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AIMS SD-1077, a selectively deuterated precursor of dopamine (DA) structurally related to L-3,4-dihydroxyphenylalanine (L-DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD-1077. METHODS Plasma and urine PK of drug and metabolites and safety after a single oral 150 mg SD-1077 dose were compared to 150 mg L-DOPA, each in combination with 37.5 mg carbidopa (CD) in a double-blind, two-period, crossover study in healthy volunteers (n = 16). RESULTS Geometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD-1077 vs. L-DOPA for Cmax , AUC0-t , and AUC0-inf were 88.4 (75.9-103.1), 89.5 (84.1-95.3), and 89.6 (84.2-95.4), respectively. Systemic exposure to DA was significantly higher after SD-1077/CD compared to that after L-DOPA/CD, with GMRs (90% CI) of 1.8 (1.45-2.24; P = 0.0005) and 2.06 (1.68-2.52; P

Background In phase 2 and 3 studies, fremanezumab, a monoclonal CGRP antibody, was an effective preventive treatment for high-frequency episodic migraine (HFEM) and chronic migraine (CM). Objective Post-hoc analyses evaluated population-wise 50%, 75% and 100% responder rates, and the extent to which individual responders sustained a 50%, 75% and 100% reduction in migraine days, moderate-to-severe (M/S) headache days and days of acute medication use during all three treatment months of the fremanezumab phase 2 studies. Design/methods HFEM patients received either placebo or three once-monthly injections of 225 mg or 675 mg. CM patients received either placebo or three once-monthly injections of 900 mg, or an initial loading dose of 675 mg and subsequent injections of 225 mg. Patients reported headache-related data daily using an electronic diary. Results In the HFEM study, the percent of patients on fremanezumab doses 225 mg and 675 mg were greater compared to the percent of placebo patients with sustained 50% reduction in migraine days (39% and 35% vs. 10% for placebo, both p Conclusions Post-hoc results must be interpreted with caution; nonetheless, a statistically significant percentage of patients who initially responded to fremanezumab within 1 month sustained this response over the subsequent 2 months. Sustained reduction in individual patients may provide a novel patient-centric, clinically meaningful endpoint for future trials assessing the effectiveness of preventive migraine treatments. Trials are registered as http://clinical trials.gov as NCT02025556 and NCT02021773.

Background: Spirometric lung age expresses lung function relative to chronological age. It has been effective in encouraging smoking cessation and has been used in the assessment of asthma. Reslizumab, a humanized anti-interleukin-5 monoclonal antibody, is approved as add-on therapy for adults with severe asthma and elevated blood eosinophils. Objective: To assess the effect of reslizumab versus placebo on the change in lung age over 52 weeks and the correlation between change in lung age and quality of life in moderate-to-severe asthma. Methods: This was a post hoc analysis of two randomized, double-blind, placebo-controlled trials. Patients ages 12-75 years with moderate-to-severe, inadequately controlled asthma and elevated blood eosinophils received intravenous reslizumab 3.0 mg/kg or placebo every 4 weeks for 1 year. Spirometry was performed every 4 weeks, and the Asthma Quality of Life Questionnaire (AQLQ) score was assessed at baseline and weeks 16, 32, and 52. Results: Mean improvement in lung-age deficit at week 52 was -8.73 years for reslizumab versus -3.80 years for placebo, a treatment difference of 5 years (p www.clinicaltrials.gov .

SD-1077, a selectively deuterated precursor of dopamine (DA) structurally related to L-3,4-dihydroxyphenylalanine (L-DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD-1077.Plasma and urine PK of drug and metabolites and safety after a single oral 150 mg SD-1077 dose were compared to 150 mg L-DOPA, each in combination with 37.5 mg carbidopa (CD) in a double-blind, two-period, crossover study in healthy volunteers (n = 16).Geometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD-1077 vs. L-DOPA for CSD-1077/CD demonstrated the potential to prolong exposure to central DA at comparable peripheral PK and safety to the reference L-DOPA/CD combination. A single dose of SD-1077 is safe for further clinical development in Parkinson's disease patients.

