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Moderate to Severe Plaque Psoriasis

Study Design

Otezla® (apremilast) was evaluated in a robust global clinical development program for plaque psoriasis that enrolled over 1200 patients1,2
 
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ESTEEM® 1 and ESTEEM 21-3

 

Schematic illustration of the design and details about the ESTEEM 1 and ESTEEM 2 clinical trials that evaluated Otezla® (apremilast) for the treatment of plaque psoriasis

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In ESTEEM 1, patients were switched to Otezla if they lost their PASI‑75, but no later than at week 52. In ESTEEM 2, patients were switched to Otezla if they lost 50% of the PASI improvement obtained at week 32 compared to baseline, but no later than at week 52.

a

Doses of Otezla were titrated during the first week of administration.

b

A responder was defined as a patient achieving ≥PASI-75; a partial responder was defined as a patient achieving PASI‑50 to PASI‑74; a nonresponder was defined as a patient achieving <PASI‑50 in both ESTEEM 1 and ESTEEM 2 at week 32.

c

At week 32, nonresponders and partial responders (ESTEEM 1) or nonresponders only (ESTEEM 2) had the option of adding topical and/or UVB therapy. The decision could be made at week 32 and was based on the discretion of the investigator.

BID, twice daily; ESTEEM, Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis; PASI, Psoriasis Area and Severity Index.

  • Weeks 0 to 16 (placebo-controlled phase): Patients were randomized 2:1 to Otezla twice daily or placebo2,3
  • Weeks 16 to 32 (maintenance phase): All patients received Otezla2,3
  • Weeks 32 to 52 (withdrawal phase)2,3
      • Patients originally randomized to Otezla who achieved at least a 75% reduction in PASI score (PASI-75) in ESTEEM 1, or at least a 50% reduction in PASI score (PASI-50) in ESTEEM 2 at week 32, were re-randomized 1:1 to either placebo or Otezla. Patients who were re-randomized to placebo and who lost their PASI-75 response (ESTEEM 1), or 50% of the improvement that they achieved at week 32 compared to baseline (ESTEEM 2), were re-treated with Otezla, but no later than week 52. Patients who did not achieve the designated PASI response by week 32 had the option of adding topical and/or UVB therapy
      • Patients originally randomized to placebo and transitioned to Otezla, who then achieved at least PASI-75 in ESTEEM 1, or at least PASI-50 in ESTEEM 2, at week 32, were allowed to continue on Otezla. Patients who did not achieve the designated PASI response by week 32 had the option of adding topical and/or UVB therapy
  • Weeks 52 to 260 (long-term extension phase)2,3
      • Patients entering a long-term extension phase could be treated through 5 years
Otezla was evaluated in 2 multicenter, double-blind, placebo-controlled trials of similar design. Patients ≥18 years of age (N = 1257) with moderate to severe plaque psoriasis were randomized to placebo (n = 419) or Otezla (n = 836) given orally twice daily. These studies had a similar design through week 32.2-4

 

ESTEEM® 1 and ESTEEM 2 criteria and endpoints

Selected inclusion criteria4:

  • BSA involvement of ≥10%
  • sPGA of ≥3 (moderate or severe disease)
  • PASI score ≥12
  • Candidates for phototherapy or systemic therapy

Selected exclusion criteria:

  • Active TB or incompletely treated TB; however, there was no requirement for latent TB screening1-3
  • Hepatitis B or hepatitis C positive at screening1
  • History of HIV1

Primary endpoint2,3:

  • The proportion of patients who achieved PASI-75 at week 16

Selected secondary endpoints:

  • Proportion of patients who achieved sPGA score of clear (0) or almost clear (1) at week 162,3
  • Change from baseline in pruritus VAS at week 161

Selected exploratory endpoints1:

  • Percent change from baseline in NAPSI score at week 16 for patients with baseline nail psoriasis
  • Proportion of patients with scalp psoriasis with improvement of ScPGA scores to 0 (clear) and 1 (minimal) at week 16

Patient demographics

Median age4:

  • 46 years (18 to 83 years)

Mean baseline BSA involvement4:

  • 25%

Mean baseline PASI score4:

  • 19

Proportion of patients with baseline sPGA score 3 (moderate)4:

