Accelerating the next wave of innovation
A major pillar of Actelion’s Clinical Development strategy is to maximize the life cycle value of Tracleer® (bosentan) by investigating new medical indications and label extensions. Tracleer® is the only orally available dual receptor antagonist of endothelin, a potent vasoconstrictor that plays a major role in a number of diseases for which there is no adequate treatment. Actelion has pioneered the use of Tracleer® in pulmonary arterial hypertension (PAH), a life-threatening disease that severely compromises the functions of the heart and lungs. TRAX PMS, a post-marketing surveillance study of 5,000 patients in Europe, confirmed the long-term safety of Tracleer® and consolidated its position as the first-line, cornerstone therapy for PAH. Clinical Development efforts are strengthening Actelion’s leadership position in the enlarged indication of pulmonary hypertension while shifting the treatment paradigm to an earlier stage of the disease and anticipating an increasing trend toward combination therapies.
In December 2006, Actelion announced initial results from the double-blind, placebo-controlled, multicenter study EARLY for mildly symptomatic PAH patients (class II). Six months of treatment with Tracleer® showed a very significant reduction in pulmonary vascular resistance, a strong trend toward improved exercise capacity and a significant delay in the time to clinical worsening. Actelion has submitted this new data to regulatory authorities for a possible label extension of Tracleer® (currently approved for PAH class III and IV). This would represent a major improvement in patient care, as earlier treatment slows the progression of this debilitating disease.
The Phase III study FUTURE-1 evaluated the safety and pharmacokinetics of a special pediatric formulation of Tracleer® in children with PAH. In 2007, Actelion expects to approach regulatory authorities regarding its children’s formulation, documented by the positive safety data from this open label trial. In parallel there is an ongoing open-label trial, FUTURE-2, with results expected in mid-2007.
In 2006, the Tracleer® label was updated in numerous markets to reflect the results of the multi-center, randomized, double-blind, placebo-controlled study BREATHE-5. This study evaluated the use of Tracleer® in pulmonary arterial hypertension related to Eisenmenger’s syndrome, a severe congenital heart defect. 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.
Actelion’s Clinical Development team is also seeking to expand the benefits of Tracleer® to other patient populations. Two Phase III trials are currently being conducted with Tracleer® in PAH related to sickle cell disease, ASSET-1 and ASSET-2, with results expected early in 2008.
Initial results from TRUST, a prospective, open-label trial in PAH patients with connective tissue disease, showed a 92% survival rate at 48 weeks for patients on Tracleer® and a marked improvement in their quality of life. Clinical Development is collaborating with physicians on screening programs such as ItinérAIR in France and UNCOVER in the US to improve the chances of identifying and diagnosing PAH associated with these diseases.
Clinical trials on the safety and efficacy of combination therapies in PAH
Actelion is taking the lead in evaluating the combination of Tracleer® with other PAH agents, with current trends showing that as many as 50% of PAH patients are already treated with more than one therapy. The COMPASS-1 open-label study in patients with PAH has demonstrated that single-dose sildenafil on top of Tracleer® therapy results in significant improvements in pulmonary vascular resistance. The COMPASS-2 is a longer-term study with up to 600 patients to evaluate the combined safety and efficacy of Tracleer® and sildenafil compared to sildenafil and placebo.
After the acquisition of CoTherix, Actelion is also continuing the VISION program to evaluate the safety and efficacy of Ventavis® (inhaled iloprost) in addition to either sildenafil or the combination of sildenafil and Tracleer®. Efforts are also underway to improve the inhalation device as well as to evaluate different re-formulation efforts. Ventavis® is a synthetic compound that is structurally similar to prostacyclins – naturally occurring molecules that cause blood vessels to dilate. Ventavis® is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in patients with NYHA Class III or IV symptoms. In controlled trials, Ventavis® improved a composite endpoint consisting of exercise tolerance, symptoms and impact on clinical worsening.
In March 2007, Actelion announced the initial results from the first-ever placebo-controlled study BENEFiT evaluating Tracleer® in inoperable chronic thrombo-embolic pulmonary hypertension (CTEPH), caused by blockage of the main arteries leading from the heart to the lungs. The study met its primary objective of a significant reduction in pulmonary vascular resistance. There was also a significant reduction in breathlessness during exercise and a trend in favor of preventing clinical worsening, with a positive safety and tolerability profile. Actelion will discuss these findings with regulatory authorities worldwide.
