Purpose (the aim of the study): Interleukin (IL)-10 is a regulator of cytokine activity and has the potential to restore homeostasis in osteoarthritis (OA) of the knee. XT-150 is a non-viral gene therapy designed to durably express a proprietary variant of the anti-inflammatory cytokine IL-10 (IL-10v). XT-150-2-0204 (NCT04124042) evaluated the safety and efficacy of single and repeat intra-articular (IA) doses of XT-150 in patients with moderate-severe knee OA. The purpose of this analysis was to evaluate the efficacy findings based on baseline demographic subgroups.

Introduction: VP-315 is an intratumorally injected, chemotherapeutic oncolytic peptide in development as a non-surgical immunotherapeutic agent to be utilized as first line therapy in a primary or neoadjuvant setting for patients with basal cell carcinoma (BCC). Objective: In Part 2 of this study, the secondary objective was to evaluate the effect of various dosing regimens on the antitumor efficacy of VP-315 in a larger population of adult subjects with biopsy proven BCC. Methods: Eighty-two (82) subjects with up to 2 target BCC tumors (total 91 tumors) were treated intratumorally with VP-315 for up to 2 weeks. Cohort 3 was not enrolled based on results from Cohorts 1-2. Each 7-day treatment week was comprised of 2 or 3 consecutive treatment days followed by a no-treatment period of at least 4 days. Dosing scheme: Cohort 1: (n=6) Tumor injected 3 days consecutively (3X/week 4 mg loading dose Day 1 followed by 8 mg dose). Cohort 2: (n=3) Tumor injected 3 days consecutively (3X/week 8 mg dose). Cohort 4: (n=36) Each tumor was injected 2 days consecutively (2X/week 8 mg split dose*). Cohort 5: (n=37) Each tumor was injected 3 days consecutively (3X/week 8 mg split dose*). * Dose split into 2 injections, 30% injected initially; 70% injected 15-30 minutes later. Efficacy endpoints included histological clearance of target tumor(s) and estimate of remaining tumor volume (tumor size reduction) at excision (Week 12-13). Results: Eighty-two (82) subjects (n=92 lesions) completed treatment for BCC with VP-315 in Part 2. Approximately 51% of tumors achieved complete histologic clearance. All tumors treated had a reduction in tumor size. Overall tumor size reduction was 86%. Tumor size reduction in subjects who still had any residual tumor was 71%. Conclusion: Complete histological clearance in a majority of VP-315 treated tumors could eliminate the need for surgical intervention in those patients in clinical practice. In subjects with residual tumor burden, the substantial reduction in tumor size after VP-315 treatment would markedly reduce the surgical incision area and the amount of potential post-surgical scarring. Based on the favorable results, further research using VP-315 as a potential non-surgical immunotherapy for BCC as a first line therapy in a primary or neoadjuvant setting is warranted.

Introduction VP-315 is an intratumorally injected, chemotherapeutic oncolytic peptide in development as a non-surgical immunotherapeutic agent to be utilized as first line therapy in a primary or neoadjuvant setting for patients with basal cell carcinoma (BCC). Objective In Part 2 of this study, the primary objective was to determine the optimal dosing regimen for VP-315 by exploring the effects of various dosing schemes on the safety and tolerability of VP-315 in a larger population of subjects with biopsy proven BCC. Methods Eighty-two (82) subjects with up to 2 target BCC tumors (total 91 tumors) were treated intratumorally with VP-315 for up to 2 weeks. Cohort 3 was not enrolled based on results from Cohorts 1-2. Each 7-day treatment week was comprised of 2 or 3 consecutive treatment days followed by a no-treatment period of at least 4 days. Dosing scheme: Cohort 1: (n=6) Tumor injected 3 days consecutively (3X/week 4 mg loading dose Day 1 followed by 8 mg dose). Cohort 2: (n=3) Tumor injected 3 days consecutively (3X/week 8 mg dose). Cohort 4: (n=36) Each tumor was injected 2 days consecutively (2X/week 8 mg split dose*). Cohort 5: (n=37) Each tumor was injected 3 days consecutively (3X/week 8 mg split dose*). * Dose split into 2 injections, 30% injected initially; 70% injected 15-30 minutes later. Safety and tolerability were assessed by documenting the occurrence of Treatment Related Adverse Events (TRAEs), including those of special interest, Treatment Related Serious Adverse Events (TRSAEs), discontinuations due to AEs and expected treatment-related cutaneous reactions including tumor necrosis. Results All 82 subjects completed one of the VP-315 treatment regimens for BCC. TRAEs were mostly mild to moderate. AEs included injection site pain (mild 13.4%, moderate 12.2%, severe 1.2%), hypertension (mild 4.9%), hypotension (mild 4.9%), erythema (mild 1.2%, moderate 2.4%), and headache (mild 2.4%). Expected cutaneous reactions were observed. No TRSAEs were reported. Conclusion VP-315 treatment was shown to be safe and well-tolerated when administered once daily 2-3 times per week per tumor for up to 2 weeks using a split dose approach. Given its favorable safety profile, VP-315 warrants continued research as a potential non-surgical immunotherapy for BCC as a first line therapy in a primary or neoadjuvant setting. Sponsored by Verrica Pharmaceuticals Inc.

