Pharmacokinetic Profile of Brepocitinib with Topical Administration in Atopic Dermatitis and Psoriasis Populations: Strategy to Inform Clinical Trial Design in Adult and Pediatric Populations.

Introduction: Topical brepocitinib, a tyrosine kinase (TYK)2/Janus kinase (JAK)1 inhibitor, is in development for psoriasis (PsO) and atopic dermatitis (AD). Quantitative analyses of prior clinical trial data were used to inform future clinical trial designs.

Methods: Two phase 2b studies in patients with AD and PsO were used to characterize the amount of topical brepocitinib and the resultant systemic trough concentration (C) using a linear mixed-effects regression (LMER).

Population PK and PD Analysis of Domagrozumab in Pediatric Patients with Duchenne Muscular Dystrophy.

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).

Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy.

We report results from a phase 2, randomized, double-blind, 2-period trial (48 weeks each) of domagrozumab and its open-label extension in patients with Duchenne muscular dystrophy (DMD). Of 120 ambulatory boys (aged 6 to <16 years) with DMD, 80 were treated with multiple ascending doses (5, 20, and 40 mg/kg) of domagrozumab and 40 treated with placebo. The primary endpoints were safety and mean change in 4-stair climb (4SC) time at week 49.

Phase 1 study of crisaborole in Japanese healthy volunteers and patients with atopic dermatitis.

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.

Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial.

Background: 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.

Objective: 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.

Systemic Tofacitinib Concentrations in Adult Patients With Atopic Dermatitis Treated With 2% Tofacitinib Ointment and Application to Pediatric Study Planning.

Atopic dermatitis is a chronic eczematous, pruritic, inflammatory skin condition affecting children and adults. Tofacitinib is a Janus kinase inhibitor. The efficacy, safety, and pharmacokinetics of 2% tofacitinib ointment twice daily have been evaluated in a 4-week phase 2a multisite randomized, double-blind, vehicle-controlled, parallel-group study (NCT02001181) in adult patients with mild to moderate atopic dermatitis and 2% to 20% body surface area (BSA) involvement.

FDA Public Meeting Report on "Drug Interactions With Hormonal Contraceptives: Public Health and Drug Development Implications".

Potential drug interactions with hormonal contraceptives are an important public health concern. A public meeting on "Drug Interactions With Hormonal Contraceptives: Public Health and Drug Development Implication" was hosted by the United States Food and Drug Administration (FDA). The meeting endeavored to provide an opportunity for the FDA to seek input from experts on the public health concerns associated with the use of hormonal contraceptives and interacting drugs that might affect efficacy and safety, including pharmacokinetic/pharmacodynamic considerations, in the design of drug interaction studies of hormonal contraceptives for drug development and approaches to translating the results of drug interaction information into informative labeling and communication.

Intravenous administration of Factor VIII-O-Phospho-L-Serine (OPLS) complex reduces immunogenicity and preserves pharmacokinetics of the therapeutic protein.

Hemophilia A is a bleeding disorder caused by the deficiency of an important coagulation factor; Factor VIII (FVIII). Replacement therapy using exogenously administered recombinant FVIII is the most commonly used method of treatment. However, approximately 30% of Hemophilia A patients develop neutralizing antibodies (Nabs) against the recombinant protein.

A phase 2 study of filibuvir in combination with pegylated IFN alfa and ribavirin for chronic HCV.

Objectives: Filibuvir is a non-nucleoside inhibitor of hepatitis C virus (HCV) polymerase. This study evaluated the safety and efficacy of filibuvir plus pegylated interferon alfa-2a (pegIFN)/ribavirin.

Material And Methods: Treatment-naïve, HCV genotype-1 patients were randomized to receive filibuvir 300 or 600 mg twice daily (BID) or placebo plus pegIFN (180 μg/wk) and ribavirin (1,000/1,200 mg BID) for 24 weeks.

Biopharmaceutic planning in pediatric drug development.