The pivotal Phase III study BUILD-3 is evaluating the safety and efficacy of Tracleer® in 390 patients suffering from idiopathic pulmonary fibrosis (IPF), a scarring or thickening of the alveoli (air sacs) in the lungs that result in a median survival rate of only three years. Enrollment is ongoing in this event-driven study carried out under a special protocol agreement from the US Food and Drug administration, and study results are expected in late 2009. In May 2006, Actelion presented evidence at the American Thoracic Society meeting in San Diego on BUILD-1, which provided a strong rationale for further clinical evaluation of Tracleer® in IPF based on a positive trend for pre-defined morbidity/mortality endpoints – especially in patients who had a lung biopsy as proof of IPF.
RAPIDS-2 is a Phase III placebo-controlled, randomized study that evaluated Tracleer® in patients with digital ulcerations associated with systemic sclerosis. The study confirmed the results of RAPIDS-1, showing a significant reduction in the number of new digital ulcers and a concomitant improvement in several hand functions, with the best results in those patients with the most severe form of digital ulcers. Discussions are underway with regulatory agencies in the EU and the US to expand the Tracleer® label in this indication.
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 Actelion open-label trial at five centers in Australia, which has the world’s highest incidence of this disease, showed that high doses of Tracleer® were well tolerated and revealed preliminary positive signs. Initial results of a placebo-controlled randomized Phase II trial are expected early in 2008.
Actelion-1, potent successor to Tracleer®, ready to begin Phase III trials
In December 2006, Actelion disclosed clinical results of the first tissue-targeting dual endothelin receptor antagonist. A successful Phase II trial underlined the significance of this targeted approach. Actelion-1 showed robust results in hypertensive patients without side effects such as peripheral edema (e.g. fluid retention and swelling of the legs). Enrollment is now underway for Phase III trials for this highly potent successor compound for Tracleer®, which is initially being developed in pulmonary hypertension, with other cardiopulmonary indications expected to follow.
Zavesca® (miglustat) is the only approved oral drug with wide tissue distribution and proven long-term efficacy in type 1 Gaucher disease, a genetic disorder that causes lipids to accumulate in the cells, resulting in enlarged liver and spleen, as well as bone manifestations (tissue and marrow). It has now become clear that clinical symptoms, such as bone pain or osteoporosis, and long-term Gaucher outcomes underscore unmet medical needs requiring an appropriate management strategy with the ultimate objective of improving patients’ daily quality of life. Clinical Development is moving ahead to improve and expand the existing label in type 1 Gaucher disease to offer new therapeutic options to patients and to contribute to a better understanding of the natural history of the disease. In addition, efforts are underway to obtain approval for a new indication in one neurological glycolipid storage disease.
The MAINTENANCE study, the largest open label, non-comparative, international study in type 1 Gaucher disease (GD1) patients, is currently testing Zavesca® as a maintenance therapy by switching patients who have been stable on enzyme replacement therapy (ERT, Cerezyme®) to miglustat for at least two years. A valuable clinical insight has already been obtained from a preliminary study showing that in patients stabilized on ERT, switching to miglustat is compatible with successful maintenance of disease stability in a high proportion of cases.
Recently, a meta-analysis of three Zavesca® clinical trials with more than 70 GD1 patients revealed that 78% of these patients – switched or treatment-naïve – who received miglustat in monotherapy remained pain-free for two years. By comparison, approximately four out of five GD1 patients were already experiencing bone pain before they began therapy with Zavesca®. None of the patients treated with miglustat reported clinical bone events such as bone crisis, pathologic fracture or avascular necrosis. In parallel, bone mineral density increased as early as six months, and bone marrow infiltration reduced; both are hallmarks of bone manifestations in Gaucher disease.
With the Gaucher Natural History Study, Actelion’s objective is to determine the prevalence and incidence (over two years) of peripheral neuropathy as an unrecognized clinical manifestation of the disease, and of other co-morbidities in adult GD1 patients. In an interim analysis conducted with the first 74 patients, 11% of them (treatment-naïve or on ERT) had a polyneuropathy as defined by combined abnormal electrophysiology, and signs and symptoms. For a non-Gaucher population, the prevalence ranges between only 0.12% and 3.6%. No co-morbidities were identified.
Niemann-Pick type C (NP-C) is an autosomal recessive genetic disease affecting children, juvenile and adults, characterized by progressive, severe and heterogeneous neurological manifestations, and reduced life expectancy. Glycolipid accumulation and impaired cholesterol trafficking in tissues is the underlying cause of the disease. There is currently no treatment approved for this disease. In a controlled Phase II trial, NP-C patients, including children, have received miglustat for two years. The analysis of the first year of treatment showed trends of improvement or stabilization in treated patients – namely, eye movement velocity, swallowing capacity, ambulation and cognition. The results showed that 58% of Zavesca®-treated patients with moderate-to-severe disease at baseline remained at least stable, compared to 0% without treatment. The safety profile was comparable to that observed in GD1 patients with miglustat. The 24-month data is under evaluation. On the basis of the one-year results, Actelion has initiated a regulatory filing in the European Union, and orphan drug designation has already been granted.
