Clinical Trials

Date: 2016-09-28

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the European Academy of Dermatology and Venereology (EADV) Annual Congress in Vienna, Austria

Company: Celgene (USA - NJ)

Product: Otezla® (apremilast)

Action mechanism:

• phosphodiesterase 4 inhibitor. Otezla® is an oral, small-molecule, selective inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels. Otezla® was approved on September 23, 2014 by the FDA for the treatment of patients with moderate to severe plaque psoriasis for whom phototherapy or systemic therapy is appropriate.
• Otezla® is approved for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy and for the treatment of adults with active psoriatic arthritis.

Disease: plaque psoriasis

Therapeutic area: Autoimmune diseases - Dermatological diseases

Country:

Trial details:

• ESTEEM 1 and 2 are two large pivotal phase III randomized, placebo-controlled studies evaluating Otezla® 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 Otezla® 30 mg twice daily or placebo after an initial five-day titration period, for the first 16 weeks, followed by a maintenance phase from weeks 16-32 in which placebo patients were switched to Otezla® 30 mg twice daily through week 32, and a randomized withdrawal phase for responders from week 32 to week 52 based on their initial Otezla® randomization and Psoriasis Area and Severity Index (PASI)-75 response. 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. The primary endpoint of the ESTEEM 1 and ESTEEM 2 studies was the proportion of patients who achieved PASI-75 at week 16. The major secondary endpoint was the proportion of patients who achieved a static Physician Global Assessment score of clear (0) or almost clear (1) at Week 16.
• PSOR-005 is a phase IIb, multicenter, randomized, placebo-controlled, dose-ranging study evaluating Otezla® in patients with a diagnosis of moderate to severe plaque psoriasis for at least six months prior to screening, and who are also candidates for phototherapy and/or systemic therapy. 352 patients were randomized 1:1:1:1 to receive oral placebo or Otezla® 10, 20, or 30 mg twice daily after an initial five-day titration period, for the first 16 weeks, followed by a maintenance phase from weeks 16-24 in which placebo patients were randomly switched to Otezla® 20 mg or 30 mg twice daily through week 24.

Latest news:

