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American Academy of Dermatology 2014
The American Academy of Dermatology hosted approximately 16,874 attendees in Denver from March 21 to 25. There was heightened interest in agents for the treatment of psoriasis; four such sessions are described here.
Results After at Least 52 Weeks of Open Label Treatment with Ixekizumab, an Anti-IL-17A Monoclonal Antibody, in a Phase 2 Study in Chronic Plaque Psoriasis
Clinical responses to ixekizumab treatment over 52 weeks in an open-label extension trial were maintained in a high proportion of patients with plaque psoriasis. The proportion, Dr. Gordon reported, was similar to that observed in the prior randomized treatment period.
Ixekizumab is a monoclonal antibody that neutralizes interleukin-17A (IL-17A), a pro-inflammatory cytokine that plays a critical role in the pathogenesis of psoriasis. In the prior randomized, placebo-controlled phase 2 study, IL-17A was shown to produce positive responses in patients with moderate-to-severe chronic plaque psoriasis.
The 20-week randomized, blinded portion of the trial was followed by a washout period extending to week 32. The 129 patients completing the 20 weeks of treatment could enter the open-label extension (OLE) period at week 32 and receive subcutaneous ixekizumab 120 mg given every four weeks. If their clinical response fell below PASI (Psoriasis Area and Severity Index) 75, they could enter the OLE before week 32. PASI scores are calculated based on psoriatic plaque redness, scaling, and thickness and the extent of involvement of various regions of the body. A PASI 75 response indicates a 75% improvement in PASI score from baseline.
Dr. Gordon presented data on four groups: all patients enrolled in the OLE; those initially assigned to placebo; week 20 responders (at PASI 75, 90, or 100 levels); and week 20 nonresponders.
At week 20, 51 patients had less than a PASI 75 response, as did 24 additional patients between weeks 24 and 32. Forty-five patients maintained PASI 75 and entered the OLE at week 32.
Among patients assigned initially to placebo, about 80% (22) achieved and maintained PASI 75. “That’s about equivalent to what was seen in the initial randomized part of the study for all patients,” Dr. Gordon said. In addition, a slightly lower proportion of patients achieved and maintained PASI 90, and slightly more than 50% attained and maintained PASI 100. “To put that in context, if you remember the alefacept trials, there we were looking at PASI 75 rates of 21%. Now we have PASI 100s of twice that level,” Dr. Gordon said.
Among week 20 responders, about 80% had PASI 90 responses through 52 weeks. “This is very distinct from the other medicines we’ve been using recently,” Dr. Gordon said. PASI 100 responses in this group went from 25% at week 0 of the OLE to about 80% within 20 weeks and were sustained.
Among those who lost responses and then were treated again, PASI 75 was achieved in approximately 70% after about 20 weeks. “The great majority of these patients regain response. Likewise for PASI 90 and 100, the numbers remain high (approximately 50% and approximately 40%, respectively) and are consistent throughout,” Dr. Gordon said.
No unexpected safety signals were observed. Discontinuations for adverse events were uncommon (2.4%). The most common treatment-emergent events were nasopharyngitis (10.0%), upper respiratory tract infections (7.5%), sinusitis (4.2%), and diarrhea (4.2%). Minor candidiasis was reported in 4.2%.
Dr. Gordon concluded, “Overall, a high proportion of patients responded to ixekizumab therapy and maintained the response over 52 weeks in this open-label extension.”
Secukinumab Efficacy Stratified by Body Weight: A Subanalysis From the FIXTURE Phase 3 Study in Psoriasis
A systematic review and meta-analysis of observational studies1 conducted in 2012 showed higher rates of obesity among patients with psoriasis (odds ratio 1.66 overall, 2.23 with severe psoriasis), and other research2 has suggested that obesity may reduce responses to biologic agents used to treat psoriasis. A subanalysis of FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using 2 Dosing Regimens to Determine Efficacy in Psoriasis) evaluated the effect of body weight on response to treatment with secukinumab in a pivotal phase 3 program in moderate-to-severe plaque psoriasis.
