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Key clinical-trial evidence for apremilast

Author:Anoma Ranaweera B.V.Sc; PhD (Clinical Biochemistry, University of Liverpool, UK); Chief Editor: Dr Amanda Oakley, Dermatologist, Hamilton, New Zealand, January 2015.


Key clinical-trial evidence for apremilast — codes and concepts
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Introduction

Apremilast (Otezla®; Cellgene, New Jersey, USA) is an oral small-molecule inhibitor of the enzyme phosphodiesterase 4, which plays an important role in chronic inflammation associated with psoriasis.

On September 23, 2014, the US Food and Drug Administration (FDA) approved apremilast for the treatment of patients with moderate-to-severe plaque psoriasis mostly on the basis of results from 2 multicentre clinical trials — ESTEEM 1 and ESTEEM 2.

In July 2019, apremilast was also approved by the FDA for treatment of oral ulcers associated with Behçet disease.

ESTEEM trials

  • FDA approval for moderate-to-severe plaque psoriasis was based on results from the ESTEEM trials.
  • In these trials, 1257 patients with moderate-to-severe plaque psoriasis were randomized 2:1 to apremilast 30 mg twice daily (after a titration period) or placebo.
  • The primary endpoint was the number of patients with a 75% improvement in the Psoriasis Area and Severity Index (PASI-75).
  • In ESTEEM 1, significantly more patients receiving apremilast achieved a 75% reduction in PASI (psoriasis area severity index – a tool used to measure the severity and extent of psoriasis) score compared to placebo (33.1% vs 5.3%; P<.0001) at 16 weeks.
  • In ESTEEM 2, significantly more patients receiving apremilast also achieved PASI-75 compared to placebo (28.8% vs 5.8%; P<.0001) at 16 weeks.
  • In the ESTEEM trials, the majority of adverse events with apremilast were considered mild to moderate in severity and consisted primarily of nausea and vomiting, which generally resolved within 1 month.
  • Notably, key clinical trials with Enbrel® (etanercept) have found that approximately 38% to 40% of patients achieve PASI-75 within a similar timeframe. Key trials with Remicade® (infliximab) and Humira® (adalimumab) have found that approximately 60% to 64% and 49% to 59%, respectively, achieve PASI-75 within a similar time frame.

The proportion of subjects who achieved PASI-75 responses, and sPGA (static physician global assessment score — physician's impression of the disease at a single point) of clear (0) or almost clear (1), are presented in Table 1.

Table 1: Clinical Response at Week 16 in Studies ESTEEM-1 and ESTEEM-2
ESTEEM - 1 ESTEEM 2
  Placebo Apremilast Placebo Apremilast
No. randomised 282 562 137 274
PASI 75%; no. (%) 15 (5.3) 186 (33.1) 8 (5.8) 79 (28.8)
sPGA no. (%) 11 (3.9) 122 (21.7) 6 (4.4) 56 (20.4)

Adverse reactions

  • The safety of apremilast has been assessed in 3 randomised, double-blind, placebo-controlled trials involving 1426 adult subjects with moderate to severe plaque psoriasis.
  • Subjects were randomized to 30 mg twice daily apremilast or placebo.
  • Subjects ranged in age from 18 to 83 years, with an overall median age of 46 years.
  • Adverse reactions are summarised in Table 2.

Table 2 Adverse reactions reported in >1% of subjects on apremilast and with greater frequency than in subjects on placebo; up to day 112 (Week 16)

Adverse reaction Placebo (N= 506) no. (%) Apremilast (N= 920) no. (%)
Diarrhoea 32 (6) 160 (17)
Nausea 35 (7) 155 (17)
Upper respiratory tract infection 31 (6) 84 (9)
Tension headache 21 (4) 75 (8)
Headache 19 (4) 55 (6)
Abdominal pain 11 (2) 39 (4)
Vomiting 8 (2) 35 (4)
Fatigue 9 (2) 29 (3)
Dyspepsia 6 (1) 29 (3)
Decrease appetite 5 (1) 26 (3)
Insomnia 4 (1) 21 (2)
Back pain 4 (1) 20 (2)
Migraine 5 (1) 19 (2)
Frequent bowel movements 1 (0) 17 (2)
Depression 2 (0) 12 (1)
Bronchitis 2 (0) 12 (1)
Tooth abscess 0 (0) 10 (1)
Folliculitis 0 (0) 9 (1)
Sinus headache 0 (0) 9 (1)

Future directions

  • Apremilast has demonstrated safety and efficacy in the treatment of psoriatic arthritis and plaque psoriasis.
  • However, apremilast has not been compared to other approved treatments for psoriasis, and results from the placebo-controlled trials suggest a degree of efficacy that may be less than most FDA-approved biologic alternatives.
  • Apremilast likely offers an oral alternative to biologics in patients not responding adequately to biologics (e.g. adalimumab, infliximab, etanercept, ustekinumab), those with a diminished response over time, and those who are unable to take or tolerate the biologic agents.
  • Further clinical trial data and real-world experience are required to assess apremilast's true value versus other agents in the management of psoriasis.

New Zealand approved datasheets are the official source of information for prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.

If you are not based in New Zealand, we suggest you refer to your national drug approval agency for further information about medicines (eg, the Australian Therapeutic Goods Administration and the US Food and Drug Administration) or a national or state-approved formulary (eg, the New Zealand Formulary and New Zealand Formulary for Children and the British National Formulary and British National Formulary for Children).

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References

  • Papp K, Griffiths C, Leonardi C, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: results from the randomized treatment withdrawal phase of a phase 3, randomized, controlled trial (ESTEEM 1). Poster session: The American Academy of Dermatology 72nd Annual Meeting; 2014 March 21–25; Denver, CO.
  • Paul C, Crowley J, Cather J, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: 16-week results of a phase 3 randomized, controlled trial (ESTEEM 2). Poster session: The American Academy of Dermatology 72nd Annual Meeting; 2014 March 21–25; Denver, CO.
  • Hatemi G, Mahr A, Ishigatsubo Y, et al Trial of Apremilast for Oral Ulcers in Behçet's Syndrome. N Engl J Med. 2019 Nov 14;381(20):1918-1928. doi:10.1056/NEJMoa1816594. PubMed.

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