EU OKs Liraglutide in Kids; Rejects Romosozumab for Osteoporosis


June 28, 2019

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended granting an extension of indication to the GLP-1 agonist liraglutide (Victoza, Novo Nordisk) so as to include the treatment of children and adolescents aged 10 years or older who have type 2 diabetes.

This follows a similar recent decision in the United States, where the drug was formally approved for this additional indication. In both instances, liraglutide is the first noninsulin drug recommended for approval or to have been approved for treating pediatric type 2 diabetes in almost 20 years.

Liraglutide, which is a subcutaneous injectable GLP-1 agonist, has been available for treating adults with type 2 diabetes for almost a decade.

Separately, the EMA has recommended refusal of marketing authorization for the humanized monoclonal antibody romosozumab (Evenity, Amgen), a medicine intended for the treatment of osteoporosis.

This decision is in contrast to that of the US Food and Drug Administration (FDA), which in April approved romosozumab for the treatment of osteoporosis in postmenopausal women who have a history of osteoporotic fracture or multiple risk factors for fracture, or those who have failed to respond to or are intolerant of other osteoporosis therapies.

The EMA said: "The Agency's opinion was that the benefits of Evenity did not outweigh its risks and it recommended refusing marketing authorization."

Type 2 Diabetes in Adolescents Is a More Aggressive Disease

Although type 2 diabetes was previously considered a condition primarily of older adults, incidence has been increasing in young adults and children, as described recently by physicians at the American Diabetes Association conference, in what they characterized as "alarming" and "scary" trial findings from both the TODAY 2 and RISE studies.

The RISE study shows that neither metformin nor insulin appears to work well in pediatric type 2 diabetes, which seems to be a much more aggressive disease than type 2 diabetes in adults. So there is a big unmet medical need for alternative treatments for children and adolescents with type 2 diabetes.

According to the World Health Organization, in some parts of the world, type 2 diabetes has now overtaken type 1 diabetes as the main type of diabetes diagnosed in children and adolescents.

The FDA approval and the positive opinion from the CHMP were granted on the basis of data from the Efficacy and Safety of Liraglutide in Combination With Metformin Compared to Metformin Alone, in Children and Adolescents With Type 2 Diabetes (ELLIPSE) trial. This study was presented in April 2019 at the Pediatric Academic Societies meeting and was simultaneously published online in the New England Journal of Medicine.

At the time, ELLIPSE lead investigator William V. Tamborlane, MD, of Yale University, New Haven, Connecticut, told Medscape Medical News that the study was "practice changing" because "metformin fails quickly as monotherapy in type 2 diabetes kids, and insulin is the only second-line drug approved for kids with type 2 diabetes."

The EMA said the recommended treatment for pediatric type 2 diabetes is "similar to that in adults, with emphasis on a step-wise approach starting with lifestyle modifications, particularly healthy eating and exercise, followed by the use of a single medical therapy and later by two therapies in combination."

The opinion adopted by the CHMP is an intermediary step on Victoza's path to patient access for this new indication, which will now be sent to the European Commission (EC) for the adoption of a decision on an EU-wide marketing authorization within about 60 days. Such EC authorization is normally a formality. Once it has been granted, decisions about price and reimbursement will take place within each EC member state.

Romosozumab Rejected Owing to CV Safety Concerns and Deaths in the Elderly

Romosozumab inhibits sclerostin, a protein expressed in osteocytes. The main function of sclerostin is to block bone formation. One dose of romosozumab consists of two injections, one immediately following the other, given once a month. The bone-forming effect of the drug wanes after a year, so more than 12 doses should not be used.

Earlier this year, the FDA's Bone, Reproductive and Urologic Drugs Advisory Committee voted 18-1 in favor of romosozumab for the treatment of osteoporosis in postmenopausal women who are at high risk for osteoporotic fracture or for those who have failed to respond to or are intolerant of other osteoporosis therapies, as reported by Medscape Medical News. The FDA approved the agent on the basis of this recommendation.

But on its first pass for approval in July 2017, the FDA rejected romosozumab and requested more data on cardiovascular risk. The risk for cardiovascular events is now included in a black box warning on the US label for romosozumab.

The EMA said it is "concerned" because trial results suggest that patients given the agent have an increased risk for serious cardiovascular events, such as heart attacks or strokes.

In addition, "when all the data were looked at together, there were more deaths in patients aged over 75 years given the medicine. As it was unclear why the medicine appeared to increase the risk of heart and circulatory problems, and there was no obvious group of patients in whom the risk of these was lower, measures to reduce the risk could not readily be put in place," the EMA stated.

However, with respect to its beneficial effects, romosozumab was effective in reducing the risk for fracture in patients with severe osteoporosis, although the benefit was not as convincing for patients with less severe disease, the agency noted.

Under the circumstances, the overall opinion was that the benefits did not outweigh the risks, the EMA concluded.

Follow Lisa Nainggolan on Twitter: @lisanainggolan1

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