Efficacy and safety of a novel topical minocycline foam for the treatment of moderate to severe acne vulgaris: A phase 3 study.

BACKGROUND: FMX101 4% topical minocycline foam has been shown to be an effective and safe treatment for acne vulgaris (AV). OBJECTIVE: To further evaluate the efficacy and safety of FMX101 4% in treating moderate to severe acne vulgaris. METHODS: A 12-week, multicenter, randomized (1:1), double-blind, vehicle-controlled study was conducted. Coprimary end points were the absolute change in inflammatory lesion count from baseline and the rate of treatment success (Investigator's Global Assessment score of 0 or 1 with a ≥2-grade improvement). RESULTS: There were 1488 participants in the intent-to-treat population. The FMX101 4% group had significantly greater reductions in the number of inflammatory lesions from baseline (P < .0001) and a greater rate of treatment success based on Investigator's Global Assessment (P < .0001) versus the foam vehicle group at week 12. FMX101 4% was generally safe and well tolerated. LIMITATIONS: The efficacy and safety of FMX101 4% were not characterized in participants with mild AV. CONCLUSION: FMX101 4% topical minocycline foam was effective and safe for the treatment of moderate to severe AV.

Minocycline 1.5% foam for the topical treatment of moderate to severe papulopustular rosacea: Results of 2 phase 3, randomized, clinical trials.

BACKGROUND: Efficacious topical medications for rosacea are needed. FMX103 1.5% is a novel topical minocycline foam that may have therapeutic benefits in treating rosacea while minimizing systemic adverse effects due to its topical route of delivery. OBJECTIVE: To determine the efficacy, safety, and tolerability of 12 weeks of treatment with FMX103 1.5% topical minocycline foam for papulopustular rosacea. METHODS: Two 12-week, phase 3, randomized, multicenter, double-blind, vehicle-controlled, 2-arm studies were performed in patients with moderate to severe papulopustular rosacea. RESULTS: Participants who received FMX103 1.5%, versus control individuals treated with vehicle, exhibited a significantly greater reduction in the number of inflammatory lesions (FX2016-11: -17.57 vs -15.65; P = .0031; FX2016-12: -18.54 vs -14.88; P < .0001) and higher rates of Investigator Global Assessment treatment success (FX2016-11: 52.1% vs 43.0%; P = .0273; FX2016-12: 49.1% vs 39.0%; P = .0077). No serious treatment-related treatment-emergent adverse events occurred. LIMITATIONS: The generalizability of these data from a controlled clinical trial should be examined in a real-world setting. CONCLUSIONS: FMX103 1.5% was efficacious for moderate to severe papulopustular rosacea and maintained a favorable safety profile.

Susceptibility of Cutibacterium acnes to topical minocycline foam.

FMX101 4% minocycline foam (FMX101 4%) is a novel, topical minocycline formulation for treatment of acne vulgaris. We report that FMX101 4% had an MIC90 of 0.25 µg/ml and was ≥4-fold more active than comparator antimicrobials against a panel of 98 clinical Cutibacterium acnes isolates. The panel was diverse by clonal complex and sequence type, having 20 novel multi-locus sequence types including clonal complexes and sequence types associated with acne (CC1, CC3, and CC4; ST1 and ST3). Some isolates were phenotypically resistant to clindamycin (6.1%), erythromycin (14.3%), and tetracycline (2.0% intermediate resistance). Six isolates (6.4%) carried a mutation in the quinolone resistance-determining region of gyrA. With C. acnes, spontaneous resistance to FMX101 4% occurred at frequencies ranging from ≤5 × 10-9 to <1 × 10-8; mutations were identified in rpsJ, a gene encoding 30S ribosomal protein S10. No mutant exhibited a minocycline MIC above 0.5 µg/ml. No second-step mutation in previously isolated mutants or strains containing rpsJ ± 16S rRNA mutations was detected following minocycline challenge. Minocycline retained antibacterial activity against C. acnes over 15 multiple passages; thus, no selective growth advantage for minocycline-resistant mutants occurred under the experimental conditions. FMX101 4% has the potential to retain the favorable resistance profile of minocycline in diverse C. acnes isolates while providing the benefits of a topical formulation for treatment of acne vulgaris.

