Balancing the risks and benefits of biologic drugs in rheumatic disease: the case for romosozumab?

The paper by Adami and colleagues (an informal group of senior European rheumatologists) published in this journal¹ should reassure regulators that specialists managing patients with rheumatic diseases are very familiar with how to mitigate risk using approved biologic drugs in the management of their patients; The paper highlights mitigating techniques used in the case of antitumour necrosis factor therapies in the management of inflammatory arthritis while even in the field of osteoporosis, rheumatic disease specialists are well aware of risk mitigation with denosumab.

Adami and coworkers highlight the case for romosozumab, outlining possible risk mitigation approaches to avoid the potential risk of cardiovascular events which were demonstrated in one of the two phase III trials undertaken to underpin an application for registration. In 2013, we published in this journal a review showing the potential value of sclerostin antibodies in the management of osteoporosis² and followed that 5 years later, showing how that potential had been met in three phase III trials.³ Two large trials with several thousand postmenopausal women demonstrated superior efficacy on improving bone mineral density (BMD) and reducing fracture rates compared with placebo⁴ and alendronate.⁵ The latter report was the first randomized controlled trial in postmenopausal women to demonstrate superiority in fracture reduction of a drug over an active comparator, although subsequently, teriparatide was demonstrated as superior to risedronate in preventing new vertebral fractures.⁶ The summation from these two trials give support to the view that, in those with incident vertebral fractures and thus high risk of immediate subsequent fracture, an anabolic agent should be considered early rather than using an antiresorptive agent first. The 12-month Structure study comparing the value of teriparatide with romosozumab demonstrated a trend to higher BMD changes at the spine with romosozumab, and significantly greater increase in total hip BMD.

If superiority of one agent over another has been proven, it is important to ensure that there is no imbalance in adverse events. With romosozumab in the three phase III trials, the adverse events were generally balanced between the arms but the exception was a numeric imbalance in serious adverse effects affecting the cardiovascular system in the romosozumab/alendronate trial during the first 12 months of the study in those receiving romosozumab, an imbalance which had largely reversed after 24 months of the trial, although, of course, patients only received romosozumab during the initial 12 months.⁵ This finding, which was not found in the romosozumab/placebo trial,⁴ remains unexplained.

It is interesting to reflect on how regulators recognize and manage these risks. Romosozumab has been approved by regulators for use in severe postmenopausal osteoporosis in Australia, Canada, Japan, South Korea and the USA. The US Food and Drug Administration approval for use of the drug in postmenopausal women at high risk of fracture⁷ came with a black-box warning on the potential risk of myocardial infarction, stroke and cardiovascular death but gave prescribers methods of mitigating risk. The European Medicines Agency (EMA) took a different view of the same data and refused marketing authorization in June 2019⁸ indicating that the benefits of treatment did not outweigh its risks.

However, following a re-examination procedure, the EMA’s Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for the use of romosozumab, for the ‘treatment of severe osteoporosis in postmenopausal women at high risk of fracture’.⁹ Accordingly, imminent marketing authority is awaited, along with details of any restrictions for use being highlighted in the summary of product characteristics. It seems likely, therefore, that we can expect, as proposed by the CHMP, that treatment will be initiated and supervised by specialist physicians experienced in the treatment of osteoporosis. Balancing the risk and benefits of romosozumab will, thus, become specialist responsibility, as argued by Adami and colleagues.¹