Expanding the foundation for future success
Actelion’s Clinical Development department has the proven ability to take a drug candidate through all the clinical and regulatory steps necessary for approval and to provide the supporting efficacy and safety data needed to create a successful pharmaceutical product. This 140-member, multi-disciplinary team is conducting 25 Phase I to Phase III trials at 400 centers in 24 countries, involving some 3,000 patients. Clinical Development has two major priorities: extending the company’s currently approved drugs, Tracleer® and Zavesca®, into new medical indications while simultaneously moving forward in clinical trials on a number of new molecules promoted from Drug Discovery.
Opportunities for Tracleer® in multiple indications
A major pillar of Actelion’s Clinical Development strategy is to leverage the proven efficacy and safety of Tracleer® (bosentan) in new medical indications. Tracleer® is the only antagonist of endothelin receptors approved as an oral therapy. Endothelin has a variety of deleterious effects such as vasoconstriction, hypertrophy, inflammation and fibrosis. Tracleer® causes selective vasodilation and shows anti-proliferative, anti-fibrotic and anti-inflammatory effects in a pre-clinical setting. Therefore, it has the potential to play a major role in a number of diseases for which there is either no current therapy or insufficient treatment options. Actelion is conducting multiple clinical trials to realize the potential of this innovative therapy.In November 2005, Actelion presented Phase IV results from BREATHE-5, the first ever placebo-controlled trial for Eisenmenger's syndrome, at CHEST 2005 (American College of Chest Physicians) in Montreal. The BREATHE-5 study showed that Tracleer® improved exercise capacity and decreased pulmonary vascular resistance in patients not amenable to any other therapy, including surgery. Patients suffering from Eisenmenger's syndrome develop a severe form of PAH as a complication of a congenital heart defect (“hole in the heart”).
At the American College of Rheumatology (ACR) meeting in San Diego in November 2005, Actelion made a poster presentation on Phase III results from RAPIDS-2, a placebo-controlled, randomized study that evaluated bosentan in preventing or treating digital ulcerations in patients with systemic sclerosis. The 188-patient study achieved its first co-primary endpoint in reducing the occurrence of new digital ulcerations, confirming the positive findings from the earlier trial RAPIDS-1. The recent results from RAPIDS-2 also confirmed that bosentan did not impact the healing process of digital ulcerations. Bosentan was well tolerated and the safety profile was consistent with earlier findings in clinical studies that led to the approval of Tracleer® in PAH. Discussions with regulatory authorities for filing are ongoing.
Also in November 2005, Actelion announced the Phase II/III results of the BUILD-1 and BUILD-2 trials, evaluating the efficacy and safety of bosentan in two forms of pulmonary fibrosis: idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis related to systemic scleroderma. While statistical significance was not reached on the primary endpoints (exercise capacity measured by the six-minute-walk test), a positive trend did emerge in IPF. These findings suggest an important role for Tracleer® in IPF that needs to be confirmed in a larger Phase III mortality/morbidity study (BUILD-3). The observed safety profile in the BUILD program was consistent with earlier findings in clinical studies that led to the approval of Tracleer® in PAH.
At the European Society of Cardiology conference in Stockholm in September 2005, Actelion presented results from the Tracleer® Excellence Post Marketing Surveillance Program (TRAX PMS™), which confirms the long-term safety profile of Tracleer® in various pulmonary arterial hypertension subgroups such as chronic thrombo-embolic pulmonary hypertension (CTEPH) and congenital heart disease (CHD). Almost 5,000 PAH patients were enrolled in the European Union in TRAX PMS™.
In August 2005, the Journal of the American College of Cardiology published a new study on the long-term outcome of children with pulmonary arterial hypertension (PAH) treated with Tracleer®. The authors concluded that Tracleer®, with or without concomitant prostanoid therapy, was efficacious for the treatment of PAH in children, and the safety profile appeared similar to that in adult PAH patients. In order to develop a special pediatric formulation of Tracleer®, Actelion is conducting the Phase III trial FUTURE-1, with results expected in mid-2006. Once this is completed, the trial will be extended to FUTURE-2.
In June 2005, Actelion presented abstracts at the Annual European Congress of Rheumatology in Vienna that showed the positive long-term impact of Tracleer® in treating pulmonary arterial hypertension in patients with systemic sclerosis (scleroderma). As many as 15% of scleroderma patients develop PAH and the prognosis is extremely poor. Untreated, there is a median survival of just 12 months for these patients, according to published data.
