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

Application for a new indication was foreseen for nilotinib in patients with Ph+ CML in whom imatinib has not led to a complete molecular response

On 21 May 2014, Novartis Europharm Ltd officially notified the European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) that it wishes to withdraw its application for a new indication for nilotinib (Tasigna) to treat patients with Philadelphia-chromosome-positive (Ph+) chronic myelogenous leukaemia (CML) in whom treatment with imatinib has not led to a complete molecular response.

Tasigna is a cancer medicine that contains the active substance nilotinib. It is available as capsules (150 and 200 mg). It has been authorised in the EU since 19 November 2007. It is used to treat CML in patients who have the Ph+ CML. It is used to treat the chronic and accelerated phases of CML in patients who have not responded to other treatments, including imatinib, or when they cannot tolerate these treatments. It is also used to treat newly diagnosed patients with CML in the chronic phase. It was designated an orphan medicine, a medicine to be used in rare diseases on 22 May 2006 for CML.

What was nilotinib expected to be used for?

Nilotinib was also expected to be used to treat adults with Ph+ CML in the chronic phase in whom treatment with imatinib did not lead to a complete molecular response.

A complete molecular response is achieved when Bcr-Abl can no longer be detected in the patient’s blood. This would have meant that patients who had only partially responded to treatment with imatinib could have been switched to nilotinib.

How is nilotinib expected to work?

In the new indication, nilotinib was expected to work in the same way as it does in its existing indications. The active substance in Tasigna, nilotinib, is a tyrosine kinase inhibitor which acts by blocking Bcr-Abl kinase, an abnormal enzyme which is produced by leukaemia cells and causes them to multiply uncontrollably. By blocking Bcr-Abl kinase, nilotinib helps to control the multiplication of leukaemia cells.

What did the company present to support its application?

The company presented the results from one main study with nilotinib involving 207 patients with Ph+ CML in the chronic phase and who did not have a complete molecular response following imatinib treatment for at least two years. Patients in the study either received nilotinib or had further treatment with imatinib. The main measure of effectiveness was based on the percentage of patients who had a complete molecular response during the first 12 months of the study.

How far into the evaluation was the application when it was withdrawn?

The application was withdrawn after the CHMP had evaluated the documentation provided by the company and formulated lists of questions.

What was the recommendation of the CHMP at that time?

Based on the review of the data and the company’s response to the CHMP lists of questions, at the time of the withdrawal, the CHMP had some concerns and was of the provisional opinion that nilotinib could not have been approved for the treatment of patients with Ph+ CML who did not have a complete molecular response following imatinib treatment.

This was because the study failed to demonstrate that treatment with nilotinib significantly increased the percentage of patients who had a complete molecular response by 12 months.

In addition, it was unclear how a complete molecular response would translate into an improvement of patient’s outcome.

The CHMP was also concerned that the dose of imatinib that was used in the study may have been too low.

Regarding safety, more side effects were reported with nilotinib than with imatinib.

Therefore, at the time of the withdrawal, the CHMP was of the opinion that the benefits of nilotinib in this new indication did not outweigh its risks.

What were the reasons given by the company for withdrawing the application?

In its letter notifying the Agency of the withdrawal of application, the company stated that the withdrawal was due to the fact that data gathered so far are insufficient for the CHMP to recommend approval of the new indication.

What consequences does this withdrawal have for patients in clinical trials or compassionate use programmes?

The company informed the CHMP that there are no consequences for patients currently included in clinical trials using nilotinib.

What is happening with nilotinib for the treatment of other diseases?

There are no consequences on the use of nilotinib in its authorised indications.