New developments in the management of psoriasis and psoriatic arthritis: a focus on apremilast

Figures & data

Figure 1 Psoriasis and PsA. (A) Psoriasis is associated with a hyperproliferative epidermal layer, abnormal keratinocyte growth, and an inflammatory cell infiltrate including T cells and macrophages. This manifests in inflamed skin and raised plaques with silvery scales and can cover large areas of the body. (B) Glossary of clinical features associated with classification of psoriatic arthritis. Adapted from Bren L. Psoriasis: more than cosmetic. FDA Consumer. 2004 Sept–Oct. Available from: http://permanent.access.gpo.gov/lps1609/www.fda.gov/fdac/features/2004/504_psoriasis.html. Accessed February 8, 2013.⁶³

Abbreviation: PsA, psoriatic arthritis.

Table 1 Summary of current biological therapies for the treatment of moderate to severe psoriasis and PsA

Drug	Treatment	Mechanism of action	Efficacy	Safety
Anti-TNF
Adalimumab	PsA 40 mg SC every other week, psoriasis 80 mg SC at week 0; 40 mg SC every other week thereafter^Citation5	Fully human monoclonal antibody	PASI-75 achieved in 71% of psoriasis and 59% of PsA patients. PsA ACR20 achieved in 58%^Citation5	Association with increased prevalence of bacterial, viral, and fungal infections. Reactivation of hepatitis B. Increased tuberculosis recurrence^Citation5,Citation6
Etanercept	PsA 25 mg SC twice a week. Psoriasis 50 mg SC twice weekly for 3 months, 50 mg/week thereafter^Citation5	Fusion protein to link TNF receptor to the Fc component of human IgG	PASI-75 achieved in 49% of psoriasis and 26% of PsA patients. PsA ACR20 achieved in 59%^Citation5
Golimumab	PsA 50 mg SC every month^Citation5	Human monoclonal antibody (2-week half-life) Phase II trials for psoriasis	PASI-75 achieved in 58% of psoriasis and 58% of PsA patients. PsA ACR20 achieved in 5I%^Citation5
Infliximab	PsA and psoriasis 5 mg/kg at weeks 0, 2, and 6, and at every 8 weeks thereafter^Citation5	Chimeric (mouse-human) monoclonal antibody	PASI-75 achieved in 80% of psoriasis and 68% of PsA patients. PsA ACR20 achieved in 58%^Citation5
Anti-IL-17
Brodalumab	Subcutaneous injection	Anti-IL-17 receptor monoclonal antibody	PASI-75 achieved in up to 82% of PsA patients at 12 weeks (placebo, 0%)^Citation13	AE reported include nasopharyngitis, injection, nausea, and arthralgia^Citation13
Ixekizumab	Subcutaneous injection	Monoclonal anti-IL-17 antibody	Up to 82% PASI-75 improvement at 12 weeks (placebo 7.7%)^Citation11	AE include infections, headaches, and nasopharyngitis^Citation11
Secukinumab	Subcutaneous injection	Monoclonal anti-IL-17 antibody	81.5% achieved PASI-75 (150 mg) at 12 weeks (placebo, 9.1%)^Citation12	AE include pharyngitis, fatigue, and peripheral edema^Citation12
Anti-IL-12/ IL-23
Briakinumab	Subcutaneous injection	Human monoclonal antibody anti-p40 subunit	Up to 82% achieved PASI 75 (placebo 6%–7%)^Citation20,Citation21	AE include nasopharyngitis headache and infections^Citation20,Citation21
Ustekinumab	Subcutaneous injection	Human monoclonal antibody anti-p40 subunit	Up to 67% achieved PASI-75 (placebo 3.1%)^Citation17	AE include headache, myocardial infarction, and stroke. Potential increase of latent infection^Citation5,Citation17
Anti-T cell activation
Abatacept	Subcutaneous injection	Fully human CTLA-4-lgG 1 fusion protein that binds CD80/CD86	Up to 48% of PsA patients achieved ACR20 in Phase II trial (placebo, 19%)^Citation5	AE include dizziness, headache, and hypertension. Increased risk of infection^Citation5
Alefacept	Intramuscular injection 15 mg once weekly for 12 weeks^Citation6,Citation34	Inhibits T cell activation and proliferation	Phase III trial; 33% achieved PASI-75 versus with 13% placebo. PsA (plus MTX) 54% ACR20 versus MTX alone^Citation6,Citation34	No increased incidence for infections^Citation6

Abbreviations: PsA, psoriatic arthritis; SC, subcutaneous; PASI, Psoriasis Area and Severity Index; ACR20, American College of Rheumatology-20; TNF, tumor necrosis factor; IgG, immunoglobulin G; IL, interleukin; AE, adverse events; CTLA-4, cytotoxic T-lymphocyte antigen 4; MTX, methotrexate.

