Pharmacokinetics, pharmacodynamics, and tolerability of an aqueous formulation of rusfertide (PTG-300), a hepcidin mimetic, in healthy volunteers: A double-blind first-in-human study.

OBJECTIVES: Rusfertide is a potent peptide mimetic of hepcidin being investigated for the treatment of polycythemia vera. This randomized, placebo-controlled, double-blind study evaluated the safety, pharmacokinetics, and pharmacodynamics of single and repeated subcutaneous doses of an aqueous formulation of rusfertide in healthy adult males. METHODS: Subjects received single doses of 1, 3, 10, 20, 40, or 80 mg rusfertide or placebo. A separate cohort of subjects received two doses of 40 mg rusfertide or placebo 1 week apart. Blood samples for pharmacokinetics and pharmacodynamics were collected, and adverse events, clinical laboratory tests, 12-lead electrocardiograms, and vital signs were monitored. RESULTS: Rusfertide was well tolerated. There were no serious or severe treatment-emergent adverse events, and no patterns of clinically important adverse events, or laboratory, vital sign, or electrocardiogram abnormalities. Mean maximum rusfertide plasma concentration (Cmax) and area under the concentration-time curve increased with dose, but less than dose proportionally. Median time to Cmax was 2-4.5 h for 40 and 80 mg rusfertide and 8-24 h for lower doses. Apparent clearance and half-life increased with dose. Single doses of rusfertide 1-80 mg were associated with dose-dependent decreases in serum iron and transferrin-iron saturation. CONCLUSIONS: Rusfertide was well tolerated and showed dose-dependent pharmacokinetics and pharmacodynamics.

PTG-100, an Oral α4ß7 Antagonist Peptide: Preclinical Development and Phase 1 and 2a Studies in Ulcerative Colitis.

BACKGROUND & AIMS: Oral therapies targeting the integrin α4ß7 may offer unique advantages for the treatment of inflammatory bowel disease. We characterized the oral α4ß7 antagonist peptide PTG-100 in preclinical models and established safety, pharmacokinetic/pharmacodynamic relationships, and efficacy in a phase 2a trial in patients with ulcerative colitis (UC). METHODS: In vitro studies measured binding properties of PTG-100. Mouse studies measured biomarkers and drug concentrations in blood and tissues. The phase 1 study involved healthy volunteers. In phase 2a, patients with moderate to severe active UC were randomized to receive PTG-100 (150, 300, or 900 mg) or placebo once daily for 12-weeks. RESULTS: PTG-100 potently and selectively blocks α4ß7. Oral dosing of PTG-100 in mice showed high levels of target engagement and exposure in gut-associated lymphoid tissues. In healthy volunteers, PTG-100 showed dose-dependent increases in plasma exposure and blood target engagement. Although this phase 2a study initially did not meet the primary endpoint, a blinded reread of the endoscopy videos by a third party indicated clinical efficacy in conjunction with histologic remission at doses correlating with less than 100% receptor occupancy in peripheral blood. CONCLUSIONS: PTG-100 showed local gastrointestinal tissue target engagement and inhibition of memory T-cell trafficking in mice. It was safe and well tolerated in phase 1 and 2 studies. Phase 2a data are consistent with biological and clinical response and showed a dose response reflecting similar activities in preclinical models and healthy individuals. These data suggest that local gut activity of an oral α4ß7 integrin antagonist, distinct from full target engagement in blood, are important for efficacy and the treatment of UC. (ClinicalTrials.gov, Number NCT02895100; EudraCT, Number 2016-003452-75).

Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial.

RATIONALE: Airway inflammation in asthma is associated with increased activated CD25(+) T cells, IL-2, and soluble IL-2 receptors (IL-2Rs). OBJECTIVES: A randomized, double-blinded, placebo-controlled study was used to evaluate the safety and efficacy of daclizumab, a humanized IgG1 monoclonal antibody against the IL-2R alpha chain (CD25) of activated lymphocytes, in adults with moderate to severe persistent asthma. METHODS: Patients with obstructive pulmonary functions, despite inhaled corticosteroids (ICS), were switched to equivalent dose inhaled triamcinolone acetate acetonide (TAA). Patients dependent on ICS were randomized (3:1) to daclizumab (intravenous loading dose, 2 mg/kg, then 1 mg/kg) or placebo every 2 weeks, added to stable-dose TAA through Week 12 (Treatment Period 1). Over Weeks 12-20 (Treatment Period 2), patients tapered TAA while on the study drug, and were followed for 16 weeks off the study drug. MEASUREMENTS AND MAIN RESULTS: Among 115 evaluable patients (88 daclizumab, 27 placebo), groups had similar age, disease duration, and length of ICS use. During Treatment Period 1, daclizumab improved FEV(1) (daclizumab, 4.4 +/- 1.80% vs. placebo, 1.5 +/- 2.39%; P = 0.05), and reduced daytime asthma symptoms (P = 0.018) and short-acting inhaled beta(2)-agonist use (P = 0.009). Daclizumab treatment prolonged time to exacerbation (P = 0.024). Adverse events were evenly distributed between groups, although there were more serious adverse events in the patients treated with daclizumab. CONCLUSIONS: Daclizumab improved pulmonary function and asthma control in patients with moderate to severe chronic asthma inadequately controlled on ICS. The mechanism of action likely involves inhibition of proinflammatory cytokine generation by IL-2R blockade in activated T cells. Clinical trial registered with www.clinicaltrials.gov (NCT00028288).

Agreement among measures of asthma status: a prospective study of low-income children with moderate to severe asthma.

