Safety, pharmacokinetics, and pharmacodynamics of ART-648, a PDE4 inhibitor in healthy subjects: A randomized, placebo-controlled phase I study.

Phosphodiesterase 4 (PDE4) inhibitor is associated with a broad-spectrum anti-inflammatory mechanism. However, securing clinically efficacious doses with sufficient safety margins remains challenging due to class specific adverse events that are often unavoidable in the clinic. ART-648 is an orally available PDE4 inhibitor being developed for the treatment of inflammatory diseases. According to the estimated clinical doses based on an in vitro whole-blood assay, a phase I study was designed. The purpose of this phase I study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) following single and multiple administration of ART-648 in healthy subjects. PD was assessed by suppression of lipopolysaccharide-induced TNFα release in ex vivo whole-blood assay. In the single rising dose study, ART-648 was safe and well tolerated with a dose-proportional increase in exposures up to 4 mg. Single doses of ART-648 demonstrated dose-dependent PD response, indicating target engagement at 2-8 mg doses. In the multiple rising dose study, doses up to 4 mg BID after careful titration were well tolerated, while doses up to 6 mg BID were tolerated not in all but the majority of subjects. In conclusion, ART-648 exhibits a favorable PK profile with robust target engagement at clinically safe and tolerated doses identified in healthy subjects.

A comparison of the safety and efficacy of tapinarof and roflumilast topical therapies in the management of mild-to-moderate plaque psoriasis.

INTRODUCTION: Psoriasis is an immune-mediated inflammatory skin disease. First-line topical treatments include steroids, calcineurin inhibitors, vitamin D analogs, and anthralin. Recently, novel topical therapeutics like tapinarof and roflumilast have emerged with unique anti-inflammatory mechanisms and promising efficacy profiles. MATERIALS AND METHODS: This review utilized PubMed, SCOPUS, and Web of Science databases to identify recent studies on tapinarof and roflumilast. Criteria focused on efficacy, safety profiles, and therapeutic roles in psoriasis treatment. RESULTS: Four primary literature articles were identified for tapinarof and five for roflumilast. Both drugs demonstrated strong efficacy with minimal adverse events in treating mild-to-moderate plaque psoriasis. Tapinarof showed more frequent but mild adverse effects, while roflumilast had less frequent but more severe side effects. DISCUSSION: Tapinarof and roflumilast offer once-daily dosing and successful treatment in restricted areas, potentially enhancing patient adherence. Cost remains a limiting factor, necessitating future comparative studies to evaluate the efficacy, safety, and cost-effectiveness between the two drugs. CONCLUSION: Tapinarof and roflumilast present promising topical treatments for psoriasis, showing efficacy and manageable safety profiles. Further research is crucial to fully elucidate their comparative benefits and drawbacks in clinical practice.

Effect of ensifentrine on dyspnea in patients with moderate-to-severe chronic obstructive pulmonary disease: pooled analysis of the ENHANCE trials.

BACKGROUND: Dyspnea is a critical component of chronic obstructive pulmonary disease (COPD). We report the effect of ensifentrine, a novel PDE3/PDE4 inhibitor, on dyspnea using pooled data from the Phase 3 ENHANCE-1/2 trials. METHODS: The pooled population (ensifentrine, n = 975; placebo, n = 574) included patients aged 40-80 years with post-bronchodilator FEV1/FVC <0.7, FEV1 30-70% predicted, mMRC Dyspnea Scale score ≥2, and a smoking history ≥10 pack-years. Patients taking dual LAMA/LABA or LAMA/LABA/ICS triple therapy were excluded. Dyspnea measures included the Transition Dyspnea Index (TDI), Evaluating Respiratory Symptoms (E-RS), and rescue medication use. RESULTS: After 24 weeks, ensifentrine significantly improved TDI scores (least-squares mean difference, 0.97; 95% CI, 0.64, 1.30; p < 0.001) and across all TDI subdomains. Ensifentrine-treated patients were more likely to be TDI responders at week 24 (p < 0.001), which was consistent across clinically relevant subgroups. Ensifentrine-treated patients had improved E-RS breathlessness subdomain scores (p = 0.053) and reduced rescue medication use (p = 0.002). CONCLUSION: Ensifentrine produced clinically meaningful improvements in multiple dyspnea measures in patients with symptomatic, moderate-to-severe COPD. A limitation of this study was the exclusion of patients taking dual LAMA/LABA and LAMA/LABA/ICS triple therapy. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifiers are ENHANCE-1: NCT04535986; ENHANCE-2: NCT04542057.

Ensifentrine: First Approval.

