Boehringer Ingelheim likely to have regulatory submission for Pradaxa delayed

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Boehringer Ingelheim is likely to have to delay the regulatory submission for its potential new oral anticoagulant blockbuster Pradaxa (dabigatran) for atrial fibrillation (AF) patients. Clinicians interviewed by Pharmawire said that the German drug company will need to conduct additional examinations of the clinical data to search for possible explanations for an “unexpected” increase in myocardial infarctions (MI) seen with the high dose.

There is a serious unmet need for a new oral anticoagulant such as Pradaxa. Warfarin, the most commonly prescribed anticoagulant in the world, can be a very dangerous drug for patients and complicated for clinicians to prescribe and monitor, clinicians agreed. One noted that only about half the patients who should have warfarin according to current guidelines receive it, and in reality, only a quarter are treated adequately to goal.

A large clinical called RE-LY, examined two doses of Pradaxa - 110 mg or 150 mg twice daily – versus warfarin in 18600 AF patients and the results were recently revealed at the European Society of Cardiology Congress in Barcelona.

Pradaxa high dose better efficacy than warfarin, but more MIs seen

The high dose of Pradaxa achieved a major feat in the trial – better overall efficacy than warfarin. This was branded by clinicians as “amazing” and “better than expected,” although the fate of this dose remains in question due to the significant increase in MIs, clinicians noted. The low dose demonstrated non-inferior efficacy to warfarin. It also demonstrated a trend towards more MI events, but this was not statistically significant.

Commenting on the results, Professor Martin Wehling, a cardiologist at the Institute for Experimental and Clinical Pharmacology and Toxicology, University of Heidelberg, Germany, said the data is not a homogenous picture and it is too early to come to any conclusions yet. At this point, there are no explanations for this MI finding, as anticoagulants are supposed to be cardioprotective, he said.

Another doctor noted that the statistical significance of the increased MI result on the high dose was very borderline, although Professor Lars Wallentin of the Uppsala Clinical Research Center University Hospital, Sweden, who served on the Steering Committee for the RE-LY trial, noted that it was more likely to be a real finding as opposed to a ”statistical fluke.” Dr Michael Ezekowitz of the Lankenau Institute for Medical Research in Pennsylvania and co-principal investigator of the RE-LY study, agreed. The MI events were adjudicated and were declared ”true” by the methods established in the protocol, so the data is accurate, he said.

The hypothesis at this stage is that maybe Pradaxa does not protect against MI as well as warfarin, which is very protective against MI, Wallentin said. Ezekowitz stressed that the finding must be interpreted in view of the fact that the MI subgroup also had an overwhelming decrease in cerebral events (e.g. strokes) with Pradaxa. ”We believe both doses are viable for different reasons and we are doing analyses that may give a better picture of the different sub-populations that the different doses may be more suitable for,” he said.

Ezekowitz said that the picture is still unclear, but what is known so far is that the MI rates were higher in patients with a previous history of MI. In addition, around 30% of the MIs occurred when patients were undergoing an angioplasty procedure, he said. The company now has to go back and look at the MI events and the circumstances around them in more detail and examine whether there are any evident differences between the MI and the non-MI population, he explained.

Fate of high dose in question

Clinicians agreed that the drug regulators will want to see a valid explanation for this increased MI finding. One physician recalled that an association with an increase in MI has been seen before in another experimental oral anticoagulant that never reached the market for other reasons.

One clinician noted that it would take the company three to six months to do the required examination of the data. Ezekowitz said that the MI issue has meant that extra analyses of the data that were not previously planned would now have to be carried out, but preferred not to speculate on timing, stating it is hard to predict.

“We still have a lot of information that we haven’t analysed yet and it will be a while before all the data can be generated as we have limited resources,” he said, noting that the MI analyses will be a top priority.

Wehling said he did not believe this issue would stop the 150mg dose from being approved. But if the company cannot come up with a plausible explanation, the regulatory agencies may come to the conclusion that since the net clinical benefit outcome is almost identical for the two doses - the higher dose is not warranted or will be restricted to certain patient groups.

The more likely scenario is that the 150mg dose is given a limited approval, while post-marketing surveillance studies are carried out. These studies will have to monitor real world patients more closely than the company would have intended, mandated by the authorities, he said.

The issue will also likely be dealt with in the drug labeling, said Wehling. Depending on the level of evidence, the label may warn of the potential MI associations, or may advise caution or contraindication in patients with a history of MI or predisposing indicators of risk; it could even be a black box warning, he said.

Another doctor described the MI finding as a “small issue;” yet others speculated that the issue could hinder or severely delay approval of the high dose due to the FDA’s current sensitivity and the potential unease it may have in authorizing a dose that may increase MI, despite the trade-off in decreasing other events such as stroke.

Regulators may wait for more safety evidence from ongoing trial

The regulatory agencies may ask for more safety evidence on the high dose, some clinicians said.

Prior to the results announcement, one of the RE-LY trial investigators, Professor Dan Atar, head of cardiology at Oslo University Hospital in Norway, noted that there is a longer-term follow-up trial to RE-LY still ongoing, called RE-LYable, looking into the safety aspect of Pradaxa in more depth, although he did not believe it will change the overall message.

Nadia Rosencher, an anesthesiologist at the Cochin Hospital in Paris, who has been involved in past novel anticoagulant trials, and Jan Steffel of the Clinic for Cardiology at the University Hospital Zurich, Switzerland, both agreed that the RE-LY trial data was very comprehensive with huge patient numbers and a long follow-up.

However, if the regulatory agencies don’t feel they have enough safety data to make an approval decision, they may hold off until more data from RE-LYable is available, Steffel suggested.

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