  • 70%

Proportion of patients with baseline sPGA score 4 (severe)4:

  • 30%

Prior psoriasis therapy:

  • Phototherapy - 30%4
  • Systemic therapy - 54%4
    • Conventional systemic therapy - 37%4
    • Biologic therapy - 30%4
    • No prior phototherapy, conventional systemic therapy, or biologics - 35%1

History of psoriatic arthritis4:

  • 18%

Concomitant psoriasis medications allowed2,3:

  • Low-potency topical corticosteroids for face, axillae, and groin psoriatic lesions
  • Coal tar shampoo and/or salicylic acid preparations for scalp lesions
  • All the above permitted except within 24 hours before each study visit

BSA, body surface area; HIV, human immunodeficiency virus; ESTEEM, Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis; NAPSI, Nail Psoriasis Severity Index; PASI, Psoriasis Area and Severity Index; ScPGA, Scalp Physician Global Assessment; sPGA, static Physician Global Assessment; TB, tuberculosis; VAS, visual analog scale.

LIBERATE® criteria and endpoints5

Study design:

  • A global, phase 3b, placebo-controlled, double-blind, double-dummy study evaluating patients with moderate to severe plaque psoriasis for up to 104 weeks
  • Patients were randomized 1:1:1 to either Otezla 30 mg (n = 83) twice daily, etanercept 50 mg (n = 83) once weekly, or placebo (n = 84) through week 16. At week 16, all patients crossed over to the Otezla arm
  • This study was not designed for apremilast vs etanercept comparisons

Selected inclusion criteria:

  • Chronic plaque psoriasis for ≥12 months
  • PASI score ≥12
  • BSA ≥10%
  • sPGA score ≥3
  • Inadequate response, intolerance or contraindication to ≥1 conventional systemic agent for treatment of psoriasis
  • Candidates for phototherapy or systemic (including etanercept) therapy
  • No prior exposure to a biologic therapy for psoriasis or psoriatic arthritis

Selected exclusion criteria:

  • Prior failure of >3 systemic agents for treatment of psoriasis
  • History of known demyelinating diseases such as multiple sclerosis or optic neuritis or history of/concurrent congestive heart failure, including medically controlled, asymptomatic congestive heart failure
  • Other clinically significant or major uncontrolled disease
  • Serious infection
  • Latent, active, or history of incompletely treated TB

Primary endpoint:

  • The proportion of patients treated with apremilast or placebo who achieved a PASI-75 at week 16

Secondary endpoint:

  • Proportion of patients treated with etanercept or placebo who achieved PASI-75 at week 16

Patient demographics5

Mean age:

  • Otezla, 46 years; placebo, 43 years; etanercept, 47 years

Mean baseline BSA involvement:

  • Otezla, 27.1%; placebo, 27.3%; etanercept, 28.4%

Mean baseline PASI score:

  • Otezla, 19.3; placebo, 19.4; etanercept, 20.3

Concomitant psoriasis medications allowed:

  • Low-potency topical corticosteroids as background therapy for treatment of face, axillae, and groin
  • Coal tar shampoo and/or salicylic acid scalp preparations for scalp lesions
  • All were permitted except within 24 hours before study visits

BSA, body surface area; LIBERATE, Evaluation in a Placebo-Controlled Study of Oral Apremilast and Etanercept in Plaque Psoriasis; PASI, Psoriasis Area and Severity Index; sPGA, static Physician Global Assessment; TB, tuberculosis.

Next: Efficacy

References: 1. Data on file, Amgen Inc. 2. Papp K, Reich K, Leonardi CL, et al. J Am Acad Dermatol. 2015;73(1):37-49. 3. Paul C, Cather J, Gooderham M, et al. Br J Dermatol. 2015;173(6):1387-1399. 4. Otezla [package insert]. Thousand Oaks, CA: Amgen Inc. 5. Reich K, Gooderham M, Green L, et al. J Eur Acad Dermatol Venereol. 2017;31:507-517.

INDICATIONS & IMPORTANT SAFETY INFORMATION

INDICATIONS

Otezla® (apremitast) is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Otezla is indicated for the treatment of adult patients with active psoriatic arthritis.

Otezla is indicated for the treatment of adult patients with oral ulcers associated with Behçet’s Disease.

