Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone). METHODS: A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2. RESULTS: A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups. DISCUSSION: Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03439670. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.

Comparison of pharmaceutical properties and biological activities of prednisolone, deflazacort, and vamorolone in DMD disease models.

Duchenne muscular dystrophy (DMD) is a progressive disabling X-linked recessive disorder that causes gradual and irreversible loss of muscle, resulting in early death. The corticosteroids prednisone/prednisolone and deflazacort are used to treat DMD as the standard of care; however, only deflazacort is FDA approved for DMD. The novel atypical corticosteroid vamorolone is being investigated for treatment of DMD. We compared the pharmaceutical properties as well as the efficacy and safety of the three corticosteroids across multiple doses in the B10-mdx DMD mouse model. Pharmacokinetic studies in the mouse and evaluation of p-glycoprotein (P-gP) efflux in a cellular system demonstrated that vamorolone is not a strong P-gp substrate resulting in measurable central nervous system (CNS) exposure in the mouse. In contrast, deflazacort and prednisolone are strong P-gp substrates. All three corticosteroids showed efficacy, but also side effects at efficacious doses. After dosing mdx mice for two weeks, all three corticosteroids induced changes in gene expression in the liver and the muscle, but prednisolone and vamorolone induced more changes in the brain than did deflazacort. Both prednisolone and vamorolone induced depression-like behavior. All three corticosteroids reduced endogenous corticosterone levels, increased glucose levels, and reduced osteocalcin levels. Using micro-computed tomography, femur bone density was decreased, reaching significance with prednisolone. The results of these studies indicate that efficacious doses of vamorolone, are associated with similar side effects as seen with other corticosteroids. Further, because vamorolone is not a strong P-gp substrate, vamorolone distributes into the CNS increasing the potential CNS side-effects.

Vamorolone: First Approval.

Vamorolone (AGAMREE®) is an oral, selective, dissociative corticosteroid developed by ReveraGen BioPharma and Santhera Pharmaceuticals for the treatment of patients with muscular dystrophy. Vamorolone was approved in October 2023 for the treatment of Duchenne muscular dystrophy (DMD) in patients 2 years of age and older in the USA and received a positive opinion in the EU in October 2023 for the treatment of DMD in patients 4 years of age and older. This article summarizes the milestones in the development of vamorolone leading to this first approval for DMD.

Multi-Gram Scale Synthesis and Characterization of Mometasone Furoate EP Impurity C.

Mometasone furoate is a synthetic corticosteroid used in the treatment of skin inflammatory conditions, hay fever and asthma. The industrial manufacturing routes to mometasone furoate are generally accompanied by the formation of numerous process impurities that need to be detected and quantified, as requested by regulatory authorities. The ready availability of such impurities in the required quantity and purity is therefore essential for toxicological studies, analytical method development and process validation. Herein, we report the multi-gram scale preparation of 21'-chloro-(16'α-methyl-3',11',20'-trioxo-pregna-1',4'-dien-17'-yl)-furan-2-carboxylate (mometasone furoate EP impurity C), one of the known impurities of mometasone furoate. This study also includes the systematic investigation of the final acylation step, as well as the characterization of the difuroate enol ether intermediate and its conversion to the target impurity C.

Considering the Promise of Vamorolone for Treating Duchenne Muscular Dystrophy.

This commentary provides an independent consideration of data related to the drug vamorolone (VBP15) as an alternative steroid proposed for treatment of Duchenne muscular dystrophy (DMD). Glucocorticoids such as prednisone and deflazacort have powerful anti-inflammatory benefits and are the standard of care for DMD, but their long-term use can result in severe adverse side effects; thus, vamorolone was designed as a unique dissociative steroidal anti-inflammatory drug, to retain efficacy and minimise these adverse effects. Extensive clinical trials (ongoing) have investigated the use of vamorolone for DMD, with two trials also for limb-girdle muscular dystrophies including dysferlinopathy (current), plus a variety of pre-clinical trials published. Vamorolone looks very promising, with similar efficacy and some reduced adverse effects (e.g., related to height) compared with other glucocorticoids, specifically prednisone/prednisolone, although it has not yet been directly compared with deflazacort. Of particular interest to clarify is the optimal clinical dose and other aspects of vamorolone that are proposed to provide additional benefits for membranes of dystrophic muscle: to stabilise and protect the sarcolemma from damage and enhance repair. The use of vamorolone (and other glucocorticoids) needs to be evaluated in terms of overall long-term efficacy and cost, and also in comparison with many candidate non-steroidal drugs with anti-inflammatory and other benefits for DMD.

