PDE4 Inhibition and Theta-burst Stimulation Transcranial Magnetic Stimulation Motor Plasticity: a Randomized Placebo-controlled Single-blind Crossover Study

Repetitive transcranial magnetic stimulation (rTMS) uses a magnetic field to non-invasively induce electrical function within the brain. Stimulation allows brain cells to change the way that they adapt and communicate with each other, known as 'synaptic plasticity'. It is thought that alterations in these adaptive brain changes underlie the ability of rTMS to treat mental illnesses like depression.
The regulation of synaptic plasticity is complex, and involves multiple interacting factors and redundant systems to ensure that plasticity is carefully regulated. To date, studies attempting to alter impact synaptic plasticity have done so using pharmacological adjuncts that target extracellular contributions to plasticity. Here, we propose the first proof of principle study targeting intracellular regulation of plasticity by using a pharmacological adjunct targeting Phosphodiesterase 4 (PDE4), a key regulator a cyclic AMP gradients in brain cells.
We will pair TMS with electromyography (EMG) to measure activity dependent changes in the motor cortex following rTMS to test the ability of a PDE4 inhibition to enhance synaptic plasticity after rTMS.

开始日期2024-08-01

申办/合作机构

University of Calgary

NCT06440473 / Recruiting临床4期

Visualization of Topical Zoryve vs. Vehicle Using Line Field Optical Coherence Tomography in Healthy Skin

The goal of this study is to visualize the deposition of topical 0.3% roflumilast (Zoryve) compared to vehicle using Line-Field Optical Coherence Tomography (LC-OCT) in vivo in healthy skin. We hypothesize that the application of topical 0.3% roflumilast (Zoryve) will result in distinct patterns of deposition within the epidermal and dermal layers compared to the vehicle. Specifically, we anticipate observing deeper penetration and more uniform distribution of roflumilast within the skin layers, indicative of enhanced efficacy, as visualized by LC-OCT imaging.

开始日期2024-05-28

申办/合作机构

Rao Dermatology

NCT05682859 / Recruiting临床4期IIT

Treatment of Chronic Hand Eczema With Oral Roflumilast (HERO) - a Randomized Controlled Trial

This study is a multicentre, double-blinded, randomized, placebo-controlled, clinical trial with open-label extension.
The purpose and aim of this study is to investigate the efficacy and safety of roflumilast (PDE4-inhibitor) in adult patients with chronic hand eczema (CHE).
Patients will receive 16-week treatment with either roflumilast or placebo tablets. Hereafter, both groups continue in open-label treatment for 12 weeks where both groups will receive treatment with roflumilast.

开始日期2023-09-25

申办/合作机构

Novo Nordisk Foundation

100 项与罗氟司特相关的临床结果

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100 项与罗氟司特相关的转化医学

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100 项与罗氟司特相关的专利（医药）

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752

项与罗氟司特相关的文献（医药）

2024-04-01·Journal of affective disorders

Roflumilast: Modulating neuroinflammation and improving motor function and depressive symptoms in multiple sclerosis

Article

作者: Zhang, Zhijun ; Chai, Jiaqing ; Wu, Yingying ; Zhang, Weiying ; Wang, Zhaowei ; Zhang, Yanxin

BACKGROUND:

Multiple sclerosis (MS) is an autoimmune disease causing central nervous system demyelination, often associated with depression. Current treatments for MS do not effectively address both physical disability and depression. Roflumilast, a phosphodiesterase-4 inhibitor with anti-inflammatory properties, has shown promise for autoimmune diseases.

METHODS:

We used an experimental autoimmune encephalomyelitis (EAE) rat model to study roflumilast's effects. Motor dysfunction and depression symptoms were assessed, and histopathological analysis evaluated its anti-inflammatory properties. Flow cytometry examined the drug's impact on brain microglia. TNF-α, IL-1β, and IL-6 levels in hippocampal tissue were assessed using ELISA kits.

RESULTS:

Roflumilast improved motor dysfunction and depression symptoms in EAE rats. Histopathological analysis revealed reduced inflammation, demyelination, and axonal loss in the spinal cord. Roflumilast suppressed microglial cell activation and conversion to pro-inflammatory M1-type cells. Flow cytometry showed roflumilast inhibited inflammatory marker expression in microglia and their activation in the hippocampus. IL-6 was identified as a roflumilast target for suppressing hippocampal inflammation.

LIMITATIONS:

This study used an animal model and did not assess long-term or potential side effects of roflumilast treatment.

CONCLUSIONS:

Roflumilast holds promise as a treatment for depression and motor impairment in MS. Its anti-inflammatory properties, reducing inflammation and inhibiting microglial activation, suggest its potential for MS therapy. However, further research is needed to evaluate long-term effects and safety in MS patients.

2024-02-01·International immunopharmacology

The IL-4/13-induced production of M2 chemokines by human lung macrophages is enhanced by adenosine and PGE2

Article

作者: Devillier, Philippe ; Glorion, Mathieu ; Naline, Emmanuel ; Brollo, Marion ; Grassin-Delyle, Stanislas ; Buenestado, Amparo ; Tiotiu, Angelica ; Descamps, Delphyne ; Salvator, Hélène ; Tenor, Hermann

BACKGROUND AND PURPOSE:

Lung macrophages (LMs) are critically involved in respiratory diseases. The primary objective of the present study was to determine whether or not an adenosine analog (NECA) and prostaglandin E₂ (PGE₂) affected the interleukin (IL)-4- and IL-13-induced release of M2a chemokines (CCL13, CCL17, CCL18, and CCL22) by human LMs.

EXPERIMENTAL APPROACH:

Primary macrophages isolated from resected human lungs were incubated with NECA, PGE₂, roflumilast, or vehicle and stimulated with IL-4 or IL-13 for 24 h. The levels of chemokines and PGE₂ in the culture supernatants were measured using ELISAs and enzyme immunoassays.

