Date: 2012-12-18
Type of information: Results
phase: 2
Announcement: results
Company: Actelion (Switzerland)
Product: ponesimod
Action
mechanism: immunomodulator/ S1P1 immunomodulator. Sphingosine-1-phosphate (S1P) is a sphingolipid 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. Ponesimod is an orally active, selective S1P1 immunomodulator. It 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 e.g. 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.
Disease: psoriasis
Therapeutic area: Autoimmune diseases - Dermatological diseases
Country:
Trial
details: Ponesimod was studied in patients with moderate-to-severe psoriasis in a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial that evaluated the efficacy, safety and tolerability of 2 dose levels of ponesimod administered during 16 weeks. This induction period was followed by a 12-week maintenance period during which patients treated with ponesimod and reaching PASI50 at week 16 were treated either with ponesimod or placebo, for a total of up to 28 weeks. This 326-patient study started enrollment in 2010 and was completed in November of 2012.
Latest
news: Actelion has announced that its selective S1P1 modulator, ponesimod, successfully met the primary endpoint - the proportion of patients with at least 75% improvement in Psoriasis Area and Severity Index (PASI) from baseline (PASI75) at week 16 - in a double blind, placebo-controlled study conducted in 326 patients with moderate to severe chronic plaque psoriasis.
Results of the primary endpoint were highly statistically significant with both tested doses. With ponesimod 20 mg, 46 % of patients improved by at least 75 % at week 16 (pAt the end of induction, ponesimod patients improving at least 50% or more in their PASI score at week 16 were re-randomized to either continuation of the same dose of ponesimod, or to placebo.
After the initial 16 week induction phase of the study, further improvement was seen with ponesimod during the 12-week double-blind, placebo-controlled maintenance period. Among patients continuing on ponesimod 20 and 40mg, 71 % and 77 % achieved PASI75 at the end of the study, respectively.
Efficacy was also demonstrated across other endpoints of the study, including Physician Global Assessment (PGA) at week 16.
Safety and tolerability data from the study are consistent with the safety profile of ponesimod observed in previous studies conducted including the Phase II study with multiple sclerosis patients. At initiation of ponesimod treatment, transient reductions in heart rate and less frequently, a transient effect on atrioventricular conduction were observed in the study as expected.
A Phase IIb dose-finding study with ponesimod in multiple sclerosis was successfully completed in July 2011. The study assessed efficacy, safety and tolerability of three ponesimod dose levels (10 mg, 20 mg or 40 mg) versus placebo, administered orally once daily for 24 weeks with 464 patients. 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. As compared to placebo, the primary endpoint was reduced by 43% (p<0.05), 83% (p<0.0001) and 77% (p<0.0001) with ponesimod 10, 20 and 40 mg, respectively.
Ponesimod exhibited an adverse event pattern in this study that, if confirmed in a Phase III program, would give ponesimod a competitive safety and tolerability profile.
The most frequent adverse events (AEs) reported for ponesimod was dose-dependent dyspnea and asymptomatic liver enzyme elevations. Overall, there were no indications of an increased infection rate with ponesimod in the study with the exposure to ponesimod up to 28 weeks. The safety data-base from all studies with ponesimod, now comprises more than 1,100 patients and healthy volunteers with some patients treated for up to 3.3 years.Once full data analysis has been concluded, Actelion will discuss the details of the upcoming Phase III program with health authorities. Actelion will present the results of this dose-finding study through scientific presentations and publications.
