Potent Phosphodiesterase Research Articles

A novel phosphodiesterase 5 inhibitor, RF26, improves memory impairment and ameliorates tau aggregation and neuroinflammation in the P301S tauopathy mouse model of Alzheimer's disease.

Phosphodiesterase-5 (PDE5) inhibitors are primarily used in the treatment of erectile dysfunction and pulmonary hypertension, but have also been reported to have a potential therapeutic effect for the treatment of Alzheimer's disease (AD). This is likely to be through stimulation of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling by elevating cGMP, a secondary messenger involved in processes of neuroplasticity. In the present study, we evaluated the efficacy of a novel PDE5 inhibitor, RF26, using P301S tauopathy mice model. A body of experimental evidence suggests that the development of tau inclusions leads to the neurodegeneration observed in tauopathies, including AD, Frontotemporal dementia (FTD), Supranuclear palsy and others. RF26 successfully targeted NO/cGMP signaling pathway and showed a significant improvement of spatial memory task performance of P301S mice using Morris Water Maze and T-maze. Furthermore, RF26 -treated mice showed a significant reduction of phosphorylated tau load, gliosis and downregulated pro-inflammatory cytokines. The presented data support the efficacy of RF26 as a potent PDE5 inhibitor and calls for further investigation as a potential therapeutic drug for Alzheimer's and other tauopathy related neurological disorders.

In Silico Identification of Promising PDE5 Inhibitors Against Hepatocellular Carcinoma Among Natural Derivatives: A Study Involving Docking and ADMET Analysis.

Hepatocellular carcinoma (HCC) represents a significant worldwide health challenge due to its high mortality rate, underscoring the need for advanced therapeutic strategies. This study employs a computer-based method to identify potential phosphodiesterase 5 (PDE5) inhibitors from a library of approved IBS_Scaff 532 natural compounds. PDE5 inhibitors have gained attention for their potential anti-tumor effects. Using molecular docking simulations, the researchers assessed how well these compounds bind to the PDE5 enzyme, which regulates cellular cGMP pathways. Additionally, ADMET profiling predicted the pharmacological and safety properties of candidate inhibitors. Notably, compounds like IBS_NC-0322 and IBS_NC-0320 exhibited favorable ADMET properties and strong binding affinities. These findings suggest their potential as therapeutic agents for treating HCC. While in silico methods serve as valuable screening tools, subsequent experimental validation and clinical trials are essential for confirmation.

Difluoromethoxide Is a Strong Leaving Group in the Photoredox Deoxyradiofluorination of 2-Phenylpyridines.

A 2-phenyl-3-difluoromethoxy-pyridinyl moiety features in potent phosphodiesterase 4D inhibitors that are considered to be candidate radiotracers for positron emission tomography if they are labeled with fluorine-18. Fluorine-18 could be installed as desired at the 3'-phenyl position with acridinium-mediated photoredox radiodeoxyfluorination in homologues bearing variously substituted 3'-aryloxy groups. However, a distal 3-difluoromethoxide (-OCHF2) group strongly competes as a leaving group, especially when an electron-deficient aryloxy group is present at position 3'. A yield of up to 50% may occur without observable 19F for 18F exchange.

Molecular Docking Approach to Identify Flavonoids as Potential Phosphodiesterase 5 Inhibitors for Erectile Dysfunction Treatment

An erection that is not strong enough for sexual activity might be caused by erectile dysfunction. Periodically experiencing difficulties achieving an erection is not always a reason for alarm. On the other hand, if erectile dysfunction persists, it may lead to stress, undermine confidence, and exacerbate interpersonal issues. In addition to being a risk factor for heart disease, difficulties achieving or maintaining an erection may also indicate an underlying medical issue that needs to be treated. Many studies have also steadily examined flavonoids' capacity to inhibit the phosphodiesterase 5 enzyme in several recent studies. This is an enzyme expressed in erectile tissue that is the most important substance that degrades cGMP in the body's smooth muscle cells. This study identified two prominent flavonoids that had inhibitory effects on the phosphodiesterase 5 enzyme: Amenoflavone and Umbralisib. Our research suggests new molecular pathways by which these substances might influence biological processes. One compound that shows promise for treating erectile dysfunction and is safe for healthy cells is Amentoflavone.