IMPORTANT SAFETY INFORMATION

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

  • Diarrhea, Nausea, and Vomiting: Cases of severe diarrhea, nausea, and vomiting were associated with the use of Otezla. Most events occurred within the first few weeks of treatment In some cases patients were hospitalized. Patients 65 years of age or older and patients taking medications that can lead to volume depletion or hypotension may be at a higher risk of complications from severe diarrhea, nausea, or vomiting. Monitor patients who are more susceptible to complications of diarrhea or vomiting; advise patients to contact their healthcare provider. Consider Otezla dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting
  • 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 depression. During clinical trials, 1.3% (12/920) of patients reported depression compared to 0.4% (2/506) on placebo. Depression was reported as serious in 0.1% (1/1 308) of patients exposed to Otezla, compared to none in placebo-treated patients (0/506). Suicidal behavior was observed in 0.1%(1/1 308) of patients on Otezla, compared to 0.2% (1/506) on placebo. One patient treated with Otezia attempted suicide; one patient on placebo committed suicide
    • Psoriatic Arthritis: Treatment with Otezla is associated with an increase in depression. During clinical trials, 1.0% (10/998) reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. Suicidal ideation and behavior was observed in 0.2% (3/1 441) of patients on Otezla, compared to none in placebo-treated patients. Depression was reported as serious in 0.2% (3/1 441) of patients exposed to Otezla, compared to none in placebo-treated patients (0/495). Two patients who received placebo committed suicide compared to none on Otezla
    • Behcet’s Disease: Treatment with Otezla is associated with an increase in depression. During the clinical trial, 1% (1/104) reported depression or depressed mood compared to 1%(1/103) treated with placebo. No instances of suicidal ideation or behavior were reported in patients treated with Otezla or treated with placebo
  • 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% (1 9/382) 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% (49/497) of patients taking Otezla and in 3.3% (16/495) of patients taking placebo
    • Behçet’s Disease: Body weight loss of >5% was reported in 4.9% (5/103) of patients taking Otezla and ¡n 3.9% (4/102) of patients taking placebo
  • Drug Interactions: Apremilast exposure was decreased when Otezla was co-administered with rilampin, a strong CYP4SO enzyme inducer; loss of Otezla efficacy may occur. Concomitant use of Otezla with CYP45O enzyme inducers (e.g., rifampin. phenobarbital, carbamazepine, phenytoin) is not recommended

Adverse Reactions

  • Psoriasis: Adverse reactions reported in ≥5% of patients were (Otezla%, ptacebo%): 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 at (east 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 (2M, 0.2)
  • Behçet’s Disease: Adverse reactions reported in 5% of patients taking Otezta, that occurred at a frequency at least 1% higher than that observed in patients taking placebo, for up to 12 weeks, were (Otezla%, placebo%): diarrhea (41.3, 20.4); nausea (19.2, 10.7); headache (14.4, 10.7); upper respiratory tract infection (11.5, 4.9); upper abdominal pain (8.7, 1.9); vomiting (8.7, 1.9); back pain (7.7, 5.8); viral upper respiratory tract infection (6.7, 4.9); arthralgia (5.8, 2.9)

Use in Specific Populations

  • Pregnancy: Otezla has not been studied in pregnant women. Advise pregnant women of the potential risk of fetal loss. Consider pregnancy planning and prevention for females of reproductive potential There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Otezla during pregnancy. Information about the registry can be obtained by calling 1-877-311-8972 or visiting https://mothertoaby.org/ongoing-study/otezla/
  • Lactation: There are no data on the presence of apremilast or its metabolites in human milk, the effects of apremilast on the breastfed infant, or the effects of the drug on milk production. The developmental and health benefits of breastleeding should be considered along with the mother’s clinical need for Otezla and any potential adverse effects on the breastled child from Otezla or from the underlying maternal condition
  • Renal Impairment: Otezla dosage should be reduced in patients with severe renal impairment (creatinine clearance less than 30 ml/mm); for details, see Dosage and Administration, Section 2, in the Full Prescribing Information

Please click here for Full Prescribing Information.

INDICATIONS & IMPORTANT SAFETY INFORMATION

INDICATIONS

Otezla® (apremitast) is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Otezla is indicated for the treatment of adult patients with active psoriatic arthritis.

