Celgene International Sàrl has presented results from additional efficacy and safety analyses of OTEZLA® (apremilast) from the ESTEEM phase III clinical trial programme at the 23rd European Academy of Dermatology and Venereology (EADV) Congress in Amsterdam. Patient-reported health outcomes data for apremilast were also presented at the congress.
"Thousands of people in the UK and Ireland suffer with Psoriasis and whilst many new treatments have been developed in the last few years, there are still some people who have to live the debilitating impact of this disease and may not be suitable for existing therapies. These latest results from the ESTEEM trial show the efficacy of apremilast in people with psoriasis in difficult-to-treat areas such as the nails and the scalp and are encouraging," commented Dr Richard Warren, Senior Lecturer and Honorary Consultant Dermatologist at The University of Manchester and Salford Royal NHS Foundation Trust. "The data also highlight that apremilast can improve skin symptoms and relieve pain and itching as quickly as two weeks after initiating treatment, which could be very beneficial to many people who currently live with psoriasis."
ESTEEM 2: 32-Week Data in Patients with Nail, Scalp, and Palmoplantar Involvement[i]
An analysis of ESTEEM 2 demonstrated that apremilast significantly improved psoriasis in difficult-to-treat areas such as: the palms of the hands and feet (known as palmoplantar psoriasis), nails and scalp compared to placebo. Among patients who had nail psoriasis at baseline (n=266), 45 percent treated with apremilast 30 mg twice daily had at least a 50 percent improvement in this symptom at week 16, compared with 19 percent of those treated with placebo (P
Of those patients who had moderate to severe psoriasis on their palms and feet at baseline (n=42), 65 percent had these symptoms reduced to clear or almost clear at week 16. Improvements over baseline in nail, scalp and palmoplantar psoriasis were seen for up to 32 weeks.
The most common adverse events (AEs) were nausea, diarrhoea, nasopharyngitis, upper respiratory tract infection (URTI), headache (including tension headache), and vomiting. Most AEs were mild to moderate in severity, and discontinuation rates due to AEs were low and similar between treatment groups (placebo: 5.1%; apremilast 30 mg twice daily: 5.5%) during Weeks 0 to 16.
ESTEEM 1 and ESTEEM 2: 32-Week Pruritus Data[ii]
An analysis of ESTEEM 1 and 2 found that apremilast improved skin discomfort/pain compared to placebo. Significantly greater improvements in pruritus (itching) scores at week 16 were seen for patients treated with apremilast 30 mg twice daily (decreases of 31.5 in ESTEEM 1 and 33.5 in ESTEEM 2) compared with placebo (decreases of 7.3 in ESTEEM 1 and 12.2 in ESTEEM 2; P
ESTEEM 2: 52-Week Efficacy Data[iii]
Long-term (52-week) results from 411 patients in the ESTEEM 2 trial showed that the Psoriasis Area and Severity Index (PASI) scores were generally maintained in patients re-randomized to apremilast 30 mg twice daily, during the randomized treatment withdrawal phase between weeks 32 and 52. For patients re-randomized to apremilast (n=61), the mean percent change from baseline in PASI score ranged from 74 percent to 77 percent between weeks 32 and 52.
Over the entire apremilast exposure period, AEs in ≥5% of patients were nausea (16.6%), diarrhoea (14.5%), nasopharyngitis (14.5%), upper respiratory tract infection (9.2%), tension headache (7.6%), vomiting (6.3%), headache (5.8%), and back pain (5.3%). Most AEs were mild or moderate in severity and did not lead to discontinuation. There were no clinically meaningful changes in laboratory parameters.
ESTEEM 2: 16-Week Health-Related Quality of Life and Work Productivity Data[iv],[v]
A new analysis of the ESTEEM 2 trial demonstrated that treatment with apremilast 30 mg twice daily after 16 weeks improved health-related quality of life compared with placebo.[iv]
At Week 16, 71 percent of patients with moderate to severe plaque psoriasis who received apremilast 30 mg twice daily achieved clinically meaningful improvement in Dermatology Life Quality Index (DLQI) of at least 5-points, compared to 43% with placebo.[iv] Approximately half of patients treated with apremilast 30 mg twice daily also achieved at least a 50 percent improvement from baseline in the PASI-50 score in addition to a 5-point or greater DLQI improvement, versus 13% with placebo,[iv] thereby meeting treatment goal criteria from National Institute for Health and Care Excellence (NICE)[vi] and European S3 guidelines.[vii]
AEs occurring in ≥5% of patients in the placebo and apremilast groups were nausea (6.6%, 18.4%), diarrhoea (5.9%, 15.8%), nasopharyngitis (4.4%, 7.4%), tension headache (1.5%, 7.4%), headache (0.7%, 6.3%), vomiting (3.7%, 5.1%), and psoriasis (5.1%, 1.5%), respectively. The proportion of patients with serious AEs, severe AEs, and AEs leading to discontinuation were low and similar between treatment groups.[iv]
The results of a work productivity analysis of pooled data from 1250 patients from the ESTEEM 1 and 2 trials demonstrated that, compared with placebo, treatment with apremilast was associated with increased work productivity (P=0.031) and corresponded to a higher mean percent of productivity loss (P=0.035) at 16 weeks.[v]
About ESTEEM 1 and 2[viii]
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 or systemic therapy. Approximately 1,257 patients were randomized 2:1 to receive either apremilast 30 mg twice daily or placebo for the first 16 weeks. Doses of apremilast were titrated during the first week of administration. This was followed by a maintenance phase from weeks 16-32 in which placebo patients were switched to apremilast 30 mg twice daily through week 32, and a randomized withdrawal phase for responders from week 32 to week 52 based on their initial apremilast randomization. A responder in ESTEEM 1 was defined as a subject achieving ≥ PASI-75 at week 32, and a responder in ESTEEM 2 was defined as a subject achieving PASI-50 at week 32. Approximately 30 percent of all patients had received prior phototherapy and 54 percent had received prior conventional systemic and/or biologic therapy. Approximately one-third of patients had not received prior phototherapy, conventional systemic nor biologic therapy. A total of 18 percent of patients had a history of psoriatic arthritis.
Analysis of data from ESTEEM 2 did not identify new or unexpected adverse events (AEs) for patients treated with apremilast, and the rate of AEs did not increase in frequency over time. AEs reported in at least five percent of patients in any treatment group during the long-term 52-week apremilast-exposure period include nausea, diarrhoea, nasopharyngitis, tension headache, headache, vomiting, psoriasis, upper-respiratory tract infection, and back pain. The discontinuation rate due to AEs for those treated with apremilast 30 mg twice daily for 52 weeks was approximately seven percent. No clinically meaningful changes in laboratory measurements were identified over the apremilast 52-week exposure period.
Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP).[ix] PDE4 inhibition results in increased intracellular cAMP levels which is thought to indirectly modulate the production of inflammatory mediators.[ix] The specific mechanism(s) by which apremilast exerts its therapeutic action in patients with psoriasis or psoriatic arthritis is not well defined.
Apremilast was approved on 21 March 2014 by the U.S. Food and Drug Administration (FDA) for the treatment of adults with active psoriatic arthritis and on 23 September 2014 for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.[x] A combined psoriatic arthritis/plaque psoriasis Marketing Authorization Application (MAA) was submitted to the European Medicines Agency in Q4 2013.