Oral mometasone furoate administration preserves anti-inflammatory action with fewer metabolic adverse effects in rats.

BACKGROUND: Exogenous glucocorticoids (CGs) possess relevant therapeutic effects but exert diabetogenic actions when in excess. Thus, ligands with potential therapeutic applications and fewer adverse effects are needed. To this, we analyzed whether mometasone furoate (MF), a CG expected to cause fewer side effects, given through systemic routes, could maintain the anti-inflammatory actions without relevant repercussions on metabolism. METHODS: The anti-inflammatory effect of MF was evaluated with both peritonitis and colitis models in rodents. Glucose and lipid metabolism were investigated in male and female rats treated daily with MF with different doses and routes of administration for seven days. The involvement of glucocorticoid receptor (GR) on MF actions was assessed in animals pretreated with mifepristone. Also, the potential reversibility of the adverse effects was assessed. Dexamethasone was used as a positive control. RESULTS: MF treatment resulted in glucose intolerance in male rats treated through intraperitoneal (ip) but not oral gavage route (og). In female rats, none of the routes led to glucose intolerance. MF treatment attenuated insulin sensitivity and increased pancreatic ß-cell mass, regardless of the sex and route of administration. MF treatment through og route did not result in dyslipidemia, as observed in rats treated through the ip route (both sexes). The anti-inflammatory and metabolic adverse effects of MF were GR-dependent, and metabolic outcomes altered by MF administration were reversible. CONCLUSION: MF maintains anti-inflammatory activity when administered by systemic routes and exerts less impact on metabolism when administered orally in male and female rats, effects that are GR-dependent and reversible. Category: Metabolic Disorders and Endocrinology.

Quail egg homogenate with zinc as adjunctive therapy in seasonal allergic rhinitis: a randomised, controlled trial.

OBJECTIVE: Because most available treatments for managing seasonal allergic rhinitis show some side effects without reducing recurrence, natural anti-allergic products could represent an interesting treatment addition. This study aimed to analyse the efficacy and tolerance of quail egg as adjunctive therapy in seasonal allergic rhinitis. METHOD: In a Consolidated Standards of Reporting Trials compliant framework, patients with seasonal allergic rhinitis were prospectively randomised to receive mometasone nasal spray for four weeks or the same topical corticosteroid therapy plus commercially available oral quail egg and zinc tablets. RESULTS: Forty patients were enrolled. The mometasone + quail egg and zinc tablets group showed a greater reduction in nasal itching, sneezing and total nasal symptom scores than the mometasone nasal spray only group. A higher proportion of participants in the mometasone + quail egg and zinc tablets group had good rhinitis control than in the mometasone nasal spray only group, with no need for rescue medications. CONCLUSION: Despite the need for a further larger study, quail egg preliminarily appears to be an effective adjunct to topical steroid therapy in seasonal allergic rhinitis.

Effects of nigella sativa oil on allergic rhinitis: an experimental animal study.