BACKGROUND: Because no validated "gold standard" for measuring asthma outcomes exists, asthma interventions are often evaluated using a large number of disease status measures. Some of these measures may be redundant, whereas others may be complementary. Use of multiple outcomes may lead to ambiguous results, increased type I error rates, and be an inefficient use of resources including caregiver and patient/participant time and effort. Understanding the relationship between these measures may facilitate more parsimonious and valid evaluation strategies without loss of information. OBJECTIVE: To assess the relationships between multiple measures of asthma disease status over time. DESIGN/METHODS: We used data from a randomized, controlled trial of a comprehensive disease management program involving 119 disadvantaged inner-city children aged 5 to 12 years with moderate to severe asthma. Spearman correlations were calculated between the following asthma disease status measures: parent-reported disease symptoms, parent-reported health care utilization, functional health status using the American Academy of Pediatrics' validated Child Health Survey for Asthma (CHSA), diary data (symptom scores, night wakings, and bronchodilator use), and pulmonary function tests at baseline, 32 weeks, 52 weeks, and changes from baseline to 52 weeks. RESULTS: Ninety-four (79%) of randomized patients participated at baseline and 52 weeks. Completion rates for outcome measures ranged from 79% (CHSA, spirometry data) to 64% (diary data). At baseline, asthma symptoms, health care utilization, and individual domains from the CHSA were significantly correlated (r = 0.21-0.53). These correlations were stable over the 52-week follow-up. Forced expiratory volume in 1 second and diary data did not correlate to any other measures at baseline, and these measures correlated only inconsistently with other measures at 32 weeks and 52 weeks. Baseline to 52-week changes in asthma symptoms, utilization, and the CHSA domains were significantly correlated (0.22-0.56), as were baseline to 52-week changes in symptom days, night wakings, and the CHSA domains (r = 0.24-0.64). Baseline to 52-week changes in forced expiratory volume in 1 second and diary data did not correlate with other measures. CONCLUSIONS: These results suggest that asthma status and change in asthma status over time after introduction of a disease management intervention are best characterized by parent-reported symptoms, parent-reported utilization, and functional health status measures. Asthma diaries and pulmonary function tests did not seem to provide additional benefit, although they may play an important role in individual patient management. Our findings suggest a parsimonious evaluation strategy would include collection of key data elements regarding symptoms, utilization, and functional health status only, without loss of vital response information.

Effectiveness of a multicomponent self-management program in at-risk, school-aged children with asthma.

BACKGROUND: Improving asthma knowledge and self-management is a common focus of asthma educational programs, but most programs have had little influence on morbidity outcomes. We developed a novel multiple-component intervention that included the use of an asthma education video game intended to promote adoption of asthma self-management behaviors and appropriate asthma care. OBJECTIVE: To determine the effectiveness of an asthma education video game in reducing morbidity among high-risk, school-aged children with asthma. METHODS: We enrolled 119 children aged 5 to 12 years from low-income, urban areas in and around San Francisco, CA, and San Jose, CA. Children with moderate-to-severe asthma and parental reports of significant asthma health care utilization were randomized to participate in the disease management intervention or to receive their usual care (control group). Patients were evaluated for clinical and quality-of-life outcomes at weeks 8, 32, and 52 of the study. RESULTS: Compared with controls, the intervention group had significant improvements in the physical domain (P = .04 and P = .01 at 32 and 52 weeks, respectively) and social activity domain (P = .02 and P = .05 at 32 and 52 weeks, respectively) of asthma quality of life on the Child Health Survey for Asthma and child (P = .02 at 8 weeks) and parent (P = .04 and .004 at 32 and 52 weeks, respectively) asthma self-management knowledge. There were no significant differences between groups on clinical outcome variables. CONCLUSIONS: A multicomponent educational, behavioral, and medical intervention targeted at high-risk, inner-city children with asthma can improve asthma knowledge and quality of life.

Humanized anti-interleukin-2 (IL-2) receptor alpha therapy: long-term results in uveitis patients and preliminary safety and activity data for establishing parameters for subcutaneous administration.

Therapy for severe uveitis is frequently long-term immunosuppression using systemic corticosteroids and cytotoxic agents, but side effects make long-term therapy difficult. A long-term (>4 year) Phase I/II single armed interventional study using intravenous anti-IL-2 receptor alpha treatments (daclizumab) and a short-term Phase II study evaluating the use of a subcutaneous daclizumab formulation were conducted. Patients were tapered off their systemic immunosuppressive therapy and received daclizumab infusions or subcutaneous injections at intervals varying from 2 to 6 weeks. In the long-term study, seven of ten enrolled patients were tapered from their original immunosuppressive medications and maintained exclusively on repeated daclizumab infusions for control of their uveitis for over 4 years. No patient was permanently removed from therapy for an adverse event ascribed to the medication. The use of 6-week infusion intervals led to recurrence of uveitis, while 2- to 4-week intervals did not. Only one patient developed measurable anti-daclizumab antibodies but this disappeared when subcutaneous therapy was begun. In the short-term study, four of the five patients receiving the subcutaneous formulation met the study endpoints for success within the first 12 weeks. All five were successful by 26 weeks. These studies provide preliminary evidence that regularly administered long-term daclizumab therapy can be given in lieu of standard immunosuppression for years to treat severe uveitis and that subcutaneously administered daclizumab appeared to be a clinically viable treatment strategy. These studies suggest that anti-IL-2 receptor blockade could be useful in the treatment of Th1-mediated autoimmune conditions.