Secukinumab has demonstrated rapid, robust, and durable efficacy with an acceptable safety profile in this population in phase 3 trials. Dr. Szepietowski and colleagues evaluated the impact of body weight on response to treatment in the 1,300-patient trial. Patients had received one of two doses of secukinumab (150 mg/300 mg, every four weeks), placebo, or etanercept (50 mg biweekly) for 52 weeks. For evaluation of the co-primary endpoints of PASI 75 and Investigators’ Global Assessment (IGA) modified 2011 scores of 0/1 (clear or almost clear), patients were stratified by body weight: less than 90 kg or at least 90 kg.
Analysis showed secukinumab demonstrated rapid, high, sustained efficacy at both doses compared with etanercept, with higher responses at the higher dose of secukinumab. Body weight subgroups did not have differing responses. In the 300-mg secukinumab arm at week 12, PASI 75 responses were reported in about 78% of the 217 patients who weighed less than 90 kg and in about 72% of the 106 patients who weighed at least 90 kg. At week 52, PASI 75 responses were found for approximately 82%, 70%, and 58% of the under-90-kg patients (secukinumab 300 mg, secukinumab 150 mg, and etanercept 50 mg, respectively) compared with approximately 70%, 60%, and 52% in the 90-kg-or-more arm.
In addition, no major weight-based differences in the safety profile were reported. The exposure-adjusted incidence rates for treatment-emergent adverse events, however, were higher in subjects weighing 90 kg or more versus less than 90 kg in any secukinumab dose group (267.7 vs. 233.1 per 100 subject-years) and in the etanercept group (297.4 vs. 222.3 per 100 subject-years). Differences were driven, Dr. Szepietowski noted, largely by infections and infestations.
Dr. Szepietowski concluded that there was little influence of body weight on response rates.
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)
Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels, modulating a wide array of inflammatory mediators.
ESTEEM 1 was a large, randomized, placebo-controlled, pivotal phase 3 study that evaluated apremilast in patients diagnosed with moderate-to-severe plaque psoriasis at least 12 months prior to screening. To be eligible, patients also had to be candidates for phototherapy and/or systemic therapy.
ESTEEM 1 investigators randomized about 1,250 patients by a 2:1 ratio to receive either apremilast 30 mg twice daily or placebo after an initial five-day titration period for the first 16 weeks. A maintenance period followed from weeks 16 to 32 during which placebo patients were switched to apremilast 30 mg twice daily and apremilast patients continued their dose. At week 32, apremilast patients with PASI 75 response were randomized to placebo (until loss of effect) or continued on apremilast. Topical agents were added to those not achieving PASI 75 response. Patients in the initial placebo arm continued with apremilast, but with topical agents added for those with less than a PASI 75 response.
The primary endpoint of PASI 75 response was reported as 33.1% in the apremilast arm and 5.3% in the placebo arm (P < 0.0001) at 16 weeks. For the major secondary endpoint of static Physician Global Assessment (sPGA) scores of 0–1 (indicating clear or almost clear), the rates were 21.7% versus 3.9%, respectively (P < 0.0001).
The mean percentage change from baseline in PASI score for the 77 patients receiving apremilast in weeks 0–52 and achieving PASI 75 at week 32 was approximately –80%. Among patients who had received placebo during weeks 0–16 and apremilast during weeks 16–52, the mean PASI score change from baseline was also approximately –80% for those achieving PASI 75 at week 32. Among patients who were not PASI 75 responders at week 32, the mean percentage change from baseline in PASI score was approximately –50% to –60%.
When apremilast patients lost their PASI 75 response after being randomized to placebo in weeks 16–32, 70.3% of them regained PASI 75 responses with re-initiation of apremilast 30-mg twice-daily treatment.