Building on the success of Tracleer® in treating class III patients in the EU and class III/IV patients in the United States, a double-blind, placebo-controlled clinical trial was launched for class II patients (EARLY). Results for this Phase III study are expected late 2006. A recent amendment to the EARLY trial will allow class II patients currently on sildenafil to participate, which will generate the first information on the combination of these two therapies.
The combination of Tracleer® and Pfizer’s sildenafil will be further explored in two Phase III studies. COMPASS-1 will evaluate the hemodynamic effects of sildenafil versus placebo in PAH patients treated with Tracleer®. COMPASS-2 will examine the morbidity/mortality outcome of the combination Tracleer® and sildenafil versus sildenafil in monotherapy. Both trials are expected to be initiated in early 2006.
Chronic thrombo-embolic pulmonary hypertension (CTEPH) is caused by blockage of the main arteries leading from the heart to the lungs by thrombotic material. Even after surgery, many of these patients have high pulmonary pressure associated with increased levels of endothelin in their blood. After several open-label studies showing that Tracleer® seems effective and well tolerated in this indication, a double-blind, placebo-controlled Phase III trial BENEFIT was launched, with results expected mid-2007.
As many as 30% of patients with sickle cell disease develop pulmonary hypertension, a complication that results in a median survival rate of only 26 months. Two Phase III trials are being conducted with Tracleer® in pulmonary hypertension secondary to sickle cell disease, ASSET-1 and ASSET-2, with results expected in mid-2007. The two trials will also explore the potential of Tracleer® to reduce the frequency of sickle crises, for which endothelin is believed to play a central role.
Endothelin is also known to play a role in metastatic melanoma (skin cancer that spreads throughout the body), which is usually fatal in its advanced stages. Current treatments have a very low response rate, underlining the high unmet medical need. An open-label trial in end-stage patients at five centers in Australia showed that high doses of bosentan were well tolerated. Based on this study, a placebo-controlled randomized trial in less advanced patients has started, with results expected sometime in 2007.
At the European Society of Cardiology conference in Stockholm in September 2005, Actelion presented results from the Tracleer® Excellence Post Marketing Surveillance Program (TRAX PMS™), which confirms the long-term safety profile of Tracleer® in various pulmonary arterial hypertension subgroups such as chronic thrombo-embolic pulmonary hypertension (CTEPH) and congenital heart disease (CHD). Almost 5,000 PAH patients were enrolled in the European Union in TRAX PMS™.
In August 2005, the Journal of the American College of Cardiology published a new study on the long-term outcome of children with pulmonary arterial hypertension (PAH) treated with Tracleer®. The authors concluded that Tracleer®, with or without concomitant prostanoid therapy, was efficacious for the treatment of PAH in children, and the safety profile appeared similar to that in adult PAH patients. In order to develop a special pediatric formulation of Tracleer®, Actelion is conducting the Phase III trial FUTURE-1, with results expected in mid-2006. Once this is completed, the trial will be extended to FUTURE-2.
In June 2005, Actelion presented abstracts at the Annual European Congress of Rheumatology in Vienna that showed the positive long-term impact of Tracleer® in treating pulmonary arterial hypertension in patients with systemic sclerosis (scleroderma). As many as 15% of scleroderma patients develop PAH and the prognosis is extremely poor. Untreated, there is a median survival of just 12 months for these patients, according to published data.
Building on the success of Tracleer® in treating class III patients in the EU and class III/IV patients in the United States, a double-blind, placebo-controlled clinical trial was launched for class II patients (EARLY). Results for this Phase III study are expected late 2006. A recent amendment to the EARLY trial will allow class II patients currently on sildenafil to participate, which will generate the first information on the combination of these two therapies.
The combination of Tracleer® and Pfizer’s sildenafil will be further explored in two Phase III studies. COMPASS-1 will evaluate the hemodynamic effects of sildenafil versus placebo in PAH patients treated with Tracleer®. COMPASS-2 will examine the morbidity/mortality outcome of the combination Tracleer® and sildenafil versus sildenafil in monotherapy. Both trials are expected to be initiated in early 2006.
