Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue.

Spinal muscular atrophy type 1 (SMA1) is a debilitating neurodegenerative disease resulting from survival motor neuron 1 gene (SMN1) deletion/mutation. Onasemnogene abeparvovec (formerly AVXS-101) is a gene therapy that restores SMN production via one-time systemic administration. The present study demonstrates widespread biodistribution of vector genomes and transgenes throughout the central nervous system (CNS) and peripheral organs, after intravenous administration of an AAV9-mediated gene therapy. Two symptomatic infants with SMA1 enrolled in phase III studies received onasemnogene abeparvovec. Both patients died of respiratory complications unrelated to onasemnogene abeparvovec. One patient had improved motor function and the other died shortly after administration before appreciable clinical benefit could be observed. In both patients, onasemnogene abeparvovec DNA and messenger RNA distribution were widespread among peripheral organs and in the CNS. The greatest concentration of vector genomes was detected in the liver, with an increase over that detected in CNS tissues of 300-1,000-fold. SMN protein, which was low in an untreated SMA1 control, was clearly detectable in motor neurons, brain, skeletal muscle and multiple peripheral organs in treated patients. These data support the fact that onasemnogene abeparvovec has effective distribution, transduction and expression throughout the CNS after intravenous administration and restores SMN expression in humans.

Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial.

BACKGROUND: Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy. METHODS: STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes per kg) for 30-60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed). FINDINGS: From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36-100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79-100]) survived free from permanent ventilation at age 14 months (vs 6 [26%], 8-44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus). INTERPRETATION: Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit-risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1. FUNDING: Novartis Gene Therapies.

An updated cost-utility model for onasemnogene abeparvovec (Zolgensma®) in spinal muscular atrophy type 1 patients and comparison with evaluation by the Institute for Clinical and Effectiveness Review (ICER).

Background: Recent cost-utility analysis (CUA) models for onasemnogene abeparvovec (Zolgensma®, formerly AVXS-101) in spinal muscular atrophy type 1 (SMA1) differ on key assumptions and results. Objective: To compare the manufacturer's proprietary CUA model to the model published by the Institute for Clinical and Economic Review (ICER), and to update the manufacturer's model with long-term follow-up data and some key ICER assumptions. Study design: We updated a recent CUA evaluating value for money in cost per incremental Quality-adjusted Life Year (QALY) of onasemnogene abeparvovec versus nusinersen (Spinraza®) or best supportive care (BSC) in symptomatic SMA1 patients, and compared it to the ICER model. Setting/Perspective: USA/Commercial payer Participants: Children aged <2 years with SMA1. Interventions: Onasemnogene abeparvovec, a single-dose gene replacement therapy, versus nusinersen, an antisense oligonucleotide, versus BSC. Main outcome measure: Incremental-cost effectiveness ratio and value-based price using traditional thresholds for general medicines in the US. Results: Updated survival (undiscounted) predicted by the model was 37.60 years for onasemnogene abeparvovec compared to 12.10 years for nusinersen and 7.27 years for BSC. Updated quality-adjusted survival using ICER's utility scores and discounted at 3% were 13.33, 2.85, and 1.15 discounted QALYs for onasemnogene abeparvovec, nusinersen, and BSC, respectively. Using estimated net prices, the discounted lifetime cost/patient was $3.93 M for onasemnogene abeparvovec, $4.60 M for nusinersen, and $1.96 M for BSC. The incremental cost per QALY gained for onasemnogene abeparvovec was dominant against nusinersen and $161,648 against BSC. These results broadly align with the results of the ICER model, which predicted a cost per QALY gained of $139,000 compared with nusinersen, and $243,000 compared with BSC (assuming a placeholder price of $2 M for onasemnogene abeparvovec), differences in methodology notwithstanding. Exploratory analyses in presymptomatic patients were similar. Conclusion: This updated CUA model is similar to ICER analyses comparing onasemnogene abeparvovec with nusinersen in the symptomatic and presymptomatic SMA populations. At a list price of $2.125 M, onasemnogene abeparvovec is cost-effective compared to nusinersen for SMA1 patients treated before age 2 years. When compared to BSC, cost per QALY of onasemnogene abeparvovec is higher than commonly used thresholds for therapies in the USA ($150,000 per QALY).

