ApoPharma's Ferriprox Clears FDA, But Needs Cardiac Safety Study

FDA's Oct. 14 accelerated approval of ApoPharma's second-line oral iron chelation therapy Ferriprox (deferiprone) includes a requirement that the sponsor conduct a post-marketing QT prolongation study, which the agency did not mention in background documents before the key advisory panel vote.

The approval is not surprising in light of severe unmet medical need for thalassemia patients and a 10-2 vote in favor of approval by the Oncologic Drugs Advisory Committee Sept. 14 (Also see "ApoPharma's Ferriprox Clears ODAC Based In Part On Dosing Convenience" - Pink Sheet, 14 Sep, 2011.).

While it is not unprecedented for FDA to impose a PMR for the sponsor to conduct a QT prolongation study after accelerated approval, neither is it inevitable.

The standard of care for thalassemia, an inherited blood disorder that the Cooley's Anemia Foundation estimates affects approximately 500 to 1,000 U.S. patients, is deferoxamine (Novartis' Desferal and generics). This drug is administered via subcutaneous or intramuscular infusion with a pump for some 10-12 hours five days each week, and patients may also need blood transfusions.

Ferriprox is available in 58 countries in tablet or oral solution form, and patient testimony during the ODAC meeting made it clear how important the dosing convenience is to many of them.

Moreover, according to the company, "the Thalassemia Clinical Research Network found that 30% of deferasirox patients and 25% of deferoxamine patients do not have their iron overload properly managed. As Ferriprox is approved as second line therapy, a portion of these patients may be prescribed Ferriprox."

Deferasirox, Novartis' Exjade, is an orally administered iron chelating agent, but its indication is different – it was approved in 2005 for the treatment of chronic iron overload due to blood transfusions in patients ages 2 and up (Also see "Novartis Exjade Clears FDA As First Oral Chelating Agent" - Pink Sheet, 2 Nov, 2005.).

Despite Ferriprox's evident advantages and extensive overseas approvals, at the ODAC meeting Richard Pazdur, director of FDA's Office of Hematology Oncology Products, expressed exasperation with ApoPharma for not doing the randomized, controlled trial the agency proposed in the November 2009 "complete response" letter.

Committee members made it clear post-marketing trials would need to be done. ApoPharma submitted the NDA in January 2009 and resubmitted in April of this year after the complete response letter, this time asking for second-, rather than first-line, approval.

Next Up, Sickle Cell Disease

The confirmatory trial for Ferriprox will be a study in sickle cell patients, with transfusional hemosiderosis patients also to be included. ApoPharma had already proposed a study before the advisory panel's vote (Also see "ApoPharma's Preemptive Safety Strategy For Ferriprox Includes Centralized Pharmacy Distribution" - Pink Sheet, 13 Sep, 2011.).

In this study, both sets of patients will receive Ferriprox as a second-line drug.

Estimates of the number of sickle cell disease patients in the U.S. are less precise than for thalassemia, ApoPharma said. According to some estimates, there are approximately 5,000 U.S. patients who may benefit from blood transfusions.

The QT prolongation study, though, comes as more of a surprise as a post-marketing requirement; not only didn't the agency mention this issue in its background documents, the advisory panel didn't discuss it either.

Even the two ODAC members who voted against recommending approval – Mikkael Sekeres of the Cleveland Clinic and William Kelly of Thomas Jefferson University – did not raise this issue, instead saying they were dissatisfied with the clinical data ApoPharma had presented.

Similar concerns led the advocacy group Public Citizen to call on FDA to reject Ferriprox, in a statement released two days before FDA announced the drug's approval.

Public Citizen highlighted the fact that ApoPharma had submitted data from a single trial at first, and charged that "the FDA subsequently acquiesced to pressure from ApoPharma and allowed the company to seek approval of deferiprone without conducting any additional prospective clinical studies. Instead, the agency granted accelerated approval status for the drug based solely on a retrospective analysis of data from a subset of subjects enrolled in 12 previously conducted clinical trials of deferiprone that varied widely in their study designs."

“FDA approval of deferiprone based on such inadequate data would set a recklessly dangerous precedent for drugs reviewed under an accelerated approval process in the future,” said Michael Carome, deputy director of Public Citizen’s Health Research Group.

However, Pazdur made it clear at the ODAC meeting that the agency's prospective approval of the drug should not be considered a precedent.

While evidently reticent about approving Ferriprox, FDA does not appear to have placed more onerous post-marketing requests on the product than it has on other products recently given accelerated approval (see chart, (Also see "Keeping It Average: Post-Marketing Requirements and Commitments For Ferriprox" - Pink Sheet, 24 Oct, 2011.)).

The QT prolongation PMR may not come as a complete shock to ApoPharma, given Ferripox's effect on the heart. In Study LA16-0102, the single controlled trial the sponsor initially offered to support the NDA, the primary endpoint was cardiac MRI T2*, a measure of cardiac iron burden.

FDA had criticized that endpoint as not being of proven clinical meaningfulness, a critique that is reflected on the label: "Approval is based on a reduction in serum ferritin levels. There are no controlled trials demonstrating a direct treatment benefit, such as improvement in disease-related symptoms, functioning, or increased survival."

The label also bears a boxed warning about the risk of neutropenia and agranulocytosis and the need for monitoring for these conditions, which ODAC was very concerned about.

Marketing Plans Focus On Hemotologists

As it makes plans to conduct the PMCs and PMRs for Ferriprox, ApoPharma is also preparing for rollout. "The drug will be made available as soon as possible," the company said. The company said the product will be "competitively priced," and that marketing will be restricted to specialists.

"This medication is to be prescribed by hematology specialists, who will be our primary focus. … These are the specialists we will be seeing with our sales team. The size and structure of the team will be appropriate for the product and indication," the firm said.

"Given the limited population of treating specialists we will develop appropriate programs to ensure that health care professionals are well informed," the company added.

By Martin Berman-Gorvine