Roflumilast Cream 0.3% in Patients With Chronic Plaque Psoriasis: Individual Patient PASI and PASI-HD Responses: Pooled DERMIS-1 and DERMIS-2 Phase 3 Trials

Background: Roflumilast cream 0.3% is a highly potent phosphodiesterase 4 inhibitor approved as a nonsteroidal, once-daily treatment for patients with plaque psoriasis. Pooled efficacy and safety results from two Phase 3 clinical trials (DERMIS-1 and DERMIS-2) have been presented previously. The Psoriasis Area and Severity Index (PASI) is used to assess the severity of plaque psoriasis in clinical trials; however, PASI is not precise when the area of involvement is <10% of a given anatomic region. A modified version of the PASI, the PASI-high discrimination (PASI-HD), allows more precise assessment of psoriasis in body regions where <10% area is affected. We present individual patient responses using PASI and PASI-HD.
 Methods: Patients aged ≥2 years with at least mild plaque psoriasis involving 2-20% body surface area were randomized 2:1 to apply roflumilast cream 0.3% or vehicle cream once daily for 8 weeks. The primary efficacy endpoint was Investigator Global Assessment (IGA) Success (score of Clear or Almost Clear plus ≥2-grade improvement from baseline) at Week 8. PASI and PASI-HD were used to measure disease severity; individual patient PASI and PASI-HD responses were plotted graphically. Safety and tolerability were also evaluated and were reported previously.
 Results: Roflumilast- and vehicle-treated patients had similar baseline demographic and disease characteristics. At Week 8, statistically significantly more roflumilast- than vehicle-treated patients achieved IGA Success (39.9% vs. 6.5%; P<0.0001). Statistically significant differences favoring roflumilast were observed at Week 8 for percentages of patients achieving a 50% reduction in PASI (72.1% vs. 25.5%; P<0.0001), 75% reduction (40.3% vs. 6.5%, P<0.0001), 90% reduction (19.7% vs 2.3%; P<0.0001), and 100% reduction (12.3% vs 0.8%; P<0.001). Likewise, statistically significant differences favoring roflumilast were observed at Week 8 for percentages of patients achieving 50% reduction in PASI-HD (79.4% vs. 33.1%; P<0.0001), 75% reduction (59.9% vs. 17.9%, P<0.0001), 90% reduction (39.9% vs 9.1%; P<0.0001), and 100% reduction (12.3% vs 0.8%; P<0.0001). Roflumilast cream demonstrated low rates of application-site adverse events (AEs), treatment-related AEs, and discontinuations due to AEs, comparable to vehicle. At the first application of roflumilast cream 0.3% (day 1), 96% of patients reported no or mild sensation, increasing to 99% of patients at Weeks 4 and 8.
 Conclusions: Roflumilast cream 0.3% provided greater improvement in IGA Success, PASI, and PASI-HD versus vehicle with favorable safety and tolerability in patients with psoriasis in two Phase 3 trials. PASI-HD provided higher discrimination of effects of treatment in areas with <10% involvement than the traditional PASI.
 ClinicalTrials.gov Identifiers: DERMIS-1: NCT04211363; DERMIS-2: NCT04211389
 Financial Disclosures: Arcutis Biotherapeutics, Inc.

504 - Investigator- and patient-rated local tolerability in phase 3 trials of topical roflumilast in patients with psoriasis, seborrheic dermatitis, and atopic dermatitis

