New anti-clotting drugs: stopping the silent killers

pharmafile | June 28, 2010 | Feature | Research and Development, Sales and Marketing |  Pradaxa, VTE, Xarelto, atrial fibrilation, thrombosis 

Blood clots are a major killer, but the threat they pose is poorly understood by the general public compared to more high profile conditions.

Thrombosis arises in a number of common forms, and collectively these represent one of the major causes of death. Venous thromboembolism (VTE) alone kills half a million people in the EU annually – more than double the total number of deaths from AIDS, breast cancer, prostate cancer and traffic accidents combined.

A new wave of drugs, led by Boehringer Ingelheim’s Pradaxa (dabigatran etexilate) and Bayer’s Xarelto (rivaroxaban) are now reaching the market to help treat these killer blood clots in two key settings – those arising after surgery, and those caused by atrial fibrilation (AF).

Warfarin is currently the only oral anti-clotting agent approved by the FDA, both in post-surgery prevention of VTE, and in preventing atrial fibrilation. Over 50 years of use, warfarin has proved relatively effective and safe, but it has drawbacks. Warfarin interacts with many common medications, and with some foods, and its activity has to be monitored by GPs using the international normalised ratio (INR) blood tests to ensure an adequate yet safe dose is taken.

The new drugs were developed with the aim of matching the efficacy and safety of warfarin, but having the extra convenience of no interactions and reduced need for monitoring.

The drugs are also aimed at competing with another well-established drug – Sanofi-Aventis’s enoxaparin, known as Clexane in Europe and Lovenox in the US.

The first of the new drugs to reach the market was Boehringer’s Pradaxa, launched in Europe in early 2008. Pradaxa is a direct inhibitor of thrombin, a key enzyme in blood clot formation. The drug has been developed to replace warfarin – the standard treatment for the prevention of hospital-acquired blood clots, since 1954.

Bayer’s Xarelto arrived just behind Pradaxa, launched in Europe in October 2008. The drug is from a slightly different class of anti-coagulant, being an oral factor Xa inhibitor. Both drugs have been approved in Europe, and several other countries, for the prevention of blot clots after total knee, or hip, replacement surgery. Both companies have filed their drugs with the FDA, but neither has been approved in the US, by far the most important market for the drugs.

Post-surgery VTE

Venous thromboembolism (VTE) is the collective term for deep venous thrombosis (DVT) and pulmonary embolism (PE), and the most at-risk patients are those who have undergone total hip replacement (THR) or total knee replacement (TKR) surgery. It is estimated that 50% of THR patients and 60% of TKR develop a clot after surgery.

All this has, of course, significant economic implications. The Office for Health Economics estimates that hospital-acquired DVT and PE costs the NHS a staggering £222.8 million each year in diagnostic tests, drugs and hospital days. If we also consider the indirect costs involved, this figure soars to £640 million, to which one needs to add an annual £400 million for the long-term treatment of those patients (about 25%), who later in life develop venous leg ulceration as a consequence of having suffered from a blood clot.1

The hurdles

Much of the success of Pradaxa and Xarelto will depend on how they can penetrate the existing market and then expand its current scope. But there are a number of factors that could constrain their uptake.

Decision Resources Analyst, Matthew Killeen, Ph.D says: “Current therapies are well entrenched in physicians’ minds and benefit from large amounts of clinical data; overcoming this physician familiarity will be difficult.”

Warfarin has been in use for more than half a century, and Sanofi-Aventis’ Clexane/Lovenox, which has achieved deep market penetration as a result of extremely effective marketing campaigns. Last year, Lovenox generated about $4.1 billion (£2.7 billion) in worldwide sales.

“Moreover, all anti-clotting agents carry a risk of unwanted bleeding events, and the new oral anticoagulants are no exception,” Killen continues. “The effects of many of the older anti-clotting agents can be reversed if a patient presents with bleeding, whereas, as it stands, Pradaxa and Xarelto will not be able to be reversed quickly. And, although antidotes for these drugs are in pre-clinical development, it will not be available in the short term.”

Prices could be another significant hurdle, particularly at a time of drastic cost-containment strategies in healthcare systems, as some payers will go for the less expensive option. Another factor in the market is the expected approval of biosimilar versions of enoxaparin, which will lead to greater interest in this field and potentially lower prices.