Background An estimated 7% of patients with asthma have chronic rhinosinusitis with nasal polyps (CRSwNP), and more than 80% have at least some radiographic evidence of sinonasal inflammation. Aspirin sensitivity is strongly associated with elevated blood eosinophil levels and increased asthma severity. Intravenous (IV) reslizumab has been shown to improve asthma control in patients with nasal polyps. Objective These post hoc analyses of pooled data from 2 BREATH phase 3 clinical trials, studies 1 and 2 (NCT01287039 and NCT01285323), examined asthma-related outcomes in patients with comorbid, self-reported CRSwNP with and without aspirin sensitivity. Methods Patients aged 12-75 years with elevated blood eosinophils (≥400 cells/μL) and inadequately controlled asthma were randomized to receive placebo or reslizumab (3 mg/kg IV) every 4 weeks for 52 weeks. Patients continued their background asthma maintenance therapy during the study. Information regarding the presence of CRSwNP was obtained through patient-reported medical history. Results Add-on reslizumab treatment reduced the frequency of clinical asthma exacerbations by 83% versus placebo among patients with CRSwNP. Among patients with and without aspirin sensitivity, reductions of 79% and 84%, respectively, were observed. Patients with CRSwNP (with and without aspirin sensitivity) treated with reslizumab add-on therapy also had significant improvements in lung function, as measured by forced expiratory volume in 1 second, compared with placebo. Among patients with CRSwNP, reslizumab was also associated with improvements in patient-reported asthma control and asthma quality of life. Conclusions Patients with eosinophilic asthma and self-reported CRSwNP, with and without aspirin sensitivity, are highly responsive to treatment with reslizumab for asthma-related outcomes. These findings suggest that prospective investigation of reslizumab in this patient population is warranted.

Introduction: In two duplicate multicentre placebo-controlled Phase 3 (BREATH) studies, reslizumab (RES) reduced exacerbations and improved lung function and quality of life (QOL) in adult patients (pts) with uncontrolled severe eosinophilic asthma (Castro et al Lancet Respir Med 2015:3:355-66). Aims/Objectives: To report a long-term (up to 2 yrs) single centre experience (France) evaluating the efficacy and safety of RES in pts who participated in a phase 3 placebo-controlled trial (PCT) and entered the open-label extension study (OLE). Methods: Pts (≥18 yrs) who completed a PCT with IV RES 3 mg/kg Q4W (52 wks) entered an OLE and received open-label IV RES 3 mg/kg Q4W for up to 2 yrs. Changes in lung function (FEV1), asthma symptoms and control (ASUI; ACQ7), and QOL (AQLQ) were assessed from baseline of PCT to the end of the OLE. Results: Of the 10 pts, 60% were female (median age: 57.5 yrs [range: 36.0–73.0]; median BMI: 24.7 kg/m2 [19.0–33.8]). Median duration of RES exposure was 367 days (289–708). Most pts (60%) had improved FEV1. The median change in FEV1 was 105 mL (–230 to 600, or –15.5% to +54.0% of baseline). The median improvements in ASUI, ACQ7, and AQLQ versus baseline were 0.30 (–0.10 to 0.5), –1.29 (0 to –2.7), and 1.3 (–0.1 to 2.3), respectively (exceeding the minimally important differences). Ovarian and prostate cancers were reported during the OLE (n=1 each); neither was considered related to study drug by the investigator. The overall safety profile in this cohort was similar to that of the pivotal phase 3 trials (Castro 2015). Conclusions: Patients treated with long-term reslizumab maintained clinically significant improvements in FEV1, asthma symptoms, asthma control and quality of life.