Abstract Introduction Formulating a topical medication that does not irritate the skin is an important factor contributing to patient treatment adherence and satisfaction. Many topical prescription products use penetration enhancers (including propylene glycol, polyethylene glycol, and ethanol) to overcome barrier properties of the skin. However, these excipients may irritate the skin causing tolerability reactions such as burning and stinging, which can reduce patient treatment adherence. Topical roflumilast is a highly potent (Kd∼0.7 nM) phosphodiesterase 4 inhibitor formulated as a water-based cream or foam that does not contain penetration enhancers or fragrances. Objectives We present prospectively assessed investigator- and patient-rated local tolerability from Phase 3 trials of topical roflumilast for patients with psoriasis (DERMIS-1, DERMIS-2, ARRECTOR) seborrheic dermatitis (SD; STRATUM), and atopic dermatitis (AD; INTEGUMENT-1, INTEGUMENT-2). Methods Patients were randomized to apply topical roflumilast (DERMIS: 0.3% cream; ARRECTOR and STRATUM: 0.3% foam; INTEGUMENT: 0.15% cream) or vehicle once daily for 8 weeks (DERMIS, ARRECTOR, and STRATUM) or 4 weeks (INTEGUMENT). Investigators assessed local tolerability on an 8-point scale (0 [no evidence of irritation] to 7 [strong reaction spreading beyond application site]) in the clinic before investigational product (IP) application. Patients reported local tolerability on a 4-point scale (0 [none: no sensation] to 3 [severe: hot, tingling/stinging sensation that has caused definite discomfort]) in the clinic 10-15 minutes after IP application. Tolerability was also assessed by reviewing documented adverse events. Results As assessed by investigators, ≥96.5% of patients in the roflumilast-treated groups had no evidence of irritation at the application site across all trials at all timepoints. Patient-rated local tolerability was favorable and improved with treatment: across all trials, 1% of roflumilast-treated patients reported a score of 3 (severe; defined as a “hot tingling/stinging sensation that has caused definite discomfort”) after the first application (day 1) and <1% at each subsequent assessment. Rates of adverse events, including those at the application site, were low for all trials. Conclusions Roflumilast cream and foam formulations demonstrated favorable local tolerability based on investigator- and patient-rated assessments in patients with psoriasis, SD, and AD, including application to sensitive areas such as the face and intertriginous areas. ClinicalTrials.gov Identifiers: DERMIS-1: NCT04211363; DERMIS-2: NCT04211389; ARRECTOR: NCT05028582; STRATUM: NCT04973228; INTEGUMENT-1: NCT047​73587; INTEGUMENT-2: NCT04773600.

505 - Once-daily roflumilast cream 0.15% for atopic dermatitis: pooled results from INTEGUMENT-1/2 phase 3 trials

Abstract Introduction Roflumilast cream 0.15% is a selective, highly potent phosphodiesterase 4 inhibitor under investigation as a non-steroidal, once-daily treatment for atopic dermatitis (AD). Objectives Here, pooled results from two identical Phase 3 randomized controlled trials (INTEGUMENT-1: NCT04773587 and INTEGUMENT-2: NCT04773600) are presented. Methods Patients with AD aged ≥6 years with baseline Eczema Area and Severity Index (EASI) score ≥5 and Validated Investigator Global Assessment-AD (vIGA-AD) score of Mild or Moderate were randomized 2:1 to apply roflumilast (n=884) or vehicle (n=453) once daily for 4 weeks. Results A significantly greater percentage of roflumilast- versus vehicle-treated patients achieved the primary endpoint, vIGA-AD Success (Clear or Almost Clear vIGA-AD plus ≥2-grade improvement from baseline) at Week 4 (31.3% vs. 14.1%; P<0.0001). Significant differences favoring roflumilast were observed for multiple secondary endpoints at Week 4: percentage of patients achieving vIGA-AD of Clear or Almost Clear (41.1% vs. 21.4%; P<0.0001), percentage achieving 75% reduction in EASI (42.7% vs. 20.6%; P<0.0001), and percentage with baseline Worst Itch-Numeric Rating Scale ≥4 achieving a 4-point reduction (31.9% vs. 16.6%; P<0.0001). Improvement in itch was reported as early as 24 hours. Both groups had low incidences of treatment-emergent adverse events (TEAE), serious adverse events, and TEAEs leading to discontinuation. Local tolerability was favorable, with >90% of patients reporting no or mild sensation across both treatment groups at all timepoints. Conclusions Once-daily roflumilast cream 0.15% provided improvement across multiple efficacy endpoints by Week 4 with favorable safety and tolerability in patients aged ≥6 years with AD in two Phase 3 trials.

Investigator- and Patient-Rated Local Tolerability in Phase 3 Trials of Topical Roflumilast in Patients With Psoriasis, Seborrheic Dermatitis, and Atopic Dermatitis

Investigator- and patient-rated local tolerability in phase 3 trials of topical roflumilast in patients with psoriasis, seborrheic dermatitis, and atopic dermatitis
 