Pediatric drug development is a required consideration for all drug development programs. Age-appropriate formulations such as suspensions, chewable tablets, oral disintegrating tablets, etc., are typically developed and used in the pediatric clinical studies.

Antiviral activity of the hepatitis C virus polymerase inhibitor filibuvir in genotype 1-infected patients.

Unlabelled: More effective and better-tolerated therapies are needed for chronic hepatitis C virus (HCV) infection. Among the direct-acting anti-HCV agents in development is the nonstructural 5B protein (NS5B polymerase) non-nucleoside inhibitor filibuvir. We investigated the antiviral activity, pharmacokinetics, safety, and tolerability of multiple doses of filibuvir in treatment-naive and treatment-experienced patients who were chronically infected with HCV genotype 1 in two phase 1b clinical studies (study 1 was a randomized, placebo-controlled dose escalation study and study 2 was a nonrandomized, open-label study).

IL-12 delivered intratumorally by multilamellar liposomes reactivates memory T cells in human tumor microenvironments.

Using a novel loading technique, IL-12 is reported here to be efficiently encapsulated within large multilamellar liposomes. The preclinical efficacy of the cytokine loaded liposomes to deliver IL-12 into human tumors and to reactive tumor-associated T cells in situ is tested using a human tumor xenograft model. IL-12 is released in vivo from these liposomes in a biologically active form when injected into tumor xenografts that are established by the subcutaneous implantation of non-disrupted pieces of human lung, breast or ovarian tumors into immunodeficient mice.

O-phospho-L-serine, multi-functional excipient for B domain deleted recombinant factor VIII.

Factor VIII (FVIII) is an important cofactor in the blood coagulation cascade. A deficiency or dysfunction of FVIII causes hemophilia A, a life-threatening bleeding disorder. FVIII circulates in plasma as a heterodimer comprising 6 domains (heavy chain, A1-A2-B and light chain, A3-C1-C2).

Phosphatidylserine containing liposomes reduce immunogenicity of recombinant human factor VIII (rFVIII) in a murine model of hemophilia A.

Factor VIII (FVIII) is a multidomain protein that is deficient in hemophilia A, a clinically important bleeding disorder. Replacement therapy using recombinant human FVIII (rFVIII) is the main therapy. However, approximately 15-30% of patients develop inhibitory antibodies that neutralize rFVIII activity.

Interaction of dicaproyl phosphatidylserine with recombinant factor VIII and its impact on immunogenicity.

Replacement therapy with exogenous recombinant factor VIII (rFVIII) to control bleeding episodes results in the development of inhibitory antibodies in 15% to 30% of hemophilia A patients. The inhibitory antibodies are mainly directed against specific and universal immunodominant epitopes located in the C2 domain. Previously we have shown that complexation of O-phospho-L-serine (phosphatidylserine head group) with the phospholipid binding region of the C2 domain can lead to an overall reduction in the immunogenicity of rFVIII.

Influence of aggregation on immunogenicity of recombinant human Factor VIII in hemophilia A mice.

Recombinant human factor VIII (rFVIII), a multidomain glycoprotein is used in replacement therapy for treatment of hemophilia A. Unfortunately, 15%-30% of the treated patients develop inhibitory antibodies. The pathogenesis of antibody development is not completely understood.

Lipid binding region (2303-2332) is involved in aggregation of recombinant human FVIII (rFVIII).

Factor VIII (FVIII) is a multi-domain protein that is important in the clotting cascade. Its deficiency causes Hemophilia A, a bleeding disorder. The unfolding of protein domains can lead to physical instability such as aggregation, and hinder their use in replacement therapy.

Lower inhibitor development in hemophilia A mice following administration of recombinant factor VIII-O-phospho-L-serine complex.

Factor VIII is a multidomain protein composed of A1, A2, B, A3, C1, and C2 domains. Deficiency or dysfunction of factor VIII causes hemophilia A, a bleeding disorder. Administration of exogenous recombinant factor VIII as a replacement leads to development of inhibitory antibodies against factor VIII in 15-30% of hemophilia A patients.