OBJECTIVES: Nigella sativa oil is known antiallergic and immunomodulatory effects. We aimed to compare this oil with mometasone furoate, a topical steroid, on a rat model in the prevention of allergic rhinitis symptoms. METHODS: A total of 28 two-to-four-month-old Wistar Hannover rats weighing 250-350 g were randomly divided into four groups of seven, which included control, allergic rhinitis, mometasone furoate, and Nigella sativa oil groups. Loss of cilia, an increase of goblet cells, vascular proliferation, inflammatory cell count, eosinophil infiltration, and the degree of hypertrophy in chondrocytes were assessed by light microscopy. RESULTS: The frequency of nasal scratching in the Nigella sativa oil group was found to be significantly lower compared with the allergic rhinitis group (p < 0.05). Typical inflammatory changes seen in allergic rhinitis were not detected in the Nigella sativa oil group. No inflammation was observed in 85.7% of both the healthy control group and the Nigella sativa oil group. In addition, no inflammation was observed in 71.4% of the mometasone furoate group, and this difference was found to be significant compared with the control group (p < 0.05). In addition, eosinophil infiltration, cilia loss, chondrocyte hypertrophy, vascular proliferation, and goblet cell increase were found to be significantly decreased in the mometazone furoate and Nigella sativa oil groups compared to the allergic rhinitis group (p < 0.05). CONCLUSION: According to the findings obtained from this study, we found anti-inflammatory and anti-allergic effects of Nigella sativa oil as equally effective as mometasone furoate in the treatment of experimentaly generated allergic rhinitis. LEVEL OF EVIDENCE: IV.

Mometasone furoate nasal spray in Italian children with seasonal allergic rhinitis: a comprehensive assessment.

OBJECTIVE: Seasonal allergic rhinitis (SAR) is a common disease of childhood and is characterized by type 2 inflammation, bothersome symptoms, and impaired quality of life (QoL). Intranasal corticosteroids are effective medications in managing SAR. In addition, mometasone furoate nasal spray (MFNS) is a well-known therapeutic option. However, the literature provided no data about the effects of MFNS in European children with SAR. Thus, this study addressed this unmet requirement. METHODS: MFNS was compared to isotonic saline. Both treatments were prescribed: one drop of spray per nostril, twice a day, for 3 weeks. Nasal cytology, total symptom score (TSS), visual analogic scale concerning the parental perception of severity of symptoms, and the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) were assessed at baseline, after 7 and 21 days, and 1 month after discontinuation. RESULTS: MFNS significantly reduced eosinophil and mast cell counts, improved QoL, and relieved symptoms, as assessed by doctors and perceived by parents. These effects persisted over time, even after discontinuation. Both treatments were safe and well-tolerated. CONCLUSIONS: The present study documented that a 3-week MFNS treatment was able to significantly dampen type 2 inflammation, improve QoL, and reduce severity of symptoms in Italian children with SAR, and was safe.

Pharmacokinetic Evidence of Steady and Sustained Drug Release from Long-Acting Implantable Corticosteroid Matrices for Chronic Rhinosinusitis.

BACKGROUND: The efficacy of topical corticosteroids is limited in chronic rhinosinusitis (CRS) due to rapid clearance from the nasal cavity and insufficient drug delivery to inflamed sinonasal passages. LYR-210 is an implantable corticosteroid matrix designed to provide up to 24 weeks of treatment to patients with CRS by locally delivering mometasone furoate (MF) to the sinonasal mucosa. In a randomized, controlled, dose-ranging LANTERN study, LYR-210 (7500 µg) achieved clinically relevant improvement in CRS cardinal symptom composite scores, the 22-item Sinonasal Outcome Test (SNOT-22), ethmoid opacification, and the need for rescue treatment at 24 weeks. OBJECTIVE: As the plasma MF concentrations of LYR-210 (2500 µg) and LYR-210 (7500 µg) were evaluated at weeks 4, 12, and 24 in the LANTERN study (data on file at Lyra Therapeutics, Inc.), this study aims to characterize the pharmacokinetic profiles of both doses of LYR-210 at earlier timepoints post-placement in patients with CRS. METHODS: Twenty-four surgically naïve adult patients with CRS were enrolled in an open-label, multicenter study and underwent in-office bilateral administration of LYR-210 (2500 µg) (n = 12 patients) or LYR-210 (7500 µg) (n = 12 patients) into the middle meatus. Plasma MF concentrations were determined pre-placement and 1-h post-placement (day 1), and on days 2, 3, 7, 14, 21, 28, 42, and 56 by liquid chromatography-tandem mass spectrometry. RESULTS: Both LYR-210 doses were well-tolerated with no serious adverse events. Systemic MF levels were dose-dependent and lower than reported values of other respiratory MF products. Plasma MF concentrations showed steady drug release from LYR-210 (2500 µg) and LYR-210 (7500 µg) that persisted through day 56. CONCLUSION: LYR-210 achieved dose-dependent, continuous local MF delivery at a steady rate with low systemic exposure for months.