KEY RESULTS:

Exposure to IL-4 (10 ng/mL) and IL-13 (50 ng/mL) was associated with greater M2a chemokine production but not PGE₂ production. PGE₂ (10 ng/mL) and NECA (10^-6 M) induced the production of M2a chemokines to a lesser extent but significantly enhanced the IL-4/IL-13-induced production of these chemokines. At either a clinically relevant concentration (10^-9 M) or at a concentration (10^-7 M) that fully inhibited phosphodiesterase 4 (PDE4) activity, roflumilast did not increase the production of M2a chemokines and did not modulate their IL-13-induced production, regardless of the presence or absence of PGE₂.

CONCLUSIONS:

NECA and PGE₂ enhanced the IL-4/IL-13-induced production of M2a chemokines. The inhibition of PDE4 by roflumilast did not alter the production of these chemokines. These results contrast totally with the previously reported inhibitory effects of NECA, PGE₂, and PDE4 inhibitors on the lipopolysaccharide-induced release of tumor necrosis factor alpha and M1 chemokines in human LMs.

Calcified tissue international

Effect of Roflumilast, a Selective PDE4 Inhibitor, on Bone Phenotypes in ADO2 Mice

Article

作者: Acton, Dena ; Hong, Jung Min ; Parker, Reginald S ; Econs, Michael J ; Gerard-O'Riley, Rita L ; Hardman, Sara L ; Bruzzaniti, Angela ; Alam, Imranul

Autosomal Dominant Osteopetrosis type II (ADO2) is a rare bone disease of impaired osteoclastic bone resorption that usually results from heterozygous missense mutations in the chloride channel 7 (CLCN7) gene. We previously created mouse models of ADO2 (p.G213R) with one of the most common mutations (G215R) as found in humans and demonstrated that this mutation in mice phenocopies the human disease of ADO2. Previous studies have shown that roflumilast (RF), a selective phosphodiesterase 4 (PDE4) inhibitor that regulates the cAMP pathway, can increase osteoclast activity. We also observed that RF increased bone resorption in both wild-type and ADO2 heterozygous osteoclasts in vitro, suggesting it might rescue bone phenotypes in ADO2 mice. To test this hypothesis, we administered RF-treated diets (0, 20 and 100 mg/kg) to 8-week-old ADO2 mice for 6 months. We evaluated bone mineral density and bone micro-architecture using longitudinal in-vivo DXA and micro-CT at baseline, and 6-, 12-, 18-, and 24-week post-baseline time points. Additionally, we analyzed serum bone biomarkers (CTX, TRAP, and P1NP) at baseline, 12-, and 24-week post-baseline. Our findings revealed that RF treatment did not improve aBMD (whole body, femur, and spine) and trabecular BV/TV (distal femur) in ADO2 mice compared to the control group treated with a normal diet. Furthermore, we did not observe any significant changes in serum levels of bone biomarkers due to RF treatment in these mice. Overall, our results indicate that RF does not rescue the osteopetrotic bone phenotypes in ADO2 heterozygous mice.

