This article is provided to FT.com readers by Pharmawire—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.pharmawire.com
--------------------------------------------------------------------------------------------------------

Bayer and Johnson & Johnson’s new oral Factor Xa anticoagulant, rivaroxaban, has shown superiority over Sanofi-Aventis’ Lovenox (enoxaparin), but the agent is still under close watch for potential liver toxicity concerns, according to physicians interviewed by Pharmawire.

AstraZeneca’s Exanta, an orally active direct thrombin inhibitor, was pulled off the market in 2006 due to concerns over liver toxicity and a report of serious liver damage. There have been safety concerns over potential liver toxicity concerns with oral anticoagulants in general, following on from Astrazeneca’s failure in 2006, physicians said.

Dr Alexander Turpie, Principal Investigator in the RECORD program and Professor of Medicine at McMaster University in Canada said in the short-term, there is no evidence of ongoing liver toxicity.

”We do see elevation of liver enzymes, but it is not higher than the enoxaparin arm. The levels go back to normal,” said Turpie.

Although there is no hard evidence of liver toxicity in short-term use of rivaroxaban, Turpie added that there has to be careful rigorous evaluation of the potential for elevated liver enzymes.

The elevated liver enzymes in the Lovenox arm were benign. The question now remains whether elevated liver enzymes in the rivaroxaban arm are also benign - and more data is needed.

However, similar to other drugs in this class, rivaroxaban has not been plagued by an increased risk in bleeding. According to data presented at the American Society of Hematology meeting in Atlanta, Bayer’s new oral anticoagulant showed no increased risk of bleeding.

In the RECORD-1 study, there was a 70% relative risk reduction in patients on Bayer’s rivaroxaban in total venous thromboembolism when compared with Sanofi’s Lovenox - and a 88% relative risk deduction in major VTE. In RECORD-3, a trial evaluating knee-replacement patients, rivaroxaban showed a 49% vs. 62% improvement in reduction of major clots.

Bayer’s rivaroxaban, if approved, has the potential to revolutionize treatment and change clinical practice across many indications.

Dr Louis Kwong, an orthopedic surgeon at Harbor-UCLA Medical Center in Los Angeles said there has been a consistent cry for simple and effective anticoagulants, as there has not been a new agent approved in the last three decades.

”It is far more preferable for patients to take an oral agent such as rivaroxaban for 3-4 weeks instead of injectables,” said Kwong. The approval of this agent will have a great impact on changing the current treatment.

Dr Sylvia Haas, an investigator on the RECORD trials, said the company is also conducting studies evaluating this agent into other indications such as the treatment of DVT (deep vein thrombosis) and stroke prevention.

Rivaroxaban has a goal to replace the current standard of treatment with injectables (such as low molecular weight heparin), but also the oral vitamin-K antagonists.

Dr Frank Misselwitz, an investigator and head of the cardiovascular therapeutic area in Global Clinical Development at Bayer HealthCare said the once-daily dose of rivaroxaban versus the twice daily dosing competitor Bristol-Myer’s has selected for its anticoagulant, apixaban, ultimately comes down to a question of a difference in pharmacokinetic profile between these two agents.

With regards to Bristol-Myer’s apixaban, Misselwitz said after the failure of Exanta, ”they obviously want to catch up.” He also added that BMS has ”less Phase II data” compared to Bayer’s rivaroxaban program.

Bayer conducted large Phase II programs and four individual trials. ”We did tests for twice daily dosing versus once-daily. It was a data driven decision,” he said. ”We selected what was the best approach, based on data. There was no safety disadvantage,” he added.

The higher peak does not correlate with lower safety. However, he added that the ”clinical data needs to be reviewed.”

The atrial fibrillation (AF) trial is the longest trial, and is continuing patient enrollment until next year - with a target of 14,000 patients.

”All trials are event driven trials,” added Misselwitz. As they are event driven trials, he could not give a time frame for the ongoing trial.

”We are indeed very confident. Now it’s clear we don’t have dose dependency compared to enoxaparin (Lovenox),” said Misselwitz. He added that in the two remaining cases, there was some concern, but in both cases, the liver advisory panel ruled that the elevated liver enzymes were related to the enoxaparin arm.

The final proof will be in the chronic data. Bayer will conduct post-marketing safety studies on this agent, and is rapidly enrolling another large trial for ACS (acute coronary syndromes).

It will be key to see rivaroxaban’s safety profile on top of dual-platelet inhibition, added Misselwitz.

--------------------------------------------------------------------------------------------------------

For more information or to inquire about a trial please email sales@pharmawire.com or call Americas: +1 212-500-1384 or Europe: + 44 (0)20 7059 6251