Celgene Announces Long-Term Safety Data for Oral OTEZLA®

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

——-ENDS——-

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 programme⁶
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 programme⁶
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 Otezlais
  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.^8,9Up 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 yearsbefore 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,
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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 etal.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. (https://www.worldpsoriasisday.com/web/page.aspx?refid=129)
¹⁷ Arthritis Foundation. Psoriatic Arthritis Diagnosis. https://www.arthritis.org/about-arthritis/types/psoriatic-arthritis/diagnosing.php