 Christopher G. Bunick1 on behalf of the authors
 
 INTRODUCTION: Formulating a topical medication that does not irritate the skin is an important factor contributing to patient treatment adherence and satisfaction. Many topical prescription products use penetration enhancers (including propylene glycol, polyethylene glycol, and ethanol) to overcome barrier properties of the skin. However, these excipients may irritate the skin causing tolerability reactions such as burning and stinging, which can reduce patient treatment adherence. Topical roflumilast is a highly potent (Kd~0.7 nM) phosphodiesterase 4 inhibitor formulated as a water-based cream or foam that does not contain penetration enhancers or fragrances. We present prospectively assessed investigator- and patient-rated local tolerability from Phase 3 trials of topical roflumilast for patients with psoriasis (DERMIS-1, DERMIS-2, ARRECTOR) seborrheic dermatitis (SD; STRATUM), and atopic dermatitis (AD; INTEGUMENT-1, INTEGUMENT-2).
 METHODS: Patients were randomized to apply topical roflumilast (DERMIS: 0.3% cream; ARRECTOR and STRATUM: 0.3% foam; INTEGUMENT: 0.15% cream) or vehicle once daily for 8 weeks (DERMIS, ARRECTOR, and STRATUM) or 4 weeks (INTEGUMENT). Investigators assessed local tolerability on an 8-point scale (0 [no evidence of irritation] to 7 [strong reaction spreading beyond application site]) in the clinic before investigational product (IP) application. Patients reported local tolerability on a 4-point scale (0 [none: no sensation] to 3 [severe: hot, tingling/stinging sensation that has caused definite discomfort]) in the clinic 10-15 minutes after IP application. Tolerability was also assessed by reviewing documented adverse events.
 RESULTS: As assessed by investigators, ≥96.5% of patients in the roflumilast-treated groups had no evidence of irritation at the application site across all trials at all timepoints. Patient-rated local tolerability was favorable and improved with treatment: across all trials, 1% of roflumilast-treated patients reported a score of 3 (severe; defined as a “hot tingling/stinging sensation that has caused definite discomfort”) after the first application (day 1) and <1% at each subsequent assessment. Rates of adverse events, including those at the application site, were low for all trials and <0.5% of roflumilast-treated patients discontinued due to adverse events at the application site across all trials.
 CONCLUSION: Roflumilast cream and foam formulations demonstrated favorable local tolerability based on investigator- and patient-rated assessments in patients with psoriasis, SD, and AD, including application to sensitive areas such as the face and intertriginous areas.
 Sponsored by Arcutis Biotherapeutics, Inc.
 ClinicalTrials.gov Identifiers: DERMIS-1: NCT04211363; DERMIS-2: NCT04211389; ARRECTOR: NCT05028582; STRATUM: NCT04973228; INTEGUMENT-1: NCT04773587; INTEGUMENT-2: NCT04773600

Roflumilast Cream 0.3% in Patients with Chronic Plaque Psoriasis: Individual Patient Response from the Pooled DERMIS-1 and DERMIS-2 Phase 3 Trials

Roflumilast cream 0.3% in patients with chronic plaque psoriasis: individual patient response from the pooled DERMIS-1 and DERMIS-2 phase 3 trials
 
 James Del Rosso1 on behalf of the authors
 
 INTRODUCTION: Roflumilast cream 0.3% is a highly potent phosphodiesterase 4 inhibitor approved as a nonsteroidal, once-daily treatment for patients with plaque psoriasis. The efficacy and safety of the pooled results of two Phase 3 clinical trials (DERMIS-1 and DERMIS-2) in patients aged ≥2 years with plaque psoriasis have been previously presented. We present individual patient responses using the Psoriasis Area and Severity Index (PASI).
 METHODS: Patients aged ≥2 years with at least mild plaque psoriasis involving 2-20% of body surface area were randomized 2:1 to apply roflumilast cream 0.3% or vehicle cream once daily for 8 weeks. The primary efficacy endpoint was Investigator Global Assessment (IGA) Success (score of Clear or Almost Clear plus ≥2-grade improvement from baseline) at Week 8; IGA of Clear or Almost Clear was a secondary endpoint. PASI was used to measure disease severity; individual patient PASI responses were plotted graphically. Safety and tolerability were also evaluated and have been previously reported.
 RESULTS: Roflumilast- and vehicle-treated patients had similar baseline demographic and disease characteristics. At Week 8, statistically significantly more roflumilast- than vehicle-treated patients achieved IGA Success (39.9% vs. 6.5%; P<0.0001) and IGA of Clear or Almost Clear (48.0% vs. 9.5%; nominal P<0.0001). Statistically significant differences favoring roflumilast were observed at Week 8 for percentages of patients achieving a 50% reduction in PASI (72.1% vs. 25.5%; P<0.0001), 75% reduction (40.3% vs. 6.5%, P<0.0001), 90% reduction (19.7% vs 2.3%; P<0.0001), and 100% reduction (12.3% vs 0.8%; P<0.001). At the first post-treatment timepoint evaluated (Week 2), 85.7% of roflumilast-treated patients had a measurable improvement in PASI, increasing to 95.0% by the last timepoint (Week 8). Roflumilast cream demonstrated low rates of application-site adverse events (AEs), treatment-related AEs, and discontinuations due to AEs, comparable with vehicle. Approximately 96% of patients reported no or mild sensation after the first application of roflumilast cream 0.3%, improving to more than 99% of patients at Week 4 and Week 8, similar to vehicle.
 CONCLUSIONS: Roflumilast cream 0.3% provided greater improvement in IGA Success, IGA of Clear or Almost Clear, and PASI versus vehicle with favorable safety and tolerability in patients with psoriasis in two Phase 3 trials.
 Sponsored by Arcutis Biotherapeutics, Inc.
 ClinicalTrials.gov Identifiers: DERMIS-1: NCT04211363; DERMIS-2: NCT04211389

