Roflumilast 500microgram tablets

BACKGROUND: The topical phosphodiesterase 4 inhibitor roflumilast has been studied in several dermatologic conditions. OBJECTIVE: Roflumilast foam 0.3% is being investigated as a topical treatment for seborrheic dermatitis (SD). METHODS: In this phase 3, double-blinded trial, patients with SD were randomly assigned (2:1 ratio) to once-daily roflumilast foam 0.3% or vehicle foam for 8 weeks. The primary efficacy outcome was Investigator Global Assessment (IGA) Success at week 8, defined as IGA of 0 (Clear) or 1 (Almost Clear) plus ≥2-point improvement from baseline. Safety was also assessed. RESULTS: 79.5% of roflumilast-treated and 58.0% of vehicle-treated patients met the primary endpoint (P < .001); statistically significant differences in IGA Success also favored roflumilast at week 2 (roflumilast: 43.0%; vehicle: 25.7%; P < .001) and week 4 (roflumilast: 73.1%; vehicle: 47.1%; P < .001). Roflumilast was well-tolerated with a low rate of treatment-emergent adverse events. LIMITATIONS: Study limitations include the 8-week treatment period for this chronic condition. CONCLUSIONS: Once-daily roflumilast foam was superior to vehicle in leading to IGA of Clear or Almost Clear plus ≥2-point improvement from baseline at 8 weeks in patients with SD. Longer trials are needed to determine durability and safety of roflumilast foam in SD.

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Importance: Current topical treatments for scalp psoriasis are limited by formulation, efficacy, and/or safety. Objective: To assess safety and efficacy of roflumilast foam, 0.3%, in patients with psoriasis of the scalp and body. Design, Setting, and Participants: This was a phase 3 double-blinded, vehicle-controlled randomized clinical trial conducted between August 24, 2021, and June 3, 2022, at 49 sites in Canada and the US. Eligible participants were 12 years and older with plaque psoriasis affecting up to 25% of the scalp and body, at least 10% of the scalp, and up to 20% of nonscalp areas, with a minimum Scalp-Investigator Global Assessment (S-IGA) score of 3 (moderate), and minimum Body-IGA (B-IGA) score of 2 (mild). Data analyses were performed from September 9 to December 30, 2022. Interventions: Once-daily roflumilast foam, 0.3%, or vehicle for 8 weeks. Main Outcomes and Measures: Coprimary end points were S-IGA and B-IGA success (clear [0] or almost clear [1] plus ≥2-grade improvement) at week 8. Secondary end points included S-IGA success at weeks 2 and 4, change in Scalp Itch-Numeric Rating Scale (SI-NRS), and SI-NRS and Worst Itch-NRS (WI-NRS) success (≥4-point improvement in patients with baseline score of ≥4). Safety and tolerability were also assessed. Results: A total of 432 patients (mean [SD] age, 47.3 [14.8] years; 243 women [56.3%]) were randomized to roflumilast foam (n = 281) or vehicle (n = 151). At week 8, 66.4% of the roflumilast group achieved S-IGA success vs 27.8% of the vehicle group (P < .001); and 45.5% of the roflumilast group achieved B-IGA success compared with 20.1% of the vehicle group (P < .001). Rates for S-IGA success at week 2 and SI-NRS and WI-NRS success at weeks 2, 4, and 8 were significantly higher for roflumilast vs vehicle. Improvements in SI-NRS were greater for the roflumilast vs the vehicle group as early as the first assessment (24 hours after the first application). Both study groups had low rates of adverse events and favorable tolerability profiles. Conclusions and Relevance: This randomized clinical trial found that roflumilast foam, 0.3%, improved signs and symptoms of psoriasis on the scalp and body, including pruritus, with low rates of adverse events in patients 12 years and older. These results demonstrate the potential of roflumilast foam, 0.3%, as monotherapy for patients with psoriasis of the scalp and body. Trial Registration: ClinicalTrials.gov Identifier: NCT05028582.