AVXS-101 (Onasemnogene Abeparvovec) for SMA1: Comparative Study with a Prospective Natural History Cohort.

BACKGROUND: Spinal muscular atrophy type 1 (SMA1) is the leading genetic cause of infant mortality for which therapies, including AVXS-101 (onasemnogene abeparvovec, Zolgensma®) gene replacement therapy, are emerging. OBJECTIVE: This study evaluated the effectiveness of AVXS-101 in infants with spinal muscular atrophy type 1 (SMA1) compared with a prospective natural history cohort and a cohort of healthy infants. METHODS: Twelve SMA1 infants received the proposed therapeutic dose of AVXS-101 (NCT02122952). Where possible, the following outcomes were compared with a natural history cohort of SMA1 infants (n = 16) and healthy infants (n = 27) enrolled in the NeuroNEXT (NN101) study (NCT01736553): event-free survival, CHOP-INTEND scores, motor milestone achievements, compound muscle action potential (CMAP), and adverse events. RESULTS: Baseline characteristics of SMA1 infants in the AVXS-101 and NN101 studies were similar in age and genetic profile. The proportion of AVXS-101-treated infants who survived by 24 months of follow-up was higher compared with the NN101 study (100% vs 38%, respectively). The average baseline CHOP-INTEND score for NN101 SMA1 infants was 20.3, worsening to 5.3 by age 24 months; the average baseline score in AVXS-101-treated infants was 28.2, improving to 56.5 by age 24 months. Infants receiving AVXS-101 achieved motor milestones, such as sitting unassisted and walking. Improvements in CMAP peak area were observed in AVXS-101-treated infants at 6 and 24 months (means of 1.1 and 3.2 mV/s, respectively). CONCLUSIONS: In this study, AVXS-101 increased the probability of survival, rapidly improved motor function, and enabled motor milestone achievement in SMA1 infants.

Impact of Age and Motor Function in a Phase 1/2A Study of Infants With SMA Type 1 Receiving Single-Dose Gene Replacement Therapy.

BACKGROUND: This study characterizes motor function responses after early dosing of AVXS-101 (onasemnogene abeparvovec) in gene replacement therapy in infants with severe spinal muscular atrophy type 1 (SMA1). METHODS: This study is a follow-up analysis of 12 infants with SMA1 who received the proposed therapeutic dose of AVXS-101 in a Phase 1 open-label study (NCT02122952). Infants were grouped according to age at dosing and baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores: (1) early dosing/low motor, dosed age less than three months with scores <20 (n = 3), (2) late dosing, dosed at age three months or greater (n = 6), and (3) early dosing/high motor, dosed age less than three months with scores ≥20 (n = 3). RESULTS: Early dosing/low motor group demonstrated a mean gain of 35.0 points from a mean baseline of 15.7, whereas the late dosing group had a mean gain of 23.3 from a mean baseline of 26.5. The early dosing/high motor group quickly reached a mean score of 60.3, near the scale maximum (64), from a mean baseline of 44.0. Despite a lower baseline motor score, the early dosing/low motor group achieved sitting unassisted earlier than the late dosing group (mean age: 17.0 vs 22.0 months). The early dosing/high motor group reached this milestone earliest (mean age: 9.4 months). CONCLUSIONS: The rapid, significant motor improvements among infants with severe SMA1 treated with AVXS-101 at an early age highlight the importance of newborn screening and early treatment and demonstrate the therapeutic potential of AVXS-101 regardless of baseline motor function.

Cost-effectiveness analysis of using onasemnogene abeparvocec (AVXS-101) in spinal muscular atrophy type 1 patients.