External genital warts are caused by various subtypes of the human papilloma virus and spread through direct skin-to-skin contact. Approximately 1% of the US population have external genital warts. Although cantharidin has been used to treat external genital warts for decades, there are no US Food and Drug Administration-approved cantharidin products and no reliable or controlled sources of cantharidin available. VP-102 is a drug-device combination product containing cantharidin (0.7% w/v) in a single-use shelf-stable applicator. The objective of this randomized, double-blind, vehicle-controlled, phase II clinical trial was to determine the optimal regimen for the treatment, safety, and efficacy of VP-102 in external genital warts. The study was conducted in two parts. Part A was dose finding and Part B was performed following the completion of Part A for a safety and efficacy evaluation. Following completion of Part A, 6-h and 24-h VP-102 regimens under occlusion were selected to be evaluated in Part B. Pooled results from Part B and Part A of the 6-h and 24-h VP-102 treatment regimens showed that 36.7% and 33.3% of participants achieved complete clearance of all treatable external genital warts at the end of treatment vs 4.2% (p < 0.0048) and 0% (p < 0.0075) with the vehicle. Adverse events experienced by the VP-102-treated participants were consistent with the pharmacodynamic action of cantharidin as a vesicant and were primarily mild to moderate in severity. The most common adverse events included application-site vesicles, pain, and erythema. No participants discontinued the study because of adverse events and no serious adverse events were deemed treatment related. The adverse event profile and efficacy of VP-102 under occlusion demonstrated in this study support the conclusion that a 6-h or up to 24-h exposure regimen represents an acceptable risk:benefit profile and justifies the conduct of a larger vehicle-controlled phase III study in external genital warts. NCT03981822, actual study start date: 25 June, 2019; actual primary completion date: 21 May, 2020; actual study completion date: 8 July, 2020.

Verrucae vulgaris, or common warts, is a common skin condition for which there is no US Food and Drug Administration-approved treatment. Compounded cantharidin has been used to treat warts for years but lacks a controlled formulation, consistent application schedule and methods, and robust safety and efficacy studies. VP-102 is a proprietary drug-device combination product containing a topical formulation of 0.7% (w/v) cantharidin in a single-use delivery device. This objective of the phase 2 study was to evaluate the efficacy, safety, tolerability, and optimal regimen of VP-102 in the treatment of common warts. In this open-label trial, participants aged ≥ 2 years with one to six common warts were administered VP-102 topically to treatable common warts once every 14 days (Cohort 1) or once every 21 days in conjunction with paring (Cohort 2), for up to four treatments. Participants were evaluated through to day 84 (Cohort 1) or day 147 (Cohort 2). The primary endpoint was the percentage of participants with complete clearance of all treatable common warts (baseline and new) at day 84. Secondary endpoints included percentage of participants achieving complete clearance of all treatable common warts at other visits. Safety assessments included treatment-emergent adverse events (TEAEs), including local skin reactions (LSRs). A total of 21 and 35 participants were enrolled in Cohort 1 and Cohort 2, respectively. Complete clearance at day 84 was seen in 19.0% of participants in Cohort 1 and 51.4% of those in Cohort 2. The most common TEAEs were expected LSRs and included application site vesicles, pain, pruritus, erythema, and scab. Most LSRs were mild or moderate in severity. VP-102 showed efficacy in complete clearance of common warts from baseline to day 84, as well as at follow-up visits. Due to the higher percentage of patients exhibiting complete clearance in Cohort 2, the treatment regimen of Cohort 2 will be pursued in future studies. TEAEs were expected due to the pharmacodynamic action of cantharidin, a vesicant. Clinical Trials ID: NCT03487549

