025.
Leerink analysts said prior to ARCH, they had forecasted total romosozumab revenue to Amgen of $18m in 2107E, growing to $282m in 2020E and a peak of $552mm in 2024E.