Pradaxa and Xarelto also face some serious competition from other competitor drugs now in development.

Findings from the ADVANCE-2 study, published in March in The Lancet, show that Pfizer and Bristol-Myers Squibb’s anti-clotting agent apixaban, a highly selective factor Xa inhibitor, is more effective than Lovenox in preventing VTE after knee replacement surgery; and is not associated with increased bleeding.

It has been anticipated that the drug’s manufacturers will file for regulatory approval in Europe this year.

Another novel oral factor Xa inhibitor under development is Portola and Merck’s betrixaban. Not only has betrixaban demonstrated anti-clotting activity in VTE prevention trials of total knee replacement surgery patients, and shows promises for use in the more lucrative market of stroke prevention in atrial fibrillation, it is also the only novel oral anti-clotting agent being tested in patients with renal malfunction. So, it has the potential to become the only one available for people with severe kidney disease.

AstraZeneca is developing Brilinta (ticagrelor) an oral antiplatelet agent for the prevention of blood clots that can lead to stroke in heart patients, and for which the company is awaiting approval in Europe and the US. Analysts forecast that together with Pradaxa and Xarelto, the novel oral anti-clotting agents currently in the pipeline could lead to blockbuster annual sales of more than $14 billion (£9 billion) by 2018.

NICE recommended

In two separate technology appraisals, UK cost effectiveness body NICE recommended the use of Pradaxa and Xarelto for the prevention of orthopaedic surgery-related blood clots. Their recommendation is based on the results of a number of phase III studies that compared Pradaxa or Xarelto with the established treatment for VTE prevention, Sanofi-Aventis’ Lovenox (enoxaparin) – an injectable low molecular weight heparin (the anti-clotting agent naturally present in the blood), which currently dominates the market.

All the studies conducted on Xarelto (RECORD 1, 2, 3 and 4) found that it has superior efficacy to Lovenox and carries a low risk of bleeding. On the other hand, the studies conducted on Pradaxa (RE-NOVATE and RE-MODEL) could only demonstrate that this drug is not worse, in term of efficacy, than Lovenox. It is, however, as safe to use as Xarelto.2

Europe sales: ‘a solid start’

Pradaxa and Xarelto have both been tipped to reach blockbuster status – peak sales forecast of of up to £6 billion for the former, and about £2 billion for the latter.

So how are they performing so far? A spokesperson for Boehringer Ingelheim says sales for Pradaxa “are in line with the expectations,” but declined to disclose actual figures. As for Xarelto, Bayer reports for the business year 2009 worldwide sales of €24 million (£20 million) – a modest achievement so far. However, both Xarelto and Pradaxa have been launched in countries worldwide only over the past two years, so it is probably too early to draw a conclusion.

“In Europe, Pradaxa and Xarelto had a combined 2009 market share of 10-15 per cent; a solid start, especially considering the conservative prescribing habits of orthopaedic surgeons,” says Killeen. “We expect, however, a slower uptake of the novel oral anticoagulants for VTE primary prophylaxis as this is characterised by shorter periods of hospital-based therapy, where delivering an injectable agent, like Lovenox, is not a significant disadvantage.”

Atrial fibrillation

Regardless of the challenges, experts believe that the sales potential of Pradaxa and Xarelto is strong, and that both drugs will likely assert themselves in the market.

Killen says: “We still expect them to become blockbusters. One reason for this is that, in the coming years, Pradaxa and Xarelto stand to be approved for a number of far more lucrative VTE indications, including stroke prevention in atrial fibrillation, and the prevention of recurrent VTE. Based on the uptake of Pradaxa and Xarelto so far, we expect rapid uptake and deep penetration of these drugs in other markets.”

Boehringer Ingelheim has already filed an application with the FDA for use of Pradaxa in the prevention of stroke in patients with atrial fibrillation, and expects approval by the end of 2010 or early 2011. This would result in worldwide sales of $1.3 billion (£1 billion) by 2018, according to estimates. Bayer is expected to file an application for use of Xarelto in the mass market of stroke prevention later this year.

The drugs do not have this area to themselves, however, as there are numerous companies shaping up to compete in this therapy area as well. Sanofi-Aventis’ Multaq was launched in the autumn of 2009 as a treatment for AF. However, the drug has so far failed to generate revenues to match forecast sales, suggesting it is difficult to convince prescribers and payers of its advantages of current standard treatment amiodorone.