Otezla is indicated for the treatment of adult patients with oral ulcers associated with Behçet’s Disease.

IMPORTANT SAFETY INFORMATION

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

  • Diarrhea, Nausea, and Vomiting: Cases of severe diarrhea, nausea, and vomiting were associated with the use of Otezla. Most events occurred within the first few weeks of treatment In some cases patients were hospitalized. Patients 65 years of age or older and patients taking medications that can lead to volume depletion or hypotension may be at a higher risk of complications from severe diarrhea, nausea, or vomiting. Monitor patients who are more susceptible to complications of diarrhea or vomiting; advise patients to contact their healthcare provider. Consider Otezla dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting
  • 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 depression. During clinical trials, 1.3% (12/920) of patients reported depression compared to 0.4% (2/506) on placebo. Depression was reported as serious in 0.1% (1/1 308) of patients exposed to Otezla, compared to none in placebo-treated patients (0/506). Suicidal behavior was observed in 0.1%(1/1 308) of patients on Otezla, compared to 0.2% (1/506) on placebo. One patient treated with Otezia attempted suicide; one patient on placebo committed suicide
    • Psoriatic Arthritis: Treatment with Otezla is associated with an increase in depression. During clinical trials, 1.0% (10/998) reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. Suicidal ideation and behavior was observed in 0.2% (3/1 441) oF patients on Otezla, compared to none in placebo-treated patients. Depression was reported as serious in 0.2% (3/1 441) of patients exposed to Otezla, compared to none in placebo-treated patients (0/495). Two patients who received placebo committed suicide compared to none on Otezla
    • Behcet’s Disease: Treatment with Otezla is associated with an increase in depression. During the clinical trial, 1% (1/104) reported depression or depressed mood compared to 1%(1/103) treated with placebo. No instances of suicidal ideation or behavior were reported in patients treated with Otezla or treated with placebo
  • 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% (1 9/382) 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% (49/497) of patients taking Otezla and in 3.3% (16/495) of patients taking placebo
    • Behçet’s Disease: Body weight loss of >5% was reported in 4.9% (5/103) of patients taking Otezla and ¡n 3.9% (4/102) of patients taking placebo
  • Drug Interactions: Apremilast exposure was decreased when Otezla was co-administered with rilampin, a strong CYP4SO enzyme inducer; loss of Otezla efficacy may occur. Concomitant use of Otezla with CYP45O enzyme inducers (e.g., rifampin. phenobarbital, carbamazepine, phenytoin) is not recommended

Adverse Reactions

  • Psoriasis: Adverse reactions reported in ≥5% of patients were (Otezla%, ptacebo%): 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 at (east 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 (2M, 0.2)
  • Behçet’s Disease: Adverse reactions reported in 5% of patients taking Otezta, that occurred at a frequency at least 1% higher than that observed in patients taking placebo, for up to 12 weeks, were (Otezla%, placebo%): diarrhea (41.3, 20.4); nausea (19.2, 10.7); headache (14.4, 10.7); upper respiratory tract infection (11.5, 4.9); upper abdominal pain (8.7, 1.9); vomiting (8.7, 1.9); back pain (7.7, 5.8); viral upper respiratory tract infection (6.7, 4.9); arthralgia (5.8, 2.9)

Use in Specific Populations

  • Pregnancy: Otezla has not been studied in pregnant women. Advise pregnant women of the potential risk of letal loss. Consider pregnancy planning and prevention for females of reproductive potential There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Otezla during pregnancy. Information about the registry can be obtained by calling 1-877-311-8972 or visiting https://mothertobaby.org/ongoing-study/otezla/
  • Lactation: There are no data on the presence of apremilast or its metabolites in human milk, the effects of apremilast on the breastfed infant, or the effects of the drug on milk production. The developmental and health benefits of breastleeding should be considered along with the mother’s clinical need for Otezla and any potential adverse effects on the breastled child from Otezla or from the underlying maternal condition
  • Renal Impairment: Otezla dosage should be reduced in patients with severe renal impairment (creatinine clearance less than 30 ml/mm); for details, see Dosage and Administration, Section 2, in the Full Prescribing Information

Please click here for Full Prescribing Information.