Efficacy and Safety of Vamorolone in Duchenne Muscular Dystrophy: A 30-Month Nonrandomized Controlled Open-Label Extension Trial.

Importance: Vamorolone is a synthetic steroidal drug with potent anti-inflammatory properties. Initial open-label, multiple ascending dose-finding studies of vamorolone among boys with Duchenne muscular dystrophy (DMD) found significant motor function improvement after 6 months treatment in higher-dose (ie, ≥2.0 mg/kg/d) groups. Objective: To investigate outcomes after 30 months of open-label vamorolone treatment. Design, Setting, and Participants: This nonrandomized controlled trial was conducted by the Cooperative International Neuromuscular Research Group at 11 US and non-US study sites. Participants were 46 boys ages 4.5 to 7.5 years with DMD who completed the 6-month dose-finding study. Data were analyzed from July 2020 through November 2021. Interventions: Participants were enrolled in a 24-month, long-term extension (LTE) study with vamorolone dose escalated to 2.0 or 6.0 mg/kg/d. Main Outcomes and Measures: Change in time-to-stand (TTSTAND) velocity from dose-finding baseline to end of LTE study was the primary outcome. Efficacy assessments included timed function tests, 6-minute walk test, and NorthStar Ambulatory Assessment (NSAA). Participants with DMD treated with glucocorticoids from the Duchenne Natural History Study (DNHS) and NorthStar United Kingdom (NSUK) Network were matched and compared with participants in the LTE study receiving higher doses of vamorolone. Results: Among 46 boys with DMD who completed the dose-finding study, 41 boys (mean [SD] age, 5.33 [0.96] years) completed the LTE study. Among 21 participants treated with higher-dose (ie, ≥2.0 mg/kg/d) vamorolone consistently throughout the 6-month dose-finding and 24-month LTE studies with data available at 30 months, there was a decrease in mean (SD) TTSTAND velocity from baseline to 30 months (0.206 [0.070] rises/s vs 0.189 (0.124) rises/s), which was not a statistically significant change (-0.011 rises/s; CI, -0.068 to 0.046 rises/s). There were no statistically significant differences between participants receiving higher-dose vamorolone and matched participants in the historical control groups receiving glucocorticoid treatment (75 patients in DNHS and 110 patients in NSUK) over a 2-year period in NSAA total score change (0.22 units vs NSUK; 95% CI, -4.48 to 4.04]; P = .92), body mass index z score change (0.002 vs DNHS SD/mo; 95% CI, -0.006 to 0.010; P = .58), or timed function test change. Vamorolone at doses up to 6.0 mg/kg/d was well tolerated, with 5 of 46 participants discontinuing prematurely and for reasons not associated with study drug. Participants in the DNHS treated with glucocorticoids had significant growth delay in comparison with participants treated with vamorolone who had stable height percentiles (0.37 percentile/mo; 95% CI, 0.23 to 0.52 percentile/mo) over time. Conclusions and Relevance: This study found that vamorolone treatment was not associated with a change in TTSTAND velocity from baseline to 30 months among boys with DMD aged 4 to 7 years at enrollment. Vamorolone was associated with maintenance of muscle strength and function up to 30 months, similar to standard of care glucocorticoid therapy, and improved height velocity compared with growth deceleration associated with glucocorticoid treatment, suggesting that vamorolone may be an attractive candidate for treatment of DMD. Trial Registration: ClinicalTrials.gov Identifier: NCT03038399.