Ensifentrine, an inhaled, selective phosphodiesterase (PDE) 3 and PDE4 inhibitor, is being developed by Verona Pharma plc for the treatment of respiratory diseases, including chronic obstructive pulmonary disease (COPD). In June 2024, ensifentrine (OHTUVAYRE™) inhalation suspension was approved for the maintenance treatment of COPD in adult patients in the USA. This article summarizes the milestones in the development of ensifentrine leading to this first approval for the maintenance treatment of COPD.

Efficacy and Safety of Topical Roflumilast for the Treatment of Psoriasis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND OBJECTIVE: Plaque psoriasis is commonly treated topically with glucocorticoids and vitamin D derivatives. However, potential side effects such as skin atrophy underscore the need for safe and effective alternative topical therapies. Recently, the US Food and Drug Administration (FDA) and Health Canada approved roflumilast 0.3% cream as an option for treating this disease. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to assess the efficacy and safety of topical roflumilast 0.3% compared with vehicle for plaque psoriasis. METHODS: PubMed, Embase, ClinicalTrials.gov, and Cochrane databases were searched from inception to 1 May 2024, assessing the outcomes of Investigator's Global Assessment (IGA) or body-IGA success (clear or almost clear status plus an at least 2-grade improvement from baseline), Psoriasis Area and Severity Index (PASI)-50, PASI-75, PASI-90, intertriginous-IGA success (clear or almost clear status on the intertriginous-IGA plus an at least 2-grade improvement from baseline), and adverse events (AEs). Statistical analysis was performed using Review Manager, R software, and RStudio. Heterogeneity was determined using the Cochran Q test and I2 statistics. RESULTS: Four RCTs were included, comprising a total of 1403 patients, of whom 885 (63.1%) received topical roflumilast 0.3% and 518 (36.9%) received vehicle. At week 8, the achievement of IGA or body-IGA success was significantly higher among those treated with topical roflumilast than in the vehicle group [relative risk (RR) 5.07; 95% confidence interval (CI) 3.55-7.23; p < 0.01]. Similar findings were observed at week 8 for PASI-50 (RR 2.73; 95% CI 2.27-3.29; p < 0.01), PASI-75 (RR 4.48; 95% CI 2.26-8.89; p < 0.01), and PASI-90 (RR 5.61; 95% CI 2.57-12.25; p < 0.01). Corresponding outcomes were found at weeks 2, 4, and 6. Additionally, a higher percentage of patients treated with topical roflumilast 0.3% once daily achieved intertriginous-IGA success, compared with those receiving vehicle, at week 8 (71.9% versus 20.5%; RR 3.32; 95% CI 2.11-5.22; p < 0.01), with similar findings at weeks 2, 4, and 6. While a significant difference was observed in the overall incidence of AEs between the topical roflumilast and vehicle groups, there was no difference in treatment-related AEs, serious AEs, or AEs leading to study discontinuation. CONCLUSION: These findings support the superiority of topical roflumilast 0.3% over vehicle and suggest its use as a valuable asset for the treatment of plaque psoriasis. PROTOCOL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO), CRD42023456494.

Early Inhibition of Phosphodiesterase 4B (PDE4B) Instills Cognitive Resilience in APPswe/PS1dE9 Mice.

Microglia activity can drive excessive synaptic loss during the prodromal phase of Alzheimer's disease (AD) and is associated with lowered cyclic adenosine monophosphate (cAMP) due to cAMP phosphodiesterase 4B (PDE4B). This study aimed to investigate whether long-term inhibition of PDE4B by A33 (3 mg/kg/day) can prevent synapse loss and its associated cognitive decline in APPswe/PS1dE9 mice. This model is characterized by a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9 (dE9), both under the control of the mouse prion protein promoter. The effects on cognitive function of prolonged A33 treatment from 20 days to 4 months of age, was assessed at 7-8 months. PDE4B inhibition significantly improved both the working and spatial memory of APPswe/PSdE9 mice after treatment ended. At the cellular level, in vitro inhibition of PDE4B induced microglial filopodia formation, suggesting that regulation of PDE4B activity can counteract microglia activation. Further research is needed to investigate if this could prevent microglia from adopting their 'disease-associated microglia (DAM)' phenotype in vivo. These findings support the possibility that PDE4B is a potential target in combating AD pathology and that early intervention using A33 may be a promising treatment strategy for AD.

An update on topical therapies for psoriasis.

