Abstract Crisaborole ointment, 2%, is a non‐steroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis (AD). This parallel‐cohort, phase 1 study was conducted to investigate skin irritation potential and safety of crisaborole in healthy Japanese adults (cohort 1) and the safety and pharmacokinetic profile of crisaborole and metabolites AN7602 and AN8323 in Japanese adults with mild to moderate AD (cohort 2). In cohort 1, 20 healthy volunteers received single applications of crisaborole and vehicle simultaneously on separate locations under 48‐h occlusion. In cohort 2, 12 patients with mild to moderate AD received crisaborole ( n = 10) or vehicle ( n = 2) twice daily for 8 days. Skin irritation and safety were assessed in cohort 1. Pharmacokinetics and safety were assessed in cohort 2. Skin irritation index (scale 0–400) was 40.0 for crisaborole and 5.0 for vehicle. No treatment‐emergent adverse events (TEAE) were reported in cohort 1. The most common TEAE in the crisaborole group in cohort 2 were application site irritation ( n = 7) and application site pain ( n = 4). Crisaborole was rapidly absorbed, with limited systemic exposure between days 1 and 8 that was comparable with that seen in US‐based participants in previous trials. Crisaborole had higher skin irritation than vehicle under occlusion in healthy Japanese adults and had an acceptable safety profile in Japanese adults with mild to moderate AD.
Substantial number of patients with persistent low back pain (LBP) are treated with multimodal spectrum of conservative and invasive therapies. Few have investigated the utility of pharmacotherapy and epidural steroid injections (ESI) in large practice setting. We sought to gather comprehensive data about the characteristics, efficacy, tolerability and quality of life (QoL) of patients with LBP with these therapies. Information was collected on a standardized form. Information included patient characteristics, type and duration of therapies, adverse events, pain relief using visual analogue scale (VAS) and QoL by measuring disability using modified ODQ at each month of follow-up. Consecutive 81 patients were recruited and followed for 6 months. Average baseline pain duration was found to be 45.5 months. Combination of drugs and ESI was given in 75 (92%) patients. Anticonvulsants (75%) and Antidepressants (57%) were most commonly prescribed medications. Change in VAS & ODQ score from baseline to each follow-up at 3 months (VAS - 15), 6 months (VAS -25) was significantly (P < 0.05) improved. Pregabalin and amitriptyline were most commonly used drugs with maximum pain relief and improved Qol. Desired pain relief fluctuated with time. ESI can be promising choice when desirable pain relief is not achieved with medications.
BackgroundCrisaborole ointment 2% is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). The mechanism of action of crisaborole and its effects on lesional measures of disease severity are not yet well defined.ObjectiveThis phase 2a, single-center, vehicle-controlled, intrapatient study was designed to further characterize the mechanism of action of crisaborole through evaluation of clinical efficacy and changes in skin biomarkers in adults (n = 40) with mild-to-moderate AD.MethodsTwo target lesions were randomized in an intrapatient (1:1) manner to double-blind crisaborole/vehicle applied twice daily for 14 days. Patients then applied crisaborole (open-label) to all affected areas for 28 days. Punch biopsy specimens were collected for biomarker analysis at baseline, day 8 (optional), and day 15.ResultsCrisaborole treatment resulted in early improvement in lesional signs/symptoms versus vehicle, with improvement in pruritus (pruritus numeric rating scale) observed as early as 24 hours after the first application. Crisaborole-treated lesions showed significant percentage improvement from baseline in lesional transcriptomic profile compared with vehicle at day 8 (91.15% vs 36.02%, P < 10−15) that was sustained until day 15 (92.90% vs 49.59%, P < 10−15). Crisaborole significantly modulated key AD biomarkers versus vehicle, including TH2 and TH17/TH22 pathways and epidermal hyperplasia/proliferation. Molecular profiles and epidermal pathology normalized toward nonlesional skin and correlated with clinical changes in lesion severity and barrier function.ConclusionCrisaborole reversed biomarker profiles of skin inflammation and barrier function, with associated improvements in clinical efficacy measures, highlighting the therapeutic utility of targeting phosphodiesterase 4 in patients with AD. Crisaborole ointment 2% is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). The mechanism of action of crisaborole and its effects on lesional measures of disease severity are not yet well defined. This phase 2a, single-center, vehicle-controlled, intrapatient study was designed to further characterize the mechanism of action of crisaborole through evaluation of clinical efficacy and changes in skin biomarkers in adults (n = 40) with mild-to-moderate AD. Two target lesions were randomized in an intrapatient (1:1) manner to double-blind crisaborole/vehicle applied twice daily for 14 days. Patients then applied crisaborole (open-label) to all affected areas for 28 days. Punch biopsy specimens were collected for biomarker analysis at baseline, day 8 (optional), and day 15. Crisaborole treatment resulted in early improvement in lesional signs/symptoms versus vehicle, with improvement in pruritus (pruritus numeric rating scale) observed as early as 24 hours after the first application. Crisaborole-treated lesions showed significant percentage improvement from baseline in lesional transcriptomic profile compared with vehicle at day 8 (91.15% vs 36.02%, P < 10−15) that was sustained until day 15 (92.90% vs 49.59%, P < 10−15). Crisaborole significantly modulated key AD biomarkers versus vehicle, including TH2 and TH17/TH22 pathways and epidermal hyperplasia/proliferation. Molecular profiles and epidermal pathology normalized toward nonlesional skin and correlated with clinical changes in lesion severity and barrier function. Crisaborole reversed biomarker profiles of skin inflammation and barrier function, with associated improvements in clinical efficacy measures, highlighting the therapeutic utility of targeting phosphodiesterase 4 in patients with AD.