187

项与罗氟司特相关的新闻（医药）

2024-07-01

·BioSpace

FDA Action Alert: Arcutis, Orexo, Phantom and More

Pictured: A scientist with pill bottles in front of FDA headquarters/Taylor Tieden for BioSpace Coming off of a busy month, July is looking relatively quiet for the FDA, with only five big target action dates and one pivotal advisory committee meeting. Read below for more. Arcutis Proposes New Atopic Dermatitis Cream for Patients as Young as Six By July 7, the FDA is expected to release its verdict on Arcutis Biotherapeutics’ supplemental New Drug Application (sNDA), seeking approval for a 0.15% formulation of roflumilast cream for the treatment of atopic dermatitis in patients as young as 6 years. Roflumilast is a topical inhibitor of the phosphodiesterase 4 (PDE4) enzyme, which plays a role in increasing the production of pro-inflammatory mediators while dampening the body’s anti-inflammatory mechanisms. A 0.3% formulation of roflumilast is approved under the brand name Zoryve for the treatment of psoriasis in patients 6 years and older. The FDA in December 2023 expanded roflumilast’s indication, allowing its use for seborrheic dermatitis in patients aged 9 and above. Arcutis is backing roflumilast’s atopic dermatitis application with data from three Phase III programs, including INTEGUMENT-1 and INTEGUMENT-2, two identical parallel-group, double-blinded and vehicle-controlled studies. The 0.15% roflumilast cream aced these two studies, hitting four-week success rates of 32.0% and 28.9%, respectively. In January 2024, Arcutis released additional pooled analysis from these two trials, demonstrating that 91.5% of patients treated with 0.15% roflumilast saw an improvement in the Eczema Area and Severity Index, measured at 4 weeks. Roflumilast’s data package also included a Phase II dose-ranging study and a Phase I pharmacokinetic trial. Orexo’s Opioid Overdose Drug Awaits FDA Verdict Orexo AB is proposing its high-dose naloxone drug candidate OX124 as a nasal rescue treatment for opioid overdose. The FDA’s deadline for a decision is July 15. Originally approved under the brand name Narcan, naloxone is a well-known treatment for opioid overdose. Currently available as an injectable and as a nasal spray, it works by competing with opioids for the same receptor sites, thereby undoing and dampening the drugs’ effects. Naloxone is effective at reversing the respiratory depression, hypotension and sedation often seen in patients who overdose on opioids. Orexo’s investigational formulation of naloxone makes use of its “world-class drug delivery platform,” dubbed amorphOX, according to the company’s news release accompanying the acceptance of its NDA. Through amorphOX, Orexo delivers a powder formulation of naloxone that is rapidly absorbed, highly bioavailable and highly stable. AmorphOX also makes naloxone more convenient and easier to use for patients, according to the company, making the product more robust to temperature changes. For instance, its efficacy is unaffected even if stored at freezing temperatures. If approved, Orexo expects to kick off commercial activities in the second half of this year, with a broader retail launch scheduled in early 2025, CEO Nikolaj Sørensen said in a statement. Phathom Pushes Voquezna into Heartburn in GERD The FDA is reviewing Phathom Pharmaceuticals’ application to use its oral drug Voquezna (vonoprazan) for the treatment of heartburn associated with non-erosive gastroesophageal reflux disease (GERD). Its decision is due on July 19. Afflicting around 38 million adults in the U.S., non-erosive GERD is the most common type of GERD and is characterized by reflux symptoms without mucosal erosions in the esophagus. Among its most common signs is episodic heartburn, which typically occurs at night. Patients with non-erosive GERD also suffer from regurgitation and chest pain and often have trouble swallowing. Voquezna, a potassium-competitive acid blocker, works by suppressing acid secretion and acts with preference on parietal cells found in the stomach. This mechanism of action helped the drug win its first FDA approval in November 2023, allowing its use for the treatment of erosive GERD and the relief of heartburn in erosive GERD. The NDA, which Phathom filed in September 2023, is backed by a randomized, placebo-controlled and double-blinded trial with 772 enrolled patients. Results showed that both the 10-mg and 20-mg doses of Voquezna aced the trial's primary endpoint, resulting in a 45% and 44% mean percentage of heartburn-free days over the 4-week treatment period, respectively, whereas this figure was only 28% in placebo comparators. During the study’s 20-week extension phase, the mean percentage of heartburn-free days in the 10-mg and 20-mg treatment groups increased to 62% and 63%, respectively. Alpha Cognition Targets Second Oral Alzheimer’s Drug of the Past Decade By July 27, the FDA is set to release its decision on Alpha Cognition’s NDA for ALPHA-1062, a next-generation acetylcholinesterase inhibitor being proposed for the treatment of mild-to-moderate Alzheimer’s disease. Formulated as a delayed-release oral tablet, ALPHA-1062 is the prodrug of an already-approved acetylcholinesterase inhibitor, galantamine, according to Alpha Cognition. The candidate works through a similar pathway, boosting the activity of acetylcholine on nicotinic receptors and the cholinergic neurotransmission in the central nervous system, in turn inducing cognitive improvements. Compared with galantamine, however, ALPHA-1062 promises a cleaner safety profile. It carries additional benzoyl ester moieties, which allow it to bypass acetylcholine receptors in the gastrointestinal nervous system, thereby avoiding the unwanted stimulation of local neurons and reducing side effects, according to Alpha Cognition’s website. ALPHA-1062’s NDA, which the FDA accepted in December 2023, is supported by studies establishing the bioequivalence of the drug candidate to galantamine. If approved, ALPHA-1062 would be the second oral Alzheimer’s therapy in a decade, according to a February 2024 release from Alpha Cognition. Xspray Tries Again for CML Therapy Dasynoc In February 2024, the FDA accepted Xspray Pharma’s NDA resubmission for Dasynoc (dasatinib), being proposed for the treatment of chronic myeloid leukemia. The regulator’s verdict is due on July 31. According to Xspray’s news release alongside the NDA’s acceptance, Dasynoc is an “optimized version” of Bristol Myers Squibb’s dasatinib, which the pharma sells under the brand name Sprycel. For instance, Dasynoc is unaffected by stomach pH and can be used together with omeprazole, as per Xspray’s website. Dasynoc also has a more consistent uptake pro can be given at lower doses than Sprycel. In July 2023, the FDA rejected Xspray’s initial bid to win approval for Dasynoc. At the time, the regulator accepted the proposed brand name and did not identify deficiencies with the application’s stability and clinical data. Instead, the FDA requested additional information regarding Dasynoc’s dosing in order to avoid confusion among doctors and patients. The regulator also asked for more information regarding a third-party manufacturer. In a February 2024 news release, CEO Per Andersson said that despite the initial rejection, Xspray remains “on track” to launch Dasynoc on September 1, if approved. FDA’s ODAC Convenes to Discuss AstraZeneca’s Imfinzi Regimen in NSCLC On July 25, the FDA’s Oncologic Drugs Advisory Committee will meet to discuss AstraZeneca’s supplemental Biologics License Application for its antibody therapy Imfinzi (durvalumab) for the treatment of resectable non-small cell lung cancer (NSCLC). The panel of external experts will evaluate AstraZeneca’s application for neoadjuvant treatment with Imfinzi and chemotherapy, followed by Imfinzi monotherapy after surgery. The advisory committee will also evaluate whether the pharma should be required to justify Imfinzi treatment before and after surgery. Imfinzi is a monoclonal antibody designed to target and block the PD-L1 protein, in turn inhibiting its downstream signaling cascade. This mechanism hampers cancer cells’ ability to weaken and evade the immune system, while also boosting the body’s innate anti-cancer activity. The FDA first approved Imfinzi in May 2017 for the treatment of advanced bladder cancer. The treatment has since been indicated for several other cancers, including unresectable stage III NSCLC, biliary tract cancer, pancreatic cancer and advanced or recurrent endometrial cancer. In April 2023, AstraZeneca published data from the Phase III AEGEAN study showing that neoadjuvant Imfinzi with chemotherapy, followed by maintenance Imfinzi monotherapy, significantly improved event-free survival in patients with resectable early-stage NSCLC versus chemotherapy alone. The Imfinzi-based regimen also resulted in a significantly higher pathologic complete response. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

