Celgene International Sárl Release: Oral OTEZLA® (Apremilast) Approved By The European Commission For The Treatment Of Both Patients With Psoriasis And Psoriatic Arthritis

OTEZLA^®, a selective PDE4 inhibitor, is the first oral treatment in 20 years to receive approval for patients with psoriasis and in the last 15 years to receive approval for psoriatic arthritis^1,2,3

OTEZLA^® has demonstrated proven and durable efficacy in psoriasis, including difficult to treat areas such as scalp and nail, and in psoriatic arthritis, with improvement in swollen and tender joints, as well as dactylitis and enthesitis¹

OTEZLA^® has shown a favourable safety profile, with no European labelling requirement for drug-specific pre-screening or ongoing laboratory monitoring¹

BOUDRY, Switzerland--(BUSINESS WIRE)--Celgene International Sàrl (NASDAQ: CELG), a wholly-owned subsidiary of Celgene Corporation, today announced that the European Commission (EC) has granted marketing authorisation for OTEZLA^® (apremilast), the company’s oral selective inhibitor of phosphodiesterase 4 (PDE4), in two therapeutic indications:¹

“OTEZLA® has also been generally well tolerated and does not require routine laboratory monitoring, which can be beneficial for both physicians and patients.”

• For the treatment of moderate-to-severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or psoralen and ultraviolet-A light (PUVA).
• Alone or in combination with Disease Modifying Antirheumatic Drugs (DMARDs), for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior DMARD therapy.

“The approval of OTEZLA^® is an important new option for the treatment of patients who are not experiencing adequate relief for their conditions. OTEZLA^® has shown significant and clinically meaningful improvements in psoriasis and psoriatic arthritis, including difficult to treat areas such as nail, scalp, and itch, which can all be the cause of great burden for patients,” said Dr. Diamant Thaci, Professor of Dermatology and the Head of the Comprehensive Center of Inflammation and Medicine at the University of Lübeck, in Germany. “OTEZLA^® has also been generally well tolerated and does not require routine laboratory monitoring, which can be beneficial for both physicians and patients.”

OTEZLA^® is the first in a new class of medicines for the treatment of both psoriasis and psoriatic arthritis, two diseases involving dysregulated immune system activity. Psoriasis is a systemic inflammatory condition characterised by raised scaly lesions on the skin. It affects approximately 14 million people across Europe⁴ and about 125 million people worldwide.⁵ Plaque psoriasis, also called psoriasis vulgaris, is the most common form of the disease, representing approximately 80 percent of cases.⁶ Additionally, up to 30 percent of people with psoriasis may develop psoriatic arthritis. Psoriatic arthritis, which is also an immune-mediated disease, is estimated to affect nearly 38 million people worldwide⁷. It is a chronic condition characterised by pain, stiffness, swelling and tenderness of the joints, and a decrease in physical functioning.⁸ Enthesitis (inflammation at sites where tendons or ligaments insert into bone) and dactylitis (inflammation of fingers and toes, commonly known as “sausage fingers and toes”) are specific disease manifestations related to psoriatic arthritis, which can contribute to significant disability.^8,9

“The approval of OTEZLA^® in Europe marks an important juncture in Celgene’s mission to follow the path of science and innovation where the greatest unmet need resides, and where we can make a considerable difference in the lives of people living with debilitating, inflammatory diseases,” stated Tuomo Pätsi, President, Celgene Europe, the Middle East and Africa (EMEA). “Patients with psoriasis and psoriatic arthritis may require lifelong treatment due to the chronic nature of their conditions, and we believe it is our responsibility to offer them a new option which could significantly reduce their symptoms and allow them to live a better life.”

