Withdrawal of the Application for a Change to the Marketing Authorisation for Denosumab

EMA announced that the application to extend the indication of denosumab to treat hypercalcaemia of malignancy has been withdrawn

On 13 January 2017, Amgen Europe BV officially notified the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) that it wishes to withdraw its application for denosumab (Xgeva) to be used to treat hypercalcaemia of malignancy.

Xgeva is a medicine used to prevent bone complications in adults with a solid tumour that has spread to the bone. These complications include fractures, spinal compression, or complications requiring radiotherapy or surgery.

Xgeva is also used to treat a giant cell tumour of bone in adults and adolescents whose bones have fully developed. It is used in patients who cannot be treated by surgery or in whom surgery would cause severe problems.

Xgeva has been authorised since July 2011. It contains the active substance denosumab and is available as a solution to be injected under the skin.

Xgeva was also expected to be used to reduce hypercalcaemia of malignancy that did not respond to previous treatment with bisphosphonates.

The active substance in Xgeva, denosumab, is a monoclonal antibody, a protein that has been designed to recognise and attach to RANKL. RANKL is involved in activating osteoclasts. By attaching to and blocking RANKL, denosumab reduces the formation and activity of the osteoclasts. This reduces the loss of bone, making fractures and other serious bone complications less likely to happen, and also lowers calcium levels in the blood.

To support the application, the company presented the results of a study involving 33 patients with hypercalcaemia. Xgeva was not compared with any other treatment in this study. The main measure of effectiveness was based on the number of patients who had a response to treatment, defined as having their blood calcium levels reduced to 2.9 mmol/l or lower within 10 days of the first dose.

The application was withdrawn after the CHMP had evaluated the initial documentation provided by the company and formulated a list of questions. The company had not yet responded to the questions at the time of the withdrawal.

Based on the review of the data, at the time of the withdrawal the CHMP had some concerns and was of the provisional opinion that Xgeva could not have been approved for the treatment of hypercalcaemia caused by cancer and which did not respond to treatment with bisphosphonates.

The CHMP considered that there were several problems with the main study which did not allow the Committee to conclude on the effectiveness of Xgeva: the study did not compare Xgeva with any other treatments and only included a small number of patients; it was not certain whether the patients’ condition had responded to bisphosphonates, as the patients’ previous calcium levels were not available. Additionally, since patients were being treated with other hypercalcaemia treatments or had recently stopped treatment with bisphosphonates, it was not possible to determine the scale of the effect or whether

the benefits observed in the study were due to Xgeva or were the effects of these other treatments. Therefore, at the time of the withdrawal, the CHMP was of the opinion that the results of the study were not sufficient and concluded that the medicine could not have been approved based on the data presented by the company.

In its letter notifying the Agency of the withdrawal of application, the company stated that it was withdrawing the application because the CHMP considered the data provided insufficient to conclude that the benefits of Xgeva outweighed its risks in the treatment of hypercalcaemia caused by cancer.

The company informed the CHMP that there are currently no ongoing clinical trials or compassionate use programmes with Xgeva. There are no consequences for the use of Xgeva in its authorised indications.