Actelion's selective S1P1 receptor agonist ponesimod successful in mid-stage trial for multiple sclerosis - Ponesimod to proceed to Phase III final stage of clinical development
ALLSCHWIL/BASEL, SWITZERLAND - 02 August 2011 - Actelion (SIX: ATLN) announced today that the primary endpoint - reduction in the number of new active inflammatory lesions in the brain - has been met with its selective S1P1 receptor agonist, ponesimod, in a Phase IIb dose-finding study in patients with relapsing-remitting multiple sclerosis.
The study assessed efficacy, safety and tolerability of three ponesimod doses (10 mg, 20 mg or 40 mg) versus placebo, administered orally once daily for 24 weeks. With 464 patients enrolled, this is the largest ever dose-finding study conducted in this autoimmune disorder of the central nervous system.
In this study, ponesimod significantly reduced the cumulative number of new active lesions on monthly magnetic resonance imaging (MRI) brain scans performed from weeks 12 to 24, with the most effective dose at p<0.0001.
Martine Clozel, M.D. and Chief Scientific Officer at Actelion commented: "This is the first report of a selective S1P1 receptor agonist reporting a statistically significant treatment effect in patients suffering from relapsing multiple sclerosis. The relationship between lymphocyte count reduction and efficacy will be an important topic for further scientific scrutiny. The rapid reversibility of lymphocyte count observed upon treatment discontinuation already highlights a key differentiation attribute of this selective S1P1 receptor agonist and its pharmacokinetic profile."
As in previous healthy volunteer studies with ponesimod, average lymphocyte counts in patients with relapsing multiple sclerosis were reduced in a dose-dependent fashion. Average lymphocyte counts returned to baseline values within a week in patients who discontinued treatment with ponesimod.
Guy Braunstein, M.D. and Head of Clinical Development at Actelion commented: "I am very pleased to observe that this large study shows a clear dose response relationship. This gives us confidence that we can identify the appropriate dosing regimen for the upcoming Phase III program."
Despite the small overall number of confirmed relapses in this study, there was also a clinically meaningful effect observed on annualized relapse rate, an important secondary endpoint. Multiple sclerosis is most commonly diagnosed in young adults and is associated with diverse recurrent neurological symptoms.
Ponesimod exhibited an adverse event pattern in this study that, if confirmed in the upcoming Phase III program, would give ponesimod a competitive safety and tolerability profile.
Jean-Paul Clozel, M.D. and Chief Executive Officer commented: "This large Phase IIb study highlights the efficacy of ponesimod and provides us with key information on the potential differentiation of this agent from all other oral MS agents, either marketed or in development. I am very pleased that our drug discovery and development efforts have resulted in such a promising compound."
Once full data analysis has been concluded, Actelion will discuss the details of the upcoming Phase III program with health authorities worldwide. At a later stage, Actelion will discuss and present the findings of this Phase IIb study as well as the Phase III program in scientific presentations and publications.
Notes to the Editor
About Multiple sclerosis
Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) and is the most common cause of progressive neurological disability in young adults [1,2]. MS is a disease caused by a cascade of events involving an activation of the immune system, acute focal inflammatory demyelinating lesions with limited remyelination and axonal loss, culminating in chronic multifocal sclerotic plaques in the brain and spinal cord.
Patients suffering from MS experience a heterogeneous collection of clinical symptoms, an unpredictable course and a variable prognosis. A large variety of symptoms and signs of MS result from axonal demyelination and axonal loss, with a corresponding slowing or blockade of axonal conduction at affected sites of the brain and spinal cord. Repeated episodes of disease activity may lead to a progressive loss of neurological function.
The incidence of MS is about 7 cases per 100,000 persons per year  and, although the etiology of MS is still unknown, the prevalence rate varies between ethnic origins and geographical latitudes, ranging from 50 to 120 per 100,000 . It is widely accepted that it is an immune-mediated, demyelinating disease precipitated by unknown environmental factors in genetically susceptible people.
