Novartis announces NEJM publication of two phase III studies demonstrating high efficacy of secukinumab (AIN457) in psoriasis patients

  • Results of two phase III psoriasis studies consistently show rapid, very high skin clearance, sustained efficacy and an acceptable safety profile with secukinumab[1]
  • More than 70% of secukinumab 300 mg patients experienced clear (PASI 100) or almost clear skin (PASI 90) during the first 16 weeks of treatment[1]
  • If approved, secukinumab could address a high unmet need for new psoriasis treatments, as up to 50% of patients are dissatisfied with current therapies[2],[3]
  • Secukinumab is the first IL-17A inhibitor with phase III data presented in psoriasis and regulatory submissions filed with global health authorities

Basel, 9 July 2014 - Novartis today announced that detailed results from two pivotal phase III studies evaluating the interleukin-17A (IL-17A) inhibitor secukinumab (AIN457) were published online today in the New England Journal of Medicine (NEJM). Secukinumab met all primary and key secondary endpoints at Week 12 in the ERASURE and FIXTURE studies, showing superiority to Enbrel®* (etanercept) in improving moderate-to-severe plaque psoriasis symptoms in the FIXTURE study, and superiority over placebo in both studies[1].

Over half of secukinumab 300 mg patients experienced clear (PASI 100) or almost clear (PASI 90) skin, described as Psoriasis Area and Severity Index 90 or 100 (PASI 90/PASI 100) by Week 12 (59.2% for ERASURE and 54.2% for FIXTURE, p<0.001)[1]. In comparison, only 20.7% of Enbrel-treated patients experienced PASI 90 or 100 in FIXTURE[1]. Secukinumab 300 mg patients' response continued to improve from Week 12, with more than 70% experiencing clear or almost clear skin by Week 16 (72.4% and 36.8% for PASI 90 and 100, respectively) in the FIXTURE study, which was maintained in the majority of patients up to Week 52 (with continued treatment)[1].

PASI measures the redness, scaling and thickness of psoriatic plaques and the extent of involvement in each region of the body. Treatment efficacy is assessed by the reduction of the score from baseline (i.e. a 75% reduction is known as PASI 75, a 90% reduction is known as PASI 90, and PASI 100 is completely clear skin). PASI 90 and 100 are more robust measures of the extent of skin clearance compared to standard measures[4], such as PASI 75, that have been used in most psoriasis clinical studies.

"The publication of two pivotal phase III studies in NEJM showing consistently high efficacy of secukinumab validates IL-17A as a preferred treatment target in psoriasis," said David Epstein, Division Head, Novartis Pharmaceuticals. "These data, which are part of our regulatory submissions, are important as there is a high need for effective new therapies for people living with this debilitating disease."

Psoriasis is a chronic autoimmune disease characterized by thick and extensive skin lesions, called plaques, known to cause itching, scaling and pain[5] that is associated with significant impairment of physical and psychological quality of life[6],[7]. Up to 50% of patients are dissatisfied with their current psoriasis therapies, including approved biologics[2],[3], indicating a high need for new therapies that act rapidly with prolonged duration to relieve the debilitating symptoms[8],[9].

Data published in NEJM also show that secukinumab-treated patients had their symptoms resolved faster than those treated with Enbrel in the FIXTURE study[1]. Clinically relevant differences were observed as early as Week 2, and on average secukinumab 300 mg patients had their symptoms halved by Week 3, compared to Week 7 for Enbrel patients[1].

In addition to high rates of clear to almost clear skin, secukinumab patients also reported superior improvements in itching, pain and scaling, compared to placebo at Week 12, in ERASURE[1]. Similarly, health-related quality of life (HRQoL) was significantly improved among secukinumab-treated patients at Week 12 compared to placebo in both studies, as assessed by the Dermatology Quality of Life Index (DLQI)[1]. The effect of psoriasis on quality of life has been shown to be similar to diseases such as cancer, heart disease, arthritis, type 2 diabetes and depression[10].

In ERASURE and FIXTURE secukinumab exhibited an acceptable safety profile consistent with phase II studies[1]. In both studies, the incidence of adverse events (AEs) was similar between both secukinumab treatment arms (300 mg and 150 mg), and were slightly higher than in the placebo group during the 12-week induction period, mostly consisting of mild to moderate upper respiratory tract infections[1]. Incidences of AEs in the secukinumab groups during induction and the entire 52-week treatment period in FIXTURE were comparable with Enbrel[1].