Anti-inflammatory and anti-oxidant action of tadalafil in testicular regeneration process after heat stress.

Tadalafil, a potent phosphodiesterase inhibitor 5 (PDE-5), is commonly used for the management of erectile dysfunction. However, its therapeutic potential extends beyond this indication. This study aimed to investigate the impact of tadalafil on the recovery of testicular parenchyma in male Wistar rats exposed to testicular thermal stress. Fifty-four Wistar rats were subjected to testicular thermal stress and randomly assigned to receive either tadalafil treatment (TAD) or no treatment (control). TAD was administered intraperitoneally at a dose of either 0.9 mg/kg or 1.8 mg/kg. Biometric parameters, histopathological assessment of the testis, serum testosterone levels, oxidative stress, and interleukin levels were evaluated on days 7, 15, and 30 after thermal shock. The animals were euthanized at the end of each experimental period, and samples were collected. TAD treatment maintained testicular weight and reduced the testicular degenerative process up to day 7 post-injury. However, despite TAD therapy, serum testosterone levels were decreased in the treated groups at days 7 and 15 post-thermal stress. TAD also decreased TNF-α and NO levels at different doses but had no effect on IL-6. The treatment with TAD after heat shock demonstrated anti-inflammatory and antioxidant properties but did not prevent the aggravation of testicular lesions in subsequent periods, even with the systematic reduction in TNF-α and NO levels. Therefore, this selective PDE-5 inhibitor, at the dosages used, did not have a positive impact on testosterone levels during the post-thermal stress period, which could compromise the resumption of the spermatogenic process.

Drug repurposing and structure-based discovery of new PDE4 and PDE5 inhibitors

Phosphodiesterase-4 (PDE4) and PDE5 responsible for the hydrolysis of intracellular cAMP and cGMP, respectively, are promising targets for therapeutic intervention in a wide variety of diseases. Here, we report the discovery of novel, drug-like PDE4 inhibitors by performing a high-throughput drug repurposing screening of 2560 approved drugs and drug candidates in clinical trial studies. It allowed us to identify eight potent PDE4 inhibitors with IC50 values ranging from 0.41 to 2.46 μM. Crystal structures of PDE4 in complex with four compounds, namely ethaverine hydrochloride (EH), benzbromarone (BBR), CX-4945, and CVT-313, were further solved to elucidate molecular mechanisms of action of these new inhibitors, providing a solid foundation for optimizing the inhibitors to improve their potency as well as selectivity. Unexpectedly, selectivity profiling of other PDE subfamilies followed by crystal structure determination revealed that CVT-313 was also a potent PDE5 inhibitor with a binding mode similar to that of tadalafil, a marketed PDE5 inhibitor, but distinctively different from the binding mode of CVT-313 with PDE4. Structure-guided modification of CVT-313 led to the discovery of a new inhibitor, compound 2, with significantly improved inhibitory activity as well as selectivity towards PDE5 over PDE4. Together, these results highlight the utility of the drug repurposing in combination with structure-based drug design in identifying novel inhibitors of PDE4 and PDE5, which provides a prime example for efficient discovery of drug-like hits towards a given target protein.

