Tracleer (Bosentan) Receives New Indication In Patients With Systemic Sclerosis And Active Digital Ulcer Disease

Main Category: Cardiovascular / Cardiology
Also Included In: Dermatology;  Regulatory Affairs / Drug Approvals
Article Date: 29 Apr 2008 - 1:00 PDT

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Actelion Pharmaceuticals UK Ltd announced that Tracleer® (bosentan), a dual endothelin receptor antagonist, has been approved in the UK and Ireland for the reduction of the number of new digital ulcers (DUs) in patients with systemic sclerosis (SSc) and ongoing DU disease.1

DUs are a frequent, extremely painful and disabling complication of SSc2, caused by a reduced blood flow to the fingers and toes. DUs can result in difficult to heal open sores and adversely affect the ability to perform work and daily activities, particularly those associated with fingertip function. In severe cases, infection can lead to osteomyelitis and gangrene, where surgery and even amputation may be required.3

SSc affects at least 7,000 people in the UK,4 and research indicates that up to 50% of SSc patients develop DUs.2 Until now there have been no licensed therapies for the reduction of new DUs in SSc patients with ongoing DU disease. Tracleer® targets the underlying vasculopathy in SSc by blocking the damaging effects of endothelin. The new indication extends the previous licence of Tracleer® for the treatment of pulmonary arterial hypertension (PAH).

Dr Arianne Herrick, Reader of Rheumatology at the University of Manchester, added: "Digital ulcers can be severely disabling as well as extremely painful, affecting peoples ability to undertake activities of everyday living and interfering with their working and social lives. We know that digital ulcers can be slow to heal and may lead to serious complications, such as infection (sometimes involving underlying bone) and gangrene. This new indication offers a valuable therapy for patients with scleroderma and ongoing digital ulceration, to help reduce the number of new ulcers."

Results from two randomised, placebo-controlled, double-blind studies, RAPIDS-1 and RAPIDS-2, supported the licence approval. Tracleer® compared to placebo significantly reduced the mean occurrence of new DUs in patients with SSc and ongoing DU disease by 48% (1.4 versus 2.7; p=0.0083) and by 30% (1.9 versus 2.7; p=0.035) in RAPIDS-1 and RAPIDS-2 respectively. Although new DUs were prevented, no improvement in ulcer healing with Tracleer® was observed. In both trials the safety profile was consistent with that seen in previous trials of Tracleer® in pulmonary arterial hypertension with Gastrointestinal reflux disease, infected ulcers, peripheral oedema (including worsening) and abnormal raised liver function tests being the most common side effects.5,6

A survey of 1,050 SSc patients conducted by the Raynaud's and Scleroderma Association in October 2007 found that 86% of those with DUs were affected by pain and 53% by some loss of function, both of which were negatively impacting on their ability to carry out everyday tasks such as cooking, dressing, driving and washing.7

A disease registry has also been set up to collect and analyse data on this poorly characterised patient population where currently little information is available. The registry will provide further insights into DUs, their disabling manifestations and response to treatments across a range of patients with systemic sclerosis and ongoing DU disease.

About RAPIDS-1

RAPIDS-1 (RAndomized Placebo-controlled Investigation of Digital ulcers in Scleroderma) was a placebo-controlled double-blind clinical trial that evaluated the prevention of ischaemic digital ulcers (DUs) in 122 patients with systemic sclerosis (SSc) at 17 centres in Europe and North America. RAPIDS-1 was the first specifically designed study to look at prevention of ulcer formation. Furthermore the study is among very few to demonstrate clinical efficacy in SSc.5 Patients with SSc who had either a history of at least one DU over the past 12 months or active DUs at the time of enrolment, were treated with either bosentan (62.5mg bid for four weeks, then 125mg bid for the next 12 weeks) or placebo. The total number of new ulcers during the treatment period was 1.4 for patients on bosentan versus 2.7 for patients on placebo (p=0.0083) representing a 48% reduction in the number of new DUs.5

About RAPIDS-2

In late 2003, Actelion initiated a second pivotal Phase III clinical trial, RAPIDS-2 (RAndomized Placebo-controlled Investigation of Digital ulcers in Scleroderma) investigating bosentan in ischaemic DUs secondary to SSc. In contrast to the earlier RAPIDS-1 trial, this study evaluated prevention and healing in a population with more severe forms of the disease at the time of enrolment.

The treatment duration was longer and a withdrawal period was implemented in order to assess the evolution of DUs after treatment interruption. The study enrolled a total of 188 patients in 41 centers worldwide.6

Patients with SSc and at least one DU were treated with either bosentan (62.5mg bid for four weeks, then 125mg bid for at least 20 weeks and up to 32 weeks) or placebo. The total number of new ulcers over 24 weeks was 1.9 ± 0.2 for patients on bosentan versus 2.7 ± 0.3 for patients on placebo (p=0.035) representing a 30% reduction in the number of new DUs. The reduction in DUs was more pronounced in patients with more than three active DUs at the start of the study.6

About Tracleer® in Pulmonary Arterial Hypertension (PAH)

Tracleer is licensed in the UK for the treatment of PAH to improve exercise capacity and symptoms in patients with grade III functional status. Efficacy has been shown in primary (idiopathic and familial) PAH, PAH secondary to scleroderma without significant interstitial pulmonary disease and PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger's physiology. Tracleer is also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing DU disease.1

Attention required regarding two significant safety concerns

Potential for serious liver injury (including rare cases of liver failure and unexplained hepatic cirrhosis in a setting of close monitoring) - liver monitoring of all patients is essential prior to initiation of treatment, 2 weeks after any dose increase and monthly thereafter. High potential for major birth defects - pregnancy must be excluded and prevented by two forms of birth control; monthly pregnancy tests should be obtained. Because of these risks, Tracleer is only supplied through a controlled distribution.

About Actelion Pharmaceuticals UK & Ireland Ltd

"Actelion" is an independent biopharmaceutical company that focuses on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion Pharmaceuticals UK & Ireland is a subsidiary of Actelion Ltd, which has its corporate headquarter in Allschwil/Basel, Switzerland. Actelion markets Tracleer®, an orally available dual endothelin receptor antagonist, for pulmonary arterial hypertension (PAH) and Zavesca®, a small molecule oral therapy for the treatment of type 1 Gaucher's disease, both in the UK and Ireland. Further information is available from http://www.actelion.com.

References:

1. Actelion Pharmaceuticals UK Limited. Tracleer® (bosentan) Summary of Product Characteristics. 15 May 2007.

2. Chung L, Fiorentino D. Digital ulcers in patients with systemic sclerosis. Autoimmun Rev 2006; 5(2):125128.

3. Ford Jones N et al. Surgery for scleroderma of the hand. J Hand Surg [Am] 1987;12(3):391400.

4. Raynaud's & Scleroderma Association. November 2007. Press Release - Scleroderma Survey. Viewed 20 December 2007.

5. Korn J. et al. Digital ulcers in systemic sclerosis: Prevention by treatment with bosentan, an oral endothelin receptor antagonist Arthritis Rheum 2004, Issue 12; 50:3985-3993.

6. Seibold J. et al. Bosentan prevents occurrence but does not speed healing of digital ulcers in patients with systemic sclerosis (SSc). ACR 2005. Poster presentation L2: 552.

7. Raynaud's & Scleroderma Association. Scleroderma Questionnaire. October 2007. Conducted by the Raynaud's & Scleroderma Association and sponsored by an educational grant from Actelion Pharmaceuticals UK Ltd.

http://www.actelion.com