The marketing authorisation is based on efficacy and safety data from two Phase III programs, ESTEEM AND PALACE, which demonstrate a maintained clinical response among patients with psoriasis (ESTEEM) and psoriatic arthritis (PALACE) treated with OTEZLA^® through 52 weeks, across multiple endpoints.^1,10

In the ESTEEM studies, treatment resulted in significant and clinically meaningful improvements in plaque psoriasis as measured by PASI-75 (a 75 percent improvement in the Psoriasis Area Severity Index) scores at week 16, the primary endpoint. Patients on apremilast also benefited from significant improvements in difficult to treat areas, such as nail and scalp, and itch,¹ known to have a marked impact on patients’ quality of life and perception of disease severity.¹¹

In the PALACE program, treatment resulted in significant and clinically meaningful improvements in the signs and symptoms of psoriatic arthritis, as measured by the modified ACR-20 (a 20 percent improvement in the American College of Rheumatology disease activity criteria) response at week 16, the primary endpoint. Patients on apremilast showed improvement across multiple disease manifestations specific to psoriatic arthritis, such as swollen and tender joints, dactylitis, enthesitis and overall physical function and quality of life.^1,9

Consistently, across these Phase III clinical studies, the most commonly reported adverse reactions were diarrhoea, nausea, upper respiratory tract infection, tension headache and headache. Gastrointestinal (GI) adverse reactions were mostly mild to moderate in severity, with 0.3% of diarrhoea and 0.3% of nausea reported as being severe. These adverse reactions generally occurred within the first two weeks of treatment and usually resolved within four weeks. Overall, most adverse reactions were considered to be mild or moderate in severity.¹

The EC decision follows the positive opinion issued by the Committee for Medicinal Products for Human Use (CHMP) in November 2014.¹² OTEZLA^® will be launched in the European Union in the coming months in accordance with local requirements.

OTEZLA^® was approved on March 21, 2014 by the U.S. Food and Drug Administration (FDA) for the treatment of adults with active psoriatic arthritis and on September 23, 2014 for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Marketing authorisation applications are ongoing in other countries, including Australia and Switzerland.

**ENDS**

Note to editors: Additional information can be found at: http://smp.businesswire.com/pages/oral-otezla-apremilast-approved-european-commission-treatment-both-patients-psoriasis-and-psor

About OTEZLA^®

OTEZLA^® is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic AMP (cAMP). PDE4 inhibition results in increased intracellular cAMP levels which is thought to indirectly modulate the production of inflammatory mediators.¹³ Find out more about PDE4 inhibition, by clicking here: http://www.discoverpde4.com/

About the ESTEEM program

ESTEEM 1 and 2 are two large pivotal Phase III randomized, placebo-controlled studies evaluating apremilast in patients with a diagnosis of moderate to severe plaque psoriasis for at least 12 months prior to screening, and who were also candidates for phototherapy or systemic therapy. Approximately 1,250 patients were randomized 2:1 to receive either apremilast 30 mg twice daily or placebo after an initial five-day titration period, for the first 16 weeks, followed by a maintenance phase from weeks 16-32 in which placebo patients were switched to apremilast 30 mg twice daily through week 32. The trial also consisted of a randomized withdrawal phase for responders from week 32 to week 52 based on their initial apremilast randomization and Psoriasis Area and Severity Index (PASI) response. Approximately 30 percent of all patients had received prior phototherapy and 54 percent had received prior conventional systemic and/or biologic therapy.¹

About the PALACE Program

PALACE 1, 2 and 3 are three pivotal Phase III multi-center, double-blind, placebo-controlled, parallel-group studies with two active-treatment groups. Across these studies, approximately 1,500 patients were randomized 1:1:1 to receive either apremilast 20 mg twice daily, apremilast 30 mg twice daily or identically-appearing placebo, for 16 weeks. At week 16, some placebo-treated patients were randomized to one of the two apremilast groups, while others remained on placebo through week 24. After week 24, patients began a subsequent long term, open-label, active treatment phase. The PALACE 1, 2 and 3 studies included a wide spectrum of patients with active psoriatic arthritis, who had been previously treated with oral disease-modifying anti rheumatic drugs (DMARDs), and/or biologics, with some patients who had previously failed a tumour necrosis factor (TNF) blocker.¹ Taken together, the PALACE program is the largest psoriatic arthritis program to date intended for regulatory submission.

