Publication highlights safety and efficacy
data, including disease-related quality of life measures, for
apremilast in rare inflammatory disorder
Global phase III clinical trial now enrolling
patients
Celgene Corporation (NASDAQ:CELG) today announced that results
from a multicenter, randomized, placebo-controlled phase II trial
(BCT-001) of apremilast (Otezla®) in patients with Behçet’s disease
were published in the April 16 issue of The New England Journal of
Medicine. Behçet’s disease is a rare, chronic inflammatory disorder
characterized by recurrent oral and genital ulcers, which are
considered a hallmark of the disease. Joint inflammation and
recurrent skin and eye lesions may also occur.
“Painful oral ulcers due to Behçet’s disease are the hallmark of
the condition and can have a significant impact on the lives of
many patients. Currently used drugs for this condition may not
control oral or genital ulcers in some patients or have potential
adverse events that may limit their use,” said Gulen Hatemi, M.D.,
Associate Professor, Cerrahpasa Medical School, Istanbul, Turkey.
“The publication of these phase II data in The New England Journal
of Medicine is critical to disseminating the findings to the
healthcare professional community, to keep them informed of the
latest developments in research on this rare, chronic disease.”
Findings from this study, including the primary endpoint
(reduction in mean number of oral ulcers following 12 weeks of
treatment), were initially presented at the European League against
Rheumatism (EULAR) and the American College of Rheumatology (ACR)
annual meetings in 2013 (P<0.001). In addition to the previously
reported results, the publication includes findings that the median
(min, max) number of oral ulcers was also reduced following 12
weeks of treatment with apremilast compared with placebo (0.0 (0,
6) vs. 2.0 (0, 13), respectively).
Findings from the full 24-week treatment phase were also
included in the publication. After 12 weeks, patients in the
placebo group were crossed over to apremilast treatment, and those
in the apremilast arm continued treatment. For those treated with
apremilast for the full 24 weeks, the decrease in the mean number
of oral ulcers was evident by week 2 (0.3 at week 2 vs. 2.7 at
baseline) and this decrease was sustained through week 24 (0.6). In
the placebo arm, the mean number of oral ulcers was 2.9 at baseline
and 1.7 at week 2. At week 24, following 12 weeks of apremilast
treatment, the mean number of oral ulcers in the placebo group was
0.4.
A decrease in pain associated with oral ulcers paralleled this
decrease in ulcers over time. Mean pain scores, measured using a
visual analog scale, decreased from 54.3 at baseline to 12.0 at
week 2 and 9.7 at week 24. In the placebo arm, pain scores were
51.7 at baseline and 29.8 at week 2. At week 24, following 12 weeks
of apremilast treatment, mean pain score in this group was 9.7.
Apremilast also significantly improved several measures of
disease activity and quality of life at week 12. Mean change from
baseline at week 12 was significantly better for scores on the
Behçet’s disease current activity form (-1.5 with apremilast vs.
-0.1 for placebo; P<0.001), the Behçet’s syndrome activity scale
(-21.2 vs. -6.0, respectively; P<0.001), the Behçet’s disease
quality of life instrument (-4.5 vs. -1.6; P=0.040), and the short
form 36 version 2 physical component summary (4.7 vs. -1.7;
P=0.001). No significant improvement was seen in the short form 36
version 2 mental component summary (2.0 vs. 1.6; P=NS).
The safety and tolerability data for apremilast observed in this
study were consistent with previously reported data from six other
phase III studies of apremilast in psoriatic arthritis or plaque
psoriasis. The percentages of patients who developed at least one
adverse event (AE) during the placebo-controlled phase were
comparable between apremilast (85.5 percent) and placebo (80.4
percent). Serious AEs occurred in two patients receiving apremilast
and none receiving placebo. AEs leading to drug discontinuation
occurred in four patients receiving apremilast and none receiving
placebo. Nausea, vomiting and diarrhea were more common with
apremilast compared with placebo.
“Celgene is dedicated to investigating and delivering to
patients new treatment options for rare, chronic inflammatory
disorders such as Behçet’s disease,” said Scott Smith, President,
Celgene Inflammation & Immunology. “Based on these phase II
results, Celgene has filed with regulatory authorities in Turkey
and has initiated a global phase III trial of OTEZLA in this
debilitating disease.”
These results are from an investigational phase II study.
Apremilast is not approved for the treatment of patients with
Behçet’s disease in any country.
About Behçet’s Disease
Although the root cause is unknown, Behçet’s disease is
associated with abnormalities of the immune system and inflammation
of the blood vessel network. Behçet’s is characterized by recurrent
oral and genital ulcers and skin lesions ranging from acne to
ulcerations. It can also involve venous thrombosis, aneurysms,
inflammation of the eye manifesting as uveitis, and neurologic and
gastrointestinal symptoms.
Prevalence of Behçet’s disease is highest in the Middle East,
Asia and Japan. About one in every 250 people in Turkey has
Behçet’s, translating to about 300,000 cases. The disease is much
less common in the United States (U.S.) and United Kingdom, where
it affects only one in every 100,000. Behçet’s has been classified
in the U.S. as a rare or “orphan” disease by the National
Institutes of Health. At this time, there are limited therapies to
treat Behçet’s in the U.S. and throughout Europe.
About BCT-001
BCT-001 is a phase II, multi-center, randomized,
placebo-controlled, double-blind, parallel-group study of 111
subjects with active Behçet’s disease. The study was mainly
conducted in Turkey with a small number of patients from the U.S.
After a screening period of up to 90 days, patients were randomized
1:1 to receive apremilast 30 mg twice daily or placebo for 12 weeks
after an initial seven-day titration period, followed by a 12-week
blinded extension, where the placebo group was switched to
apremilast, and a 28-day post-treatment observational
follow-up.
The primary endpoint of the study was the number of oral ulcers
at day 85 (12 weeks). Less common manifestations of Behçet’s
disease, including genital ulcers, skin lesions, inflammatory eye
disease, involvement of the gastrointestinal, vascular and central
nervous systems, and pain from oral and genital ulcers, were chosen
as secondary/exploratory efficacy variables or safety measures.
About Apremilast
Apremilast is an oral small-molecule inhibitor of
phosphodiesterase 4 (PDE4) specific for cyclic adenosine
monophosphate (cAMP). PDE4 inhibition results in increased
intracellular cAMP levels which is thought to indirectly modulate
the production of inflammatory mediators. The specific mechanism(s)
by which apremilast exerts its therapeutic action in patients with
psoriasis or psoriatic arthritis is not well defined.
Apremilast, marketed as OTEZLA, is approved:
- In the U.S. for the treatment of adults
with active psoriatic arthritis and the treatment of patients with
moderate to severe plaque psoriasis who are candidates for
phototherapy or systemic therapy
- In Canada for the treatment of patients
with moderate to severe plaque psoriasis who are candidates for
phototherapy or systemic therapy
- In the European Union:
- 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
- In Australia:
- For the treatment of signs and symptoms
of active psoriatic arthritis in adult patients
- For the treatment of adult patients
with moderate to severe plaque psoriasis who are candidates for
phototherapy or systemic therapy
Important Safety Information (based on U.S. labeling)
Contraindications
Otezla 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/behavior, 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 Specific
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.
About Celgene
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 www.celgene.com. Follow Celgene on Twitter @Celgene, and on
Pinterest and LinkedIn.
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.
Celgene CorporationInvestors:Patrick E. Flanigan III,
908-673-9969Vice President, Investor RelationsorMedia:Catherine
Cantone, 732-564-3592Director, Corporate Communications
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