临床3期临床结果上市批准临床2期申请上市

2024-06-27

·新药前沿

PDE4与呼吸系统疾病：加靶点，找亚型，开启新突破

在呼吸系统领域泛PDE4抑制剂开发中，口服给药制剂受制于其耐受性问题，而吸入给药制剂又受制于疗效不足，一直难有突破，如今这一局面正在改观—— 6月26日，Verona Pharma公司宣布，美国食品药品管理局（FDA）批准Ohtuvayre（ensifentrine）用于成人慢性阻塞性肺病（COPD）的维持治疗。 Ohtuvayre是一种first-in-class的选择性磷酸二酯酶3和磷酸二酯酶4（PDE3和PDE4）双重抑制剂，将支气管扩张和非甾体抗炎作用合二为一。不过，Ohtuvayre的PDE3/4双重作用机制中，其支气管扩功能可能要远大于其抗炎作用[1]。在吸入给药PDE4抑制剂已经历了多次因疗效不足而失败之后，Ohtuvayre终于取得成功，进而凸显其增加PDE3抑制的重要性了。 Ohtuvayre也是20多年来首款用于COPD维持治疗的具有新型作用机制（PDE3/4抑制剂）的吸入剂型药物。与此同时，除意大利Chiesi仍在坚守吸入给药PDE4抑制剂开发，而国内恒瑞和正大天晴已成为Ohtuvayre的追随者，正在开发吸入给药PDE3/4双重抑制剂（表1）。在作用机制方面，Ohtuvayre克服单靶点PDE4抑制的疗效不足，与此同时，其吸入给药途也避免了口服PDE4抑制剂耐受性问题。目前，阿斯利康开发的Daliresp（罗氟司特片）是仅有的一款获批可用于慢性阻塞性肺疾病的口服PDE4抑制剂产品。Daliresp于2011年获FDA批准治疗患有慢性支气管炎相关重度慢性阻塞性肺疾病且有疾病恶化史的患者，以降低慢性阻塞性肺疾病恶化的风险。在大型临床试验中，罗氟司特明显改善了严重COPD患者的肺功能并降低了病情恶化率，尤其是在加入长效支气管扩张剂（LABA或LAMA）时。口服PDE4抑制剂的主要问题是治疗指数较低，严重限制了可给药的剂量。基于机制的不良反应包括恶心、呕吐、腹泻和头痛。提高口服生物型PDE4抑制剂治疗指数的一个潜在方法是将PDE4亚型的选择性导向PDE4B，因为PDE4B具有许多抗炎作用[2]。呼吸系统领域口服PDE4抑制剂开发方面：恒翼生物于2018年从vTv Therapeutics引进PDE4抑制剂HPP737正在进行治疗COPD的Ⅱ期研究。值得关注的是，勃林格殷格翰开发的选择性PDE4B抑制剂Nerandomilast （BI 1015550）目前已进入到治疗特发性肺纤维化和进行性纤维化性间质性肺疾病Ⅲ期临床试验阶段。 PDE3/4机制探究环状3′,5′-腺苷酸（cAMP）和环状3′,5′-鸟苷酸（cGMP）是两种第二信使分子，参与传递神经递质、激素和其他细胞效应物质的作用，从而促进各种生理过程的调节。这些核苷酸还能通过与细胞内调控靶点结合，放大许多功能反应的信号强度。多项研究表明，细胞内cAMP水平过低与呼吸系统疾病（如COPD和哮喘）以及以免疫系统失调为特征的疾病（包括银屑病和其他慢性炎症）的发病机制有关。 cAMP，能调节各种细胞功能，包括细胞迁移、炎症介质释放和免疫细胞增殖。因此，提高细胞内cAMP水平可以通过减少促炎细胞因子的产生和增加抗炎介质的产生来抑制T细胞、单核细胞、巨噬细胞和中性粒细胞的免疫功能。细胞内的cAMP水平在亚细胞水平上受到环核苷酸磷酸二酯酶（PDE）的严格控制（图1）[3]。图1 PDE4抑制剂和cAMP参与消除炎症示意图增加的cAMP水平通过同时抑制PKA-NFkB和Epac1/2-NFkB通路，抑制促炎细胞因子的产生；通过激活PKA-CREB通路，促进抗炎介质的产生。细胞内的cAMP水平主要受腺苷酸环化酶（AC）和磷酸二酯酶4（PDE4）的活性控制。受到刺激时，AC通过将ATP转化为cAMP来提高cAMP水平。PDE4通过催化cAMP降解为AMP来控制cAMP信号的幅度和持续时间。抑制PDE4会增加细胞内的cAMP水平。 PDE是一个酶家族，通过水解环状核苷酸（cAMP和cGMP）的磷酸二酯键而起作用，从而终止这种第二信使的下游信号传导。根据其结构、序列同源性和对cAMP或cGMP的选择性，PDE可分为11个不同的家族（亚型）。通过选择性剪接或mRNA的转录修饰，这些基因可产生近百种PDE同工酶。组成PDE超家族的结构相互关联，但在功能上却各不相同。这些差异包括组织分布、细胞功能、主要结构、对cAMP和cGMP的亲和力、催化特性以及对特定激活剂、抑制剂和效应物及其调控机制的反应。PDE4、PDE7和PDE8是专门降解cAMP的PDE，而一些PDE则专门降解cGMP（PDE5、PDE6和PDE9）。大多数细胞都含有一种以上的PDE家族成员，但其数量、比例和亚细胞位置各不相同。虽然PDE的组织分布广泛，但有些细胞相对富含特定的PDE（表2）[4，5]。与此同时，PDE3的作用近年来也越来越受到重视。