Next generation anti blood clot drug on the way

By Mike Nagle

- Last updated on GMT

Related tags Coagulation

The race to find the next generation of treatments that prevent the
formation of potentially fatal blood clots heated up when
Boehringer Ingelheim announced positive Phase III trial results.

Boehringer Ingelheim announced the results of the Phase III trial of dabigatran at the 48th Annual Meeting of the American Society of Hematology, in Florida, US.

The drug is marketed as being a more convenient solution than current injection therapies because it is orally administered.

If approved, it could become the first oral treatment against blood clots in over 50 years.

The process of blood clot formation is called thrombosis, after a protein (thrombin) necessary for their formation.

When the body is wounded, blood platelets gather at the site and bind to a protein called fibrinogen.

Thrombin, in conjunction with other proteases such as factor Xa, splits this protein to form fibrin, the main constituent of blood clots.

Post surgery blood clots can break off into the blood stream in a process called venous thromboembolism (VTE).

This disorder is the third most common cardiovascular disorder after coronary heart disease and stroke.

VTE is most commonly observed as Deep Vein Thrombosis (DVT) where the clot forms in the leg or Pulmonary Embolism (PE) where the clot is carried to the lungs.

Here, it can cause severe breathing difficulties or even death.

Indeed, up to five per cent of patients who develop DVT die suddenly from PE.

Without treatment to prevent thrombosis, as many as 80 per cent of orthopaedic surgery patients would develop DVT and risk developing PE.

Current treatments target a series of proteases or, if they are specific, are aimed at factor Xa only.

Dabigatran, on the other hand, directly inhibits thrombin (factor IIa) through binding to its active site.

There is only one currently available oral therapy.

In the 1950s, warfarin was approved for use as an anticoagulant in humans having originally been developed as a rat poison.

The drug works by interfering with vitamin K metabolism because several clotting proteins are reliant on this vitamin to work.

However, warfarin is associated with many food-food and drug-drug interactions that mean it has to be constantly monitored with the dose changed suitably.

Bayer's rivaroxaban is another oral drug in development.

However, it is a direct Xa inhibitor and so works in a different way.

The drug has just entered Phase III trials.

Injection-based therapies such as heparins and low molecular weight heparins (LMWHs) have long been established in clinical use.

However, there are other injection-based therapies also being developed.

Sanofi Aventis have developed a synthetic analogue of the functional part of heparin.

Idraparinux is currently in Phase III trials.

Since the 1980s, the company have also marketed the world's best selling LMWH, Lovenox.

In terms of efficacy, the orally adminsitered potential drugs (dabigatran and rivatoxaban) showed that they were as capable at preventing blood clots effects as the establised treatment, Lovenox.

The last newly developed, orally administered, direct thrombic inhibitor was Exanta (ximelagatran) from AstraZeneca.

That drug was withdrawn in February 2006 when results from a 35 day extended clinical trial showed there was a 'potential risk of serious liver injury.'

AstraZeneca said at the time that 'any unapproved use beyond 11 days is a concern'.

However, the clinical trials of the orally administered candidates dabigatran and rivatoxaban were only conducted for up to 10 days.

Although small increases in liver enzymes were observed in the trial, they were at the same level as in patients being treated with Lovenox.

Despite this, Dr Andreas Clemens, a medic at Boehringer Ingelheim, told "We are aware of the problems with Exanta but we are confident that we won't have a problem with our drug."

"We are monitoring the relevant programme very closely."

He went on to explain that they are confident because the different chemical make up of dabigatran means it is not metabolised by the liver.

Instead it is directly degraded in the blood.

Therefore, even over longer periods of time, dabigatran should remain safe.

A spokesperson for the company confirmed that longer-term treatments with dabigatran are being investigated as part of the programme of clinical trials called Re-volution, which is the biggest thromboembolic disease clinical trial program ever.

Over 27,000 patients are being studied for a variety of disorders such as stroke, as well as of DVT and PE.

Being an oral therapy, dabigatran has the potential to solve any inconvenience issues associated with injection treatments.

Also, as it is not metablised in the liver, it is unlikely to suffer from adverse food and drug interactions like those seen with warfarin.

It also doesn't require weight-adjusted dosing or coagulation monitoring.

All of this adds up to a much more convenient therapy for the patient and doctor alike.

"A pill rather than the standard injection has great potential to decrease demands on hospital time and resources," said Bengt Eriksson, an orthopaedic surgeon from University Hospital Sahlgrenska/Ostra, Sweden.

Related topics Preclinical Research

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