Emmaus rescinds EU marketing application, following negative review
Two years ago, Emmaus Life Sciences secured FDA approval for its sickle cell disease (SCD) therapy — marking the first new approval for patients affected by the group of inherited red blood cell disorders that typically afflict those of African ancestry in two decades. But the European regulator was not satisfied with the dataset supporting the therapy — prompting its maker on Thursday to rescind its application.
Endari is a highly purified (pharmaceutical grade) version of the amino acid L-glutamine and was approved in July 2017 to reduce the severe complications that come with SCD. (Non-medical grade L-glutamine is available as a supplement over the counter).
The US approval was based largely on a 230-patient placebo-controlled study that ran for 48 weeks. Data showed patients on Endari experienced 25% fewer sickle cell crises, as well as a 33% drop in hospitalizations, compared to placebo. Additionally, patients on Endari spent fewer cumulative days in the hospital and experienced a lower incidence of acute chest syndrome.
In its assessment, the European regulator took issue with the number of dropouts in the study. The EMA’s Committee for Medicinal Products for Human Use (CHMP) said the main study on the therapy — christened Xyndari in Europe — did not show it was effective at reducing the number of sickle cell crises or hospital visits, due to the higher number of dropouts in the drug arm.
“(I)nformation on how the medicine worked for those patients (who dropped out) was not available. The CHMP considered that the way data from these patients were dealt with was not appropriate,” the agency said earlier this year.
A total of 156 patients completed the trial — 97 of 152 patients (63.8%) in the L-glutamine group and 59 of 78 patients (75.6%) in the placebo group, according to data published by Emmaus. “The reasons for discontinuation were similar in the two trial groups; the most common reasons were withdrawal of consent, ‘other’ reasons, and nonadherence,” the company wrote.
The EMA went on to flag concern about a small study used to support the application for the drug. Once again, many patients in this study dropped out early, the regulator underscored. “(I)n this study more of the patients taking Xyndari had received a medicine for sickle cell disease called hydroxyurea than patients taking placebo. This could have influenced the results.”
After its initial negative recommendation in May, Emmaus asked the EMA to review its data again in June, but the regulator stood by its original stance.
On Thursday, Emmaus — which was delisted from the Nasdaq earlier this month — disclosed it was withdrawing its European marketing application.
“Because we have demonstrated the efficacy of Xyndari, as supported by the data from the trials conducted, we are disappointed in the CHMP’s position,” chief Yutaka Niihara said in a statement.
However, Xyndari is currently supplied through early access programs based on named patient use in a number of EU member states, Turkey and the Middle East.
Meanwhile, Emmaus’ rivals in the United States are scrambling to get their SCD products on the market.
Global Blood Therapeutics $GBT unveiled positive pivotal data on its sickle cell disease drug in June — the once-daily pill voxelotor is designed to work by increasing hemoglobin’s affinity for oxygen. Novartis’ $NVS therapy for the blood disorder was granted a speedy review by the FDA in July — the monoclonal antibody, called crizanlizumab, is administered intravenously and engineered to bind to a molecule called P-selectin, one of the major drivers of the vaso-occlusive process. Other drugmakers, including Bluebird Bio, Imara, and partners CRISPR Therapeutics and Vertex, are also working on their own drugs.
Sickle cell disease patients have atypical hemoglobin molecules, which can distort red blood cells into a sickle, or crescent, shape. Symptoms such as anemia, repeated infections and periodic episodes of pain called vaso-occlusive crises (VOC) when sickle-shaped red blood cells get stuck inside blood vessels begin to appear in early childhood. These episodes deprive the body of oxygen-rich blood, which can culminate in widespread tissue and organ damage — particularly in the lungs, kidneys, spleen, heart, and brain — and drastically diminish life expectancy.
For now, bone marrow transplants offer the only potential cure for sickle cell anemia — but the procedure is not safe enough for patients older than 16 — besides securing a healthy donor is difficult and the risks can be life-threatening. Therefore, treatment is typically limited to avoiding crises, relieving symptoms and preventing complications. Hydroxyurea, a drug believed to stimulate the production of fetal hemoglobin, is often given daily to reduce the frequency of painful crises — but it increases the risk of infection, and the risks associated with long-term use are unclear.