After re-examining its initial opinion, the European Medicines Agency (EMA) has recommended approving the marketing authorisation for the medicine tagraxofusp (Elzonris) for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). EMA had initially refused the application on 23 July 2020 for Elzonris to be used for the treatment of BPDCN regardless of whether patients had been previously treated with other medicines or not. After re-examination, on 12 November 2020 the Agency recommended that marketing authorisation under exceptional circumstances could be granted, but for a restricted indication in patients who had not yet received any treatment for BPDCN.
The company that applied for authorisation is Stemline Therapeutics B.V.
Elzonris is a medicine that is to be used for treating adults with BPDCN, a rare and aggressive type of acute myeloid leukaemia. In BPDCN, the bone marrow produces large numbers of immature white blood cells called plasmacytoid dendritic cells. These build up in the bone marrow, taking the place of normal blood cells, and spread to the skin: most patients develop non-itchy damaged areas, which often look like bruises or nodules. The disease may also cause enlargement of the spleen or liver and a reduction of the number of circulating blood cells.
There is no approved treatment for BPDCN in the EU.
Elzonris was designated an orphan medicine (a medicine used in rare diseases) on 11 November 2015 for the treatment of BPDCN.
Elzonris will be available as a 1 mg/ml concentrate for solution for infusion. The active substance of Elzonris is tagraxofusp, an antineoplastic agent (ATC code: L01XX67). Tagraxofusp comprises a truncated diphtheria toxin fusion protein that is linked with recombinant human interleukin-3 (IL-3) to target CD123-expressing cells. Tagraxofusp irreversibly inhibits protein synthesis of target cells by inactivating elongation factor 2 (EF2), resulting in apoptosis.
To support its application, the company presented results from a single small study involving 84 adults with BPDCN that could not be treated in other ways. The main measure of effectiveness, which was recorded in a group of 13 patients receiving first-line treatment, was complete response after treatment or with just minimal skin damage remaining.
The main reasons for initially refusing the marketing authorisation were the Agency’s concern that due to the design of the study and the small number of patients involved, it was not possible to be sure how effective the medicine was in treating BPCDN. In addition, the medicine could cause capillary leak syndrome (an unpredictable, potentially life-threatening side effect due to increased permeability of small blood vessels), which had led to some fatal outcomes. Therefore, at the time of the initial refusal, the Agency’s opinion was that the benefits of Elzonris did not outweigh its risks and it recommended refusing marketing authorisation.
At the company’s request, the Agency re-examined its initial opinion. During the re-examination, the Agency looked at the available data and took additional advice from a group of experts specialising in haematological malignancies. EMA noted that although the study was small, the benefits shown are relevant for patients with this rare disease for which no treatment is available.
The benefits of Elzonris are that it can lead to complete response, with a rate (complete resolution of the disease [CR] or CR with residual skin abnormality not indicative of active disease) of 53.8% among 13 previously untreated patients. Patients who achieved a complete response with Elzonris were able to undergo allogeneic stem cell transplantation, which was successful and contributed to long survival for some patients.
The most common side effects are hypoalbuminaemia, increased transaminases, thrombocytopenia, nausea, fatigue and pyrexia observed in >20% pf patients. The most serious adverse reaction that may occur during treatment with Elzonris is capillary leak syndrome which was reported in 17% of patients with a median time to onset of 6 days.
The safety of Elzonris was considered acceptable with specific measures in place to minimise the risk of the most serious side effects.
After considering experts’ advice on the study results and the challenges of conducting larger studies for this rare disease, the Agency concluded that the benefits of Elzonris outweigh its risks in patients with BPCDN who had not yet received other treatments. However, the data from the group of patients in whom previous treatments did not work was not sufficient to draw the same conclusion. The Agency recommended granting a marketing authorisation for Elzonris under exceptional circumstances. This is because it was not possible to obtain complete information about Elzonris due to the rarity of the disease. To further characterise the effectiveness and safety of Elzonris, the company is required to submit the results of a study based on a registry of patients with BPCDN.
The full indication is: Elzonris is indicated as monotherapy for the first-line treatment of adult patients with BPDCN.
Elzonris should be administered under the supervision of a physician experienced in the use of anti-cancer agents.
Detailed recommendations for the use of this product will be described in the summary of product characteristics, which will be published in the European public assessment report and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.