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BACKGROUND/OBJECTIVES: Efficacy and safety of roflumilast cream 0.15% were demonstrated in patients aged ≥ 6 years with atopic dermatitis (AD) in two Phase 3 trials. This Phase 3 parallel-group, double-blind trial (INTEGUMENT-PED; NCT04845620) compared the efficacy and safety of roflumilast cream 0.05% and a vehicle in patients aged 2-5 years with AD. METHODS: Patients aged 2-5 years with mild-to-moderate AD were treated with once-daily roflumilast cream 0.05% or vehicle for 4 weeks. The primary efficacy endpoint was Validated Investigator Global Assessment for AD (vIGA-AD) Success (0 [Clear] or 1 [Almost Clear] plus ≥ 2-grade improvement from baseline) at Week 4. Other endpoints included ≥ 75% improvement in Eczema Area and Severity Index (EASI-75) and Worst Itch-Numeric Rating Score (WI-NRS) Success (≥ 4-point improvement in patients with baseline ≥ 4). Safety and tolerability were also assessed. RESULTS: Among 437 and 215 patients treated with roflumilast and vehicle, respectively, significantly greater proportions of the roflumilast group achieved Week-4 vIGA-AD Success (25.4% vs. 10.7%; p < 0.0001), EASI-75 (39.4% vs. 20.6%; p < 0.0001), and WI-NRS Success (35.3% vs. 18.0%; nominal p = 0.0002). Improvement in pruritus was observed within 24 h after the first application (nominal p = 0.0014). Treatment-emergent adverse event (TEAE) rates were low in both groups, and 98.9% were mild or moderate. At all timepoints, stinging/burning that caused definite discomfort was reported by ≤ 0.7% of caregivers of patients in the roflumilast group. CONCLUSIONS: In this Phase 3 trial, once-daily roflumilast cream 0.05% improved AD signs/symptoms in patients aged 2-5 years, with early pruritus improvement, low AE rates, and local tolerability comparable with vehicle. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04845620.

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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.

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BACKGROUND: Research into the neurobiological underpinnings of learning and memory has demonstrated the cognitive-enhancing effects associated with diverse classes of phosphodiesterase (PDE) inhibitors. Specific PDE inhibitors have been identified to improve neuronal communication through selective inhibition of PDE activity. Roflumilast, a PDE4 inhibitor, has demonstrated efficacy in enhancing episodic memory in healthy adults and elderly participants with pronounced memory impairment, indicative of amnestic mild cognitive impairment (aMCI). In alignment with these findings, the present protocol aims to provide a proof of concept phase II of the potential of roflumilast to aid patients diagnosed with (a)MCI or mild Alzheimer's disease (AD) dementia. METHODS: The study will be conducted according to a double-blind, randomized placebo-controlled, between-subjects design. Participants with (a)MCI and mild AD dementia will be recruited through the Memory Clinic at the Maastricht University Medical Centre + (MUMC +) in Maastricht, the Netherlands, alongside outreach through regional hospitals, and social media. The study will have three arms: placebo, 50 μg roflumilast, and 100 μg roflumilast, with a treatment duration of 24 weeks. The primary outcome measure will focus on the assessment of episodic memory, as evaluated through participants' performance on the 15-word Verbal Learning Task (VLT). Our secondary objectives are multifaceted, including an exploration of various cognitive domains. In addition, insights into the well-being and daily functioning of participants will be investigated through interviews with both the participants and their (informal) caregivers, we are interested in the well-being and daily functioning of the participants. DISCUSSION: The outcomes of the present study aim to elucidate the significance of the PDE4 inhibition mechanism as a prospective therapeutic target for enhancing cognitive function in individuals with (a)MCI and mild AD dementia. Identifying positive effects within these patient cohorts could extend the relevance of this treatment to encompass a broader spectrum of neurological disorders. TRIAL REGISTRATION: The Medical Ethics Committee of MUMC + granted ethics approval for the 4th version of the protocol on September 10th, 2020. The trial was registered at the European Drug Regulatory Affairs Clinical Trials (EudraCT) registered on the 19th of December 2019 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004959-36/NL ) and ClinicalTrial.gov (NCT04658654, https://clinicaltrials.gov/study/NCT04658654?intr=roflumilast&cond=mci&rank=1 ) on the 8th of December 2020. The Central Committee on Research Involving Human Subjects (CCMO) granted approval on the 30th of September 2020.