Topically applied mometasone furoate improves dysphagia in adult eosinophilic esophagitis - results from a double-blind, randomized, placebo-controlled trial.

OBJECTIVES: Topical corticosteroids are considered a cornerstone in the treatment of patients with eosinophilic esophagitis. The aim of this study was to evaluate the benefit of using mometasone furoate spray versus placebo on dysphagia and health-related quality of life in these patients. MATERIAL AND METHODS: Consecutive, newly diagnosed adult patients with eosinophilic esophagitis were randomized and treated with either 200 micrograms of orally administered topical mometasone furoate or placebo 4 times daily for 8 weeks. Symptoms and quality of life were evaluated using questionnaires including the Watson Dysphagia Scale, the European Organization for Research and Treatment of Cancer Quality of Life-Oesophageal Module 18 and the Short Form-36 before and after treatment. RESULTS: In the intention-to-treat analysis (n = 36) the Watson Dysphagia Scale score after mometasone treatment was reduced by 6.5 (median, p < .01) compared with 0 (median, ns) in the placebo group. The benefit of mometasone over placebo was significant (p < .05). In the per-protocol analysis (n = 33) the Watson Dysphagia Scale score was reduced by 5 (median, p = .01) after mometasone treatment compared with 0 (median, ns) in the placebo group. The advantage of mometasone over the placebo was significant (p < .05). The benefit of using mometasoneas evaluated by the two quality of life questionnaires was, however, insignificant. CONCLUSIONS: Our finding suggests that in adult patients with eosinophilic esophagitis, topical mometasone furoate exerts a beneficial effect compared with placebo regarding the main symptom, i.e., dysphagia. A corresponding benefit could not be verified regarding the various quality of life measurements. CLINICAL TRIAL REGISTRATION: Mometasone-furoate for Treatment of Eosinophilic Esophagitis - a Randomized Placebo Controlled Study ClinicalTrials.gov Identifier (NCT02113267).

Pharmacokinetics of mometasone furoate delivered via two dry powder inhalers.

BACKGROUND: QMF149 is an inhaled fixed-dose combination of indacaterol acetate and mometasone furoate (MF) delivered via Breezhaler®, under development for once-daily treatment of asthma. MF delivered via Twisthaler® is approved as Asmanex® Twisthaler® for the treatment of asthma. Bridging of MF delivered via Twisthaler® to MF delivered via Breezhaler® was undertaken as part of QMF149 development to enable dose comparisons between the devices. Pharmacokinetics (PK) of MF were characterized in two studies; a single dose PK study in healthy volunteers and a pharmacokinetic/pharmacodynamic (PK/PD) study in asthma patients. OBJECTIVES: The PK study in healthy volunteers evaluated the PK of single doses of MF via Breezhaler® (50-400 µg) and compared systemic exposure of MF following administration via Breezhaler® and Twisthaler® 400 µg (2 inhalations of 200 µg). The study in patients with asthma characterized the MF PK profile following once-daily inhalation of MF via Breezhaler® and Twisthaler® devices for 4 weeks. METHODS: In the open-label, single-dose, crossover study, healthy subjects sequentially received MF via Twisthaler® (400 µg, medium-dose inhaled corticosteroid [ICS]) and escalating doses via Breezhaler® (50, 100, 200, 400 µg). PK data were obtained up to 72 h post-dose. In the double-blind, double-dummy, parallel-group study, asthma patients were randomised to receive either MF 80 µg (low-dose ICS) or 320 µg (high-dose ICS) via Breezhaler®, or 200 µg (low-dose ICS) or 800 µg (2 inhalations of 400 µg; high-dose ICS) via Twisthaler® once daily for 4 weeks. PK sampling was performed on Days 1 and 28 at pre-dose and up to 24 h post-dose. RESULTS: In the healthy volunteer PK study, 20 healthy subjects completed all treatments. Dose-normalised AUClast of MF was 1.8-1.9-fold higher when delivered via Breezhaler® versus Twisthaler®. AUC and Cmax of MF increased in a dose-proportional manner over the range of 50-400 µg via Breezhaler®. Results from this study guided dose selection of MF via Breezhaler® for the asthma study. In the asthma study, in a subset of 96 patients, mean systemic exposure (AUClast and Cmax) for MF 80 and 320 µg via Breezhaler® was comparable with MF 200 and 800 µg via Twisthaler®, respectively, on Day 28. CONCLUSION: PK characterization in a healthy volunteer PK study and subsequently an asthma study enabled selection of 80 µg (low), 160 µg (medium), and 320 µg (high) delivered via Breezhaler® as MF doses comparable to the 200 µg, 400 µg and 800 µg doses delivered by Twisthaler®, respectively, as part of QMF149 formulation development.