Background: Reslizumab (RES) is a humanized anti-interleukin-5 monoclonal antibody that significantly reduces the risk of asthma exacerbations and improves asthma control, lung function, and quality of life in patients with uncontrolled eosinophilic asthma. The mean difference in FEV 1 in RES treated patients vs placebo (PBO) at 16 and 52 weeks has been shown to be statistically and clinically significant (Castro et al., Lancet Respir Med. 2015; 3:355–366), but individual responders have not been assessed. Aims/Objectives: To assess the proportion of RES-treated patients who achieved a ≥0.1L increase in FEV 1 from baseline and the duration of treatment before response occurs. Methods: This was a post-hoc analysis of the two duplicate, multicenter, randomized, 52-week, PBO-controlled phase 3 trials of RES (3 mg/kg IV Q4W) (Castro 2015). Proportion of patients achieving 0.1L FEV 1 increase at each visit in each group are reported. Results: The trials included 953 patients (RES 477; PBO 476). As early as 4 weeks, 255 patients (54%) in the RES-treated group and 188 (40%) in the PBO group achieved ≥0.1L FEV 1 increase (p Conclusions: RES was effective in producing a clinically meaningful improvement of ≥0.1L in FEV 1 as early as 4 weeks, which was sustained up to week 52. Although onset of improvement in FEV 1 was early in most patients, additional clinically important response may occur through week 24.

Background: For patients (pts) with inadequately controlled eosinophilic asthma (ICEA), intravenous administration of reslizumab (RES) has been shown to significantly reduce clinical asthma exacerbations (CAEs) and improve FEV1 irrespective of disease severity, based on treatment regimen received at baseline (inhaled corticosteroid [ICS] only, ICS plus long-acting beta agonist, or OCS) (Castro et al. Lancet Respir Med. 2015; 3:355-366 [OCS: FEV1 improved by 151 mL [95% CI: 2, 290]). Aims/Objectives: To further assess the efficacy of RES (reduction of severe CAE and improvement in lung function) in pts with ICEA and on OCS at baseline. Methods: This was a post-hoc analysis of two duplicate, double-blind, randomized, 52-wk placebo (PBO)-controlled phase 3 trials of RES (3mg/kg IV Q4W). Differences between PBO and RES groups in the rate of CAE associated with emergency department (ED) visit or hospitalization, and % predicted FEV1 and FVC are reported. Results: Of 476 PBO and 477 RES pts, 73 pts in each group were on OCS at baseline. In this subgroup, RES treatment for 52 wks reduced the rate of CAE resulting in ED visits or hospitalizations vs PBO (RR: 0.184 [95% CI: 0.037, 0.902; p=0.0369). The mean change between PBO and RES-treated groups in % predicted FEV1 was 7.6% (95% CI: 1.9, 13.3, p=0.0098) and in FVC was 219mL (95% CI: 24, 414; p=0.0281). Conclusion: RES was effective at reducing the rate of CAE-related hospitalizations and ED visits by 82% in pts with ICEA who are OCS dependent. This subgroup also experienced significant improvements in measures of lung function.