Compounded cantharidin has been used for decades to treat molluscum contagiosum but lacks rigorous clinical evidence to support its safety and efficacy. VP-102 is a shelf-stable drug–device combination product that contains topical cantharidin (0.7% weight/volume [w/v]) and is being evaluated for the treatment of molluscum. Our objective was to present pooled safety and efficacy analyses of VP-102 in the treatment of molluscum compared with vehicle. Participants aged ≥ 2 years were randomized 3:2 to topical administration of VP-102 or vehicle in two randomized, double-blind, vehicle-controlled phase III trials. Study drug was applied to all baseline and new lesions once every 21 days until clear or for a maximum of four applications. Assessors blinded to treatment counted all lesions at each study visit. All adverse events (AEs) were documented. Data were pooled for analyses. In total, 310 participants received VP-102 and 218 received vehicle. Mean age was 7.5 years (range 2–60) for VP-102 and 6.8 (2–54) for vehicle. Complete clearance of all molluscum lesions at day 84 occurred in 50% of VP-102 participants and 15.6% of vehicle recipients (p < 0.0001). Mean molluscum lesion counts decreased 76% for VP-102 and 0.3% for vehicle at day 84 (p < 0.0001). The most common AEs in the VP-102 group were application site blistering, pruritus, pain, and erythema, which were generally mild or moderate in severity. Pooled analyses showed a significantly higher percentage of participants with complete molluscum lesion clearance and larger reductions in lesion counts with VP-102 than with vehicle. AEs were anticipated because of the pharmacodynamic properties of cantharidin. ClinicalTrials.gov identifiers: NCT03377790 (first posted 19 December 2017) and NCT03377803 (first posted 19 December 2017).

Osteoarthritis results in chronic pain and loss of function. Proinflammatory cytokines create both osteoarthritis pathology and pain. Current treatments are poorly effective, have significant side effects, and have not targeted the cytokines central to osteoarthritis development and maintenance. Interleukin-10 is an anti-inflammatory cytokine that potently and broadly suppresses proinflammatory cytokine activity. However, interleukin-10 protein has a short half-life in vivo and poor joint permeability. For sustained IL-10 activity, we developed a plasmid DNA-based therapy that expresses a long-acting human interleukin-10 variant (hIL-10var). Here, we describe the 6-month GLP toxicology study of this therapy. Intra-articular injections of hIL-10var pDNA into canine stifle joints up to 1.5 mg bilaterally were well-tolerated and without pathologic findings. This represents the first long-term toxicologic assessment of intra-articular pDNA therapy. We also report results of a small double-blind, placebo-controlled study of the effect of intra-articular hIL-10var pDNA on pain measures in companion (pet) dogs with naturally occurring osteoarthritis. This human IL-10-based targeted therapy reduced pain measures in the dogs, based on veterinary and owner ratings, without any adverse findings. These results with hIL-10var pDNA therapy, well-tolerated and without toxicologic effects, establish the basis for clinical trials of a new class of safe and effective therapies for OA.

Key Points Question What is the efficacy and safety of VP-102, a drug-device combination containing cantharidin, 0.7% (w/v), in individuals aged 2 years or older with molluscum contagiosum compared with vehicle? Findings In 2 identical phase 3 trials (Cantharidin Application in Molluscum Patients [CAMP-1 and CAMP-2]) with a total of 582 participants, topical application of VP-102 or vehicle every 21 days for a maximum of 4 treatments resulted in complete lesion clearance rates of 46.3% (CAMP-1) and 54.0% (CAMP-2) with VP-102 vs 18% (CAMP-1) and 13% (CAMP-2) with the vehicle. The most common adverse events were primarily mild to moderate and included application site vesicles, pain, and pruritus. Meaning The findings of these trials support the efficacy and safety of a proprietary cantharidin-based drug-device combination for treatment of molluscum contagiosum in children and adults.

Neuropathic pain is a widespread problem which remains poorly managed by currently available therapeutics. Peripheral nerve injury and inflammation leads to changes at the nerve injury site, including activation of resident and recruited peripheral immune cells, that lead to neuronal central sensitization and pain amplification. The present series of studies tested the effects of peri-sciatic nerve delivery of single doses of adenosine 2A receptor (A2aR) agonists on pain and neuroinflammation. The data provide converging lines of evidence supportive that A2aR agonism at the site of peripheral nerve injury and inflammation is effective in suppressing ongoing neuropathic pain. After A2aR agonism resolved neuropathic pain, a return of pain enhancement (allodynia) was observed in response to peri-sciatic injection of H-89, which can inhibit protein kinase A, and by peri-sciatic injection of neutralizing antibody against the potent anti-inflammatory cytokine interleukin-10. A2aR agonist actions at the nerve injury site suppress neuroinflammation, as reflected by decreased release of interleukin-1β and nitric oxide, as well as decreased sciatic expression of markers of monocytes/macrophages and inducible nitric oxide synthase. Taken together, the data are supportive that A2aR agonists, acting at the level of peripheral nerve injury, may be of therapeutic value in treating chronic pain of neuroinflammatory origin.

