ESC 2016: Portola Announces Positive Interim Results from ANNEXA-4 Study.
By Jack Allen, Analyst
8 September 2016
I am an analyst at Datamonitor Healthcare based in the New York office, where I am currently a member of the cardiovascu...
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On 30 August 2016, Portola Pharmaceuticals presented interim data at the European Society of Cardiology (ESC) Congress from the ANNEXA-4 study of Andexxa (andexanet alfa; Portola Pharmaceuticals) in patients with acute major bleeds. The data presented were from the first 67 patients enrolled in the trial (of whom 47 were evaluated for efficacy). Of the 67 patients investigated, 32 were receiving Xarelto (rivaroxaban; Bayer/Johnson & Johnson), 31 were receiving Eliquis (apixaban; Bristol-Myers Squibb/Pfizer), and four were receiving widely genericized enoxaparin. The primary sites of bleeding were gastrointestinal (33 patients; 49%) and intracranial (28 patients; 42%), with other bleeding sites in six patients (9%).
In order to be included in the efficacy population (n=47), patients were required to have a baseline value for anti-factor Xa activity of at least 75ng per milliliter. Following the administration of Andexxa, median anti-factor Xa activity was found to decrease by 89% from baseline in Xarelto patients and by 93% in Eliquis patients. An independent adjudication committee determined that 79% of the patients in the efficacy population achieved excellent or good hemostasis. Although it is difficult to assess the clinical benefit without a control group, the results of Andexxa’s single-arm clinical study appear encouraging.
On 17 August 2016, Portola Pharmaceuticals received a complete response letter (CRL) from the US Food and Drug Administration (FDA) in response to its initial Biologic License Application for Andexxa. The FDA cited both clinical and manufacturing concerns in its rejection of Andexxa. The clinical concerns raised by the FDA included a need for additional data supporting the efficacy of the antidote in patients taking edoxaban and enoxaparin, and for additional analysis of the ANNEXA-4 trial. Given the small number of patients enrolled in the ANNEXA-4 trial that were receiving enoxaparin, it is unlikely that the results presented at the ESC Congress will enable Portola to prove efficacy in this patient population. However, the positive ANNEXA-4 data should help to support the approval of Andexxa when Portola resubmits to the FDA.
In the CRL, the FDA also highlighted the need for the validation of quality assays during the antidote’s manufacturing process. In a conference call accompanying the ESC data presentation, Portola officials noted that they had not spoken with the FDA since the CRL, but expect that they will need four to five months to answer the assay validation questions. The company went on to state that it tentatively expects that approval of Andexxa may occur within the next year.
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