Chronic thrombo-embolic pulmonary hypertension (CTEPH) is caused by blockage of the main arteries leading from the heart to the lungs by thrombotic material. Even after surgery, many of these patients have high pulmonary pressure associated with increased levels of endothelin in their blood. After several open-label studies showing that Tracleer® seems effective and well tolerated in this indication, a double-blind, placebo-controlled Phase III trial BENEFIT was launched, with results expected mid-2007.
As many as 30% of patients with sickle cell disease develop pulmonary hypertension, a complication that results in a median survival rate of only 26 months. Two Phase III trials are being conducted with Tracleer® in pulmonary hypertension secondary to sickle cell disease, ASSET-1 and ASSET-2, with results expected in mid-2007. The two trials will also explore the potential of Tracleer® to reduce the frequency of sickle crises, for which endothelin is believed to play a central role.
Endothelin is also known to play a role in metastatic melanoma (skin cancer that spreads throughout the body), which is usually fatal in its advanced stages. Current treatments have a very low response rate, underlining the high unmet medical need. An open-label trial in end-stage patients at five centers in Australia showed that high doses of bosentan were well tolerated. Based on this study, a placebo-controlled randomized trial in less advanced patients has started, with results expected sometime in 2007.
Realizing the potential of Zavesca® in lipid storage disorders
Building on the success of Zavesca® (miglustat) in treating type 1 Gaucher disease, Clinical Development is moving forward on trials in related lipid storage diseases. The Phase IV trial MAINTENANCE was initiated in late 2005. This study will test the long-term efficacy and safety of Zavesca® as maintenance therapy after a switch from enzyme replacement therapy (ERT) in adult type 1 Gaucher patients with stable disease. First interim results are expected in 2007.In 2005, Actelion also continued to evaluate the potential of Zavesca® in lipid-storage disorders other than type 1 Gaucher disease: type 3 Gaucher disease (GD3), Niemann-Pick Type C (NP-C) and Late Onset Tay-Sachs (LOTS). Unlike ERT, which helps to degrade the excess of accumulated glycosphingolipids, Zavesca® blocks the synthesis of glucosylceramide, the first intermediate in the synthesis of a large family of glycosphingolipids. In late 2005, analyses have been completed for three clinical programs, with a total of one-hundred adult and pediatric patients, evaluating the safety and efficacy of high-dose miglustat (Zavesca®) in lysosomal storage disorders with predominant neurological manifestations, namely NP-C, GD3 and LOTS. In NP-C, encouraging results have been seen at 12-months in adult and pediatric patients, with improvement or stabilization of key features of the disease such as saccadic eye movements, swallowing, cognition, and auditory function, underlying the ability of miglustat to work in the brain. After consultation with experts, Actelion has decided that these results warrant discussion with regulatory authorities. The NP-C study is continuing as planned until 24 months, as is the GD3 study, where the 12-month results were inconclusive. With respect to LOTS, the 24-month results in a group of severe, heterogeneous and advanced patients showed no change in the progression of the disease. In all three studies, the safety profile was consistent with earlier observations in patients with type 1 Gaucher disease, where only half the dose is being used.
Clazosentan reduces vasospasm after subarachnoid hemorrhage
Subarachnoid hemorrhage due to the rupture of an aneurysm (weakened blood vessel) occurs on average in 10 out of 100,000 people, with some 70-80,000 cases per year reported in North America and Europe. Of those people who survive, a large percentage will develop vasospasm (severe constriction of blood vessels), resulting in significant neurological damage and increased death rates.In July 2005, a study published in the Journal of Neurosurgery concluded that the intravenous endothelin receptor antagonist clazosentan can reduce the number and severity of cases of vasospasm following aneurysmal subarachnoid hemorrhage (SAH). The Phase IIa study demonstrated that patients given clazosentan had significantly fewer and less severe cases of vasospasm compared to placebo. Furthermore, there were fewer patients with new cerebral infarcts in the clazosentan group. Infusions of clazosentan were generally well tolerated, with no clinically relevant effects on blood pressure or other vital signs.
Following the study results and discussions with regulatory authorities, a comprehensive Phase IIb/III development program was launched for clazosentan. The multi-center, international, double-blind, randomized, placebo-controlled, parallel group, dose-finding study CONSCIOUS-1 will analyze the efficacy of three dose levels of clazosentan in preventing the occurrence of cerebral vasospasm following SAH, assessed by angiography. As a secondary endpoint, the study will also assess the ability of clazosentan to reduce the occurrence of early morbidity/mortality as well as overall safety and tolerability of the drug. In November 2005, CONSCIOUS-1 had recruited over 400 patients in 52 centers in 11 countries worldwide. Study results, expected in mid-2006, will determine the need and size of a Phase III study.
