Pooled 3-year data analyses from ESTEEM 1 and 2
and PALACE 1-3 trials showed no increase in incidence of adverse
events, no new safety signals and improved tolerability with
exposure to apremilast up to 156 weeks1
The rates of major adverse cardiovascular
events, malignancies and serious infections for apremilast were
comparable to placebo up to 16 weeks and remained low with
prolonged exposure1
Physician's Global Assessment and Body Surface
Area (PGAxBSA) composite tool evaluated for clinically meaningful
response to apremilast in ESTEEM 1 and 22
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 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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