Table 2 Summary of published pilot and Phase II studies investigating the efficacy and safety of apremilast in a variety of conditions

Lead author	Date	Disease	Type	Treatments	Number enrolled	Outcome	Adverse effects
Papp et al^Citation50	June 2012	Psoriasis	Phase IIb	10 mg, 20 mg, 30 mg BID, and placebo.	352	Subjects treated with apremilast at 10 mg, 20 mg, and 30 mg BID reached PASI-75 at the respective rates: 11%, 29%, and 41%. This was compared to 6% of the placebo group.	No serious AE seen. Headaches and nausea reported.
Papp et al^Citation45	August 2012	Psoriasis	Phase II	20 mg SID, 20 mg BID, and placebo.	259	24.4% of subjects treated with 20 mg BID of apremilast reached PASI-75. Both the 20 mg SID and placebo groups saw 10.3% of patients reach PASI-75.	Few more AE compared to apremilast, but most considered mild and tolerable.
Schett et al^Citation51	October 2012	Psoriatic arthritis	Phase II	20 mg BID, 40 mg SID, and placebo.	204	Apremilast was more successful at achieving ACR20, 20 mg BID (43.5%), 40 mg SID (35.8%), compared to placebo (11.8%). Rerandomizing the placebo group after the 12-week period also proved that apremilast was effective.	Slightly higher incidence of AE with apremilast compared to placebo, but not significant.
Samrao et al^Citation59	August 2012	Atopic dermatitis	Pilot study	20 mg, 30 mg BID, and no placebo or control.	83	Small dose-dependent effect observed with apremilast. Results were moderate, but did show statistical significance.	No serious AE seen. Headaches and nausea reported.
Pathan et al^Citation55	September 2012	AS	Phase II	30 mg BID and placebo.	38	The primary endpoint was not met, but six patients treated with apremilast met ASA20, compared to three on placebo. Significant reduction in serum RANKL was observed by apremilast treatment.	Similar AE observed between apremilast and placebo. Higher rate of headaches and loose stools in the apremilast group. Two patients withdrew from the apremilast group due to severe AE.
Gottlieb et al^Citation52	May 2008	Psoriasis	Phase II	20 mg SID and no placebo or control.	19	Epidermal thickness was reduced by a mean of 20.5 mm, and PASI score improved in 73.7% of patients. Apremilast reduced the number of T cells and CD11c cells.	73.7% patients experienced at least one AE. Headaches and nausea reported.
Paul et al^Citation60	August 2012	Lichen planus	Pilot study	20 mg BID and no placebo or control.	10	Three out of ten patients achieved a two-grade improvement in PGA. All patients demonstrated statistically significant clinical improvement.	No serious AE seen. Headaches and nausea reported.
Volf et al^Citation61	March 2012	Recalcitrant allergic contact or atopic dermatitis	Phase II	20 mg BID and no placebo or control.	10	Two patients displayed ≥ 2 improvement of Investigator Global Assessment at week 12. Secondary endpoints of EASI-75 and EASI-50 were met by 10% and 20% of patients, respectively.	No serious AE seen. Headaches and nausea reported.
De Souza et al^Citation62	October 2012	Discoid lupus erythematosus	Phase II	20 mg BID and no placebo or control.	8	Significant decrease in CLASI score after 85 days observed in patients.	No serious AE seen. Headaches and nausea reported.

Abbreviations: BID, twice a day; PASI, Psoriasis Area and Severity Index; AE, adverse events; SID, once a day; ACR20, American College of Rheumatology; AS, ankylosing spondylitis; RANKL, receptor activator of nuclear factor kappa-B ligand; EASI, Eczema Area Severity Index; CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index.

Table 3 Summary of registered Phase III clinical trials investigating the effectiveness of apremilast to treat psoriasis, psoriatic arthritis, ankylosing spondylitis, and sarcoidosis⁵⁸

Trial name	NCT number	Disease	Treatments	Number enrolled	Completion date
PALACE-1	NCT01172938	Psoriatic arthritis	20 mg, 30 mg, placebo + 20 mg, placebo + 30 mg (all BID)	495	September 2015
PALACE-2	NCT01212757	Psoriatic arthritis	20 mg, 30 mg, placebo + 20 mg, placebo + 30 mg (all BID)	495	November 2015
PALACE-3	NCT01212770	Psoriatic arthritis	20 mg, 30 mg, placebo + 20 mg, placebo + 30 mg (all BID)	495	November 2015
PALACE-4	NCT01307423	Psoriatic arthritis	20 mg, 30 mg, placebo + 20 mg, placebo + 30 mg (all BID)	495	March 2014
ESTEEM 1	NCT01194219	Plaque psoriasis	30 mg BID and placebo	844	November 2016
ESTEEM 2	NCT01232283	Plaque psoriasis	30 mg BID and placebo	413	December 2016
–	NCT01690299	Plaque psoriasis	30 mg BID, etanercept 50 mg once weekly, placebo (tablet), placebo (injection, once weekly)	240	August 2015
POSTURE	NCT01583374	Ankylosing spondylitis	20 mg, 30 mg, placebo (all BID)	456	December 2018
–	NCT00794274	Sarcoidosis; cutaneous sarcoidosis	20 mg BID, no placebo	20	December 2011

Abbreviations: NCT, National Clinical Trial; PALACE, Efficacy and Safety Study of Apremilast to Treat Active Psoriatic Arthritis; BID, twice a day; ESTEEM, Study to Evaluate Safety and Effectiveness of Oral Apremilast (CC-10004) in Patients with Moderate to Severe Plaque Psoriasis; POSTURE, Study of Apremilast to Treat Subjects with Active Ankylosing Spondylitis.

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