A novel topical minocycline foam for the treatment of moderate-to-severe acne vulgaris: Results of 2 randomized, double-blind, phase 3 studies.

BACKGROUND: FMX101 4% is a topical minocycline foam for the treatment of moderate-to-severe acne. OBJECTIVE: Evaluate the efficacy and safety of FMX101 4% in treating moderate-to-severe acne vulgaris. METHODS: Two identical phase 3 studies were conducted. Subjects were randomized 2:1 to once-daily FMX101 4% or foam vehicle for 12 weeks. The coprimary end points were the change in inflammatory lesion count from baseline and the rate of treatment success according to the Investigator's Global Assessment (a score of 0 or 1 for clear or almost clear, with a ≥2-grade improvement) at week 12. RESULTS: A total of 961 subjects were enrolled (study 04, N = 466; study 05, N = 495). Compared with vehicle, FMX101 4% demonstrated a significantly greater reduction in inflammatory lesions in both studies (P < .05) and a greater rate of treatment success in study 05 according to the Investigator's Global Assessment (P < .05). Pooled analyses of the 2 studies demonstrated statistical significance for both coprimary end points (all P < .05). Noninflammatory lesion count was also significantly reduced with FMX101 4% versus with vehicle in both studies. FMX101 4% was generally safe and well tolerated. Skin-related adverse events were reported in less than 1% of subjects treated with FMX101 4%. LIMITATIONS: Longer-term efficacy and safety outcomes are needed (ongoing). CONCLUSION: FMX101 4% topical minocycline foam significantly reduced both inflammatory and noninflammatory lesions and improved Investigator's Global Assessment scores in patients with moderate-to-severe acne.

Intelligent estimation of noise and blur variances using ANN for the restoration of ultrasound images.

Ultrasound (US) imaging is a widely used clinical diagnostic tool in medical imaging techniques. It is a comparatively safe, economical, painless, portable, and noninvasive real-time tool compared to the other imaging modalities. However, the image quality of US imaging is severely affected by the presence of speckle noise and blur during the acquisition process. In order to ensure a high-quality clinical diagnosis, US images must be restored by reducing their speckle noise and blur. In general, speckle noise is modeled as a multiplicative noise following a Rayleigh distribution and blur as a Gaussian function. Hereto, we propose an intelligent estimator based on artificial neural networks (ANNs) to estimate the variances of noise and blur, which, in turn, are used to obtain an image without discernible distortions. A set of statistical features computed from the image and its complex wavelet sub-bands are used as input to the ANN. In the proposed method, we solve the inverse Rayleigh function numerically for speckle reduction and use the Richardson-Lucy algorithm for de-blurring. The performance of this method is compared with that of the traditional methods by applying them to a synthetic, physical phantom and clinical data, which confirms better restoration results by the proposed method.

Speckle-reduction algorithm for ultrasound images in complex wavelet domain using genetic algorithm-based mixture model.

Compared with other medical-imaging modalities, ultrasound (US) imaging is a valuable way to examine the body's internal organs, and two-dimensional (2D) imaging is currently the most common technique used in clinical diagnoses. Conventional 2D US imaging systems are highly flexible cost-effective imaging tools that permit operators to observe and record images of a large variety of thin anatomical sections in real time. Recently, 3D US imaging has also been gaining popularity due to its considerable advantages over 2D US imaging. It reduces dependency on the operator and provides better qualitative and quantitative information for an effective diagnosis. Furthermore, it provides a 3D view, which allows the observation of volume information. The major shortcoming of any type of US imaging is the presence of speckle noise. Hence, speckle reduction is vital in providing a better clinical diagnosis. The key objective of any speckle-reduction algorithm is to attain a speckle-free image while preserving the important anatomical features. In this paper we introduce a nonlinear multi-scale complex wavelet-diffusion based algorithm for speckle reduction and sharp-edge preservation of 2D and 3D US images. In the proposed method we use a Rayleigh and Maxwell-mixture model for 2D and 3D US images, respectively, where a genetic algorithm is used in combination with an expectation maximization method to estimate mixture parameters. Experimental results using both 2D and 3D synthetic, physical phantom, and clinical data demonstrate that our proposed algorithm significantly reduces speckle noise while preserving sharp edges without discernible distortions. The proposed approach performs better than the state-of-the-art approaches in both qualitative and quantitative measures.