Background: Spinal muscular atrophy type 1 (SMA1) is a devastating genetic disease for which gene-replacement therapy may bring substantial survival and quality of life benefits. Objective: This study investigated the cost-effectiveness of onasemnogene abeparvovec (AVXS-101) gene-replacement therapy for SMA1. Study design: A Markov model was used to estimate the incremental cost-effectiveness ratio (ICER), expressed as cost/quality-adjusted life year ($/QALY), of AVXS-101 versus nusinersen over a lifetime. Survival, healthcare costs and QALYs were estimated using natural history data for SMA patients who achieved motor milestones (sitting/walking). Health utility weights were obtained from the CHERISH trial. Setting: USA; commercial payer perspective Participants: SMA1 infants Interventions: AVXS-101 was compared to nusinersen. Main outcome measure: The primary outcome was the ICER. Results: Expected survival (undiscounted) over a lifetime predicted by the model was 37.20 life years for AVXS-101 and 9.68 for nusinersen (discounted QALYs, 15.65 and 5.29, respectively). Using a potential AVXS-101 price range ($2.5-5.0M/treatment), the average lifetime cost/patient was $4.2-6.6M for AVXS-101 and $6.3M for nusinersen. The ICER range was (-$203,072) to $31,379 per QALY gained for AVXS-101 versus nusinersen, indicating that AVXS-101 was cost-effective with prices of ≤$5M. Conclusion: Single-dose AVXS-101 was cost-effective compared to chronic nusinersen for SMA1 patients.

Translational and Early Phase Strategies for Treatment Development: Report of ISCTM Autumn 2013 Symposium.

For decades, there has been a distinct disconnect translating a compound's effects from basic neuroscience into clinical efficacy. This disconnect has not only been in terms of generating approved compounds, but also in rejecting targets. During the drug discovery process there are key points to be adhered to that would strengthen the likelihood of a compound being translated to the clinic. These points include 1) the importance of translational pharmacology whereby preclinical pharmacological data should predict clinical efficacy; 2) rigorous early phase drug evaluation to enhance early go/no-go decisionmaking; 3) using exposure response modeling to predict drug efficacy during proof-of-concept trials; 4) designing and conducting the appropriate proof-of-concept study; and 5) optimizing Phase II studies to set the stage for success in Phase III trials. These topics were covered in The International Society for CNS Clinical Trials and Methodology (ISCTM) Autumn 2013 meeting on the topic of translational and early development strategies and tools led by Drs. Potter and Feltner. This report comprises a review of those proceedings with a concluding summary to advance future clinical trials.

Study Site Experiences and Attitudes Toward Prospective Assessments of Suicidal Ideation and Behavior in Clinical Trials: Results of an Internet-based Survey.

OBJECTIVE: The International Society for CNS Clinical Trials and Methodology Suicidal Ideation and Behavior Assessment Working Group conducted an online survey regarding clinical trial site experiences and attitudes toward suicidal ideation and behavior data collection following the 2010 release of the initial United States Food and Drug Administration draft guidance on prospective assessment of suicidal ideation and behavior in clinical trials. Sites that had participated in at least one central nervous system clinical trial in the prior two years (N=6,058) were invited, via email, to complete a 20-item online assessment survey. RESULTS: Nine hundred and seventy-nine evaluable responses were collected (42% United States). Respondents included principal investigators (36%), raters (28%), coordinators (25%), and others (10%). The majority were psychiatrists (43%) and reported using suicidal ideation and behavior assessments across many indications. Most respondents (80%) personally conducted suicidal ideation and behavior assessments. Overall, respondents indicated that suicidal ideation and behavior assessments were readily incorporated into the conduct of clinical trials and improved subject safety. The greatest challenge was obtaining an accurate baseline lifetime history (51%), while the greatest benefit was identifying subjects at risk of suicide (84%). Approximately a quarter of respondents reported implementation challenges such as training. Differences based on geographical region, respondents' roles, and responsibility for assessments were observed. Open-ended responses revealed additional challenges, e.g., use in cognitively impaired populations. CONCLUSION: Prospective suicidal ideation and behavior monitoring was generally viewed positively, though specific challenges were identified. Limitations include self-report survey methodology and recruitment of only central nervous system clinical trials sites. These findings may help guide development of better methodologies for suicidal ideation and behavior assessment in clinical trials.

Vocal acoustic biomarkers of depression severity and treatment response.