Impact of Payor-Initiated Switching of Inhaled Corticosteroids on Lung Function.

OBJECTIVES: To evaluate the impact of a payor-initiated formulary change in inhaled corticosteroid coverage on lung function in patients with asthma and on provider prescribing practices. This formulary change, undertaken in August 2016 by a Medicaid payor in Kentucky, eliminated coverage of beclomethasone dipropionate, a metered dose inhaler (MDI), in favor of mometasone furoate, available as MDI and dry powder inhaler (DPI). STUDY DESIGN: A retrospective chart review was conducted on children with asthma ages 6-18 years covered by the relevant payor from a university-based pediatric practice who were seen before the formulary change (February to July 2016) and after (February to July 2017). Spirometry data from each visit was compared using the paired Student t test. RESULTS: Fifty-eight patients were identified who were initially on beclomethasone dipropionate and had spirometry available at both visits. Those who switched from an MDI to a DPI (n = 24) saw a decline in median predicted forced expiratory volume in 1 second from 98.5% to 91% (P = .013). A decline was also seen in forced expiratory flow at 25%-75%, from 89.5% predicted to 76% predicted (P = .041). No significant changes were observed in children remaining on an MDI. Seven patients discontinued inhaled corticosteroid therapy. CONCLUSIONS: This study suggests insurance formulary changes leading to use of a different inhaler device may have a detrimental impact on pediatric lung function, which may be a surrogate measure for overall asthma control. This could be due to a lack of adequate timely educational intervention as well as the inability of some children to use DPIs.

Biomarker-focused multi-drug combination therapy and repurposing trial in mdx mice.

Duchenne muscular dystrophy is initiated by dystrophin deficiency, but downstream pathophysiological pathways such as membrane instability, NFĸB activation, mitochondrial dysfunction, and induction of TGFß fibrosis pathways are thought to drive the disability. Dystrophin replacement strategies are hopeful for addressing upstream dystrophin deficiency; however, all methods to date use semi-functional dystrophin proteins that are likely to trigger downstream pathways. Thus, combination therapies that can target multiple downstream pathways are important in treating DMD, even for dystrophin-replacement strategies. We sought to define blood pharmacodynamic biomarkers of drug response in the mdx mouse model of Duchenne muscular dystrophy using a series of repurposed drugs. Four-week-old mdx mice were treated for four weeks with four different drugs singly and in combination: vehicle, prednisolone, vamorolone, rituximab, ß-aminoisobutyric acid (BAIBA) (11 treatment groups; n = 6/group). Blood was collected via cardiac puncture at study termination, and proteomic profiling was carried out using SOMAscan aptamer panels (1,310 proteins assayed). Prednisolone was tested alone and in combination with other drugs. It was found to have a good concordance of prednisolone-responsive biomarkers (56 increased by prednisolone, 39 decreased) focused on NFκB and TGFß cascades. Vamorolone shared 45 (80%) of increased biomarkers and 13 (33%) of decreased biomarkers with prednisolone. Comparison of published human corticosteroid-responsive biomarkers to our mdx data showed 14% (3/22) concordance between mouse and human. Rituximab showed fewer drug-associated biomarkers, with the most significant being human IgG. On the other hand, BAIBA treatment (high and low dose) showed a drug-associated increase in 40 serum proteins and decreased 5 serum proteins. Our results suggest that a biomarker approach could be employed for assessing drug combinations in both mouse and human studies.