• • On September 28, 2016, Celgene announced that long-term safety findings from ongoing clinical trials of apremilast were presented at the European Academy of Dermatology and Venereology (EADV) Annual Congress in Vienna, Austria . Analyses of pooled 156-week (3-year) safety data from the ESTEEM 1 and 2 and PALACE 1-3 trials were presented, which included patients with moderate to severe plaque psoriasis (ESTEEM) and active psoriatic arthritis (PALACE) who were treated with apremilast 30 mg twice-daily. Patients with psoriatic arthritis were treated with Otezla® alone or in combination with concomitant disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate. 2,242 patients were included in the pooled safety analysis up to 16 weeks (placebo n=913; APR30 n=1,329), with 1,905 patients (3,527.5 patient years) receiving apremilast in the APR-exposure period up to 156 weeks.1 Across both trial programmes up to 16 weeks, the most common adverse events (AEs) (?5 percent of patients) among patients on apremilast were diarrhoea, nausea, headache, upper respiratory tract infection, and nasopharyngitis. Most cases of diarrhoea/nausea were mild to moderate in severity, occurred during the first 2 weeks of apremilast dosing and generally resolved in one month. Discontinuation rates of apremilast due to diarrhoea and nausea occurred at rates of 1.3 percent and 1.7 percent, respectively, during the 0 to ?52 week apremilast exposure period and 0.0 percent for both AEs during the > 104 to ?156 week apremilast exposure period. The exposure-adjusted incidence rates ( EAIR /100 patient years) for AEs, serious AEs and discontinuations due to AEs did not increase with increasing cumulative exposure during the apremilast-exposure period (0 to ?156 weeks; 3,527.5 patient-years); this was confirmed by assessment of rates on a year-by-year exposure basis.1 The incidences ( EAIR /100 patient years) of major adverse cardiovascular events (MACE), malignancies, and serious infections for patients on apremilast were comparable to placebo up to 16 weeks and remained low with prolonged exposure. No serious opportunistic infections or clinically meaningful effects on laboratory measurements were reported. Rates for depression or suicidality did not increase with increasing cumulative long-term apremilast exposure. Most patients taking apremilast maintained body weight within 5 percent of baseline; with 21.1 percent experienced > 5 percent weight loss over the 156 week apremilast-exposure periods. The rate of treatment discontinuation due to weight loss was low. In addition, a retrospective analysis of results from ESTEEM 1 and 2 trials examined the potential of an alternative tool to measure psoriasis disease severity. Improvement in Psoriasis Area and Severity Index (PASI) score remains the most commonly used severity assessment in clinical development and in practice, however its limitations - including scoring complexity and insensitivity to changes - mean that there may be opportunities to improve how psoriasis patients are assessed. The combination of the Physician's Global Assessment (PGA) and Body Surface Area (BSA) - the PGAxBSA composite tool - is a simple assessment which was shown to measure meaningful clinical responses of psoriasis patients in the ESTEEM trials including minimal disease activity and is sensitive to change in disease severity.
• • On March 20, 2015, Celgene announced that results from long-term efficacy and safety analyses of the ESTEEM phase III clinical trial program of Otezla® (apremilast) were presented at the 73rd Annual Meeting of the American Academy of Dermatology (AAD) in San Francisco, California. In ESTEEM 1 and 2, patients were randomized to treatment with  Otezla® 30 mg twice daily or placebo for the first 16 weeks. At week 16, patients either continued on  Otezla® or were switched from placebo to  Otezla® 30 mg twice daily through week 32. Patients initially randomized to  Otezla® who achieved a Psoriasis Area and Severity Index (PASI)-75 response (ESTEEM 1) or PASI-50 response (ESTEEM 2) at week 32 were then re-randomized to either  Otezla® 30 mg twice daily or placebo.
• ESTEEM 2: 52-Week Data Observed in Patients with Nail, Scalp and Palmoplantar Involvement: An analysis of data from ESTEEM 2 presented at AAD showed sustained improvements at week 52 among PASI-50 responders (patients who achieved a 50 percent reduction in PASI at week 32) in difficult-to-treat areas such as nails, scalp and the palms of the hands and soles of the feet (known as palmoplantar psoriasis). Among patients who had nail psoriasis at baseline with a Nail Psoriasis Severity Index (NAPSI) greater than or equal to one, 45 percent (78/175) of those treated with  Otezla® 30 mg twice daily had at least a 50 percent improvement in NAPSI (NAPSI-50) at week 16, compared with 19 percent (17/91) of those treated with placebo (P < 0.0001). NAPSI-50 achievement was generally maintained for up to 52 weeks in patients (69 percent, n=35) who received OTEZLA at baseline who were PASI-50 responders. Of those patients who had moderate to very severe scalp psoriasis at baseline, 41 percent (72/176) of those treated with  Otezla® 30 mg twice daily had a Scalp Physician Global Assessment (ScPGA) score