Bayer/J&J Attempt At New Lands For Xarelto Backfires With MAGELLAN
By Emily Hayes

NEW ORLEANS - A trial designed to expand the market for Bayer HealthCare/Johnson & Johnson's oral anticoagulant Xarelto (rivaroxaban) instead has highlighted that the drug has a worse bleeding profile than Sanofi-Aventis' low molecular weight heparin Lovenox (enoxparin) in patients hospitalized with acute illnesses.

A once-daily Factor Xa inhibitor, rivaroxaban is currently under review for stroke prevention in patients with non-valvular atrial fibrillation and for prevention of deep vein thrombosis and pulmonary embolism in patients undergoing knee and hip replacement surgery, following a recent resubmission answering a "complete response" letter from FDA ('Xarelto Back On Track, J&J Answers 'Complete Response' Letter And Files For Atrial Fibrillation,' 'The Pink Sheet' DAILY, Jan. 5, 2011). These are the bread-and-butter indications being targeted by a range of novel oral anticoagulants.

The MAGELLAN study tested rivaroxaban against subcutaneous Lovenox in a more unusual setting - patients hospitalized with severe illnesses like heart failure, acute respiratory disease and cancer. The aim was to see how the treatments stacked up for prevention of venous thromboembolism, including deep vein thrombosis and pulmonary embolism, in about 8,100 acutely ill patients.

Results were reported on April 5 at the American College of Cardiology meeting in New Orleans by Alexander Cohen, a vascular physician at King's College Hospital, London. Xarelto met the primary efficacy endpoints for VTE prevention, but failed when it came to the primary safety outcome, which was a composite of treatment-related major bleeding and clinically relevant non-major bleeding. Patients taking Xarelto had more bleeding events than those on Lovenox, researchers reported.

Dreams Of A Big Market

The potential patient population in seven major global markets for the acutely ill hospitalized indication is about 26 million, but only about half are treated, so this represents a very attractive potential target market for anticoagulants, with room for growth, Decision Resources analyst Matthew Killeen said in an interview.

Though Lovenox is the main treatment option for these patients, it does come with a higher risk of bleeding which can deter extended use in the acutely ill. The major trial of Lovenox in this setting, EXCLAIM, also showed efficacy but with a high rate of bleeding.

Still, Decision Resources estimates that the indication has accounted for an estimated 50% of the drug's total sales (thought to be mostly for short-term use), based on interviews with thought leaders and broker estimates. Lovenox enjoyed sales of €3 billion ($4.2 billion) in 2009, a figure that dipped in 2010 to €2.8 billion with the entry of generic competition. Decision Resources estimates that other drugs currently add another $160 million for the acutely ill indication.

The MAGELLAN trial assessed how the drugs performed based on typical short-term treatment, and whether treatment beyond this period after hospitalization would also have benefits for prevention of VTE.

In the study, patients were given Lovenox or Xarelto for six to 14 days during hospitalization. For the short-term comparison, rivaroxaban results were assessed at 10 days. Then placebo or rivaroxaban was given for an extended period up to 35 days and patients were followed to 90 days.

Xarelto demonstrated non-inferior efficacy to Lovenox after short-term treatment and superior efficacy over Lovenox/placebo for extended treatment, the investigators reported. Event rates in the study ranged from 2.7% to 5.7%, which is higher than some clinicians expected and suggests that treatment is needed in the patient population.

But the study also found that the enoxaparin group had a significantly lower rate of bleeding than the rivaroxaban group both after short-term treatment and at 35 days. Specifically, 1.2% of patients in the enoxaparin group experienced some kind of clinically relevant bleeding with short-term treatment, compared to 2.8% of patients on rivaroxaban. And at 35 days, 1.7% of enoxaparin patients had clinically relevant bleeding, compared to 4.1% of patients in the rivaroxaban group.

The researchers concluded that a consistent net clinical benefit with rivaroxaban could not be established in the heterogeneous population studied. Further sub-analyses will be done to see if certain segments of the population - for example, the sickest patients - actually did benefit.

Jeffrey Weitz, executive director of the Atherosclerosis and Thrombosis Research Institute at McMaster University and a member of the steering committee of ADOPT, a similar study using Bristol-Myers Squibb/Pfizer's apixaban, was not that surprised by the results.

He pointed out that longer-term use of a potent anticoagulant would generally be expected to increase the risk of bleeding rates as it was being compared to no treatment at all. Weitz actually found the bleeding rates in MAGELLAN to be low, but even so, it's "not going to cut it" in this indication - much like extended treatment with Lovenox has not become part of standard care for the medically ill because of the bleeding rates. Granted, as an injectable, Lovenox is also less convenient for extended treatment after hospitalization.

Also, more fundamentally, the population is very heterogeneous, with many different diseases and risk factors, and it's difficult to know which patients would actually benefit from extended treatment. That's why the acutely ill population is one of the more challenging indications for novel anticoagulants, Weitz commented.

Aside from bleeding, other adverse event rates were similar for the two treatment arms.

More Bleeding Than With Lovenox

The performance relative to Lovenox raised some competitive concerns about Xarelto's safety profile and impact on the pending regulatory reviews of the drug. The higher rate of bleeding with Xarelto versus Lovenox "is somewhat of a surprise" considering that previous trials of the drug in VTE prevention following surgery (RECORD-1 through -4) have not demonstrated a meaningful increased risk versus Lovenox, UBS analyst Richard Parkes observed in an April 5 note.

"This may reflect the more heterogeneous patient population and likely poor health status in MAGELLAN," Parkes wrote.

In an April 5 investors' call, Bayer HealthCare execs sought to reassure analysts that the negative safety findings in MAGELLAN would not affect the drug's profile in other more common indications, because the patient populations are vastly different.

Rivaroxaban could still one day find a role in treating acutely ill hospitalized patients if the sub-analyses pan out. There also could be geographic differences that explain the results because the trial patients came from 52 different countries. However, Credit Suisse analyst Catherine Arnold said, "based on today's data, we believe it will be difficult for the product to obtain regulatory approval in this indication."

Implications For Apixaban?

The results from MAGELLAN also raise questions about prospects for a positive outcome in trials of other anticoagulants in similar patient populations, in particular the ongoing Phase III ADOPT study of the Factor Xa inhibitor apixaban from Bristol and Pfizer.

The development program for apixaban has also eyed opportunities for reaching a bigger market. The drug tested successfully in patients deemed ineligible for warfarin in the AVERROES study. But a gamble on use as an add-on to antiplatelet therapy in patients with recent acute coronary syndrome ended after the Phase III APPRAISE-2 study was halted because of increased bleeding ('Bristol Study Halted But It May Not Cause Much Damage To The Program,' 'The Pink Sheet' DAILY, Nov. 19, 2010).

A negative result for rivaroxaban in acutely ill patients doesn't necessarily mean the ADOPT study of apixaban in a similar trial population is doomed. Apixaban is given two times a day and in theory this might result in less bleeding than a once-daily anticoagulant, such as rivaroxaban, Weitz commented.

In other VTE trials, apixaban was shown to have "a fairly decent bleeding profile with a trend towards less bleeding compared to Lovenox," Decision Resources' Killeen said.

But if apixaban can't get solid outcomes - at least non-inferior efficacy and comparable bleeding - in these patients, the chance of any other oral anticoagulant performing well in this setting is greatly diminished, Killeen concluded.

If the outcome is negative, the space will remain an area of high unmet need and in the near future, patients will continue to be mostly treated with Lovenox and generic enoxaparin, he said.

Return to In the News

thepinksheet.com