ADDITIONAL IMPORTANT SAFETY INFORMATION based on EU label

Contraindications

OTEZLA^® (apremilast) is contraindicated in patients with known hypersensitivity to the active substance or to any of the excipients in the formulation.

OTEZLA^® is contraindicated during pregnancy.

Warnings and precautions

Patients with rare hereditary problems of galactose intolerance, lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

The safety of apremilast was not evaluated in psoriatic arthritis or psoriasis patients with moderate or severe renal impairment in the clinical studies. OTEZLA^® should be dose reduced to 30 mg once daily in patients with severe renal impairment.

Weight decrease: The mean observed weight loss in patients treated for up to 52 weeks with apremilast was 1.99 kg. A total of 14.3% of patients receiving apremilast had observed weight loss between 5-10% while 5.7% of the patients receiving apremilast had observed weight loss greater than 10%. None of these patients had overt clinical consequences resulting from weight loss. A total of 0.1% of patients treated with apremilast discontinued due to adverse reaction of weight decreased. Patients who are underweight at the start of treatment should have their body weight monitored regularly. In the event of unexplained and clinically significant weight loss, these patients should be evaluated by a medical practitioner and discontinuation of treatment should be considered.

Pregnancy: Pregnancy should be excluded before treatment can be initiated. Women of childbearing potential should use an effective method of contraception to prevent pregnancy during treatment.

Summary of the safety profile

The most commonly reported adverse reactions in Phase III clinical studies have been gastrointestinal (GI) disorders including diarrhoea (15.7%) and nausea (13.9%). These GI adverse reactions were mostly mild to moderate in severity, with 0.3% of diarrhoea and 0.3% of nausea reported as being severe. These adverse reactions generally occurred within the first 2 weeks of treatment and usually resolved within 4 weeks. The other most commonly reported adverse reactions included upper respiratory tract infections (8.4%), headache (7.9%), and tension headache (7.2%). Overall, most adverse reactions were considered to be mild or moderate in severity.

The most common adverse reactions leading to discontinuation during the first 16 weeks of treatment were diarrhoea (1.7%), and nausea (1.5%). The overall incidence of serious adverse reactions was low and did not indicate any specific system organ involvement. Hypersensitivity reactions were uncommonly observed in apremilast clinical studies.

During the placebo-controlled period of the phase III clinical trials in psoriasis, 1.2% (14/1184) of patients treated with apremilast reported depression compared to 0.5% (2/418) treated with placebo. None of these reports of depression was serious or led to study discontinuation.

Special populations

No overall differences were observed in the safety profile of elderly patients = 65 years of age and younger adult patients < 65 years of age in the clinical studies.

The safety of apremilast was not evaluated in psoriatic arthritis or psoriasis patients with hepatic impairment.

The safety and efficacy of apremilast in children aged 0 to 17 years have not been established. There is no data available.

Please click here for Full Prescribing Information (EU Label)

About Psoriasis

Psoriasis is an immune-mediated, non-contagious, systemic inflammatory disorder of unknown cause. The disorder is a chronic recurring condition which varies in severity from minor localised patches to complete body coverage. Plaque psoriasis is the most common type of psoriasis. About 80 percent of people who develop psoriasis have plaque psoriasis, which appears as patches of raised, reddish skin covered by silvery-white scales. These patches, or plaques, frequently form on the elbows, knees, lower back, and scalp.⁶ Psoriasis occurs nearly equally in males and females and it affects many aspects of patients’ emotional and social well-being as well as daily activities and the ability to study or work.^5,11 In May 2014, the 67th World Health Assembly adopted a resolution on psoriasis encouraging Member States to engage further in advocacy efforts to raise awareness of the disease and to fight stigmatisation among people living with the condition.¹⁴

