March 22nd, 2013
Europe and U.S. Diverge on Two New Drugs
Larry Husten, PHD
The U.S. FDA and Europe’s Committee for Medicinal Products for Human Use (CHMP) have taken opposite views of two important and controversial new cardiovascular drugs. Although earlier this month the FDA rejected — for the second time — an ACS indication for the oral anticoagulant rivaroxaban (Xarelto), CHMP announced today that it had adopted a positive opinion for the same indication. In contrast, although the FDA recently approved the new cholesterol-lowering agent mipomersen (Kynamro, Isis and Genzyme), CHMP, after reviewing its previous negative position, reaffirmed today that it would not recommend approval of the drug in Europe.
CHMP said it was recommending approval of a new, low dose of rivaroxaban for the following indication:
Xarelto, co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers.
The new indication would join the already-approved indications for higher doses of rivaroxaban for the prevention of venous thromboembolism (VTE) in patients undergoing elective hip or knee replacement surgery, for the treatment of (and prevention of recurrent) DVT and PE, and for stroke prevention in patients with atrial fibrillation. The new indication is based on results from the highly praised, but also much-criticized, ATLAS ACS 2-TIMI 51 trial.
Janssen recently announced the launch of a large expanded research program with rivaroxaban. The EXPLORER program will test new potential indications for rivaroxaban in heart failure, coronary artery disease, peripheral disease, and atrial fibrillation.
By contrast, despite the FDA’s recent approval of mipomersen, CHMP said that its earlier concerns about mipomersen remained unresolved. Some patients in Europe will be able to receive the drug, either because they are in clinical trials or through a compassionate use program. Here is the CHMP explanation for the mipomersen refusal:
What were the CHMP’s main concerns that led to the refusal?
In December 2012, the CHMP was concerned that a high proportion of patients stopped taking the medicine within two years, even in the restricted group of patients with homozygous familial hypercholesterolaemia, mainly due to side effects. This was considered an important limitation because Kynamro is intended for long-term treatment. The CHMP was also concerned by the potential long-term consequences of liver test results showing a build-up of fat in the liver and increased enzyme levels, and was not convinced that the company had proposed sufficient measures to prevent the risk of irreversible liver damage. Moreover, the Committee was concerned that more cardiovascular events (problems with the heart and blood vessels) were reported in patients taking Kynamro than in patients taking placebo. This prevented the CHMP from concluding that Kynamro’s intended cardiovascular benefit, in terms of reducing cholesterol levels, outweighed its potential cardiovascular risk. Therefore, at that point in time, the CHMP was of the opinion that the benefits of Kynamro did not outweigh its risks and recommended that it be refused marketing authorisation.
During the re-examination in March 2013, the CHMP’s concerns remained unresolved and were not fully addressed by measures proposed by the company. Therefore, the CHMP refusal was confirmed after re-examination.
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