Development of a nanomaterial bio-screening platform for neurological applications.

Nanoparticle platforms are being intensively investigated for neurological applications. Current biological models used to identify clinically relevant materials have major limitations, e.g. technical/ethical issues with live animal experimentation, failure to replicate neural cell diversity, limited control over cellular stoichiometries and poor reproducibility. High-throughput neuro-mimetic screening systems are required to address these challenges. We describe an advanced multicellular neural model comprising the major non-neuronal/glial cells of the central nervous system (CNS), shown to account for ~99.5% of CNS nanoparticle uptake. This model offers critical advantages for neuro-nanomaterials testing while reducing animal use: one primary source and culture medium for all cell types, standardized biomolecular corona formation and defined/reproducible cellular stoichiometry. Using dynamic time-lapse imaging, we demonstrate in real-time that microglia (neural immune cells) dramatically limit particle uptake in other neural subtypes (paralleling post-mortem observations after nanoparticle injection in vivo), highlighting the utility of the system in predicting neural handling of biomaterials.

Investigating Internalization of Reporter-Protein-Functionalized Polyhedrin Particles by Brain Immune Cells.

Achieving sustained drug delivery to the central nervous system (CNS) is a major challenge for neurological injury and disease, and various delivery vehicles are being developed to achieve this. Self-assembling polyhedrin crystals (POlyhedrin Delivery System; PODS) are being exploited for the delivery of therapeutic protein cargo, with demonstrated efficacy in vivo. However, to establish the utility of PODS for neural applications, their handling by neural immune cells (microglia) must be documented, as these cells process and degrade many biomaterials, often preventing therapeutic efficacy. Here, primary mouse cortical microglia were cultured with a GFP-functionalized PODS for 24 h. Cell counts, cell morphology and Iba1 expression were all unaltered in treated cultures, indicating a lack of acute toxicity or microglial activation. Microglia exhibited internalisation of the PODS, with both cytosolic and perinuclear localisation. No evidence of adverse effects on cellular morphology was observed. Overall, 20-40% of microglia exhibited uptake of the PODS, but extracellular/non-internalised PODS were routinely present after 24 h, suggesting that extracellular drug delivery may persist for at least 24 h.

Safety and Pharmacokinetics of FMX103 (1.5% Minocycline Topical Foam) in Subjects with Moderate-to-Severe Papulopustular Rosacea under Maximum-use Treatment Conditions.

BACKGROUND: FMX103 1.5% is the first and only topical minocycline foam that is approved for the treatment of papulopustular rosacea in adults. OBJECTIVE: We sought to characterize the safety and pharmacokinetics of minocycline under maximal-use conditions of FMX103 1.5% in subjects with moderate-to-severe rosacea. METHODS: This Phase Isingle-center, nonrandomized, open-label, single-period pharmacokinetics and safety evaluation study evaluated multiple-dose, topical administration of FMX103 1.5%. Twenty subjects meeting study inclusion/exclusion criteria had ~2 grams of FMX103 1.5% applied to the full face once per day for 14 days. Blood samples were collected 30 minutes prior to study drug application on treatment Days 1, 2, 6, 9, 11, 12, and 14, and also at 2, 4, 8, 12, 16, and 24 hours post-administration on treatment Days 1 and 14. RESULTS: Following topical application of a 2-gram maximal-use dose of FMX103 1.5% for 14 days, minocycline plasma concentrations were low. Overall, trough levels were approximately 0.5ng/mL from 24 hours after the first dose through 24 hours after the last dose on Day 14, indicating that steady-state levels appear to have been reached within the first day of dosing. Daily application of FMX103 1.5% was generally safe and well-tolerated by all subjects. CONCLUSION: Once-daily topical application of FMX103 1.5% did not lead to appreciable systemic exposure or accumulation of minocycline, suggesting that it is a viable treatment option for papulopustular rosacea.