About Psoriatic Arthritis

Psoriatic arthritis is a painful, chronic inflammatory disease characterised by pain, stiffness, swelling and tenderness of the joints, inflammation in places where specific ligaments and tendons attach to bones, and decrease in physical functioning.¹⁵ Psoriatic arthritis can impact the ability to perform day-to-day activities and has been reported to increase work disability.⁵ Enthesitis and dactylitis are specific disease manifestations related to psoriatic arthritis.⁹

About Celgene

Celgene International Sàrl, located in Boudry, in the Canton of Neuchâtel, Switzerland, is a wholly-owned subsidiary and International Headquarters of Celgene Corporation. Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global pharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through gene and protein regulation. For more information, please visit the Company’s website at www.celgene.com. Follow Celgene on Twitter @ Celgene.

Forward-Looking Statements

This press release contains forward-looking statements, which are generally statements that are not historical facts. Forward-looking statements can be identified by the words “expects,” “anticipates,” “believes,” “intends,” “estimates,” “plans,” “will,” “outlook” and similar expressions. Forward-looking statements are based on management’s current plans, estimates, assumptions and projections, and speak only as of the date they are made. We undertake no obligation to update any forward-looking statement in light of new information or future events, except as otherwise required by law. Forward-looking statements involve inherent risks and uncertainties, most of which are difficult to predict and are generally beyond our control. Actual results or outcomes may differ materially from those implied by the forward-looking statements as a result of the impact of a number of factors, many of which are discussed in more detail in our Annual Report on Form 10-K and other reports filed with the Securities and Exchange Commission.

References

¹ Apremilast Summary of Product Characteristics, January 2015

² Arava (leflunomide) Summary of Product Characteristics. Available online at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000235/WC500026289.pdf

³ Sandimmun Neoral. Scientific conclusions and grounds for the variation to the terms of the Marketing Authorisation. Available online at: http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Sandimmun_Neoral_30/WC500158808.pdf

⁴ Augustin M, Herberger K, Hintzen S, Heigel H, Franzke N, Shäfer I. Prevalence of skin lesions and need for treatment in a cohort of 90880 workers. Br J Dermatol. 2011;165(4):865-873

⁵ International Federation of Psoriasis Associations. Psoriasis is a serious disease deserving global attention. 2012.

⁶ Villasenor-Park J. et al. Psoriasis: Evolving treatment for a complex disease. Cleveland Journal of Medicine. Volume 79 (6) 2012

⁷ World Psoriasis Day Consortium. Facts about Psoriasis. http://www.worldpsoriasisday.com/web/page.aspx?refid=129 Accessed 02 December 2014

⁸ Gladman DD. Psoriatic arthritis. Dermatologic Therapy, Vol. 22, 2009, 40–55

⁹ American College of Rheumatology. Psoriatic Arthritis. September 2012

¹⁰ Carle, P. et al. Apremilast, an Oral Phosphodiesterase 4 Inhibitor, in Patients With Moderate to Severe Psoriasis: Results of a Phase 3, Randomized, Controlled Trial (ESTEEM 2)

¹¹ Armstrong, A.W., et al. Quality of life and work productivity impairment among psoriasis patients: findings from the National Psoriasis Foundation survey data 2003-2011. PLoS One. 7.12 (2012): e52935. doi: 10.1371/journal.pone.0052935.

¹² European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Summary of opinion – Otezla (available online at: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/003746/WC500177621.pdf

¹³ PH Schafer et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. British Journal of Pharmacology (2010), 159, 842–855

¹⁴ World Health Assembly progress on noncommunicable diseases and traditional medicine Press release. Available online at http://www.who.int/mediacentre/news/releases/2014/WHA-20140523/en/

¹⁵ Gottlieb A, Korman NJ, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol. 2008;58:851 864.

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