Orexin antagonist: the promise of a more natural sleep
One of the most interesting compounds under development at Actelion is an orexin receptor antagonist. This compound, starting Phase II in early 2006, has the potential to completely shift the paradigm for treating sleep disorders. Most products on the market, which focus on the GABA receptor, suffer from a major tradeoff: the greater the efficacy, the stronger the “hangover” effect the next day in terms of impaired mental and physical performance. Usually, sedatives decrease the length of the REM (rapid eye movement) sleep phase, which – together with accompanying dream sequences – is hypothesized to impact memory consolidation.In animal models, Actelion’s orexin receptor antagonist has shown an increase of total sleep and REM sleep. In addition, preclinical results have revealed a reduction in the time needed to fall asleep. In animals there has been no evidence of tolerance and motor impairment. Phase I findings in healthy human subjects have shown that the compound is well tolerated, with quick absorption and disposition. A Phase II program with patients suffering from insomnia, the primary target indication, is scheduled to start early 2006.
Phase II trials for undisclosed compound
The compound known as Actelion-1, undisclosed for competitive reasons, was discovered in-house and has significant potential in several cardiovascular indications. Tests with healthy human subjects began in September 2004 and Phase I trials were completed in 2005. The pharmacodynamic findings showed that the compound is well tolerated, with the highest dose tolerated already identified, and is suitable for once-daily oral administration. A Phase IIa study started in 2005.Reevaluating potential indications for tezosentan
Tezosentan (Veletri™) is an intravenous endothelin receptor antagonist that was originally developed for acute heart failure. Although the drug is well tolerated and had very clear hemodynamic effects, these were not translated into relevant clinical endpoints. As a result, this compound is now being reevaluated for a number of other acute vascular indications.Palosuran development put on hold pending further analysis
In May 2005, Actelion announced preliminary results in the proof-of-concept program on the urotensin-II receptor antagonist palosuran, identified by the company’s researchers in Drug Discovery. The efficacy data in the indication diabetic nephropathy did not support the initiation of a full-fledged clinical development program. The company is further analyzing the data generated in three individual studies involving close to 100 patients and discussing the results with key medical experts. There were no safety findings that would preclude further development. As further scientific insights become available in this field, Actelion may re-initiate clinical development for palosuran. Isaac Kobrin
Head of Clinical Development
Head of Clinical Development
For more extensive details on clinical trials, visit www.actelion.com
Recently published articles in key scientific journals
Clozel M. & Salloukh H. Role of endothelin in fibrosis and anti-fibrotic potential of bosentan. Annals of Medicine 37, 2-12 (2005).
Pastores G.M. et al. An open-label, noncomparative study of miglustat in type 1 Gaucher Disease: Efficacy and tolerability over 24 months of treatment. Clinical Therapeutics 27(8), 1215-27 (2005).
Rosenzweig E.B. et al. Effects of long-term bosentan in children with pulmonary arterial hypertension. JACC 46 (4) 697-704 (2005).
Vajkoczy P, Meyer B, Weidauer S et al. Clazosentan (AXV-034343), a selective endothelin A receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: a randomized, double-blind, placebo-controlled, multicenter, Phase IIa study. Journal of Neurosurgery 103, 9-17 (2005).
Recently published articles in key scientific journals
Clozel M. & Salloukh H. Role of endothelin in fibrosis and anti-fibrotic potential of bosentan. Annals of Medicine 37, 2-12 (2005).
Pastores G.M. et al. An open-label, noncomparative study of miglustat in type 1 Gaucher Disease: Efficacy and tolerability over 24 months of treatment. Clinical Therapeutics 27(8), 1215-27 (2005).
Rosenzweig E.B. et al. Effects of long-term bosentan in children with pulmonary arterial hypertension. JACC 46 (4) 697-704 (2005).
Vajkoczy P, Meyer B, Weidauer S et al. Clazosentan (AXV-034343), a selective endothelin A receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: a randomized, double-blind, placebo-controlled, multicenter, Phase IIa study. Journal of Neurosurgery 103, 9-17 (2005).