Central neuropathic pain is a debilitating outcome of spinal cord injury (SCI) and current treatments to alleviate this pain condition are ineffective. A growing body of literature suggests that activating adenosine Am receptors (A(2A)Rs) decreases the production of proinflammatory cytokines and increases the production of anti-inflammatory cytokines. Here, the effect of administering intrathecal A(2A)R agonists on central neuropathic pain was measured using hindpaw mechanical allodynia in a rat model of SCI termed spinal neuropathic avulsion pain (SNAP). Other models of SCI cause extensive damage to the spinal cord, resulting in paralysis and health problems. SNAP rats with unilateral low thoracic (T13)/high lumbar (L1) dorsal root avulsion develop below-level bilateral allodynia, without concomitant motor or health problems. A single intrathecal injection of the A(2A)R agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine HCl (CGS21680) reversed SCI-induced allodynia for at least 6 weeks. The reversal is likely in part mediated by interleukin (IL)-10, as intrathecally administering neutralizing IL-10 antibodies 1 week after CGS21680 abolished the anti-allodynic effect of CGS21680. Dorsal spinal cord tissue from the ipsilateral site of SCI (T13/L1) was assayed 1 and 6 weeks after CGS21680 for IL-10, CD11b, and tumor necrosis factor (TNF) gene expression. CGS21680 treatment did not change IL-10 gene expression but did significantly decrease CD11b and TNF gene expression at both timepoints. A second A2AR agonist, 4-(3-(6amino-9-(5-cyclopropylcarbamoy1-3,4-dihydroxytetrahydrofuran-2-y1)-9H-purin-2-yl)prop-2-ynyl)pipe ridine-1-carboxylic acid methyl ester (ATL313), was also able to significantly prevent and reverse SCI induced allodynia for several weeks after a single intrathecal injection, providing converging lines of evidence of A2AR involvement. The enduring pain reversal after a single intrathecal injection of A2AR agonists suggests that A2AR agonists could be exciting new candidates for treating SCI-induced central neuropathic pain. (C) 2018 Elsevier Inc. All rights reserved.

A single intrathecal dose of adenosine 2A receptor (A2AR) agonist was previously reported to produce a multi-week reversal of allodynia in two different models of neuropathic pain in addition to downregulating glial activation markers in the spinal cord. We aimed to determine whether a single intrathecal administration of an A2AR agonist was able to attenuate motor symptoms induced by experimental autoimmune encephalopathy. Two A2AR agonists (CGS21680 and ATL313) significantly attenuated progression of motor symptoms following a single intrathecal administration at the onset of motor symptoms. OX-42, a marker of microglial activation, was significantly attenuated in the lumbar spinal cord following A2AR administration compared to vehicle. Therefore, A2AR agonists attenuate motor symptoms of EAE by acting on A2AR in the spinal cord.

This paper presents cross sections for the production of a W boson in association with jets, measured in proton–proton collisions at √ s = 7 TeV with the ATLAS experiment at the large hadron collider. With an integrated luminosity of 4.6 fb−1, this data set allows for an exploration of a large kinematic range, including jet production up to a transverse momentum of 1 TeV and multiplicities up to seven associated jets. The production cross sections for W bosons are measured in both the electron and muon decay channels. Differential cross sections for many observables are also presented including measurements of the jet observables such as the rapidities and the transverse momenta as well as measurements of event observables such as the scalar sums of the transverse momenta of the jets. The measurements are compared to numerous QCD predictions including next-toleading-order perturbative calculations, resummation calculations and Monte Carlo generators.

The adenosine A(2A) receptor (A(2A)R) plays an important role in the regulation of inflammatory and immune responses. Our previous work has demonstrated that A(2A)R agonists exhibit atheroprotective effects by increasing expression of reverse cholesterol transport proteins in cultured human macrophages. This study explores the impact of pharmacologic activation/inhibition and gene silencing of A(2A)R on cholesterol homeostasis in both THP-1 human monocytes/macrophages and primary human aortic endothelial cells (HAEC). THP-1 human monocytes/macrophages and HAEC exposed to the A(2A)R-specific agonist ATL313 exhibited upregulation of proteins responsible for cholesterol efflux: the ABCA1 and G1 transporters. Further, activation of A(2A)R led to upregulation of the cholesterol metabolizing enzyme P450 27-hydroxylase, accompanied by intracellular changes in level of oxysterols. We demonstrate that anti-atherogenic properties of A(2A)R activation are not limited to the regulation of lipid efflux in vasculature, but include protection from lipid overload in macrophages, particularly via suppression of the CD36 scavenger receptor. The reduced lipid accumulation manifests directly as a diminution in foam cell transformation. In THP-1 macrophages, either A(2A)R pharmacological blockade or gene silencing promote lipid accumulation and enhance foam cell transformation. Our pre-clinical data provides evidence suggesting that A(2A)R stimulation by ATL313 has the potential to be a viable therapeutic strategy for cardiovascular disease prevention, particularly in patients with elevated risk due to immune/inflammatory disorders.