Actelion to investigate all-oral combination therapy for patients with relapsing multiple sclerosis

Actelion Pharmaceuticals Ltd / Actelion to investigate all-oral combination therapy for patients with relapsing multiple sclerosis . Processed and transmitted by Nasdaq Corporate Solutions. The issuer is solely responsible for the content of this announcement.

ALLSCHWIL/BASEL, SWITZERLAND - 29 September 2016 - Actelion Ltd (SIX: ATLN) announced today that it will investigate the use of combination therapy with ponesimod and dimethyl fumarate (Tecfidera^®) for patients with relapsing multiple sclerosis (RMS). The POINT study - which will be conducted under a Special Protocol Assessment (SPA) agreement with the FDA - is the first to assess an all-oral treatment paradigm with the objective to better control this progressive, debilitating neurological disorder.  

Despite recent advances in the treatment of RMS, there remains a considerable medical need for improved long-term disease control without compromising patient safety. While combination therapy is a logical next step, it has likely been limited due to the potential risks associated with the long duration of action of existing products. Ponesimod, with its short half-life and rapid reversibility, could provide physicians with greater flexibility and control of patient treatment. Actelion has generated encouraging preclinical data that suggests the combination of ponesimod and dimethyl fumarate can be beneficial while not compromising safety.

Jean-Paul Clozel, MD and Chief Executive Officer, commented: "I have always believed that combination therapy is the future for the treatment of relapsing multiple sclerosis. The properties of ponesimod, supported by our preclinical knowledge and clinical results, all point towards ponesimod being ideally suited for use in combination. I am very excited that we've gained agreement with health authorities on this innovative approach, and I look forward to Actelion generating the data that could change the treatment paradigm in this devastating disorder."

Guy Braunstein, MD and Head of Global Clinical Development, commented: "Our clinical development program for ponesimod in multiple sclerosis was already innovative when we decided to move into Phase III. OPTIMUM is the first study in MS to target superiority over a commercialized oral therapy. It also includes a number of patient oriented outcome assessments. With POINT, the first trial in active RMS adding one oral drug to another, we will assess the clinical utility of combination therapy with ponesimod, to offer patients better control of their disease."

Actelion initiated the Phase III program in RMS in April 2015 with OPTIMUM, a superiority study to compare the efficacy and safety of ponesimod to that of teriflunomide (Aubagio^®). Enrollment for this study is expected to be completed around the end of 2016.
The company will provide an update on the ponesimod program and an opportunity for Q&A at the upcoming quarterly reporting investor conference call on 20 October 2016.

ABOUT THE POINT STUDY
POINT (POnesImod aNd Tecfidera) is a prospective, multicenter, randomized, double-blind, parallel group, add-on, placebo-controlled, superiority study with ponesimod in patients with RMS. The study is designed to compare the efficacy, safety, and tolerability of add-on therapy with ponesimod 20 mg vs. placebo in adult patients with active RMS who are treated with dimethyl fumarate (Tecfidera^®).

Approximately 600 patients receiving dimethyl fumarate twice daily for at least 6 months will be randomized in a 1:1 ratio to ponesimod 20 mg or placebo. Treatment will be given until the last patient enrolled into the study has been treated for 60 weeks, with expected average treatment duration of 2 years, and for a maximum duration of 3 years. Enrollment is expected to start before the end of 2016.

The primary objective of the study is to determine whether add-on therapy with ponesimod reduces relapse frequency as compared to placebo in patients with active relapsing multiple sclerosis who are treated with Tecfidera. The primary endpoint is the Annualized Relapse Rate (ARR), which is defined as the number of confirmed relapses per patient and year, from randomization up to the end of the study.

Secondary objectives focus on assessing the efficacy, safety and tolerability of add-on therapy with ponesimod versus placebo in patients with relapsing multiple sclerosis who are treated with Tecfidera. Corresponding efficacy and safety endpoints include the time to 12-week CDA (Confirmed Disability Accumulation) and Adverse Events leading to premature discontinuation of treatment.

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ABOUT PONESIMOD
Ponesimod is an orally active, selective sphingosine-1-phosphate receptor 1 (S1P₁) immunomodulator. 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. Initial results suggest that ponesimod does not cause lymphotoxicity by destroying lymphocytes or interfering with their cellular function. Other blood cells e.g. cells of the innate immune system are largely unaffected. Ponesimod is therefore considered a promising new oral agent for the treatment of a variety of autoimmune disorders.

ABOUT OPTIMUM
OPTIMUM (Oral Ponesimod versus Teriflunomide In relapsing MUltiple sclerosis) is a Phase III multi-center, randomized, double-blind, parallel group, active-controlled superiority study to compare the efficacy and safety of ponesimod to teriflunomide in patients with relapsing multiple sclerosis (RMS). The study aims to determine whether ponesimod is more efficacious than teriflunomide in reducing relapses. The study is expected to enroll approximately 1'100 patients, randomized in 2 groups in a 1:1 ratio to receive ponesimod 20 mg/day or teriflunomide 14 mg/ day. Treatment period is 108 weeks, and the study is expected to last a little over 3 years.

ABOUT THE PHASE IIb STUDY WITH PONESIMOD IN MS
Actelion's decision from April 2015 to move into Phase III development was based on the Phase IIb dose-finding study with ponesimod in patients with relapsing-remitting multiple sclerosis. A total of 464 patients were randomized into this study and the efficacy, safety and tolerability of three ponesimod doses (10, 20 and 40 mg/day) 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 key secondary endpoint of this study was the annualized relapse rate over 24 weeks of treatment.
Patients who completed 24 weeks of treatment were offered the opportunity to enter into an extension study. This ongoing trial is investigating the long-term safety, tolerability, and efficacy of 10 and 20 mg/day of ponesimod in patients with relapsing-remitting multiple sclerosis, in a double-blind fashion. The study continues to provide extensive safety and efficacy information for ponesimod in this indication, with some patients treated for more than 6 years.

