EMA’s CHMP Offers Negative Opinion for Sickle Cell Drug Approved by US FDA

Regulatory NewsRegulatory News | 29 May 2019 |  By 

In a sign that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) is being more cautious than the US Food and Drug Administration (FDA), CHMP on Wednesday adopted a negative opinion recommending the refusal of a marketing authorization for Emmaus’s sickle cell disease drug Xyndari (glutamine).

The negative opinion follows FDA’s decision to approve the drug (known by the brand name Endari in the US) almost two years ago and hail it as the first treatment in almost 20 years for the inherited blood disorder.

Whereas FDA said the approval was based on a trial showing that patients treated with Endari experienced fewer hospital visits for sickle cell crises, on average, when compared to placebo, EMA’s CHMP said it “considered that the main study did not show that Xyndari was effective at reducing the number of sickle cell crises or hospital visits.”

CHMP also noted how more patients in the study who were taking Xyndari than taking placebo dropped out of the study before it was finished, “and information on how the medicine worked for those patients was not available. The CHMP considered that the way data from these patients were dealt with was not appropriate.”

In 2018, CHMP also adopted negative opinions for two medicines approved by FDA in 2017 — Dexxience (betrixaban) to prevent venous thromboembolism and Eladynos (abaloparatide) for the treatment of postmenopausal women with osteoporosis at high risk for fracture.

ALS Drug Application Withdrawn

Like Xyndari, CHMP also raised questions with Mitsubishi Tanabe Pharma’s Radicava (edaravone), a treatment for amyotrophic lateral sclerosis (ALS), and the company withdrew its application to market the drug.

FDA, however, approved Radicava in May 2017, saying that individuals in a trial of 137 ALS patients in Japan receiving edaravone declined less on a clinical assessment of daily functioning compared to those receiving a placebo.

And although CHMP agreed with FDA on the trial’s rating scale findings, CHMP said, “There was not enough evidence of improvements in other important measures, such as those related to survival, breathing and muscle strength.”

CHMP also noted differences between the placebo and treatment groups, “which could have influenced the final results – such as the fact that a higher number of patients in the Radicava group had less severe disease.
When patients in the placebo group were later switched to Radicava there was no noticeable effect.

“CHMP was also concerned about the duration of any benefits from Radicava, noting that 24 weeks (a cut-off point in the main study) was too short and that data from the extension phase of the study were difficult to interpret,” the agency said.

Mitsubishi said in a statement: "We believe it is not in the patient’s best interest to place a person who has a rapidly progressive, fatal disease on a placebo when edaravone already has been shown in a clinical trial to slow the loss of physical function by a 33 percent change in slope of the ALSFRS-R. 
"An additional one-year placebo-controlled clinical trial investigating survival, which is required for EMA regulatory approval, was not a requirement for approval in other countries including Japan, South Korea, United States, Canada, and Switzerland," the company said.

In addition to Radicava, Zentiva decided to withdraw its marketing application for its generic version of ambrisentan, which was intended to treat pulmonary arterial hypertension. CHMP raised concerns about the manufacturing process for the generic drug, and the company cited additional investments as the reason for the application’s withdrawal.

Other CHMP Actions

In addition to the negative opinion and the withdrawn applications, CHMP recommended two new medicines (Univar's Cufence (trientine dihydrochloride) for the treatment of Wilson’s disease and Advanced Accelerator Applications' LysaKare (arginine/lysine) for protecting the kidneys against radiation during radioactive therapy with lutetium oxodotreotide) and two generic drugs for approval.

CHMP also began a review, at the request of the German medicines agency BfArM, on the effectiveness of medicines containing a combination of methocarbamol and paracetamol for the treatment of painful muscle spasms.

CHMP Meeting Highlights


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