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Cognitive impairment affiliated with neurological disorders has a severe impact on daily life functioning and the quality of life of patients. This is associated with a significant and long-lasting health, social and financial burden, not only for the patients, but also for families and the wider society. However, treatment for cognitive impairment is only available for the indication Alzheimer's disease (AD) and its prodromal stage Mild Cognitive Impairment (MCI), although with major adverse effects, i.e. gastrointestinal effects (drugs) or hemorrhages (antibodies). Roflumilast (selective phosphodiesterase type 4 (PDE4) inhibitor) has been approved as an anti-inflammatory drug for the treatment of chronic obstructive pulmonary disease (COPD), although still 5 % of the patients experience nausea or even vomiting at the approved dose of 500 μg. Nonclinical studies demonstrated that roflumilast appears a promising drug the treat cognitive impairment in healthy rodents and a wide variety of animal models of CNS disorders. These effects are attributed to pro-neuroplasticity and anti-inflammatory effects, which appeared dose dependent. Roflumilast has also been tested in clinical studies and showed cognition enhancement at low dosing (100-250 µg) in healthy adults, healthy elderly, MCI and schizophrenia. Currently, clinical trials are underway for testing the pro-cognitive effects in early AD, post stroke cognitive impairment and Fragile X. Overall, the data showed that roflumilast has beneficial effects on cognitive performance. These cognition-enhancing effects are found at doses that were well-tolerated. Based on this favorable therapeutic window, the repurposing of roflumilast for treating cognitive impairments in CNS diseases may offer an affordable treatment option for patients.

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AVRO is an adjunctive four-drug regimen designed to increase the effectiveness of current standard treatment of glioblastoma (GB). AVRO is a repurposed drug regimen consisting of the antinausea drug aprepitant, the antidepressant vortioxetine, the emphysema treatment drug roflumilast, and the antipsychotic drug olanzapine. All four are EMA/FDA approved for nononcology indications, all four have strong research evidence showing inhibition of GB growth, and all four carry a low side effect risk. The goal of adding AVRO is to further retard GB growth, improving survival. Aprepitant is an antinausea drug that blocks NK-1 signaling, with a database of 59 studies showing growth inhibition in 22 different cancers, 12 of which were specific to GB. Fully 30 studies demonstrated that the SSRI class of antidepressants inhibited GB growth; accordingly, we chose one such agent, vortioxetine, to add to AVRO. Elevation of intracellular cAMP slowed GB growth in 21 independent studies. Accordingly, we added the emphysema treatment drug roflumilast, which inhibits cAMP degradation. Among the 27 currently marketed D2-blocking antipsychotic drugs, 24 have preclinical evidence of GB growth inhibition in a combined 84 independent study database. One of these 24 drugs is olanzapine, added to AVRO. Given the short median survival of GB as of mid-2025, the clinician and researcher community will benefit from wider awareness of the anti-GB effects of these four nononcology drugs.

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Phosphodiesterase 4 (PDE4) catalyzes cyclic adenosine monophosphate (cAMP) hydrolysis, playing a crucial role in the cAMP signaling pathway. cAMP is a secondary messenger involved in numerous physiological functions, such as inflammatory responses, immune responses, neural activity, learning, and memory. PDE4 inhibition is important for controlling anti-inflammatory and neuroprotective effects. In this review, we provide a comprehensive overview of the molecular functions and properties of human PDE4s. The study presents detailed sequence information for the PDE4 isoforms and the structural properties of the catalytic domain in members of the PDE4 family. We also review the inhibitory effects of the PDE4 inhibitors roflumilast and cilomilast related to respiratory diseases in PDE4. The crystal structures of PDE4 in complex with roflumilast and cilomilast are also analyzed. This review provides useful information for the future design of novel PDE4 inhibitors.

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