ABOUT MULTIPLE SCLEROSIS
Multiple sclerosis is an autoimmune disorder of the central nervous system and is the most common cause of progressive neurological disability in young adults. It 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 multiple sclerosis experience a heterogeneous collection of clinical symptoms, an unpredictable course and a variable prognosis. A large variety of symptoms and signs of multiple sclerosis 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 multiple sclerosis is about 7 cases per 100,000 persons per year and, although the etiology of multiple sclerosis 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.

Relapsing-remitting multiple sclerosis (RRMS) is the most common type of multiple sclerosis (MS), affecting approximately 85% of MS patients at time of diagnosis. RRMS is characterized by unpredictable episodes, called relapses, of acute worsening of neurologic function. With RRMS, these relapses are typically followed by periods of remission. A patient diagnosed with RMS (relapsing multiple sclerosis) has experienced at least 2 relapses and has brain lesions consistent with RMS. Some patients with early stage secondary progressive MS will still experience relapses. In our Phase III program we enroll patients who experience relapses, no matter which form of MS they have.

REFERENCES

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2. Tramacere I, Del Giovane C, Salanti G, D'Amico R, Filippini G. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev. 2015 Sep 18; 9:CD011381.
3. D'Ambrosio D, Freedman MS, Prinz J. Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases. Ther Adv Chronic Dis. 2016 Jan; 7(1):18-33.
4. Olsson T, Boster A, Fernandez O, Freedman O, Freedman MS, Pozzilli C, Bach D, Berkani O, Mueller MS, Sidorenko T, Radue EW, Melanson M. Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial. J Neurol Neurosurg Psychiatry. 2014 Nov; 85(11):1198-208.
5. Investigator's Brochure for ponesimod S1P1 receptor agonist, version 10. Actelion Pharmaceuticals, Ltd, May 2015.
6. Longbrake EE, Naismith RT, Parks BJ, Wu GF, Cross AH. Dimethyl fumarate-associated lymphopenia: Risk factors and clinical significance. Mult Scler J Exp Transl Clin. 2015 Jan-Dec; 1.
7. Kappos L, Mehling M, Arroyo R, Izquierdo G, Selmaj K, Curovic-Perisic V, Keil A, Bijarnia M, Singh A, von Rosenstiel P. Randomized trial of vaccination in fingolimod-treated patients with multiple sclerosis. Neurology. 2015 Mar 3; 84(9):872-9.
8. Mehling M, Johnson T, Antel J, Kappos L, Bar-Or A. Clinical immunology of the sphingosine 1-phosphate receptor modulator fingolimod (FTY720) in multiple sclerosis. Neurology. 2011 Feb 22;76: S20-S27.
9. D'Ambrosio D, Steinmann J, Brossard P, Dingemanse J. Differential effects of ponesimod, a selective S1P1 receptor modulator, on blood-circulating human T cell subpopulations. Immunopharmacol Immunotoxicol. 2015 Feb; 37(1):103-9.
10. Francis G, Kappos L, O'Connor P, Collins W, Tang D, Mercier F, Cohen JA. Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy. Mult Scler. 2014 Apr; 20(4):471-80.

Actelion Ltd.
Actelion Ltd. is a leading biopharmaceutical company focused on the discovery, development and commercialization of innovative drugs for diseases with significant unmet medical needs.

Actelion is a leader in the field of pulmonary arterial hypertension (PAH). Our portfolio of PAH treatments covers the spectrum of disease, from WHO Functional Class (FC) II through to FC IV, with oral, inhaled and intravenous medications. Although not available in all countries, Actelion has treatments approved by health authorities for a number of specialist diseases including Type 1 Gaucher disease, Niemann-Pick type C disease, Digital Ulcers in patients suffering from systemic sclerosis, and mycosis fungoides type cutaneous T-cell lymphoma.

Founded in late 1997, with now over 2,500 dedicated professionals covering all key markets around the world including Europe, the US, Japan, China, Russia and Mexico, Actelion has its corporate headquarters in Allschwil / Basel, Switzerland.

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®). All trademarks are legally protected by their respective owners.

For further information please contact:
Andrew Weiss
Senior Vice President, Head of Investor Relations & Corporate Communications
Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil
+41 61 565 62 62
www.actelion.com

The above information contains certain "forward-looking statements", relating to the company's business, which can be identified by the use of forward-looking terminology such as "estimates", "believes", "expects", "may", "are expected to", "will", "will continue", "should", "would be", "seeks", "pending" or "anticipates" or similar expressions, or by discussions of strategy, plans or intentions. Such statements include descriptions of the company's investment and research and development programs and anticipated expenditures in connection therewith, descriptions of new products expected to be introduced by the company and anticipated customer demand for such products and products in the company's existing portfolio. Such statements reflect the current views of the company with respect to future events and are subject to certain risks, uncertainties and assumptions. Many factors could cause the actual results, performance or achievements of the company to be materially different from any future results, performances or achievements that may be expressed or implied by such forward-looking statements. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those described herein as anticipated, believed, estimated or expected.

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Actelion Pharmaceuticals Ltd
Gewerbestrasse 16 Allschwil Switzerland

ISIN: CH0010532478;