of clear (zero) or minimal (one) at week 16, compared with 17 percent (16/93) of those treated with placebo (P < 0.0001). ScPGA score of zero or one achievement was generally maintained for up to 52 weeks in patients (63 percent, n=32) who received OTEZLA at baseline who were PASI-50 responders. Among patients who had moderate to severe psoriasis on their palms and feet at baseline, 65 percent (17/26) of those treated with  Otezla® 30 mg twice daily had a Palmoplantar Psoriasis Physician Global Assessment (PPPGA) score of clear (zero) or almost clear (one) at week 16, compared with 31 percent (5/16) of those treated with placebo (P=0.0315). PPPGA score of zero or one achievement was sustained up to week 52 (n=4 of 4 patients) in patients randomized to OTEZLA who were PASI-50 responders at week 32.
• PSOR-005, ESTEEM 1 and ESTEEM 2: 16-Week Palmoplantar Data:An analysis of PSOR-005, ESTEEM 1 and ESTEEM 2 found that Otezla® improved palmoplantar psoriasis in a subset of patients with moderate to severe chronic plaque psoriasis who had palmoplantar involvement. Of those patients who had any palmoplantar psoriasis at baseline (PPPGA score of one or greater, n=427 across the three studies - 49 in PSOR-005, 254 in ESTEEM 1 and 124 in ESTEEM 2), a higher percentage of patients treated with  Otezla® 30 mg twice daily had PPPGA reduced to clear or almost clear compared with placebo at week 16 in all three trials [PSOR-005: 70 percent (19/27) vs. 32 percent (7/22), respectively, P=0.0072; ESTEEM 1: 63 percent (107/169) vs. 45 percent (38/85), respectively, P=0.0047; ESTEEM 2: 71 percent (55/78) vs. 37 percent (17/46), respectively, P=0.0003]. Among patients who had moderate to severe palmoplantar psoriasis at baseline (PPPGA score of three or greater) (n=144 across the three studies — 19 in PSOR-005, 83 in ESTEEM 1 and 42 in ESTEEM 2), a higher percentage of patients treated with Otezla® 30 mg twice daily had PPPGA reduced to clear or almost clear compared with placebo at week 16 in PSOR-005 [67 percent (6/9) vs. 20 percent (2/10), respectively, P=0.0397] and ESTEEM 2 [65 percent (17/26) vs. 31 percent (5/16), respectively, P=0.0315]. There was no significant difference between the Otezla® and placebo groups at week 16 in ESTEEM 1 [39 percent (22/57) vs. 31 percent (8/26), respectively, P=0.4912].
• ESTEEM 1: Two-Year Safety Data: Long-term (104-week) results from the ESTEEM 1 trial showed that no new safety signals were identified in patients treated with  Otezla® 30 mg twice daily for up to two years (844 patients were randomized, 444 continued in the second year). As with adverse events (AEs) reported during the first 52 weeks of exposure, most AEs reported during weeks 52 to 104 were mild or moderate in severity and did not lead to discontinuation. The most frequently reported AEs during the placebo-controlled period and the  Otezla®-exposure periods were diarrhea, upper respiratory tract infection, nausea, nasopharyngitis, tension headache and headache. The exposure adjusted incidence rate (EAIR) for serious AEs did not increase with longer Otezla® exposure, compared with the placebo-controlled period. There were no clinically meaningful changes in laboratory measurements identified over the  Otezla® 104-week exposure period. Incidence rates of major cardiac events, solid tumors, hematological malignancies and serious infections were comparable between the placebo and  Otezla® arms during the placebo-controlled period. No increase in incidence rates was noted with longer-term exposure to  Otezla® between weeks 52 to 104.
• * On October 10, 2014, Celgene International Sàrl, a wholly-owned subsidiary of Celgene Corporation, announced that results from additional efficacy and safety analyses of Otezla® (apremilast) from the ESTEEM phase III clinical trial program were released at the 23rd European Academy of Dermatology and Venereology (EADV) Congress in Amsterdam . Patient-reported health outcomes data were also presented
• ESTEEM 2: 32-Week Data in Patients with Nail, Scalp, and Palmoplantar Involvement: 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. 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 < 0.0001). After 32 weeks of treatment with apremilast 30 mg twice daily, 55 percent of patients achieved at least a 50 percent improvement.
• 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. ESTEEM 1 and ESTEEM 2: 32-Week Pruritus Data: An analysis of ESTEEM 1 and 2 found that apremilast improved skin discomfort/pain. Patients report that pruritus (itching) is one of the most common and bothersome symptoms of psoriasis. Significantly greater improvements in 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 < 0.0001 for both trials). A post-hoc analysis found that improvements in itching and in skin discomfort/pain with apremilast 30 mg twice daily were observed as early as week 2 and were maintained through week 32. ESTEEM 2: 52-Week Efficacy Data: Long-term (52-week) results from 411 patients in the ESTEEM 2 trial demonstrated durability of clinical responses achieved with apremilast. For those patients who were treated with apremilast 30 mg twice daily for 52 weeks and who achieved a 50 percent improvement in Psoriasis Area and Severity Index (PASI) at week 32, mean improvements in PASI remained stable between weeks 32 and 52 (74 percent to 77 percent).