Myostatin, a negative regulator of skeletal muscle growth, is a therapeutic target in muscle-wasting diseases. Domagrozumab, a humanized recombinant monoclonal antibody, binds myostatin and inhibits activity. Domagrozumab was investigated in a phase II trial (NCT02310763) as a potential treatment for boys with Duchenne muscular dystrophy (DMD). Pharmacokinetic/pharmacodynamic (PK/PD) modeling is vital in clinical trial design, particularly for determining dosing regimens in pediatric populations. This analysis sought to establish the PK/PD relationship between free domagrozumab and total myostatin concentrations in pediatric patients with DMD using a prior semimechanistic model developed from a phase I study in healthy adult volunteers (NCT01616277) and following inclusion of phase II data. The refined model was developed using a multiple-step approach comprising structural, random effects, and covariate model development; assessment of model adequacy (goodness-of-fit); and predictive performance. Differences in PKs/PDs between healthy adult volunteers and pediatric patients with DMD were quantitatively accounted for and evaluated by predicting myostatin coverage (the percentage of myostatin bound by domagrozumab). The final model parameter estimates and semimechanistic target-mediated drug disposition structure sufficiently described both domagrozumab and myostatin concentrations in pediatric patients with DMD, and most population parameters were comparable with the prior model (in healthy adult volunteers). Predicted myostatin coverage for phase II patients with DMD was consistently > 90%. Baseline serum myostatin was ~ 65% lower than in healthy adult volunteers. This study provides insights into the regulation of myostatin in healthy adults and pediatric patients with DMD. Clinicaltrials.gov identifiers: NCT01616277 and NCT02310763.
Despite unmet need, 15 years have passed since a topical therapy with a new mechanism of action for atopic dermatitis (AD) has been approved. Janus kinase (JAK) inhibitor treatment effect via topical application in patients with AD is unknown. Tofacitinib, a small‐molecule JAK inhibitor, was investigated for the topical treatment of AD. In this 4‐week, phase IIa, randomized, double‐blind, vehicle‐controlled study (NCT02001181), 69 adults with mild‐to‐moderate AD were randomized 1:1 to 2% tofacitinib or vehicle ointment twice daily. Percentage change from baseline (CFB) in Eczema Area and Severity Index (EASI) score at week 4 was the primary end point. Secondary efficacy end points included percentage CFB in body surface area (BSA), CFB in EASI Clinical Signs Severity Sum Score, proportion of patients with Physician's Global Assessment (PGA) response and CFB in patient‐reported pruritus. Safety, local tolerability and pharmacokinetics were monitored. The mean percentage CFB at week 4 in EASI score was significantly greater (P < 0·001) for tofacitinib (−81·7%) vs. vehicle (−29·9%). Patients treated with tofacitinib showed significant (P < 0·001) improvements vs. vehicle across all prespecified efficacy end points and for pruritus at week 4. Significant improvements in EASI, PGA and BSA were observed by week 1 and improvements in pruritus were observed by day 2. Safety/local tolerability were generally similar for both treatments, although more adverse events were observed for vehicle vs. tofacitinib. Tofacitinib ointment showed significantly greater efficacy vs. vehicle across end points, with early onset of effect and comparable safety/local tolerability to vehicle. JAK inhibition through topical delivery is potentially a promising therapeutic target for AD.
Abstract The protein therapeutics have unique handling and development requirements relative to the small organic molecule‐based drugs and pose exclusive challenges for the formulation scientist. The formulation and delivery issues of therapeutic proteins can contribute to difficulties in pharmaceutical development such as stability, immune toxicity, and pharmacodynamics‐related problems. This article focuses on formulation and delivery strategies of therapeutic proteins.
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