In silico screening of drug Bank data base to PDE10: A drug repurposing approach

Drug repurposing has emerged as a promising strategy for expediting drug development by identifying new therapeutic applications for existing drugs. In this study employed in silico screening approach to explore the DrugBank database for potential phosphodiesterase 10 (PDE10) inhibitors with applications in neurological, psychiatric disorders and cancer treatment. PDE10 plays a crucial role in regulating cyclic nucleotide levels in the brain and has been implicated in various diseases, including schizophrenia, Parkinson’s, Huntington’s diseases, and certain types of cancer. Through molecular docking, we evaluated the interactions and energetics of 28 candidate inhibitors with PDE10. Notably, 17 candidates met all selection criteria, presenting excellent potential for further investigation. The theoretical inhibitors demonstrated favorable ADMETx properties, and their adverse effects were comparable or lower than controls. These findings indicate the viability of repurposing existing drugs, such as Nebivolol, Fluvastatin, Pioglitazone and others, for PDE10 inhibition in diverse pathologies. Validation of these candidates in preclinical studies may open new avenues for drug development and clinical applications, addressing unmet medical needs in various disorders and cancer treatment.

PDE5 inhibitor drugs for use in dementia.

Potent phosphodiesterase-5 (PDE5) inhibitors are in clinical use as vasodilators.In animals PDE5 inhibitors enhance synaptic function and cognitive ability.In humans the PDE5 inhibitor sildenafil is associated with reduced risk of Alzheimer's disease.Licensed PDE5 inhibitors have potential for repurposing in dementia.Prospective clinical trials of PDE5 inhibitors are warranted.

Immunomodulatory, apoptotic and anti-proliferative potentials of sildenafil in Ehrlich ascites carcinoma murine model: In vivo and in silico insights.

Sildenafil is a potent phosphodiesterase-5 (PDE5) inhibitor that effectively inhibits cGMP and increases the strength of nitric oxide. PDE5 was overexpressed in several carcinomas, including breast cancer, which inhibited tumor growth and cell division. The current research aims to investigate the in vivo sildenafil's immunomodulatory and antineoplastic potentials against Ehrlich Ascites Carcinoma. This study looked at the effects of sildenafil mono-treatment and co-treatment with cisplatin; tumor cell count, viability and the inhibition rate were determined. Apoptosis, cell cycle distribution, alterations in tumor cells and splenocytes proliferation, changes in splenocytes immunophenotyping using flowcytometry, plasma levels of malondialdehyde (MDA), reduced glutathione (GSH), interferone (IFN)-γ, granzyme B, alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, creatinine and hematological alterations were detected. Additionally, docking study was conducted to get further insights on how Sildenafil exerts its activity. Sildenafil mono-treatment and co-treatment with cisplatin markedly reduced tumor cell count, viability, growth rate and proliferative capability accompanied by apoptosis enhancement and G0/G1 and sub G1 cells cycle arrest. Fortunately, sildenafil evoked efficient cellular immune response by increasing plasma levels of granzyme B and IFN-γ, proportion of splenic T cytotoxic (CD3+CD8+) and T helper (CD3+CD4+), accompanied by decrease in the proportion of splenic regulatory T cells. . Moreover, in silico data suggest LcK and MAPKs as the potential targets of sildenafil. Furthermore, sildenafil rebalanced the oxidant-antioxidant status by decreasing MDA and increasing GSH plasma levels. Sildenafil successfully retrieved various hematological values besides renal and hepatic functions in EAC-bearing animals. In conclusion, our results suggest that sildenafil could be potential safe anti-tumor agent with immuno-modulatory properties against Ehrlich ascites carcinoma.

CO45 Durability of Efficacy and Safety of Roflumilast Cream 0.3% in Adults with Chronic Plaque Psoriasis from a 52-Week, Phase 2 Open-Label Safety Trial

Roflumilast cream is a potent phosphodiesterase 4 inhibitor recently approved in the United States for treatment of plaque psoriasis. An open-label trial was conducted to evaluate long-term safety (52 weeks) of once-daily roflumilast cream (NCT03764475). Durability of response was measured using Investigator Global Assessment (IGA) score of Clear or Almost Clear, percentage improvement in Psoriasis Area Severity Index (PASI) score, and reduction in body surface area (BSA) affected.

CO230 Efficacy and Safety of Roflumilast Foam 0.3% in Patients with Seborrheic Dermatitis in a Phase 3 Trial: Assessment of Pruritus

Itch is a major complaint among patients with seborrheic dermatitis (SD). Roflumilast is a selective, nonsteroidal, highly potent phosphodiesterase 4 inhibitor under investigation as a once-daily foam for treatment of SD. This phase 3 randomized, parallel-group, double-blind, vehicle-controlled trial (NCT04973228) was conducted in patients ≥9 years old with at least moderate SD affecting scalp and/or non-scalp areas.