In vitro model of traumatic brain injury to screen neuro-regenerative biomaterials.

Penetrating traumatic brain injury (pTBI) causes serious neurological deficits with no clinical regenerative therapies currently available. Tissue engineering strategies using biomaterial-based 'structural bridges' offer high potential to promote neural regeneration post-injury. This includes surgical grade materials which can be repurposed as biological scaffolds to overcome challenges associated with long approval processes and scaleup for human application. However, high throughput, pathomimetic models of pTBI are lacking for the developmental testing of such neuro-materials, representing a bottleneck in this rapidly emergent field. We have established a high throughput and facile culture model containing the major neural cell types which govern biomaterial handling in the central nervous system. We show that induction of traumatic injuries was feasible in the model, with post-injury implantation of a surgical grade biomaterial. Cellular imaging in lesions was achievable using standard epifluorescence microscopy methods. Key pathological features of pTBI were evident in vitro namely immune cell infiltration of lesions/biomaterial, with responses characteristic of cell scarring, namely hypertrophic astrocytes with GFAP upregulation. Based on our observations, we consider the high-throughput, inexpensive and facile pTBI model can be used to study biomaterial 'implantation' and evaluate neural cell-biomaterial responses. The model is highly versatile to test a range of laboratory and clinical grade materials for neural regeneration.

Open-label Extension Study Evaluating Long-term Safety and Efficacy of FMX103 1.5% Minocycline Topical Foam for the Treatment of Moderate-to-Severe Papulopustular Rosacea.

BACKGROUND: Efficacy and safety of FMX103 1.5% for papulopustular rosacea were previously demonstrated in two 12-week, Phase 3 studies. OBJECTIVE: We sought to evaluate the safety and efficacy of FMX103 1.5% foam for up to 52 weeks of treatment. METHODS: Following the completion of two 12-week, double-blind, vehicle-controlled, Phase 3 studies, subjects were invited to enter a 40-week open-label extension study in which all subjects applied FMX103 1.5% once daily. Efficacy endpoints were the reduction in inflammatory lesions and the rate of IGA treatment success from the double-blind baseline. Safety assessments included adverse events, vital signs, laboratory tests, and facial tolerability signs and symptoms. RESULTS: The favorable safety profile of FMX103 1.5% observed in the double-blind studies was maintained over extended treatment lasting up to one year. There were no serious treatment-related adverse events. Long-term treatment with FMX103 1.5% was associated with a greater than 82-percent reduction in inflammatory lesions from baseline and with over 79 percent of subjects achieving treatment success. At the end of the open-label treatment period, over 82 percent of subjects indicated they were overall "satisfied" or "very satisfied" with FMX103 1.5%. All facial local tolerability symptoms improved through Week 52. LIMITATIONS: Due to the nature of the open-label study, lacking a vehicle-treated control, no statistical comparisons can be made. CONCLUSION: FMX103 1.5% demonstrated a favorable safety and tolerability profile for up to 52 weeks. Long-term efficacy was demonstrated by progressive reductions in inflammatory lesions and increasing IGA treatment success, suggesting that FMX103 1.5% may be a suitable option for the treatment for papulopustular rosacea.

Formulation and Profile of FMX101 4% Minocycline Topical Foam for the Treatment of Acne Vulgaris.