About the ERASURE and FIXTURE studies[1] 
ERASURE (Efficacy of Response And Safety of two fixed secUkinumab REgimens in psoriasis) and FIXTURE (the Full year Investigative eXamination of secukinumab vs. eTanercept Using 2 dosing Regimens to determine Efficacy in psoriasis) are part of the largest phase III program in moderate-to-severe plaque psoriasis completed to date, which involved more than 3,300 patients in over 35 countries.

ERASURE and FIXTURE assessed the efficacy, safety and tolerability of induction period (at Week 12) and maintenance therapy (at Week 52) with subcutaneous secukinumab 300 mg or 150 mg in patients with moderate-to-severe plaque psoriasis. Both studies were multicenter, randomized, double-blind, placebo-controlled (FIXTURE: also active controlled), parallel-group phase III trials involving 738 patients and 1,306 patients with moderate-to-severe plaque psoriasis, respectively. Each study consisted of a 1-to-4-week screening period, a 12-week induction period, a 40-week maintenance period and an 8-week follow-up period. FIXTURE is the first full-year blinded, direct comparison of biologic therapies for psoriasis in a phase III study.

The co-primary endpoints in both studies, PASI 75 response and Investigator's Global Assessment (IGA mod 2011) 0/1 response at Week 12, were used to demonstrate superiority of secukinumab vs. placebo (p<0.001 for all comparisons). Secukinumab 300 mg demonstrated significant improvements in PASI 75 at Week 12 (81.6% vs. 4.5% for placebo in ERASURE and 77.1% vs. 44.0% for Enbrel vs. 4.9% for placebo in FIXTURE). Secukinumab 300 mg was also superior to comparator arms in IGA mod 2011 0/1 response at Week 12. Response over time suggests that PASI and IGA response rates improved from Week 12 to Week 16 and then maintained after Week 16[1]. The 300 mg dose showed numerically and clinically relevant improvements compared to 150 mg in both studies[1].

Key secondary endpoints in both studies included comparisons with placebo according to PASI 90 at Week 12, patient-reported outcomes of itching, pain and scaling from the Psoriasis Symptom Diary© at Week 12 and HRQoL according to the DLQI. In addition, the FIXTURE study assessed secukinumab superiority vs. Enbrel across several measures including PASI 90 at Week 12, maintenance of PASI 75 from Week 12 to Week 52, and maintenance of IGA mod 2011 0/1 from Week 12 to Week 52.

About secukinumab (AIN457) and interleukin-17A (IL-17A)
Secukinumab (AIN457) is a fully human monoclonal antibody that selectively binds to and neutralizes interleukin-17A (IL-17A)[11]-[13]. IL-17A is a central cytokine (messenger protein) involved in the development of psoriasis and is found in high concentration in skin affected by the disease[14],[15]. Research shows that IL-17A plays a key role in driving the body's autoimmune response in disorders such as moderate-to-severe plaque psoriasis and is a preferred target for investigational therapies[11]-[13],[16],[17].

Secukinumab is the first therapy selectively targeting IL-17A to publish phase III results. Regulatory submissions for secukinumab in the EU and US were completed in 2013.

Phase III results for secukinumab in moderate-to-severe plaque psoriasis were first presented in October 2013, with additional results to be presented in 2014 for both moderate-to-severe plaque psoriasis and arthritic conditions (psoriatic arthritis and ankylosing spondylitis). Phase IIIb studies are also ongoing, including the head-to-head CLEAR study of secukinumab versus Stelara®** in moderate-to-severe plaque psoriasis and studies in palmo-plantar psoriasis, nail psoriasis and palmo-plantar pustulosis. Phase II studies are also ongoing in other indications.

About Novartis in specialty dermatology 
Novartis is committed to developing innovative, life-changing specialty dermatology therapies, redefining treatment paradigms and transforming patient care in severe skin diseases where there are remaining high unmet medical needs. The Novartis specialty dermatology portfolio includes Xolair® (omalizumab) and secukinumab (AIN457). Xolair is a targeted therapy that is approved as an add-on therapy for the treatment of refractory chronic spontaneous urticaria (CSU) in the EU and in more than 10 other countries, and for refractory chronic idiopathic urticaria (CIU) as it is known in the US. Regulatory reviews are currently ongoing in more than 20 countries, including Canada, Australia and Switzerland. Secukinumab is the first IL-17A inhibitor to have completed phase III registration studies in moderate-to-severe plaque psoriasis. There are also more than 10 compounds in early stage development for a wide range of severe skin diseases in the Novartis specialty dermatology portfolio. For more information about the Novartis commitment to severe skin disease care, please visit:www.skintolivein.com.