Durability of Efficacy and Safety of Roflumilast Cream 0.3% in Adults With Chronic Plaque Psoriasis From a 52-Week, Phase 2 Open-Label Safety Trial

Background: Roflumilast cream is a potent phosphodiesterase 4 inhibitor recently approved in the United States for treatment of plaque psoriasis with no limitations on duration of use. An open-label trial was conducted to evaluate long-term safety (52 weeks) of once-daily roflumilast cream (NCT03764475). This abstract presents data on durability of response as measured by the percentage of patients with an Investigator Global Assessment (IGA) score of Clear or Almost Clear, percentage improvement in Psoriasis Area Severity Index (PASI) score, and reduction in body surface area (BSA) affected. Methods: Patients who completed a parent, phase 2b, 12-week randomized controlled trial could continue on open-label roflumilast cream 0.3% (Cohort-1, n=230), and patients naïve to roflumilast were also enrolled (Cohort-2, n=102). All psoriasis lesions (except scalp) were treated, including face and intertriginous areas for up to 52 weeks. If affected, palms and soles were treated, but not evaluated towards any efficacy assessments. Median duration of response was determined using the Kaplan-Meier method. Results: With cumulative treatment up to 64 weeks in Cohort-1 and 52 weeks in Cohort-2, long-term safety and tolerability were consistent with the 12-week, phase 2b study. Overall, 73.5% of patients completed the study; 3.9% discontinued due to adverse events (AE) and 0.9% discontinued due to lack of efficacy. Treatment-related AEs were reported in 2.7% patients; none were deemed serious. Investigator tolerability assessments at each visit demonstrated 99% of patients rated “no evidence of irritation.” At Week 52, IGA Success (demonstrating Clear/Almost Clear plus 2-grade improvement from baseline) was achieved by 34.8% of patients in Cohort-1 and 39.5% in Cohort-2. Of patients in Cohort-2, 40% of patients achieved IGA success at week 12. IGA Clear/Almost Clear was achieved by 46.8% of patients across both cohorts at week 12 and consistent through week 52 (44.8%). Similarly, a 60.5% mean PASI improvement and 60.1% mean BSA improvement from baseline were observed at week 12 and consistent through week 52 (59.4% and 63.3%, respectively). Of the 185 patients who achieved IGA Clear/Almost Clear during the open-label trial, the median durability of IGA of Clear/Almost Clear was 10 months (40.1 weeks). Among patients who achieved an IGA of Clear or Almost Clear, 50% maintained Clear or Almost Clear status for at least 10 months. Conclusions: In this long-term safety study, roflumilast cream was well tolerated with a safety profile consistent with the parent Ph2b trial, and effectively maintained clear/almost clear skin with no tachyphylaxis observed. Sponsored by Arcutis Biotherapeutics, Inc.

Pharmacology of orismilast, a potent and selective PDE4 inhibitor.

There remains an unmet need for oral medications that are safe and efficacious for long-term management of chronic inflammatory skin diseases (CISD). Inhibition of phosphodiesterase 4 (PDE4) can modulate a broad range of pro-inflammatory cytokines that play a major role in CISD pathogenesis. Orismilast is a second generation PDE4 inhibitor in clinical development for CISD treatment. The objective of this study was to examine the PDE4 enzymatic activity and anti-inflammatory effects of orismilast in vitro, ex vivo, and in vivo. The PDE1-11 enzymatic activity of orismilast was tested in vitro using a single concentration of 308 nM orismilast. The PDE4 selectivity and inhibitory potency was further examined in a radiometric assay. Orismilast was tested on human whole blood and human peripheral blood mononuclear cells (PBMC) to determine effects on its cytokine secretion and inhibition profile ex vivo. Orismilast was orally administered in a murine model of chronic oxazolone-induced ear skin inflammation. Ear thickness, a marker of inflammation, and inflammatory cytokines were analysed. Orismilast selectively inhibited PDE4 and demonstrated potent inhibition of PDE4B and PDE4D subtype splice variants in vitro. Orismilast inhibited whole blood and PBMC production of tumour necrosis factor α (TNFα), and the secretion of T-helper (Th)1 (TNFα and IFNγ), Th17 (IL-22 and IL-23), and Th2 (IL-4, IL-5, and IL-13) related cytokines in PBMC. In vivo, 10 and 30 mg/kg doses of orismilast significantly reduced ear thickness and inflammation markers (p < 0.0001, respectively). Orismilast displayed selective and potent PDE4 inhibition and broad-spectrum anti-inflammatory activity in several pre-clinical models. The results of the study support clinical development of oral orismilast as a novel treatment option for CISD including psoriasis, atopic dermatitis, and hidradenitis suppurativa.