The Effect of Nasal Steroid and Antihistamine Use on Total Oxidative Stress and Antioxidant Status in the Treatment of Allergic Rhinitis.

INTRODUCTION: The purpose of this study is to determine the post-treatment levels of total oxidant status (TOS) and total antioxidant status (TAS), that are increased due to pathophysiology, and to compare those with pre-treatment levels in allergic rhinitis patients.Material-Methods: Among 84 patients clinically diagnosed with allergic rhinitis, 31 patients were started only on nasal steroid treatment (mometasone furoate), and 53 patients were started on nasal steroid and oral antihistamine treatment (mometasone furoate + rupatadine fumarate 10 mg). Blood samples were taken from the patients at the first examination and at post-treatment month 1.TAS and TOS were measured from the blood samples. RESULTS: While no significant change was determined in mean TAS levels with treatment, a statistically significant decrease was determined in TOS values in post-treatment period (P < .01). There was no significant change in TAS and TOS values of patients only using nasal steroids, while a significant decrease was determined in post-treatment TOS values of patients using both nasal steroids and oral antihistamines (P < .001). It was determined that TOS values of women were significantly lower compared to men, and it was also reduced in seasonal allergic rhinitis compared to perennial allergic rhinitis (P < .05 for both). CONCLUSION: In allergic rhinitis patients, concomitant use of nasal steroids and antihistamines significantly decreases total oxidative stress. It may be stated that the addition of antihistamines to allergic rhinitis treatment positively affects treatment.

Comparison of Outcomes Between Mometasone Furoate Intranasal Spray and Oral Montelukast in Patients with Allergic Rhinitis.

BACKGROUND: Allergic rhinitis is a common ailment with rising trend and worldwide prevalence of some 400 million. METHODS: This prospective randomized crosssectional study was done at the Department of Otorhinolaryngology and Head and Neck Surgery, Tribhuvan University, Teaching Hospital, Kathmandu, Nepal from June 2016 to August 2017. They were randomly assigned to two groups by lottery method. Group A received mometasone furoate intranasal spray and Group B received oral montelukast for a total duration of one month. Prior to starting medication and one month after medications, total nasal symptom score was documented. Statistical analysis was done using SPSS version 18. RESULTS: Total of 126 patients between 16 to 52 years were enrolled in the study. The mean duration of symptoms was 3.93 years. The mean value of serum total IgE was 833.49 IU/ml. The mean pre and post medication score for mometasone furoate intranasal spray group was 16.32 and 5.44 respectively, which was significant. Similarly, the mean pre and post medication score for oral montelukast group was 15.24 and 7.87 respectively which was also found to be significant. Comparing the means of scores for both the groups, mometasone furoate was found to be more effective than oral montelukast. CONCLUSIONS: Both mometasone furoate intranasal spray and oral montelukast were effective in the treatment of patient with allergic rhinitis. Oral montelukast can therefore be used as a first line treatment for patients with allergic rhinitis.

Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study.