PDE3可水解cAMP和cGMP，但对cAMP的催化率比对cGMP的催化率高5-10倍。 PDE3是气道平滑肌中主要的PDE，与PDE4B和PDE4D一起表达，但PDE4抑制剂无法诱导急性支气管扩张，开发针对炎症细胞的PDE4抑制剂和主要针对气道平滑肌的PDE3抑制剂开始受到重视。既然抑制PDE3而不是PDE4会导致气道平滑肌松弛，而PDE4同工酶是大多数与COPD和哮喘发病机制有关的炎症细胞中的主要同工酶，开发对PDE3和PDE4具有双重抑制活性的药物就顺理成章了。事实上，同时抑制PDE3和PDE4的化合物应能应能通过松弛平滑肌来增加气道口径，同时抑制气道炎症反应[6]。总之，PDE3/4抑制剂可增加细胞内cAMP水平，引起支气管扩张，具有抗炎作用，改善内皮和上皮屏障功能。作为PDE3和PDE4双重抑制剂，目前尚无可靠证据表明Ensifentrine能够在COPD或哮喘患者中激发类似PDE4抑制剂的抗炎活性，而且Ensifentrine的大部分临床效果可能仅归因于PDE3抑制作用。磷酸二酯酶4（PDE4）由四个亚家族（PDE4A、B、C和D）组成，都能水解cAMP，主要在大脑、免疫系统细胞和心血管组织中表达。通过催化cAMP的水解，PDE4在干扰肿瘤坏死因子α（TNF-α）、白细胞介素10（IL-10）和白细胞介素12（IL-12）等促炎和/或抗炎介质的释放和作用方面起着至关重要的作用，在调节炎症反应方面有多种影响。抑制PDE4亚型可提高细胞内cAMP水平，影响炎症和免疫反应以及纤维化过程，包括减少促炎介质的释放和炎症细胞的招募。因此，PDE4是治疗肺纤维化的潜在靶点。每个PDE4亚家族又包括一些由独特基因编码的亚型，每种异构体在细胞和组织中都有不同的表达水平和功能（表3，图2）[5]。 ØPDE4A普遍存在，在脂肪组织、大脑、心脏和睾丸中表达相对较高； ØPDE4B也广泛分布，特别是在肺、免疫细胞、大脑、心脏和骨骼肌中具有高水平表达； ØPDE4C主要表达于睾丸和其他组织，在肺中表达低，在血液和免疫细胞中没有表达； ØPDE4D主要表达于脑、免疫细胞和骨骼肌细胞。图2 泛磷酸二酯酶4 （PDE4）/PDE4B在体内平衡和疾病中的作用 PDE4A、PDE4B和PDE4D被发现在大多数免疫系统细胞中高度表达。抑制PDE4B和PDE4D亚型被认为是PDE4抑制剂抗炎作用的主要驱动因素，因为这两种亚型是唯一在免疫细胞（如人类CD4+T细胞和外周血单核细胞（PBMC））中高水平表达的亚型。相反，PDE4C在免疫细胞和血液细胞中基本不存在[3]。研究显示，PDE4B/D，尤其是PDE4B2、PDE4D1和PDE4D2，是阻断以达到抗炎效果的关键同工酶。由于PDE4B亚型相比其他亚型在肺部表达程度更高，PDE4B具有许多抗炎作用，而PDE4D则与呕吐有关，因此，目前口服PDE4抑制剂的不良反应似乎与PDE4D的抑制有关。参考资料： [1]Ensifentrine, a Novel Phosphodiesterase 3 and 4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease: Randomized, Double-Blind, Placebo-controlled, Multicenter Phase III Trials (the ENHANCE Trials) [2]Inhaled Phosphodiesterase 4 （PDE4） Inhibitors for Inflammatory Respiratory Diseases [3]Next Generation PDE4 Inhibitors that Selectively Target PDE4B/D Subtypes: A Narrative Review [4]Perspectives of PDE inhibitor on treating idiopathic pulmonary fibrosis [5]Phosphodiesterase 4B inhibition_ a potential novel strategy for treating pulmonary fibrosis [6]Ensifentrine （RPL554）: an investigational PDE3/4 inhibitor for the treatment of COPD 本文由「新药前沿」微信公众号根据公开资料整理编辑，欢迎个人转发至朋友圈。媒体或机构转载授权请在「新药前沿」微信公众号留言公众号名称，审核通过后开通白名单获取转载授权，转载请标识来源。免责声明：本文仅作信息交流之目的，非投资建议或者治疗方案推荐，「新药前沿」微信公众号不对任何主体因使用本文内容而导致的任何损失承担责任。限于作者水平和专业知识所限，如有谬误，欢迎指正！