About the Phase IIb study with ponesimod in multiple sclerosis
The study was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase IIb dose-finding clinical trial in patients with relapsing-remitting multiple sclerosis. A total of 464 patients were randomized and the efficacy, safety and tolerability of three ponesimod doses versus placebo, administered once daily for 24 weeks, was evaluated.
The primary endpoint of this study was defined as the cumulative number of new gadolinium-enhancing lesions on T1-weighted magnetic resonance imaging (MRI) scans at weeks 12, 16, 20 and 24 after study drug initiation. A gadolinium-enhancing lesion is a bright spot that appears on the MRI scan as a consequence of blood-brain barrier disruption during an immune attack against myelin, the fatty substance surrounding and protecting nerve fibers in the brain and spinal cord.
A key secondary endpoint of this study was the annualized relapse rate over 24 weeks of treatment. A relapse is defined as the occurrence of an acute episode of one or more new symptoms or the worsening of existing MS symptoms (e.g. numbness, muscle weakness, speech or visual problems) not associated with fever or infection and lasting for at least 24 hours after a stable period of at least 30 days.
Patients who completed 24 weeks of treatment were offered the opportunity to enter an extension study where patients initially randomized to placebo in the core study were re-randomized to one of the three ponesimod doses; patients initially randomized to ponesimod were maintained on the same dose of active treatment. The extension study is ongoing.
About S1P receptors
Sphingosine-1-phosphate (S1P) is a phospholipid released by erythrocytes, platelets, mast cells and other cell types. It is currently established that S1P stimulates at least five different cell surface resident G-protein coupled receptors (GPCRs) - S1P1,2,3,4, and 5. Activation of these GPCRs mediates a complex variety of biological responses such as lymphocyte migration, endothelial cell proliferation, blood vessel constriction and heart rate modulation.
About the selective S1P1 agonist ponesimod
Ponesimod is an orally active, selective sphingosine 1-phosphate receptor 1 (S1P1) agonist. Ponesimod prevents lymphocytes from leaving lymph nodes, thereby reducing circulating blood lymphocyte counts and preventing infiltration of lymphocytes into target tissues. The lymphocyte count reduction is rapid, dose-responsive, is sustained with continued dosing and quickly reversed upon discontinuation. Ponesimod does not cause lymphotoxicity: it does not destroy lymphocytes or interfere with their cellular function. Other blood cells of the innate immune system are unaffected and remain available to fight off infection. Ponesimod is therefore considered a promising new oral agent for the treatment of a variety of autoimmune disorders.
About ponesimod in psoriasis
Ponesimod is also being developed as a potential oral agent in psoriasis, an autoimmune disease of the skin. Ponesimod is currently evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel-group, once-daily dosing study designed to evaluate the efficacy, safety and tolerability of two ponesimod doses in patients with moderate to severe chronic plaque psoriasis. This 320-patient study started enrollment in 2010 and is expected to report results in H2 2012.
About Actelion and selective S1P1 agonists
Actelion's efforts in the field of selective S1P1 receptor agonists started in 1999 by focusing on GPCRs found on the endothelium, the inner lining of blood vessels. The result of these research efforts is Actelion's orally active selective S1P1 receptor agonist, ponesimod.
1. Compston A, Coles A. Multiple sclerosis. Lancet 2002;359:1221-31.
2. Compston A, Coles A. Multiple sclerosis. Lancet 2008;372:1502-18.
Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion's first drug Tracleer®, an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets Tracleer® through its own subsidiaries in key markets worldwide, including the United States (based in South San Francisco), the European Union, Japan, Canada, Australia and Switzerland. Actelion, founded in late 1997, is a leading player in innovative science related to the endothelium - the single layer of cells separating every blood vessel from the blood stream. Actelion's over 2,500 employees focus on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion shares are traded on the SIX Swiss Exchange (ticker symbol: ATLN) as part of the Swiss blue-chip index SMI (Swiss Market Index SMI®).
Posted: August 2011