BACKGROUND: Treatment with corticosteroids is recommended for Duchenne muscular dystrophy (DMD) patients to slow the progression of weakness. However, chronic corticosteroid treatment causes significant morbidities. Vamorolone is a first-in-class anti-inflammatory investigational drug that has shown evidence of efficacy in DMD after 24 weeks of treatment at 2.0 or 6.0 mg/kg/day. Here, open-label efficacy and safety experience of vamorolone was evaluated over a period of 18 months in trial participants with DMD. METHODS AND FINDINGS: A multicenter, open-label, 24-week trial (VBP15-003) with a 24-month long-term extension (VBP15-LTE) was conducted by the Cooperative International Neuromuscular Research Group (CINRG) and evaluated drug-related effects of vamorolone on motor outcomes and corticosteroid-associated safety concerns. The study was carried out in Canada, US, UK, Australia, Sweden, and Israel, from 2016 to 2019. This report covers the initial 24-week trial and the first 12 months of the VBP15-LTE trial (total treatment period 18 months). DMD trial participants (males, 4 to <7 years at entry) treated with 2.0 or 6.0 mg/kg/day vamorolone for the full 18-month period (n = 23) showed clinical improvement of all motor outcomes from baseline to month 18 (time to stand velocity, p = 0.012 [95% CI 0.010, 0.068 event/second]; run/walk 10 meters velocity, p < 0.001 [95% CI 0.220, 0.491 meters/second]; climb 4 stairs velocity, p = 0.001 [95% CI 0.034, 0.105 event/second]; 6-minute walk test, p = 0.001 [95% CI 31.14, 93.38 meters]; North Star Ambulatory Assessment, p < 0.001 [95% CI 2.702, 6.662 points]). Outcomes in vamorolone-treated DMD patients (n = 46) were compared to group-matched participants in the CINRG Duchenne Natural History Study (corticosteroid-naïve, n = 19; corticosteroid-treated, n = 68) over a similar 18-month period. Time to stand was not significantly different between vamorolone-treated and corticosteroid-naïve participants (p = 0.088; least squares [LS] mean 0.042 [95% CI -0.007, 0.091]), but vamorolone-treated participants showed significant improvement compared to group-matched corticosteroid-naïve participants for run/walk 10 meters velocity (p = 0.003; LS mean 0.286 [95% CI 0.104, 0.469]) and climb 4 stairs velocity (p = 0.027; LS mean 0.059 [95% CI 0.007, 0.111]). The vamorolone-related improvements were similar in magnitude to corticosteroid-related improvements. Corticosteroid-treated participants showed stunting of growth, whereas vamorolone-treated trial participants did not (p < 0.001; LS mean 15.86 [95% CI 8.51, 23.22]). Physician-reported incidences of adverse events (AEs) for Cushingoid appearance, hirsutism, weight gain, and behavior change were less for vamorolone than published incidences for prednisone and deflazacort. Key limitations to the study were the open-label design, and use of external comparators. CONCLUSIONS: We observed that vamorolone treatment was associated with improvements in some motor outcomes as compared with corticosteroid-naïve individuals over an 18-month treatment period. We found that fewer physician-reported AEs occurred with vamorolone than have been reported for treatment with prednisone and deflazacort, and that vamorolone treatment did not cause the stunting of growth seen with these corticosteroids. This Phase IIa study provides Class III evidence to support benefit of motor function in young boys with DMD treated with vamorolone 2.0 to 6.0 mg/kg/day, with a favorable safety profile. A Phase III RCT is underway to further investigate safety and efficacy. TRIAL REGISTRATION: Clinical trials were registered at www.clinicaltrials.gov, and the links to each trial are as follows (as provided in manuscript text): VBP15-002 [NCT02760264] VBP15-003 [NCT02760277] VBP15-LTE [NCT03038399].

Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment.

Duchenne muscular dystrophy is a genetic disorder that shows chronic and progressive damage to skeletal and cardiac muscle leading to premature death. Antiinflammatory corticosteroids targeting the glucocorticoid receptor (GR) are the current standard of care but drive adverse side effects such as deleterious bone loss. Through subtle modification to a steroidal backbone, a recently developed drug, vamorolone, appears to preserve beneficial efficacy but with significantly reduced side effects. We use combined structural, biophysical, and biochemical approaches to show that loss of a receptor-ligand hydrogen bond drives these remarkable therapeutic effects. Moreover, vamorolone uniformly weakens coactivator associations but not corepressor associations, implicating partial agonism as the main driver of its dissociative properties. Additionally, we identify a critical and evolutionarily conserved intramolecular network connecting the ligand to the coregulator binding surface. Interruption of this allosteric network by vamorolone selectively reduces GR-driven transactivation while leaving transrepression intact. Our results establish a mechanistic understanding of how vamorolone reduces side effects, guiding the future design of partial agonists as selective GR modulators with an improved therapeutic index.