PURPOSE OF REVIEW: Topical therapies are a mainstay of treatment for mild psoriasis and may be a useful adjunct in treatment of moderate-to-severe psoriasis. This review summarizes recent advances in topical therapies for psoriasis and currently available treatments. RECENT FINDINGS: Topical aryl hydrocarbon receptor modulators (tapinarof) and topical phosphodiesterase-4 inhibitors (roflumilast) have been proven effective in randomized controlled trials for psoriasis. Although topical JAK inhibitors have also been studied, none are currently licensed for treatment of psoriasis. Topical corticosteroids and vitamin D analogues remain the most commonly used and widely available topical treatments for psoriasis. Cost may limit use of novel topical agents. SUMMARY: Although the novel topical agents tapinarof and roflumilast are licensed for treatment of psoriasis by the FDA in the United States, they have not yet been licensed in Europe, and it remains to be seen whether they will be limited by cost.

Crisaborole-Enthused Glycerosomal Gel for an Augmented Skin Permeation.

BACKGROUND: Crisaborole (CB), a boron-based compound, is the first topical PDE4 inhibitor to be approved by the US Food and Drug Administration (2016) for the treatment of Atopic Dermatitis. It is marketed as a 2% ointment (Eucrisa, Pfizer). However, CB is insoluble in water; therfore, CB glycersomes were formulated to enhance its permeation flux across the skin. OBJECTIVE: We developed a glycerosomal gel of CB and compared its in vitro release and permeation flux with the 2% conventional ointment. METHODS: Glycerosomes were prepared using thin film hydration method employing CB, soya phosphatidylcholine, and cholesterol. The formed film was further hydrated employing a mixture of phosphate buffer pH 7.4 /glycerin solution containing varying percentages (20,30, 40, and 50 %) of glycerol. The glycerosomes obtained were characterized by their size, polydispersity index (PDI), and Zeta potential. The entrapment efficiency of the optimized formulation (F1) was determined. The in vitro release of F1 was compared with its 2% conventional ointment. F1 was further incorporated into carbopol 934 P gel. The gel was characterized by pH, viscosity, spreadability, and drug content. The permeability flux of the glycerosomal gel was compared with its 2% conventional ointment. RESULTS: The optimized CB glycerosomes had a vesicle size of 137.5 ± 50.58 nm, PDI 0.342, and zeta potential -65.4 ± 6.75 mV. CB glycerosomal gel demonstrated a 2.13-fold enhancement in the permeation flux. CONCLUSION: It can thereby be concluded that glycerosomes can be an effective delivery system to enhance the penetration of CB across the skin.

Real-world efficacy of 2% crisaborole ointment on chronic hyperplasia lesions in 49 patients with atopic dermatitis.

BACKGROUND: Crisaborole, as a phosphodiesterase 4 (PDE4) inhibitor (PDE4i), effectively inhibits inflammatory pathways, showing promising results in atopic dermatitis (AD), particularly in chronic hyperplasia lesions. OBJECTIVES: Based on real-world data from China, this study assesses the effectiveness and safety of 2% PDE4i ointment as monotherapy for chronic hyperplastic AD lesions. MATERIALS AND METHODS: A total of 49 AD patients aged 12 and above with chronic hyperplastic lesions and Investigator's Static Global Assessment scores of mild or moderate were enrolled. They received 2% PDE4i ointment twice daily until the lesions completely cleared. The effectiveness endpoints comprised the onset time of pruritus and lesion remission and the time of complete lesion clearance. RESULTS: PDE4i demonstrated high effectiveness with minimal irritation, notable improvement in hyperpigmentation, and early remission of pruritus and lesions. The response varied across age groups; elderly patients experienced quicker pruritus relief compared to adolescents and adults, while adolescents showed earlier lesion remission by about 3 days. No significant difference was observed across age groups in the time for complete lesion clearance. Additionally, AD duration (less or more than 3 years) did not significantly impact pruritus or lesion remission. CONCLUSIONS: PDE4i monotherapy is effective and safe for chronic hyperplasia lesions in AD across all age groups, and its effectiveness appears to be independent of AD duration.

The Dosing Strategy to Improve Adherence to Roflumilast in Treatment for Chronic Obstructive Lung Disease: A Systemic Review and Meta-Analysis.