• 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, diarrhea, 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.
• The analyses from the phase III ESTEEM clinical trial program assessed the effect of apremilast on health-related quality of life measures and on work productivity/work limitation. A new analysis of the ESTEEM 2 trial demonstrated that treatment with apremilast 30 mg twice daily after 16 weeks significantly improved health-related quality of life compared with placebo. Significant improvement was seen in a variety of these standardized measures, including the Dermatology Quality of Life Index (DLQI), the Patient Health Questionnaire, the European Quality of Life 5 Dimensions Questionnaire and the Short-Form Health Survey mental component summary and physical component summary.
• At Week 16, more than 70 percent of patients who received apremilast 30 mg twice daily achieved clinically meaningful improvement in DLQI of at least 5-points. 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 versus placebo, along with a 5-point or greater DLQI improvement, thereby meeting treatment goal criteria from National Institute for Health and Care Excellence (NICE) and European S3 guidelines. 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 significantly increased work productivity (P=0.031) and reduced work limitations (P=0.035) at 16 weeks. Patients in this study completed the Work Limitation Questionnaire (WLQ)—a 25-item questionnaire that assessed the degree to which employed individuals are experiencing on-the-job limitations due to their health problems as well as the health-related productivity loss—at baseline and week 16. Four categories of work limitations were used to calculate the WLQ index—physical demands, mental demands, time management demands and output demands. The WLQ scale scores were then converted into an estimate of productivity loss.
• Apremilast was approved on March 21, 2014 , by the FDA for the treatment of adults with active psoriatic arthritis and on September 23, 2014 for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. A New Drug Submission (NDS) based on the combined data from the PALACE 1, 2 and 3 trials for psoriatic arthritis was submitted to health authorities in Canada in the second quarter of 2013. A NDS for psoriasis in Canada as well as a combined psoriatic arthritis/plaque psoriasis Marketing Authorization Application (MAA) in Europe were all submitted to health authorities in the fourth quarter of 2013.
• * On October 7, 2014, Celgene announced that the latest research findings on Otezla® (apremilast), the Company's oral, selective inhibitor of phosphodiesterase 4 (PDE4), in plaque psoriasis will be presented at the 23rd European Academy of Dermatology and Venereology (EADV) Congress in Amsterdam, October 8 - 12, 2014. Otezla® data to be presented include long-term (52-week) results from Celgene's pivotal trial, ESTEEM 2 and pooled analyses of safety and tolerability results from the ESTEEM 1 and 2 studies in patients with moderate to severe plaque psoriasis. Additional analyses will evaluate the effect of Otezla® on pruritus (itching), difficult-to-treat areas such as nail and scalp, and palmoplantar (hand and feet) psoriasis, work productivity and improvements in health-related quality of life. The following abstracts on Otezla® will be presented in oral and/or e-Poster sessions as an exchange of scientific and clinical information by clinical investigators :
• - Apremilast, an Oral Phosphodiesterase 4 Inhibitor, in Patients with Moderate to Severe Psoriasis: Results of a Phase 3, Randomized, Controlled Trial (ESTEEM 2); Carle Paul, MD
• - Long-term Safety and Tolerability of Apremilast in Patients with Psoriasis: Pooled Safety Analysis of Two Phase 3, Randomized, Controlled Trials (ESTEEM 1 and 2); Kristian Reich, MD
• - Effect of Apremilast on Patient Reported Outcomes in Patients with Moderate to Severe Plaque Psoriasis in the ESTEEM 1 trial; April Armstrong, MD
• - Change in Weight with Apremilast, an Oral Phosphodiesterase 4 Inhibitor: Pooled Analysis of the ESTEEM 1 and ESTEEM 2 Trials; Kristian Reich, MD
• - Psychiatric Disorders and Depression Incidence with Apremilast, an Oral Phosphodiesterase 4 Inhibitor: Pooled Analysis of the ESTEEM 1 and ESTEEM 2 Trials; Alan Menter, MD
• - Effects of Apremilast on Health-Related Quality of Life in Patients with Moderate to Severe Plaque Psoriasis: 16-Week Results From the ESTEEM 2 Trial; Melinda Gooderham, MD - Apremilast in Moderate to Severe Plaque Psoriasis: 32-Week Results in Patients with Nail, Scalp, and Palmoplantar Involvement (ESTEEM 2); Jeffrey Crowley, MD - Effects of Apremilast on Pruritus in Patients with Moderate to Severe Plaque Psoriasis: Results from the ESTEEM 1 and 2 Trials; Gil Yosipovitch, MD - The Impact of Apremilast Therapy on Work Productivity Among Patients with Moderate to Severe Plaque Psoriasis: Pooled Analysis of 2 Phase 3 Studies; Ulrich Mrowietz, MD - The Impact of Apremilast Therapy on Work Productivity Among Patients with Moderate to Severe Plaque Psoriasis: Pooled Analysis of 2 Phase 3 Studies; Tom Tencer, MD.

Is general: Yes