临床2期临床3期申请上市临床结果

2024-06-10

·GlobeNewswire-Health Care

Arcutis Announces New Long-Term Data of Roflumilast Cream 0.15% for the Treatment of Mild to Moderate Atopic Dermatitis (AD) in Adults and Children Down to Age Six Presented at Revolutionizing Alopecia Areata, Vitiligo, and Eczema Conference

Investigational roflumilast cream 0.15% showed continued improvements in the signs and symptoms of AD, including itch, through 56 weeks of treatment66.2% of participants treated with once-daily roflumilast cream 0.15% in both the 4-week parent study and the 52-week open label extension achieved a 75% improvement in Eczema Area and Severity Index (EASI-75) at Week 56For participants who achieved disease clearance and switched to proactive twice weekly application of roflumilast cream, the median duration of disease control was 281 daysOnce-daily, roflumilast cream 0.15% was well tolerated, with no new safety signals observed for up to 56 weeks of treatment CHICAGO and WESTLAKE VILLAGE, Calif., June 10, 2024 (GLOBE NEWSWIRE) -- Arcutis Biotherapeutics, Inc. (Nasdaq: ARQT), a commercial-stage biopharmaceutical company focused on developing meaningful innovations in immuno-dermatology, today announced new results from the INTEGUMENT-OLE long-term open-label study of investigational once-daily roflumilast cream 0.15% in adults and children ages 6 years and older with AD presented at the Revolutionizing Alopecia Areata, Vitiligo, and Eczema Conference. In the study, roflumilast cream was well-tolerated, with no new safety signals observed over 56 weeks of treatment. Efficacy was not only maintained but improved over time, with 56.6% of participants who continued use of roflumilast cream from the initial trial and 53.8% of participants who switched to roflumilast cream 0.15% from vehicle after the initial trial achieving validated Investigator Global Assessment-Atopic Dermatitis (vIGA-AD) success, defined as vIGA-AD value of 0 or 1 plus a 2-grade improvement from baseline, at Week 56. Starting at Week 4 of INTEGUMENT-OLE, participants who achieved a vIGA-AD score of clear (0), switched to proactive twice-weekly application (130 participants; 19.8% of study population). For these participants, after their first switch to twice-weekly application, the median duration of disease control (maintaining vIGA-AD of 0 or 1 with adequate control of signs and symptoms on the twice-weekly schedule application) was 281 days (95% CI: 147, not evaluable). In addition, 57.7% of these participants maintained disease control on the twice weekly schedule through their final study day. “AD is a chronic, burdensome skin condition that requires clinicians and patients to seek a treatment option that can be safely and effectively used long-term for an adult or child,” said Melinda Gooderham, MSc, MD, FRCPC, medical director, SKiN Centre for Dermatology, investigator with Probity Medical Research, and study presenter. “Importantly, investigational roflumilast cream 0.15% showed continued improvement through the course of the study, demonstrating that once approved, roflumilast cream may be an effective long-term, steroid-free treatment option that can be used for proactive flare-free disease control. These results also reinforce the durable efficacy and tolerability of roflumilast cream in AD, which could translate to improved treatment adherence.” “Adults and children with AD deserve treatment standards that focus on maintaining long-term disease control, rather than reactively managing flares. This novel pivotal study design evaluated proactive twice-weekly application with a targeted topical treatment, and demonstrates that after achieving disease clearance, patients can maintain disease control for at least 281 days,” said Emma Guttman-Yassky, MD, PhD, Waldman Professor of Dermatology and Immunology, Icahn School of Medicine at Mount Sinai, chair of the Kimberly and Eric J. Waldman Department of Dermatology, Mount Sinai Health System, and director of the Laboratory for Inflammatory Skin Diseases at Mount Sinai. “These results provide support for shifting the paradigm from reactively chasing flares to long-term flare-free disease management.” Dr. Guttman-Yassky is a paid consultant with Arcutis Biotherapeutics. Additional results presented include: 66.2% and 64.6% of participants who rolled over from the roflumilast cream arm in INTEGUMENT-1 or -2 or switched to once-daily roflumilast cream 0.15% from the vehicle arm demonstrated a 75% improvement from baseline in EASI-75 after 56 weeks, respectively.56.9% and 50.0% of participants who rolled over from or switched to once-daily roflumilast cream 0.15% treatment achieved a significant reduction (≥4-point) in itch based on daily Worst Itch Numeric Rating Scale (WI-NRS) (among patients aged ≥12 years with baseline WI-NRS ≥4) at Week 56, respectively. These long-term study results provide further support for the safety and tolerability profile of roflumilast cream already seen in the pivotal INTEGUMENT-1 and INTEGUMENT-2 clinical trials, with no new safety signals observed up to 56 weeks. Overall incidence of adverse events was low, with most being mild to moderate in severity. The most frequently reported adverse events (≥2%) included: COVID-19, upper respiratory tract infection, nasopharyngitis, and headache. Overall, only 3.0% of trial participants discontinued the study due to adverse events. “Investigational roflumilast cream 0.15% is designed to provide clinicians and individuals with AD with a long-term treatment option that is formulated free of known ingredients or allergens that may disrupt and compromise skin barrier integrity,” said Patrick Burnett, MD, PhD, FAAD, chief medical officer at Arcutis. “Based on these positive results, individuals can expect long-term efficacy and improvement in the signs and symptoms of AD, including itch, from roflumilast cream. If approved, we believe that roflumilast cream offers patients with AD an important steroid-free topical option that can provide lasting symptom relief which is maintained over time.” Roflumilast cream is uniquely formulated as a non-greasy emollient cream that absorbs quickly and does not disrupt the skin barrier. In addition, roflumilast cream