Background: Reslizumab (RES), a humanized anti-interleukin-5 monoclonal antibody, has been demonstrated to significantly reduce the risk of clinical asthma exacerbation (CAE), and improve lung function, asthma symptoms and quality of life (QOL) in patients (pts) with inadequately controlled eosinophilic asthma (ICEA) and ≥1 CAE in the prior 12 mos despite standard of care therapy (Castro et al., Lancet Respir Med 2015; 3:355-366). Aims/Objectives: To assess the efficacy of RES in a subgroup of pts with ICEA who experienced only 1 CAE in the 12 mos prior to trial enrolment. Methods: This was a post-hoc analysis of the two duplicate 52-wk, placebo (PBO)-controlled phase 3 trials of RES (3 mg/kg IV Q4W). Differences between PBO and RES groups in the rate of CAE, lung function (FEV1), asthma control (ACQ-7), QOL (AQLQ) and asthma symptoms (ASUI) are reported. Results: Of 953 pts, 559 (59%) experienced a single CAE in the 12 mos prior to enrolment (RES 282; PBO 277). In these pts, RES therapy vs PBO reduced the rate of CAE (rate ratio: 0.68 [95% CI: 0.49, 0.95], p=0.0242), and improved FEV1 (difference of 0.069 [0.015, 0.124], p=0.0124), ACQ-7 (difference of -0.190 [-0.311, -0.069], p=0.002), AQLQ (difference of 0.181 [0.028, 0.335], p=0.0208) and ASUI (difference of 0.037 [0.017, 0.057], p=0.0003). Conclusions: RES was effective in reducing CAE rate and improving lung function, asthma control, QOL, and symptoms in pts with ICEA who had experienced only 1 CAE in the previous year, suggesting that prescribers might consider starting RES therapy after the first CAE in these pts rather than waiting until multiple CAEs have occurred.

The reactive sulfhydryls of human adult and fetal hemoglobin and the single sulfhydryl of isolated gamma chains have been spin labeled with N-(1-oxyl-2,2,5,5-tetramethyl-3-pyrrolidinyl) iodoacetamide. Similar electron paramagnetic spectral differences between oxy- and deoxy-modified hemoglobins were observed for both these hemoglobins and for the isolated chains, indicating that ligand-induced conformational changes occur in isolated hemoglobin subunits as well as intact hemoglobin tetramers. Ligand induced changes in the reactivity of p-hydroxymercuribenzoate with the sulfhydryl groups of both intact hemoglobins and isolated subunits, observed by McDonald and Noble (1974) J. Biol. Chem. 249, 3161-3165), led them to draw a similar conclusion. Following carboxypeptidase A digestion of these modified hemoglobins and gamma chains, a procedure which specifically removes the two C-terminal residues of the beta or gamma chains, spectral differences between the liganded and unliganded spin-labeled derivatives still persisted. However, the magnitude of this difference was not only more reduced in the case of the hemoglobins than in that of the subunits but the spectra of both the oxy and deoxy derivatives of the hemoglobins were characteristic of the oxy derivative of a cooperative tetrameric hemoglobin. These findings support the premise that the COOH-terminal end of the beta or gamma chain contributes, although possibly to different extents, to the spectral differences exhibited by both the spin-labeled hemoglobins and chains.

Background Intravenous reslizumab, a monoclonal IL-5 antibody, is approved for treating severe asthma with eosinophilia. Limited structured information is available on the safety of reslizumab in larger populations. Objective To investigate the safety profile of intravenous reslizumab 3.0 mg/kg by analyzing data from 6 asthma clinical trials: 5 placebo-controlled (duration ≤52 weeks) and 1 open-label extension (up to 2 years of treatment). Methods Patients were aged 12 to 75 years with inadequately controlled asthma with eosinophilia. In the placebo-controlled trials, 730 patients received placebo and 1028 received reslizumab 3.0 mg/kg. Results Adverse events (AEs) and serious AEs occurred in higher percentages of patients in the placebo group (81% and 9%) than in the reslizumab group (67% and 6%). Asthma, nasopharyngitis, and upper respiratory tract infection were the most common AEs with placebo and reslizumab. Three cases of anaphylaxis, related to reslizumab, were successfully managed with standard therapies. No significant difference in the incidence of malignancies was seen when compared with placebo or the general population. Among 756 patients with more than 12 months of reslizumab exposure, the AE rate was lower than in the placebo-controlled trials (367.3 vs 433.9 events/100 patient-years). The incidence of AEs in patients on treatment for more than 12 months was no higher than in patients with shorter treatment durations. Conclusions This analysis confirms that treatment with intravenous reslizumab for more than 12 months is well tolerated in patients with asthma, with no evidence of rare safety events that were not detected in individual trials.