BACKGROUND: Valid, reliable biomarkers of depression severity and treatment response would provide new targets for clinical research. Noticeable differences in speech production between depressed and nondepressed patients have been suggested as a potential biomarker. METHODS: One hundred five adults with major depression were recruited into a 4-week, randomized, double-blind, placebo-controlled research methodology study. An exploratory objective of the study was to evaluate the generalizability and repeatability of prior study results indicating vocal acoustic properties in speech may serve as biomarkers for depression severity and response to treatment. Speech samples, collected at baseline and study end point using an automated telephone system, were analyzed as a function of clinician-rated and patient-reported measures of depression severity and treatment response. RESULTS: Regression models of speech pattern changes associated with clinical outcomes in a prior study were found to be reliable and significant predictors of outcome in the current study, despite differences in the methodological design and implementation of the two studies. Results of the current study replicate and support findings from the prior study. Clinical changes in depressive symptoms among patients responding to the treatments provided also reflected significant differences in speech production patterns. Depressed patients who did not improve clinically showed smaller vocal acoustic changes and/or changes that were directionally opposite to treatment responders. CONCLUSIONS: This study supports the feasibility and validity of obtaining clinically important, biologically based vocal acoustic measures of depression severity and treatment response using an automated telephone system.

An 8-week, randomized controlled trial of atomoxetine, atomoxetine plus buspirone, or placebo in adults with ADHD.

OBJECTIVE: To examine the efficacy and safety of atomoxetine combined with buspirone versus atomoxetine monotherapy and placebo in adult attention-deficit/hyperactivity disorder (ADHD). METHOD: In this randomized, 8-week, 3-arm, double-blind, placebo-controlled trial conducted from November 2004 through December 2005, 241 adults with ADHD were randomly assigned in a 2:2:1 ratio to receive up to twice-daily atomoxetine and thrice-daily buspirone (n = 97), twice-daily atomoxetine (n = 97), or placebo (n = 47). Participants met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for ADHD. The primary efficacy measure was the adult ADHD Investigator Symptom Rating Scale (AISRS). RESULTS: Decrease in the AISRS total score was significantly greater for atomoxetine-buspirone than placebo at all time points from weeks 1 to 7, with an estimated mean difference of -4.80 (P = .001). Reduction in the mean AISRS total score was numerically greater for atomoxetine-buspirone than for atomoxetine at all time points, but statistically significant at week 4 only (estimated difference = -2.04, P < .10). The effect size for atomoxetine plus buspirone was 0.51, and for atomoxetine alone, it was 0.40. Insomnia, nausea, dry mouth, headache, and asthenia were frequently reported adverse events for both active treatment groups, and dizziness was also frequently reported for the atomoxetine-buspirone group. Discontinuations due to treatment-related adverse effects were 15.5% for atomoxetine-buspirone, 11.3% for atomoxetine, and 14.9% for placebo. CONCLUSIONS: There was little indication of improvement for atomoxetine plus buspirone versus atomoxetine monotherapy, as most efficacy measures showed only slightly greater quantitative improvement for the combination, generally without statistical significance. It is of note, however, that the quantitative differences between these 2 groups were virtually all in the direction of greater efficacy for the atomoxetine plus buspirone group. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00174226.

Efficacy of pregabalin in generalized social anxiety disorder: results of a double-blind, placebo-controlled, fixed-dose study.

The objective of this study was to evaluate the efficacy and tolerability of pregabalin for the treatment of generalized social anxiety disorder (SAD). Patients with generalized SAD, who met the Diagnostic and Statistical Manual of Mental Disorders (fourth edition) criteria (total N=329), were randomly assigned to 11 weeks of double-blind treatment with fixed daily doses of either pregabalin (300, 450, and 600(mg) or placebo. The treatment with pregabalin (600(mg) was associated with a significantly greater mean reduction in the Liebowitz Social Anxiety Scale total score, from baseline to endpoint, compared with placebo (-29.8 vs. -19.7; P= 0.0099), whereas reduction on pregabalin (300(mg, -20.2) and pregabalin (450(mg, -25.5) was not significant Treatment with pregabalin (600(mg) was also associated with a significantly greater improvement than placebo on the fear and avoidance subscales of the Liebowitz Social Anxiety Scale, as well as the majority of other secondary measures. Onset of improvement occurred by week 1 in the pregabalin 600-mg dose group. The most common adverse events on all three doses of pregabalin were somnolence and dizziness. Consistent with a previous study, the results of this study suggest that the 600-mg dose of pregabalin per day may be efficacious in the treatment of SAD.