Background: The clinical efficacy of roflumilast, an oral phosphodiesterase-4 inhibitor, has been demonstrated in patients with severe chronic obstructive pulmonary disease (COPD). However, roflumilast has shown frequent adverse drug reactions (ADRs). This study was performed to investigate the dosing strategy that will improve adherence to roflumilast in COPD. Methods: We conducted a systematic review and meta-analysis using PubMed, Embase, and Cochrane Central Register. The dosing strategy for roflumilast was classified into a dose-escalation group and a low-dose group. We investigated clinical outcomes according to dosing strategy. Results: Five clinical trials involving 2424 patients were included. Both the dose-escalation and the low-dose groups showed a decrease in discontinuation rate compared to the standard dosing group for roflumilast (risk ratio [RR], 0.81; 95% confidence interval [CI], 0.67-0.97; P = 0.02 and RR, 0.62; 95% CI, 0.48-0.80; P < 0.01, respectively). In the two strategies, the pooled proportions of discontinuation were 27.9% and 11.7%, respectively. Although the pooled proportion of any ADR was not statistically decreased in the two strategies, diarrhea was significantly reduced in the low-dose group compared to the standard group (RR, 0.58; 95% CI, 0.42-0.82; P < 0.01). The pooled incidence of acute exacerbations was similar between the low-dose and the standard groups (22.9% and 20.1%, respectively; P = 0.27). Conclusion: Our findings show that the two alternative dosing strategies might have the benefit of improving adherence to roflumilast in COPD. Further large-scale trials are required to support our findings.

Long-term safety and effectiveness of roflumilast cream 0.3% in adults with chronic plaque psoriasis: A 52-week, phase 2, open-label trial.

BACKGROUND: Efficacy and/or safety profiles limit topical psoriasis treatments. OBJECTIVE: Evaluate long-term effects of once-daily roflumilast cream 0.3% in patients with psoriasis. METHODS: In this open-label phase 2 trial, adult patients (N = 332) with psoriasis who completed the phase 2b parent trial or were newly enrolled applied roflumilast once-daily for 52 weeks. Safety and effectiveness were assessed. RESULTS: Overall, 244 patients (73.5%) completed the trial; 13 patients (3.9%) discontinued due to adverse events (AEs) and 3 (0.9%) due to lack of efficacy. Twelve patients (3.6%) reported treatment-related AEs; none were serious. ≥97% of patients had no irritation. No tachyphylaxis was observed with 44.8% of the patients achieving Investigator Global Assessment (IGA) Clear or Almost Clear at Week 52. LIMITATIONS: Intertriginous-IGA and Psoriasis Area and Severity Index (PASI) were not evaluated in all patients. CONCLUSIONS: In this long-term trial, once-daily roflumilast cream was well-tolerated and efficacious up to 64 weeks in patients in the earlier trial, suggesting it is suitable for chronic treatment, including the face and intertriginous areas.

Effects of oral roflumilast therapy on body weight and cardiometabolic parameters in patients with psoriasis - results from a randomized controlled trial (PSORRO).

BACKGROUND: Weight loss is reported with oral roflumilast, which is approved for chronic obstructive pulmonary disease (COPD). Recently, the drug has shown efficacy in psoriasis, a disease strongly linked to overweight/obesity. OBJECTIVE: To describe the effects of oral roflumilast on body weight and cardio-metabolic parameters in patients with psoriasis. METHODS: Posthoc analyses from the PSORRO study, where patients with moderate-to-severe plaque psoriasis were randomized 1:1 to oral roflumilast 500 µg once-daily or placebo for 12 weeks, followed by active, open-label treatment through week 24 in both groups. Changes in body weight, blood pressure, gastrointestinal symptoms, and laboratory tests were registered. No lifestyle or dietary interventions were applied. RESULTS: Forty-six patients were randomized. Baseline characteristics across groups were comparable; mean weight was 103.6 kg. In patients receiving roflumilast, median weight change was -2.6% and -4% at week 12 and 24, respectively. Corresponding numbers were 0.0% and 1.3% in patients initially allocated to placebo. Reduced appetite was more frequent with active therapy. No changes in blood pressure or laboratory tests were observed. LIMITATIONS: Posthoc analyses and low numbers. CONCLUSION: Oral roflumilast induced weight loss and reduced appetite, which support the growing evidence of roflumilast as an attractive treatment alternative for patients with psoriasis.

Efficacy and safety of apremilast in pediatric patients with moderate-to-severe plaque psoriasis: 16-week results from SPROUT, a randomized controlled trial.