Among the 46 patients who had nail psoriasis at baseline, a mean 60.2% decrease from baseline in the Nail Psoriasis Severity Index (NAPSI) was observed at week 52. Of the 49 patients who had scalp psoriasis defined as moderate or greater at baseline, 72.9% had reductions of their scalp symptoms to clear or almost clear (Scalp and Palmoplantar Psoriasis Global Assessment [ScPGA] 0 or 1) at week 52. Dr. Day emphasized that in plaque psoriasis in the nails and scalp—areas known to be difficult to treat—improvements were meaningful in the majority of patients.
The incidence of serious adverse events was low and comparable across treatment groups during the placebo-controlled period, with discontinuation for diarrhea and nausea of less than 2% in the apremilast 30-mg twice-daily group through week 52. Longer exposure to apremilast, Dr. Day said, did not increase adverse events.
ESTEEM 2 co-author Dr. Cather commented: “Together with the observed long-term consistent safety and tolerability profile, these findings are encouraging.”
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)
Apremilast is an oral phosphodiesterase 4 inhibitor that regulates cellular inflammatory mediators. In the phase 3 ESTEEM 2 trial, investigators enrolled 274 patients in the apremilast arm and 137 in the placebo arm. Patients had a diagnosis of moderate-to-severe plaque psoriasis (PASI 12 or more; body surface area [BSA] of 10% or more; sPGA of 3 or more) for at least 12 months prior to screening. Included patients also had to be candidates for phototherapy and/or systemic therapy.
Patients were randomized 2:1 to receive either apremilast 30 mg twice daily or placebo for the first 16 weeks, followed by a maintenance phase during weeks 16–32. In that period, placebo patients were switched to apremilast 30 mg twice daily through week 32. ESTEEM 2 also included a randomized withdrawal phase for responders from weeks 32 to 52 based on initial apremilast randomization and PASI 75 response.
The ESTEEM 2 primary endpoint was PASI 75 response at week 16.
A significantly higher percentage of patients receiving apremilast 30 mg twice daily achieved a PASI 75 response compared with patients who received placebo (28.8% vs. 5.8%; P < 0.0001) at 16 weeks. Statistical significance at week 16 was also demonstrated for the major secondary endpoint, sPGA scores of 0–1 (20.4% vs. 4.4%; P < 0.0001).
Dr. Paul noted that apremilast 30 mg twice daily compared with placebo also demonstrated beneficial effects in difficult-to-treat areas of scalp, nails, palms, and soles. Apremilast versus placebo resulted in improvements for the scalp (ScPGA 0–1: 40.9% vs. 17.2%; P < 0.0001), the nails (NAPSI 50: 44.6% vs. 18.7%; P < 0.0001), and palm and soles (Palmoplantar Physician Global Assessment [PPPGA] 0–1: 65.4% vs. 31.3%; P = 0.0315).
Most adverse events, Dr. Paul said, occurred in the first or second week of treatment, were mild or moderate in severity, and did not lead to discontinuation of therapy. Diarrhea was reported in 15.8% of apremilast patients and nausea in 18.4% (vs. 5.9% and 6.6% in the placebo arm, respectively).
“Patients need to be warned about these events. They can be managed,” he said. Dr. Paul also commented that doses of apremilast were titrated over the first few days of treatment. “You need to titrate the dose to prevent rapid occurrence of events,” he said.
“Apremilast may represent a novel oral therapy with a favorable benefit–risk profile for patients with moderate-to-severe plaque psoriasis,” Dr. Paul concluded.
- Armstrong AW, Harskamp CT, Armstrong EJ. The association between psoriasis and obesity: a systematic review and meta-analysis of observational studies. Nutr Diabetes 2012;Dec 3;2:e54. doi: 10.1038/nutd.2012.26.
- Clark L, Lebwohl M. The effect of weight on the efficacy of biologic therapy in patients with psoriasis. J Am Acad Dermatol 2008;58(3):443–446.