Design, synthesis, and biological evaluation of urolithin derivatives as potential phosphodiesterase II inhibitors

Urolithins are the gut microbiota metabolites of ellagitannins which are found in natural plants such as pomegranate, strawberry, and raspberry, and in nuts. Recently, several reports have clarified the underlying mechanism of urolithins in central nervous system inflammation. Therefore, urolithins have become potential therapeutic drug candidate molecules for central nervous system diseases. Derivatives 1–1d, 1–1f, 3–2a, and 3–2b of urolithin A, urolithin B, and methoxyurolithin A were found to have had significant inhibitory activity against phosphodiesterase II with IC50 values of 35.42, 39.96, 25.58, and 13.84 μM, respectively. Herein, we report the design and synthesis of urolithin derivatives along with a biological evaluation of their activity against phosphodiesterase II.

Pharmacokinetics of Roflumilast Cream in Chronic Plaque Psoriasis: Data from Phase I to Phase III Studies.

Most patients with chronic plaque psoriasis receive topical treatment; however, available options lack a balance of efficacy with long-term safety and tolerability. Roflumilast cream 0.3% is a highly potent phosphodiesterase 4 (PDE4) inhibitor approved by the US FDA for treatment of psoriasis. The aim of this study was to define the pharmacokinetic (PK) profile of roflumilast delivered topically from a phase I maximal usage study and data from phase II and phase III studies. PK data for roflumilast and the active metabolite, roflumilast N-oxide, were determined from a phase I PK and safety maximal usage study of roflumilast cream 0.3% applied once daily for 14 days in patients with plaque psoriasis affecting body surface area (BSA) ≥20% (N=26). Serial plasma samples were obtained on Days 1 and 15 to determine maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC). Plasma concentrations were also assessed at Weeks 3, 4, and 5 for terminal half-life (t½). Concentrations of roflumilast and roflumilast N-oxide in skin were assessed at Day 28 for 14 patients with psoriasis in a phase I/IIa study of once-daily roflumilast cream 0.5% and 0.15% for 28 days. Systemic exposure (Ctrough and AUC) of roflumilast and roflumilast N-oxide in two phase III trials (DERMIS-1, n=245; DERMIS-2, n=250) of roflumilast cream 0.3% for 8 weeks was assessed at Weeks 4 and 8. Bioavailability of roflumilast cream 0.3% after topical administration was 1.5%. Unlike after oral dosing, the plasma concentration-time curve was flat, with a peak-to-trough ratio of 1.2. Roflumilast N-oxide concentrations were eightfold higher than roflumilast concentrations. The t½ in adult patients was 4.0 days for roflumilast and 4.6 days for roflumilast N-oxide following the last dose administered. Steady state was reached by Day 15. Concentrations of roflumilast in skin were, on average, 126- and 61.8-fold higher than corresponding mean plasma Ctrough following administration of roflumilast cream 0.15% and 0.5% daily for 28 days. Roflumilast N-oxide was quantifiable in only one skin sample (N=27). Following 8 weeks of treatment in DERMIS-1, mean plasma Ctrough of roflumilast was 1.78 ng/mL, and 9.86 ng/mL for roflumilast N-oxide. In DERMIS-2, mean plasma Ctrough was 1.72 ng/mL and 10.2 ng/mL, respectively. In the maximal usage study (mean BSA: 27.5%), eight patients (30.8%) experienced adverse events (AEs) and all were mild or moderate, with no reports of diarrhea, headache, insomnia, or application-site pain; no patients discontinued treatment due to an AE. Topical administration of roflumilast cream 0.3% results in concentrations in skin 126- and 61.8-fold higher relative to plasma, which are much higher than expected to be achievable with oral dosing. PDE4 inhibition in the skin is likely due to roflumilast as compared with its active metabolite, as there is no significant conversion to roflumilast N-oxide in the skin. Consistent with reservoir formation and retention of drug in the stratum corneum, roflumilast is slowly released from the skin (t½ 4 days) and peak-to-trough ratiois 1.2. NCT04279119, NCT03392168, NCT04211363, NCT04211389.