FMX101 4% minocycline is a hydrophobic, topical foam formulation of minocycline recently approved by the United States Food and Drug Administration (FDA) for the treatment of non-nodular inflammatory lesions in moderate-to-severe acne vulgaris. It was developed to harness the anti-inflammatory and antibiotic activity of minocycline while minimizing potentially serious systemic adverse events associated with oral delivery. The composition and profile of this novel treatment have yet to be described. This article discusses the components of the foam-based product and the rationale for their selection. It reviews microbiologic data for FMX101 4% and presents previously unpublished data regarding sebum penetration, minocycline permeation, and disposition into skin structures. The effects of FMX101 4% were compared with those of several commercially available acne preparations to determine how the FMX101 4% formulation affects the physical properties of model human sebum in vitro. The hydrophobic formulation of FMX101 4% was found to lower the melting temperature of model human sebum below that of normal skin temperature, decreasing its viscosity. FMX101 4% achieved high concentrations of minocycline in the sebaceous appendage, while minimizing permeation beyond the dermal layer. Finally, this article summarizes efficacy and safety data for FMX101 4% from three Phase III studies (FX2014-04, FX2014-05, and FX2017-22). FMX101 4% appeared to be safe, effective, and well tolerated for the treatment of non-nodular inflammatory lesions in moderate-to-severe acne vulgaris. In conclusion, the topical formulation of minocycline in FMX101 4% represents a unique treatment for acne vulgaris and a viable alternative to oral administration.

Topical minocycline foam 4%: Results of four phase 1 studies evaluating the potential for phototoxicity, photoallergy, sensitization, and cumulative irritation.

FMX101 4% contains 4% micronized minocycline (as an HCl) formulated in a lipophilic foam vehicle for topical administration. FMX101 4% has been shown to be an effective and well-tolerated treatment for moderate-to-severe acne in three Phase 3 pivotal studies, however, skin sensitization and toxicity potential remains to be fully evaluated. Four single-center, randomized, controlled, within-subject comparison studies were conducted to evaluate the potential for phototoxicity, photoallergy, skin sensitization, and cumulative skin irritation with topical administration of FMX101 4% and the corresponding vehicle. Across the four studies, healthy male and non-pregnant female volunteers (age ≥18 years) were randomized to FMX101 4%, vehicle, or other controls. In the phototoxicity study, treated skin was irradiated at 3 and 24 hr post-application, and local tolerability was assessed pre- and post-irradiation. In the photoallergy study, the skin was treated and irradiated (post-24 hr) twice weekly for 3 wk (induction phase), rested for 10-17 d, and naive skin sites were treated and irradiated (challenge phase); skin reactions were assessed after patch removal and post-irradiation. In the sensitization study, the skin was treated for 3 wk (induction phase), then rested for 10-14 d, and naive skin sites were treated for 48 hr (challenge phase); contact sensitization was assessed for both phases. In the cumulative irritation study, treatment and vehicle were applied daily for 21 d; skin irritation was assessed after each application. In all studies, standard safety assessments were conducted. A total of 32, 56, 233, and 42 subjects were enrolled in the phototoxicity, photoallergy, sensitization, and skin irritation studies, respectively. There was no evidence of phototoxicity, photoallergy, skin sensitization, or skin irritation potential with FMX101 4%. Few adverse events, mostly mild to moderate, were reported. In conclusion, FMX101 4% appeared to be well tolerated and non-irritating, and was considered to be non-sensitizing, non-phototoxic, and non-photoallergic.

Open-label Extension Study Evaluating Long-term Safety and Efficacy of FMX101 4% Minocycline Foam for Moderate-to-Severe Acne Vulgaris.

Objective: This study sought to evaluate the long-term safety and efficacy of FMX101 4% topical minocycline foam for the treatment of moderate-to-severe acne. Design: This was an open-label extension of two double-blind studies, Study 04 and Study 05. Setting: Subjects were enrolled at 35 sites in the United States and one site in the Dominican Republic. Participants: Eligible subjects who completed 12 weeks of double-blind treatment with FMX101 4% or vehicle in those studies could continue for an additional nine months of open-label treatment with FMX101 4%. Eligibility required an Investigator's Global Assessment (IGA) score that had not worsened when compared to baseline at the 12-week visit. Measurements: Safety, efficacy, and satisfaction assessments were performed. Results: Of the 961 subjects enrolled in Study 04 (n=466) and Study 05 (n=495), 657 subjects entered the open-label phase (Study 04: n=284; Study 05: n=373), with 414 subjects completing the study (Study 04, n=172; Study 05, n = 242). Treatment-emergent adverse events (TEAEs) were similar to those in the double-blind studies. No serious TEAEs led to subject discontinuation. At Week 52, for facial tolerability assessment, over 95 percent of subjects had no or only mild signs and symptoms. Through Week 52, there were ongoing reductions in inflammatory lesions and increasing IGA treatment success. Conclusion: FMX101 4% minocycline foam appeared to be safe, effective, and well-tolerated for up to 52 weeks in the treatment of moderate-to-severe acne.