Evaluation of the subjective and reinforcing effects of diphenhydramine, levetiracetam, and valproic acid.

Few unscheduled sedating medications have been evaluated for their subjective and reinforcing effects in humans. To increase the information available about unscheduled sedating medications and to evaluate the ability of human laboratory measures to discriminate between scheduled and unscheduled sedating drugs, 24 subjects with a history of experience with several classes of drugs of abuse, including sedatives and/or alcohol, and who reported liking a test dose of pentobarbital 300 mg, were randomized to single doses of diphenhydramine 400 mg, levetiracetam 4000 mg, valproic acid 1500 mg, diazepam 30 mg or placebo in a double-blind, 5-way crossover study. On the Addiction Research Center Inventory-Morphine-Benzedrine Group and the Next Day Questionnaire measures 'Take Again' and 'Willing to Pay', diazepam produced a significantly greater effect than placebo; all three other active drugs did not. Levetiracetam significantly increased the crossover point on the Multiple Choice Procedure, whereas diazepam did not. For the doses studied, the rank order of statistically significant findings suggestive of abuse potential was diazepam (9/10 measures significant) > levetiracetam (6/10) > diphenhydramine (5/10) > valproic acid (2/10).

Management of generalized anxiety disorder in primary care: identifying the challenges and unmet needs.

BACKGROUND: Generalized anxiety disorder (GAD) is one of the most common psychiatric disorders in primary care, although it is often underrecognized and undertreated. GAD is chronic, disabling, and associated with other health problems. Treatment response is often unsatisfactory, but the clinical evidence base for new treatments has expanded substantially in the past decade and suggests a growing range of options for reducing the burden of GAD. The objective of this article was to review current literature on GAD and its management to provide an overview of the clinical importance of GAD in primary care and available treatments. DATA SOURCES: Recent studies (ie, over the past decade) on the epidemiology and treatment of GAD were identified by searching Medline using the term generalized anxiety disorder only and in combination with the terms epidemiology and treatment and for each drug class (benzodiazepines, azapirones, antidepressants, antihistamines, alpha-2-delta ligands, and antipsychotics) and for named drugs (buspirone, venlafaxine, duloxetine, fluoxetine, escitalopram, olanzapine, paroxetine, pregabalin, quetiapine, and risperidone in addition to psychological therapies and cognitive-behavioral therapy. The literature search was conducted in August 2008 for the period 1987-2009. STUDY SELECTION: Studies were included if judged to be relevant to a review of the epidemiology and management of GAD. Articles were excluded if they were not written in English or were published more than 10 years before the literature search was conducted. A few older studies were included for which more recent research evidence was not available. Recent national and international guidelines for the management of GAD were also reviewed. DATA EXTRACTION/SYNTHESIS: Most currently available interventions have similar overall efficacy, and treatment choices should reflect the situation of individual patients. Important unmet needs exist for treatments (1) that work rapidly, with (2) broad spectrum benefits, (3) that can improve rates of remission and well-being, (4) are devoid of risk for withdrawal symptoms, and (5) have few if any adverse interactions with other drugs. Additional needs include (6) safer drugs for the elderly, (7) safe and effective drugs for children with GAD, (8) further evaluation of psychotherapy, and (9) understanding the appropriate circumstances for, and optimal choices of, drug combination. CONCLUSION: While the development of novel treatments evolves, current management approaches can focus on improving identification and defining optimal use of available therapies for GAD.

Comparative efficacy of pregabalin and benzodiazepines in treating the psychic and somatic symptoms of generalized anxiety disorder.