does not include sensitizing excipients or irritants, such as propylene glycol, polyethylene glycol, isopropyl alcohol, ethanol, or fragrances. About INTEGUMENT-OLEThe “INterventional Trial EvaluatinG roflUMilast cream for the treatmENt of aTopic dermatitis Open Label Extension” (INTEGUMENT-OLE) was a Phase 3, multicenter, open-label extension study of the long-term safety of roflumilast cream 0.15% in adults and children ages 6 years and older with AD and roflumilast cream 0.05% in children ages 2 to 5 years. Individuals completing the INTEGUMENT-1 or INTEGUMENT-2 Phase 3 trials were eligible to enroll (n=658) for either 24 or 52 weeks. Reported here are data from adults and children down to age 6. The study evaluated monotherapy with roflumilast cream with no rescue treatment permitted. Beginning at Week 4 of INTEGUMENT-OLE, any participant who achieved vIGA-AD of ‘0-Clear’ switched to twice-weekly proactive treatment. Participants were able to continue twice-weekly proactive dosing, as long as vIGA-AD remained either ‘0-Clear’ or ‘1-Almost Clear’. Participants resumed once-daily dosing if vIGA-AD reached ≥2-Mild and could also resume once-daily dosing if signs/symptoms of AD were not adequately controlled with proactive therapy despite remaining at vIGA-AD of ‘1-Almost Clear’. The primary objective of the study was to assess the long-term safety of roflumilast cream after either 24 or 52 weeks of treatment. Secondary endpoints include vIGA-AD score of 0 or 1 at each assessment, vIGA-AD success, WI-NRS score over time, and EASI score over time. The assessment of IGA Success and EASI-75 response, as reported here, references baseline of INTEGUMENT-1 and -2. About Atopic DermatitisThe most common type of eczema, AD affects approximately 9.6 million children and 16.5 million adults in the United States. AD is a chronic, relapsing inflammatory skin disease that is genetically pre-disposed and presents across the lifespan. The disease appears as a red, intensely itchy rash that can occur anywhere on the body and may present differently in children and adults. AD presentation can rapidly fluctuate and vary based on geographic location and environment. About Roflumilast CreamRoflumilast cream is a next generation topical phosphodiesterase-4 (PDE4) inhibitor. PDE4 – an established target in dermatology – is an intracellular enzyme that increases the production of pro-inflammatory mediators and decreases production of anti-inflammatory mediators. Roflumilast cream 0.3% (ZORYVE®) is approved by the Food and Drug Administration (FDA) for the topical treatment of plaque psoriasis, including intertriginous areas, in patients 6 years of age and older. Investigational roflumilast cream was evaluated at lower doses for AD: 0.15% for adults and children 6 years of age and older and 0.05% for children aged 2 to 5 years. Roflumilast cream 0.15% is under review at the FDA for the treatment of adults and children 6 years of age and older with a Prescription Drug User Fee Act (PDUFA) target action date of July 07, 2024. Arcutis intends to submit a supplemental new drug application (sNDA) for roflumilast cream 0.05% in ages 2 to 5 following the potential approval of roflumilast cream 0.15%. About ZORYVE CreamZORYVE (roflumilast) cream is indicated for topical treatment of plaque psoriasis, including intertriginous areas, in patients 6 years of age and older. IMPORTANT SAFETY INFORMATIONZORYVE is contraindicated in patients with moderate to severe liver impairment (Child-Pugh B or C). The most common adverse reactions (≥1%) include diarrhea (3.1%), headache (2.4%), insomnia (1.4%), nausea (1.2%), application site pain (1.0%), upper respiratory tract infection (1.0%), and urinary tract infection (1.0%). Please see full Prescribing Information. About ArcutisArcutis Biotherapeutics, Inc. (Nasdaq: ARQT) is a commercial-stage medical dermatology company that champions meaningful innovation to address the urgent needs of individuals living with immune-mediated dermatological diseases and conditions. With a commitment to solving the most persistent patient challenges in dermatology, Arcutis has a growing portfolio including two FDA approved products that harness our unique dermatology development platform coupled with our dermatology expertise to build differentiated therapies against biologically validated targets. Arcutis’ dermatology development platform includes a robust pipeline with multiple clinical programs for a range of inflammatory dermatological conditions including scalp and body psoriasis, AD, and alopecia areata. For more information, visit www.arcutis.com or follow Arcutis on LinkedIn, Facebook, Instagram and X. Forward-Looking StatementsArcutis cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. These statements are based on the Company’s current beliefs and expectations. Such forward-looking statements include, but are not limited to, statements regarding the potential of roflumilast cream to simplify disease management for care of AD; the potential of real-world use results of roflumilast cream, as well as the potential approval of roflumilast cream for AD. These statements are subject to substantial known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance, or achievements to be materially different from the information expressed or implied by these forward-looking statements. Risks and uncertainties that may cause our actual results to differ include risks inherent in our business, reimbursement and access to our products, the impact of competition and other important factors discussed in the “Risk Factors” section of our Form 10-K filed with U.S. Securities and Exchange Commission (SEC) on February 27, 2024, as well as any subsequent filings with the SEC. You should not place undue reliance on any forward-looking statements in this press release. We undertake no obligation to revise or update information herein to reflect events or circumstances in the future, even if new information becomes available. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Contacts:MediaAmanda Sheldon, Head of Corporate Communicationsasheldon@arcutis.com InvestorsLatha Vairavan, Vice President, Finance and Investor Relationslvairavan@arcutis.com