BACKGROUND: Approved systemic treatment options are limited for pediatric patients with moderate to severe plaque psoriasis. OBJECTIVE: To assess the efficacy and safety of apremilast over 16 weeks in pediatric patients with plaque psoriasis. METHODS: SPROUT (NCT03701763) was a phase 3, multicenter, randomized, double-blind, placebo-controlled study of apremilast in patients aged 6-17 years with moderate-to-severe psoriasis (Psoriasis Area and Severity Index [PASI] ≥12, body surface area ≥10%, static Physician Global Assessment [sPGA] ≥3) inadequately controlled by/inappropriate for topical therapy. Patients were stratified by age group and randomized (2:1) to apremilast (20 or 30 mg BID based on weight) or placebo for 16 weeks, followed by apremilast extension to 52 weeks. RESULTS: Of 245 patients randomized (apremilast: 163; placebo: 82), 221 (90%) completed the double-blind phase (apremilast: 149; placebo: 72). Significantly more patients achieved sPGA response and ≥75% reduction in PASI with apremilast than placebo, regardless of baseline age, weight, or disease severity. No new safety signals were observed. LIMITATIONS: Sample size of subgroup analyses. CONCLUSIONS: Improvements in global disease activity and skin involvement were significantly greater in pediatric patients treated with apremilast versus placebo. Adverse events were consistent with the known apremilast safety profile.

Orismilast for the treatment of mild to severe hidradenitis suppurativa: Week 16 data from OSIRIS, a Phase 2a, open-label, single-centre, single-arm, dose-finding clinical trial.

BACKGROUND: Hidradenitis suppurativa (HS) is a disease with an unmet need for treatment. OBJECTIVE: To examine tolerability, safety and efficacy of oral phosphodiesterase-4 (PDE4) inhibitior orismilast 10-40 mg twice daily (BID) in HS. METHODS: A Phase 2a, single-arm, single-centre, open-label, 16-week trial in HS patients. Adjustments in maximal dose and titration were allowed, to improve tolerability, dividing the study population in two groups who completed and discontinued 16 weeks of treatment. Descriptive statistics were applied to efficacy data from patients who completed treatment and patients who discontinued treatment prematurely. A last-observation-carried-forward (LOCF) approach was used for patients who discontinued treatment. The primary endpoint was percent change in the total number of abscesses and nodules (AN-count) at Week 16, with the HS Clinical Response with a 50% reduction in the AN-count (HiSCR50) as key secondary endpoint. RESULTS: Of the 20 patients included, 9 completed 16 weeks of treatment and 11 discontinued treatment prematurely. The mean AN-count was reduced with 33.1% in patients who completed treatment and with 12.0% in patients who discontinued. HiSCR50 was achieved by 67.0% and 27.0% of patients who completed and discontinued treatment, respectively. Most adverse events were mild to moderate. CONCLUSIONS: Oral orismilast demonstrated a dose-dependent tolerability, with mild to moderate adverse effects. Further, the results of this exploratory trial indicate that orismilast may lead to clinical improvements in HS. However, larger trials with tolerable dose ranges are warranted. The Trial is registered at Clinicaltrials.gov (UNI50007201) and EudraCT.ema.europa.eu (2021-000049-42).

Efficacy and safety of crisaborole ointment in Chinese and Japanese patients aged ≥2 years with mild-to-moderate atopic dermatitis.

Atopic dermatitis is a chronic inflammatory skin disease with a significant impact on the overall wellbeing of patients and their families. Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor approved for the treatment of mild-to-moderate atopic dermatitis in multiple countries. However, in the key pivotal trials, a low proportion of the overall patient population was Asian, therefore the safety and efficacy of crisaborole in the Asian population with atopic dermatitis remains unclear. CrisADe CLEAR was a multicenter, randomized, double-blind, vehicle-controlled, phase 3 study (NCT04360187) to assess the efficacy and safety of crisaborole ointment in Chinese and Japanese patients aged ≥2 years with mild-to-moderate atopic dermatitis involving ≥5% treatable body surface area. Patients were randomly assigned 2:1 to receive crisaborole or vehicle twice daily for 28 days. The primary endpoint was percentage change from baseline in the Eczema Area and Severity Index total score at day 29. Additional endpoints were improvement and success per Investigator's Static Global Assessment score at day 29 and change from baseline on the Peak Pruritus Numerical Rating Scale at week 4. Safety was assessed using rates of treatment emergent adverse events, serious adverse events, and clinically significant changes in vital signs and clinical laboratory parameters. Crisaborole-treated patients showed a significantly greater reduction versus vehicle in percentage change from baseline in Eczema Area and Severity Index total score at day 29 (P = 0.0002). Response rates for achievement of Investigator's Static Global Assessment improvement and success at day 29 were significantly higher for patients treated with crisaborole versus vehicle (P = 0.0124 and P = 0.0078, respectively). Crisaborole-treated patients showed a significantly greater reduction versus vehicle in change from baseline on the Peak Pruritus Numerical Rating Scale at week 4 (P = 0.0009). No new safety signals were identified. Treatment with crisaborole was effective and well tolerated in Chinese and Japanese patients with mild-to-moderate atopic dermatitis.