The European Medicines Agency (EMA) has taken the first step to withdraw from the market Adakveo (crizanlizumab), an innovative monoclonal antibody from the pharmaceutical company Novartis approved in 2020 and indicated to prevent recurrent vaso-occlusive crises. These episodes, very painful and with a serious impact on health, affect people suffering from sickle cell disease, a rare genetic disease associated with high mortality.
The EMA has made the decision after knowing the results of new clinical trials, which reveal that the treatment is not effective in reducing the number of crises, in addition to having “serious” side effects, so that “its benefits do not outweigh the risks” . It was the EMA’s Committee for Human Medicines (CHMP), within its powers, that issued the recommendation, starting a process that in the coming weeks will end with a “binding decision” from the European Commission to withdraw the market drug.
Until the 1970s, patients suffering from this disease (also known as sickle cell anemia) used to die in their teens. Its cause is genetic and is characterized by the deformation of the red blood cells, which take on the appearance of a sickle (hence the name from the Latin root of the term). This anomaly hinders blood circulation and causes unpredictable and painful vascular obstructions that often require hospitalization and damage vital organs. The objective of Adakveo was to prevent these episodes and it was the first therapeutic novelty against the disease in two decades.
In Spain, according to data provided by Novartis at the launch of the drug, there are slightly more than 1,200 registered patients with the disease, although the number is rising for two reasons: improvements in diagnostic techniques and immigration (the disease is more prevalent among people of African and Middle Eastern origin).
In a statement, Novartis has shown its “disappointment” by the withdrawal, although it admits that the results of the new trial “do not comply with what is established” in the conditional approval that the EMA gave the drug in 2020. “There will be no new patients treated with crizanlizumab in the European Union. Medical professionals should assess with the patients who are currently taking it the available alternatives, ”says the company.
Adakveo has been an important bet for Novartis in recent years, a treatment that it aspired to turn into a blockbuster (medications that sell more than a billion euros in sales worldwide). The drug was first approved in November 2019 by the United States Medicines Agency (FDA) —which for now has not made a decision on the new results— and by the EMA in July 2020. The European Commission then authorized its marketing in the EU in October of that year (30 months ago).
Not all patients with sickle cell anemia in Spain were being treated with Adakveo because the Ministry of Health limited its public funding to only those patients intolerant of the other available treatments against the disease, the so-called cytoreducers. This is stated in the minutes of the meeting of the Interministerial Commission on the Price of Medicines in September 2022, which is when the drug was incorporated into public health. The reasons that led Health to make this decision were the uncertainty about the efficacy of the drug and its high price (close to 40,000 euros per patient and year, according to published official prices).
The initial approval of the Adakveo by the EMA in 2020 was conditional. This means that the Agency gives the green light to a medicine when the investigations are still in less advanced stages due to the good results obtained up to that moment and the need to offer new treatments to patients in diseases with few therapeutic alternatives available. This approval, however, is subject to new trials that confirm the first promising results, something in which the drug has now failed.
According to the EMA, the STAND study – carried out by Novartis at the request of the Agency and which has compared the efficacy and safety of Adakveo with placebo – has shown that the drug “did not reduce the number of painful crises”, on the contrary, these were more frequent among the patients who took it. “Patients treated with Adakveo had a mean of 2.5 painful crises with a subsequent medical visit during the first year of treatment, compared to 2.3 crises in the placebo group. In addition, the average number of crises requiring a medical visit or home treatment was 4.7 with Adakveo compared to 3.9 with placebo.
The EMA has also focused on the safety of the drug: “In terms of safety, the STAND study did not raise new concerns, but did show a higher rate of serious treatment-related side effects with Adakveo compared to placebo.”
Regarding the contradiction between the data that led to the approval of the medicine less than three years ago and the current ones, which lead to its withdrawal, the Agency states: “At the time of marketing authorization, the data showed that Adakveo was effective in reducing the number of painful crises in patients with sickle cell disease. However, the data was limited and there was some uncertainty about the magnitude of the drug’s effect. Therefore, the EMA requested the STAND study as a condition for the marketing authorization of Adakveo, which was granted in October 2020. As the results of the STAND study do not confirm the benefits previously observed with Adakveo, the CHMP has reached the conclusion that the benefits do not outweigh the risks and recommends the revocation of its authorization in the EU”.