Cost effectiveness in VTE

Pradaxa and Xarelto’s approval by NICE as treatments for VTE has provided them with a strong endorsement of their cost effectiveness. While the drugs are more costly than warfarin, the same is not true if we consider anti-clotting agents administered via injection, like Lovenox.

NICE’s cost-utility analyses found both Pradaxa and Xarelto are more cost-effective than the latter. Although it costs more to buy a month’s supply of the new drugs, the additional expense compensates for indirect costs associated with the injectable agent, such as nursing time for administering injections, laboratory tests, doctor visits, as well as equipment acquisition, maintenance and handling costs.

The success of Pradaxa and Xeralto will also depend on just how much attention healthcare authorities focus on preventing blood clots on a larger scale. New guidelines will play a major role in the market uptake of the drugs.

Some of this is already happening. For instance, the latest NICE recommendations mentioned above, endorse the use of both drugs in at-risk hospital patients. University College London Hospital’s Use of Medicines Committee also approved Xarelto, in place of Lovenox, for the long-term prevention of blood clots in patients who had total hip, or knee, replacement surgery.2

Causing 10% of all hospital deaths in the UK, blood clot risks are of great concern. Increased awareness, new guidelines and the ever increasing number of novel oral anti-clotting agents in the pipeline could eventually lead to a win-win situation: profits for the industry, substantial savings for a healthcare system under financial pressure and, most important of all, reduced mortality rates.

PATIENTS UNAWARE OF BLOOD CLOT RISKS

Many patients are not aware that they are at risk from blood clots when staying in hospital, according to new findings.

In a survey sponsored by Boehringer Ingelheim, less than half of those surveyed said they had been informed of the risk of thrombosis.

Around 25,000 people die in UK hospitals each year as a result of clots, which includes deep vein thrombosis (DVT) and pulmonary embolism.

Of those respondents who had undergone high-risk orthopaedic surgery, only 50% had the risk of VTE discussed with them. Perhaps more worryingly, the survey found that just 27% were given drug treatment for treatment or prevention of clots post-surgery.

The survey was published by Lifeblood,  the thrombosis charity­. The charity has previously estimated that it costs the NHS £222.8 million per year to treat hospital-acquired DVT – compared to £45m for the MRSA superbug.

TYPES OF THROMBOSIS

Venous thromboembolism (VTE) is a condition in which a blood clot (thrombus) forms in a vein. Blood flow through the affected vein can be limited by the clot, and may cause swelling and pain. VTE occurs most commonly in the deep veins of the leg or pelvis; this is known as a deep vein thrombosis (DVT). An embolism occurs if all or a part of the clot breaks off from the site where it forms and travels through the venous system.

Pulmonary embolism (PE) occurs if the clot lodges in the lung, and is a potentially serious and sometimes fatal condition, Venous thrombosis can occur in any part of the venous system. However, DVT and PE are the most common forms of venous thrombosis. The term VTE covers the acute conditions of DVT and PE, and also chronic conditions which may arise after acute VTE-such as post thrombotic syndrome and pulmonary hypertension – both associated with significant ill-health and disability. 

Source: Department of Health

Acute Coronary Syndrome (ACS) is another major cause of thrombosis. ACS is an umbrella term covering unstable angina and two types of myocardial infarction (MI) in which heart muscle is damaged – (ECG/EKG) as non-ST segment elevation myocardial infarction (NSTEMI) and ST segment elevation myocardial infarction (STEMI). MIs are most often triggered by acute thrombus formation within a coronary artery.

Atrial Fibrillation (AF) is the most common cardiac arrythmia, and can lead to arterial thrombosis and then cardioembolic stroke. An estimated 2.2 million people in the US and 4.5 million in the EU have atrial fibrillation.

Source: Thrombosisadvisor.com

References

1 House of Commons Health Committee. The prevention of venous thromboembolism in hospitalised patients, 2005.

2 Grosso A, Bodalia P. Dabigatran vs rivaroxaban for thromboprophylaxis. The British Journal of Clinical Pharmacy. September 2009; 1(9):240-4.

Lorena Tonarelli is an author, freelance healthcare journalist and medical writer and can be contacted at: lorenatonarelli@me.com