Oral OTEZLA® (apremilast) Long-Term Safety Data Presented at EADV Congress in Both Psoriasis and Psoriatic Arthritis

Celgene International Sàrl, a wholly owned subsidiary of Celgene Corporation (NASDAQ: CELG), today announced that long-term safety findings from ongoing clinical trials of apremilast, the Company's oral, selective inhibitor of phosphodiesterase 4 (PDE4), were presented at the European Academy of Dermatology and Venereology (EADV) Annual Congress in Vienna, Austria.

Analyses of pooled 156-week (3-year) safety data from the ESTEEM 1 and 2 and PALACE 1-3 trials were presented, which included patients with moderate to severe plaque psoriasis (ESTEEM) and active psoriatic arthritis (PALACE) who were treated with apremilast 30 mg twice-daily. Patients with psoriatic arthritis were treated with OTEZLA^® alone or in combination with concomitant disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate.

Volker Koscielny MD, Head of Medical Affairs for Celgene in Europe said: “Psoriasis is a complex, multi-faceted chronic condition which makes treatment challenging. In addition, a significant number of patients will go on to develop psoriatic arthritis. Physical symptoms and disease impact go beyond the extent of skin involvement and therefore several factors, including individual patient needs, should be taken into account when assessing appropriate treatment options. With over 100,000 patients globally already treated with OTEZLA^® since approval³, it is important to note the efficacy and safety profile of OTEZLA^® in this combined analysis of psoriasis and psoriatic arthritis three-year data."

2,242 patients were included in the pooled safety analysis up to 16 weeks (placebo n=913; APR30 n=1,329), with 1,905 patients (3,527.5 patient years) receiving apremilast in the APR-exposure period up to 156 weeks.¹

Across both trial programmes up to 16 weeks, the most common adverse events (AEs) (≥5 percent of patients) among patients on apremilast were diarrhoea, nausea, headache, upper respiratory tract infection, and nasopharyngitis. Most cases of diarrhoea/nausea were mild to moderate in severity, occurred during the first 2 weeks of apremilast dosing and generally resolved in one month.¹

Discontinuation rates of apremilast due to diarrhoea and nausea occurred at rates of 1.3 percent and 1.7 percent, respectively, during the 0 to ≤52 week apremilast exposure period and 0.0 percent for both AEs during the >104 to ≤156 week apremilast exposure period.⁴

The exposure-adjusted incidence rates (EAIR/100 patient years) for AEs, serious AEs and discontinuations due to AEs did not increase with increasing cumulative exposure during the apremilast-exposure period (0 to ≥156 weeks; 3,527.5 patient-years); this was confirmed by assessment of rates on a year-by-year exposure basis.¹

The incidences (EAIR/100 patient years) of major adverse cardiovascular events (MACE), malignancies, and serious infections for patients on apremilast were comparable to placebo up to 16 weeks and remained low with prolonged exposure. No serious opportunistic infections or clinically meaningful effects on laboratory measurements were reported. ¹

Rates for depression or suicidality did not increase with increasing cumulative long-term apremilast exposure. Most patients taking apremilast maintained body weight within 5 percent of baseline; with 21.1 percent experienced >5 percent weight loss over the 156 week apremilast-exposure periods. The rate of treatment discontinuation due to weight loss was low.⁴

In addition, a retrospective analysis of results from ESTEEM 1 and 2 trials examined the potential of an alternative tool to measure psoriasis disease severity. Improvement in Psoriasis Area and Severity Index (PASI) score remains the most commonly used severity assessment in clinical development and in practice, however its limitations – including scoring complexity and insensitivity to changes – mean that there may be opportunities to improve how psoriasis patients are assessed.²

The combination of the Physician's Global Assessment (PGA) and Body Surface Area (BSA) – the PGAxBSA composite tool – is a simple assessment which was shown to measure meaningful clinical responses of psoriasis patients in the ESTEEM trials including minimal disease activity and is sensitive to change in disease severity.²

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About apremilast

Apremilast is an oral 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.⁵

About the ESTEEM programme ⁶

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 and/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.

About the PALACE programme ⁶

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. At baseline, 64.2 percent of patients receiving apremilast in PALACE 1, 2, and 3 were receiving concomitant DMARDs, including methotrexate.

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

Therapeutic indications

OTEZLA^® is approved 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).