临床结果临床3期上市批准

100 项与罗氟司特相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D05744	罗氟司特	R03DX07	DB01656

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
脂溢性皮炎	美国	Arcutis Biotherapeutics, Inc.	2023-12-15
斑块状银屑病	加拿大	Arcutis Biotherapeutics, Inc.	2019-12-20
慢性阻塞性肺疾病	欧盟	AstraZeneca AB	2010-07-05
慢性阻塞性肺疾病	冰岛	AstraZeneca AB	2010-07-05
慢性阻塞性肺疾病	列支敦士登	AstraZeneca AB	2010-07-05
慢性阻塞性肺疾病	挪威	AstraZeneca AB	2010-07-05

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适应症	最高研发状态	国家/地区	公司	日期
特应性皮炎	申请上市	美国	Arcutis Biotherapeutics, Inc.	2023-11-29
头皮皮肤病	临床3期	美国	Arcutis Biotherapeutics, Inc.	2021-08-24
头皮皮肤病	临床3期	加拿大	Arcutis Biotherapeutics, Inc.	2021-08-24
哮喘	临床3期	美国	AstraZeneca PLC	2003-11-01
哮喘	临床3期	阿根廷	AstraZeneca PLC	2003-11-01
哮喘	临床3期	哥伦比亚	AstraZeneca PLC	2003-11-01
哮喘	临床3期	墨西哥	AstraZeneca PLC	2003-11-01
哮喘	临床3期	秘鲁	AstraZeneca PLC	2003-11-01
慢性哮喘	临床3期	美国	AstraZeneca PLC	2003-04-01
慢性哮喘	临床3期	奥地利	AstraZeneca PLC	2003-04-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04445987 (CTgov)	临床2期	脂溢性皮炎	408	ARQ-154-203 Roflumilast Foam (Cohort 1 Group 1: ARQ-154-203 Roflumilast Foam 0.3% Without Treatment Gap)	廠襯築鹽廠鬱壓簾壓襯(獵鹽網壓餘襯窪蓋築衊) = 蓋糧願鹽範鹽艱夢積構顧構範襯鏇夢餘鏇鑰憲 (繭繭淵廠餘蓋簾鏇遞糧, 醖壓淵獵獵鹽鏇簾鹽築 ~ 鏇壓醖願壓鹹膚鬱壓齋) 更多	-	2024-06-11
				ARQ-154-203 Roflumilast Foam (Cohort 2 Groups 3 and 4: ARQ-154-203 Roflumilast Foam 0.3% With Treatment Gap)	廠襯築鹽廠鬱壓簾壓襯(獵鹽網壓餘襯窪蓋築衊) = 蓋範鑰壓繭遞築積鬱艱顧構範襯鏇夢餘鏇鑰憲 (繭繭淵廠餘蓋簾鏇遞糧, 鹹壓鑰鹹糧壓獵簾鬱鑰 ~ 鏇選壓鹽夢夢鏇蓋憲膚)
NCT04804605 (INTEGUMENT-OLE, GlobeNewswire) 人工标引	临床3期	特应性皮炎	658	Roflumilast cream 0.15% (INTEGUMENT-1)	繭鬱製鹹憲齋齋夢觸鑰(餘齋夢淵選淵網窪築繭) = 蓋窪獵憲醖餘壓窪襯築鑰願構獵遞築構鑰築繭 (繭築構艱膚糧選窪餘襯 ) 更多	积极	2024-06-10
				Roflumilast cream 0.15% (INTEGUMENT-2)	繭鬱製鹹憲齋齋夢觸鑰(餘齋夢淵選淵網窪築繭) = 襯繭鬱願選蓋夢範觸遞鑰願構獵遞築構鑰築繭 (繭築構艱膚糧選窪餘襯 ) 更多
Literature 人工标引	N/A	脂溢性皮炎	-	roflumilast foam formulation	-	积极	2024-05-13
NCT04973228 (CTgov)	临床3期	脂溢性皮炎	457	Roflumilast Foam (Roflumilast Foam 0.3%)	窪餘廠窪觸築願鏇觸齋(壓製製窪遞糧鑰範網鹽) = 願範鹽膚範糧鏇獵廠積選範顧積鹹選憲願淵積 (齋積糧壓鏇鬱願夢憲範, 鬱簾艱顧範鬱餘衊鏇膚 ~ 鏇壓顧窪願遞選製製範) 更多	-	2024-03-12
				Vehicle Foam (Vehicle Foam)	窪餘廠窪觸築願鏇觸齋(壓製製窪遞糧鑰範網鹽) = 廠襯膚獵範艱糧鏇製淵選範顧積鹹選憲願淵積 (齋積糧壓鏇鬱願夢憲範, 鹽襯鏇醖襯襯構壓壓簾 ~ 蓋膚餘簾壓範蓋繭襯憲) 更多
NCT04845620 (INTEGUMENT-PED, GlobeNewswire) 人工标引	临床3期	特应性皮炎	652	Roflumilast cream 0.05%	衊鬱顧廠鏇製齋艱窪觸(遞選範範願醖襯齋艱廠) = 積憲艱構觸淵艱鏇遞網襯鏇鏇糧積齋膚獵窪獵 (衊壓鏇鹹願蓋廠醖構蓋 ) 更多	积极	2024-03-11
				Vehicle	衊鬱顧廠鏇製齋艱窪觸(遞選範範願醖襯齋艱廠) = 觸淵蓋顧網選醖醖憲選襯鏇鏇糧積齋膚獵窪獵 (衊壓鏇鹹願蓋廠醖構蓋 ) 更多
NCT04973228 (STRATUM, GlobeNewswire) 人工标引	临床3期	脂溢性皮炎	189	Roflumilast	憲觸鹽窪顧壓簾製築艱(積艱壓襯夢淵廠選蓋積) = Treatment with ZORYVE foam significantly increased the odds of achieving a meaningful improvement in quality of life at Weeks 2, 4, and 8, compared to vehicle as measured by the Dermatology Life Quality Index (DLQI) (odds ratio (OR) 6:97; 95% confidence interval (CI) 3.97, 12.24; p<0.001). 72.5% of individuals achieved a minimally important differenceii in DLQI score as early as 2 weeks, increasing to 86.6% at the end of the study, Week 8 (compared to 28.1% p=0.001 and 53.6% p=0.001 for vehicle, respectively). 糧網膚鑰範餘鬱鬱憲窪 (鏇壓壓壓膚衊艱淵餘鬱 )	积极	2024-01-14
				Vehicle
NCT04773587 \| NCT04773600 (INTEGUMENT-2 \| INTEGUMENT-II, GlobeNewswire) 人工标引	临床3期	特应性皮炎	-	Roflumilast	遞艱壓衊觸鬱遞衊鑰觸(觸築鏇齋糧醖遞糧醖壓) = 繭顧醖齋艱顧醖壓鏇衊壓網夢築蓋顧衊醖觸艱 (願蓋鹽糧衊餘壓遞顧憲 ) 更多	积极	2024-01-14
				Vehicle cream	遞艱壓衊觸鬱遞衊鑰觸(觸築鏇齋糧醖遞糧醖壓) = 築齋遞積觸獵繭窪鏇簾壓網夢築蓋顧衊醖觸艱 (願蓋鹽糧衊餘壓遞顧憲 ) 更多
NCT04091646 \| NCT04973228 (Trial 203, FDA) 人工标引	临床2/3期	脂溢性皮炎	683	ZORYVE (STRATUM)	網觸顧範壓鬱壓憲網夢(繭網獵簾網壓築製淵餘) = 膚積遞襯遞鏇艱築淵齋窪蓋鹹夢壓餘餘積願醖 (襯鬱鑰齋積醖糧範簾繭 ) 更多	积极	2023-12-15
				Vehicle (STRATUM)	網觸顧範壓鬱壓憲網夢(繭網獵簾網壓築製淵餘) = 醖艱淵觸憲繭醖願獵願窪蓋鹹夢壓餘餘積願醖 (襯鬱鑰齋積醖糧範簾繭 ) 更多
NCT04655313 (ARQ-151-215, CTgov)	临床2期	斑块状银屑病	20	ARQ-151 cream 0.3%	壓築鹽選範壓網鹹醖網(願選淵積鬱窪構夢鹹醖) = 鹹鹹壓選蓋壓觸餘艱網繭窪網顧壓鬱願鏇餘壓 (壓願積簾襯蓋糧蓋艱範, 鏇衊艱夢鑰鬱齋網築衊 ~ 遞觸願淵淵獵積艱餘獵) 更多	-	2023-12-15
NCT04211363 \| NCT04211389 (DERMIS-2, Corporate Publications) 人工标引	临床3期	斑块状银屑病	-	ZORYVE® (roflumilast) cream 0.3%	齋醖鬱憲艱鬱糧膚淵觸(繭繭淵構襯壓簾鏇鬱淵) = 醖獵構製壓獵膚壓獵顧鑰繭願夢膚蓋簾衊窪襯 (廠願觸窪憲積夢選繭壓 ) 更多	积极	2023-10-20
				Vehicle	齋醖鬱憲艱鬱糧膚淵觸(繭繭淵構襯壓簾鏇鬱淵) = 鹽襯憲鑰鹽築網淵餘齋鑰繭願夢膚蓋簾衊窪襯 (廠願觸窪憲積夢選繭壓 ) 更多