Disclaimer
The foregoing release contains forward-looking statements that can be identified by words such as "could," "indicating," "suggests," "investigational," "to be presented," "ongoing," "committed," "early stage development," "commitment," or by express or implied discussions regarding potential marketing approvals for AIN457 or any other dermatology products, potential and recently approved new indications or labeling for Xolair, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on the current beliefs and expectations of management regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that AIN457 or any other dermatology products will be submitted or approved for sale in any market, or at any particular time. Nor can there be any guarantee that Xolair will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Neither can there be any guarantee that AIN457, Xolair or any such other products will achieve any particular levels of revenue in the future. In particular, management's expectations regarding these products could be affected by, among other things, unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including ongoing pricing pressures; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; unexpected manufacturing issues; general economic and industry conditions, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis
Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2013, the Group achieved net sales of USD 57.9 billion, while R&D throughout the Group amounted to approximately USD 9.9 billion (USD 9.6 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 135,000 full-time-equivalent associates and sell products in more than 150 countries around the world. For more information, please visithttp://www.novartis.com.

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*Enbrel® is a registered trademark of Amgen Inc.
**Stelara® is a registered trademark of Janssen Biotech, Inc.

References 
[1] Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis: results of two phase three trials. New Engl J Med. 2014 [published online ahead of print 9 July 2014].
[2] Stern RS, Nijsten T, Feldman S, et al. Psoriasis Is Common, Carries a Substantial Burden Even When Not Extensive, and Is Associated with Widespread Treatment Dissatisfaction. J Invest Derm Symp P. 2004; 9: 136-9.
[3] Christophers E, Griffiths CEM, Gaitanis G, et al. The unmet treatment need for moderate to severe psoriasis: results of a survey and chart review. J Eur Acad Dermatol Venereol. 2006; 20: 921-25.
[4] Guideline on clinical investigation of medicinal products indicated for the treatment of psoriasis. European Medicines Agency Web site.http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003329.pdfPublished November 2004. Accessed April 2014.
[5] Nestle FO, Kaplan DH, Barker J. Psoriasis. New Engl J Med. 2009; 361: 496-509.
[6] Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet. 2007; 370: 263-71.
[7] de Korte J, Sprangers MA, Mombers FM, Bos JD. Quality of life in patients with psoriasis: a systematic literature review. J Invest Derm Symp P. 2004; 9:140-7.
[8] Krueger JG, Koo J, Lebwohl M, et al. The impact of psoriasis on quality of life: Results for a 1998 National Psoriasis Foundation patient membership survey. Arch Dermatol. 2001; 137: 280-84.
[9] Sterry W, Barker J, Boehncke WH, et al. Biological therapies in the systemic management of psoriasis: International Consensus Conference. Brit J Dermatol. 2004; 151 Suppl 69: 3-17.
[10] Farley E, Menter A. Psoriasis: comorbidities and associations. G Ital Dermatol Venereol. 2011 Feb; 146(1):9-15.
[11] Gaffen SL. Structure and signaling in the IL-17 receptor family. Nat Rev Immunol. 2009; 9: 556-67.
[12] Ivanov S, Linden A. Interleukin-17 as a drug target in human disease. Trends Pharmacol Sci. 2009; 30:95-103.
[13] Kopf M, Bachmann MF, Marsland BJ. Averting inflammation by targeting the cytokine environment. Nat Rev Drug Discov. 2010; 9: 703-18.
[14] Johansen C, Usher PA, Kjellerup RB, et al. Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin. Brit J Dermatol. 2009; 160: 319-24.
[15] Arican O, Aral M, Sasmaz S, et al. Serum levels of TNF-alpha, IFN-gamma, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediat Inflamm. 2005; 5: 273-9.
[16] Onishi RM, Gaffen SL. Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease. Immunology. 2010; 129: 311-21.
[17] Krueger J, Fretzin S, Suárez-Fariñas M, et al. IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis. J Allergy Clin Immun. 2012; 130: 145-54.

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