OTEZLA^®, alone or in combination with DMARDs, is also indicated for the treatment of active psoriatic arthritis in adult patients who have had an inadequate response or who have been intolerant to a prior DMARD therapy.

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)

ADDITIONAL IMPORTANT SAFETY INFORMATION based on US labeling

Therapeutic indications

OTEZLA is approved in the U.S.:

• For the treatment of adults with active psoriatic arthritis
• For the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy

Contraindications

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

Warnings and Precautions

Depression: Carefully weigh the risks and benefits of treatment with Otezla for patients with a history of depression and/or suicidal thoughts/behaviour, or in patients who develop such symptoms while on Otezla. Patients, caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and they should contact their healthcare provider if such changes occur.

• Psoriasis: Treatment with Otezla is associated with an increase in adverse reactions of depression. During clinical trials, 1.3% (12/920) of patients treated with Otezla reported depression compared to 0.4% (2/506) on placebo; 0.1% (1/1308) of Otezla patients discontinued treatment due to depression compared with none on placebo (0/506). Depression was reported as serious in 0.1% (1/1308) of patients exposed to Otezla, compared to none in placebo-treated patients (0/506). Suicidal behavior was observed in 0.1% (1/1308) of patients on Otezla, compared to 0.2% (1/506) on placebo. One patient treated with Otezla attempted suicide; one patient on placebo committed suicide.
• Psoriatic Arthritis: During clinical trials, 1.0% (10/998) of patients treated with Otezla reported depression or depressed mood compared to 0.8% (4/495) treated with placebo; 0.3% (4/1441) of patients treated with Otezla discontinued treatment due to depression or depressed mood compared with none in placebo treated patients (0/495). Depression was reported as serious in 0.2% (3/1441) of patients exposed to Otezla, compared to none in placebo treated patients (0/495). Suicidal ideation and behavior were observed in 0.2% (3/1441) of patients on Otezla, compared to none on placebo (0/495). Two patients who received placebo committed suicide compared to none on Otezla.

Weight Decrease: Monitor body weight regularly; evaluate unexplained or clinically significant weight loss, and consider discontinuation of Otezla.

• Psoriasis: Body weight loss of 5-10% occurred in 12% (96/784) of patients treated with Otezla and in 5% (19/382) of patients treated with placebo. Body weight loss of ≥10% occurred in 2% (16/784) of patients treated with Otezla compared to 1% (3/382) of patients treated with placebo.
• Psoriatic Arthritis: Body weight loss of 5-10% was reported in 10% of patients taking Otezla and in 3.3% of patients taking placebo. Monitor body weight regularly; evaluate unexplained or clinically significant weight loss, and consider discontinuation of Otezla.

Drug Interactions: Apremilast exposure was decreased when OTEZLA was co-administered with rifampin, a strong CYP450 enzyme inducer; loss of OTEZLA efficacy may occur. Concomitant use of OTEZLA with CYP450 enzyme inducers (eg, rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended.

Adverse Reactions

• Psoriasis: Adverse reactions reported in ≥5% of patients were (OTEZLA%, placebo%): diarrhea (17, 6), nausea (17, 7), upper respiratory tract infection (9, 6), tension headache (8, 4), and headache (6, 4).
• Psoriatic Arthritis: Adverse reactions reported in ≥2% of patients taking Otezla, that occurred at a frequency at least 1% higher than that observed in patients taking placebo, for up to 16 weeks (after the initial 5-day titration), were (Otezla%, placebo%): diarrhea (7.7, 1.6); nausea (8.9, 3.1); headache (5.9, 2.2); upper respiratory tract infection (3.9, 1.8); vomiting (3.2, 0.4); nasopharyngitis (2.6, 1.6); upper abdominal pain (2.0, 0.2).

Use in Special populations

Pregnancy and Nursing Mothers: OTEZLA is Pregnancy Category C; it has not been studied in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether apremilast or its metabolites are present in human milk. Caution should be exercised when OTEZLA is administered to a nursing woman.

Renal Impairment: OTEZLA dosage should be reduced in patients with severe renal impairment (creatinine clearance less than 30 mL/min); for details, see Dosage and Administration, Section 2, in the Full Prescribing Information.