Clinical trials in both type 3 Gaucher disease and late onset Tay-Sachs did not generate significant results, and, therefore, no further studies are planned in these indications.
Clazosentan to enter Phase III in aneurysmal subarachnoid hemorrhage
Subarachnoid hemorrhage (cerebral bleeding) due to the rupture of an aneurysm occurs on average in 10 out of 100,000 people. Around 84,000 patients are diagnosed in North America, Europe and Japan each year. A large percentage of these develop vasospasm (severe constriction of blood vessels), resulting in significant neurological damage and life-long disabilities.
In October 2006, an analysis of Actelion’s dose-finding study CONSCIOUS-1 was presented at the Congress of Neurological Surgeons in Chicago. All three doses of intravenous clazosentan tested (1mg/h, 5mg/h and 15mg/h) reached statistical significance versus placebo for the primary endpoint: the reduction in the occurrence of moderate or severe cerebral vasospasm. The effect was dose-related and most significantly seen with the dose of 15 mg/hour, a relative risk reduction compared to placebo of 65% (p<0.0001). Detailed pos-hoc analysis also showed a trend in favor of reducing morbidity/mortality related to vasospasm. The safety profile is compatible with use in an intensive care unit environment. The parameters for the Phase III trial CONSCIOUS-2 are currently being discussed with regulatory authorities. Actelion expects this pivotal study to start by the end of 2007, enrolling up to 1,800 patients, with results expected in late 2009.
In 2007, Actelion will start recruitment in the first Phase III study evaluating the safety and efficacy of the intravenous endothelin receptor antagonist tezosentan. The targeted indication is the reduction of clinically relevant right ventricular failure associated with difficult separation from bypass in patients undergoing cardiac surgery with cardiopulmonary bypass. The first study will enroll up to 270 patients, with results expected in 2008. If the findings are positive, Actelion will perform a second pivotal study to compile a full registration dossier.
Joint clinical development projects with Merck and Roche move forward
In 2006, the renin alliance with Merck achieved its third clinical milestone, triggering a payment to Actelion of USD 7 million, as the project moved forward into Phase I trials. Actelion and Merck formed an exclusive worldwide alliance in December 2003 to discover, develop and market new classes of renin inhibitors for patients suffering from cardio-renal diseases. The two companies are jointly funding Phase II development, with Merck responsible for funding all Phase III and outcome studies. Renin plays a key role in the regulation of blood volume, sodium status, arterial pressure, and cardiac or vascular function. Therapeutic manipulation of the renin-angiotensin pathway is believed to hold considerable potential in treating hypertension and heart or renal failure.
In July 2006, Actelion announced an exclusive worldwide collaboration with Roche to jointly develop and commercialize Actelion’s selective S1P1 receptor agonist, an immunomodulator with the potential for once-a-day oral dosing. The compound is currently in Phase I development. The two companies plan to jointly develop and commercialize S1P1 agonists for multiple autoimmune disorders.
Sphingosine-1-phosphate (S1P) is a phospholipid released by platelets, mast and other cells that leads to a variety of biological responses. At least five S1P receptors are known, affecting lymphocyte migration, endothelial cell function, blood vessel constriction, heart rate modulation and other physiological processes. Actelion’s agonist selectively activates the S1P1 receptor sub-type, an approach that is expected to be a key differentiator to other novel immunomodulators under development, such as fingolimod from Novartis (see also “Inside Story”).
Orexin antagonist: promising results in primary insomnia
Actelion’s orexin receptor antagonist has enormous potential as the first in a new class of sleep-enhancing agents. In the United States alone, a 2005 National Institutes of Health (NIH) state-of-science conference about chronic insomnia estimated that there were up to 80 million Americans suffering from sleeplessness, of which 25 million suffered from chronic insomnia.
In February 2007, Actelion announced the results of a proof-of-concept study with its orexin receptor antagonist in patients with primary insomnia. The study met its primary endpoint, an improvement in sleep efficiency measured by polysomnography. This finding obtained in the per-protocol analysis from 39 patients receiving the starting dose in this multi-center, multiple-stage, double-blind, randomized, placebo-controlled clinical trial was highly statistically significant (p<0.0001). The clinical results in patients suffering from primary insomnia add to the understanding of the role of the orexin system, as described in the February 2007 edition of Nature Medicine. This publication presents data generated by Actelion in both animal models and healthy volunteers. The data, comprising the proof of concept study together with results of other ongoing pre-clinical and clinical activities, will define the final design of the upcoming Phase III program, expected to start before year-end 2007 and to last two to three years.
For more extensive details on clinical trial results, visit www.actelion.com