Metabolism of the trisubstituted purine cyclin-dependent kinase inhibitor seliciclib (R-roscovitine) in vitro and in vivo.

Seliciclib (R-roscovitine, CYC202) is a small molecule inhibitor of cyclin-dependent kinases currently in phase II clinical trials as an anticancer agent. We examined the metabolism of seliciclib in vitro and in vivo. Using radiolabeled seliciclib we found that cytochrome P450 (P450)-mediated metabolism in liver microsomes from human, rat, mouse, rabbit, monkey, and dog was rapid to a number of metabolic species, one of the most prevalent being a carboxylate previously identified in urine from rats and mice dosed with seliciclib. Metabolism was fastest in mouse microsomes and slowest in microsomes from dog. Using characterized human microsomes, we identified the P450s responsible for this metabolism as CYP3A4 and CYP2B6. Glucuronidation of seliciclib and its metabolites was shown to be a major elimination process in bile duct-cannulated rats dosed with [(14)C]seliciclib at 10 mg/kg. Elimination by the fecal route accounted for up to 65% of the administered dose, whereas urinary excretion accounted for up to 43%. Almost half of the administered dose was found to be eliminated via the bile, and elimination was found to be rapid, with up to 88% of the dose being excreted within the first 24 h. Preliminary experiments indicated that UDP-glucuronosyltransferase (UGT) 1A3, 1A9, and 2B7 were involved in the conjugation of seliciclib. Seliciclib was further shown in vitro to inhibit the activity of some of the enzymes responsible for its metabolism. Cytochrome P450s CYP3A4 and CYP2C9 and UGT1A1 were all inhibited at concentrations achieved in human trials, which raises the possibility of drug-drug interactions in the clinic.

Discovery and characterization of 2-anilino-4- (thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agents.

The main difficulty in the development of ATP antagonist kinase inhibitors is target specificity, since the ATP-binding motif is present in many proteins. We introduce a strategy that has allowed us to identify compounds from a kinase inhibitor library that block the cyclin-dependent kinases responsible for regulating transcription, i.e., CDK7 and especially CDK9. The screening cascade employs cellular phenotypic assays based on mitotic index and nuclear p53 protein accumulation. This permitted us to classify compounds into transcriptional, cell cycle, and mitotic inhibitor groups. We describe the characterization of the transcriptional inhibitor class in terms of kinase inhibition profile, cellular mode of action, and selectivity for transformed cells. A structural selectivity rationale was used to optimize potency and biopharmaceutical properties and led to the development of a transcriptional inhibitor, 3,4-dimethyl-5-[2-(4-piperazin-1-yl-phenylamino)-pyrimidin-4-yl]-3H-thiazol-2-one, with anticancer activity in animal models.

Discovery of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors.

Through cell-based screening of our kinase-directed compound collection, we discovered that a subset of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines were potent cytotoxic agents against cancer cell lines, suppressed mitotic histone H3 phosphorylation, and caused aberrant mitotic phenotypes. It was subsequently established that these compounds were in fact potent inhibitors of aurora A and B kinases. It was shown that potency and selectivity of aurora kinase inhibition correlated with the presence of a substituent at the aniline para-position in these compounds. The anticancer effects of lead compound 4-methyl-5-(2-(4-morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine (18; K(i) values of 8.0 and 9.2 nM for aurora A and B, respectively) were shown to emanate from cell death following mitotic failure and increased polyploidy as a consequence of cellular inhibition of aurora A and B kinases. Preliminary in vivo assessment showed that compound 18 was orally bioavailable and possessed anticancer activity. Compound 18 (CYC116) is currently undergoing phase I clinical evaluation in cancer patients.