Please click here for Full Prescribing Information (US Label)

ABOUT PSORIASIS AND PSORIATIC ARTHRITIS

Psoriasis is known to affect around 14 million people in Europe. It is a chronic and systemic inflammatory skin disorder, and is immune-mediated, meaning it is caused by an immune reaction in the body.⁷

Psoriasis lesions can often be found on areas close to the joints such as the elbows and knees but can also appear on the scalp.⁷ Nail psoriasis affects up to 50% of people with psoriasis and up to 90% of people living with psoriatic arthritis.^8,9 Up to 84% of people with psoriasis experience itching, and over a third of patients actually cite itch as the most important factor contributing to their disease.^10,11

75% of people living with psoriasis believe it has a negative impact on their quality of life and 83% of patients with psoriasis actively conceal the visible signs of their disease.^12,13

Around a third of people living with psoriasis may go on to develop psoriatic arthritis, which affects the body in different ways to psoriasis and often causes pain, as well as swelling and tenderness particularly around the joints. It is clear that the two conditions are closely connected, and if left untreated, psoriatic arthritis can have a severe impact on mobility and physical function.¹⁴

Two distinct physical symptoms of psoriatic arthritis are dactylitis (enlargement of the fingers, commonly referred to as “sausage fingers”) and enthesitis (inflammation at sites where tendons or ligaments insert into bone). A substantial number – 41% - of people living with psoriatic arthritis suffer from dactylitis in the fingers and also the toes, and enthesitis is known to affect up to 71% of patients.¹⁵ People with psoriatic arthritis can often experience skin symptoms for up to 10 years before the onset of joint symptoms.¹⁶

Diagnosing psoriatic arthritis can be a tricky process because its symptoms frequently mimic those of other forms of inflammatory arthritis, such as rheumatoid arthritis (RA) and gout. It can also be confused with osteoarthritis (OA), the most common form of arthritis.¹⁷

ABOUT CELGENE

Celgene International Sàrl, located in Boudry, in the Canton of Neuchâtel, Switzerland, is a wholly-owned subsidiary and International Headquarter 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 Social Media: @Celgene, Pinterest, LinkedIn, FaceBook and YouTube.

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 Crowley, J. et al. Long-term Safety in Psoriasis and Psoriatic Arthritis Patients Treated With Apremilast: Pooled Analysis for ≥156 Weeks in the ESTEEM and PALACE 1-3 Phase 3 Trials (Abstract)

² Gottlieb, A. et al. Assessing Clinical Response and Minimal Disease Activity With the Physician Global Assessment and Body Surface Area Composite Tool: an Analysis of Apremilast Phase 3 ESTEEM Data (Abstract).

³ Celgene data on file. 2016.

⁴ Crowley, J. et al. Long-term Safety in Psoriasis and Psoriatic Arthritis Patients Treated With Apremilast: Pooled Analysis for ≥156 Weeks in the ESTEEM and PALACE 1-3 Phase 3 Trials (Poster)

⁵ 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.

⁶ Apremilast Summary of Product Characteristics, January 2015

⁷ Augustin M and The European Expert Working Group for Healthcare in Psoriasis. A framework for improving the quality of care for people with psoriasis. JEADV 2012, 26 (Suppl. 4), 1–16.

⁸ De Vries AC et al. Cochrane Database Syst Rev. 2013; 1:CD007633

⁹ Tan EST et al. Am J Clin Dermatol; 2012; 13(6):375–388.

¹⁰ Lebwohl MG et al.Patient perspectives in the management of psoriasis: Results from the population-based Multinational Assessment of Psoriasis and Psoriatic Arthritis Survey J Am Acad Dermatol 2014;70:871−81

¹¹ Yosipovitch et al. Br J Dermatol. 2000;143:969.

¹² Bhosle M, Kulkarni A, Feldman S, Balkrishnan R. Quality of life in patients with psoriasis. Health Qual Life Outcomes. 2006;4(35)

¹³ Armstrong et al. PLOS One. 2012;12:e52935.

¹⁴ Gladman, DD et al. Psoriatic arthritis: epidemiology, clinical features, course and outcome. Ann Rheum Dis. 2005;64(Suppl II):ii14–ii17. doi: 10.1136/ard.2004.032482

¹⁵ Ritchlin C et al. Ann Rheum Dis 2014; 73(6):990–999.

¹⁶ World Psoriasis Day Consortium. Facts about Psoriasis. Accessed March 2015. ( http://www.worldpsoriasisday.com/web/page.aspx?refid=129 )

¹⁷ Arthritis Foundation. Psoriatic Arthritis Diagnosis. http://www.arthritis.org/about-arthritis/types/psoriatic-arthritis/diagnosing.php

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