Prior research suggests that SSRIs may have greater efficacy for psychic compared to somatic anxiety, while benzodiazepines show greater somatic efficacy. The goal of this analysis was to evaluate the efficacy of pregabalin (PGB) in treating psychic and somatic symptoms of anxiety. Data were combined from six short-term, double-blind, placebo-controlled, fixed-dose trials of PGB in patients with generalized anxiety disorder (GAD). The following PGB daily dose groups were studied: 150 mg (n=210), 300-450 mg (n=455), and 600 mg (n=406), benzodiazepines (6 mg/d lorazepam and 1.5 mg/d alprazolam, n=299), vs. placebo (n=484). Changes in Hamilton Anxiety Rating Scale (HAMA) psychic and somatic anxiety factors and individual items were analysed. Treatment with 300-600 mg PGB significantly improved both the HAMA psychic and somatic anxiety factors. In contrast, treatment with 150 mg PGB appeared to be less effective, achieving significance only on the psychic anxiety factor. PGB (300-450 mg) was associated with significant improvement on 13 out of 14 HAMA items, while treatment with 600 mg PGB was associated with significant improvement in 10 out of 14 HAMA items. Treatment with benzodiazepines was also associated with significant improvement in both psychic and somatic anxiety factors, with significant improvement occurring in 5 out of 14 HAMA items. The results of this pooled analysis indicate that both PGB and benzodiazepines had significant efficacy in treating both HAMA psychic and somatic anxiety. A dose-response effect was evident for PGB that reached a plateau at a dose of 300 mg/d.

Effect of renal impairment on the pharmacokinetics of PD 0200390, a novel ligand for the voltage-gated calcium channel alpha-2-delta subunit.

AIMS: To investigate the pharmacokinetics and safety of PD 0200390 in healthy subjects and subjects with renal impairment (RI) and to examine the relationship between oral and renal PD 0200390 clearance and estimated creatinine clearance (CLcr). METHODS: In this open-label study, 26 subjects were categorized into four groups based on renal function: no RI (CLcr >80 ml min(-1); n= 6); mild RI (CLcr 51 to < or =80 ml min(-1); n= 6); moderate RI (CLcr >30 to 50 ml min(-1); n= 6); and severe RI (CLcr < or =30 ml min(-1); n= 8). Subjects received a single, oral dose of PD 0200390 25 mg. Noncompartmental pharmacokinetic parameters were determined from plasma and urine concentration-time data. RESULTS: PD 0200390 was rapidly absorbed; mean time to maximum plasma concentration was 1.66-3.24 h. Mean half-life in subjects with normal renal function was 5.36 h, and increased with worsening RI. Oral (CL/F) and renal (CL(R)) clearance rates decreased with deteriorating renal function, whereas area under the concentration-time curve (AUC(0-infinity)) values increased by 56, 117 and 436% in subjects with mild, moderate and severe RI, respectively, indicating increased PD 0200390 exposure. Regression analysis demonstrated that CL/F and CL(R) correlated with CLcr (r= 0.953 and 0.961, respectively). PD 0200390 was well tolerated in subjects with mild, moderate or no RI. The most common adverse events were somnolence, dizziness and headache; these occurred with greatest intensity in the severe RI group. CONCLUSIONS: PD 0200390 pharmacokinetic parameters (CL/F, CL(R) and AUC(0-infinity)) vary predictably with decreases in renal function; therefore dose adjustment may be required in individuals with RI.

Clinical evaluation of the Daily Assessment of Symptoms-Anxiety (DAS-A): a new instrument to assess the onset of symptomatic improvement in generalized anxiety disorder.

INTRODUCTION: Rapid onset of symptomatic improvement is a desirable characteristic of new generalized anxiety disorder (GAD) treatments. A validated rating scale is needed to assess GAD symptoms during the first days of treatment. AIMS: To provide clinical data to support the validation of the Daily Assessment of Symptoms-Anxiety (DAS-A), a new instrument to assess onset of symptomatic improvement in GAD. METHODS: We assessed the ability of the DAS-A to detect onset of symptomatic improvement during the first week of therapy in 169 GAD patients randomized to paroxetine 20 mg/day, lorazepam 4.5 mg/day, or placebo for 4 weeks. RESULTS: On the primary outcome measure, average change from baseline over the first 6 days of DAS-A assessments, lorazepam (-14.5 +/- 1.8 [LS mean, SE]; P= 0.006 vs. placebo) showed a significant improvement versus placebo (-7.85 +/- 1.7), whereas paroxetine (-8.3 +/- 1.7; P= 0.83 vs. placebo) did not. Lorazepam produced a significant treatment effect on the DAS-A at 24 h (P= 0.0004), whereas paroxetine did not (P= 0.5666). Both active drugs produced statistically significant improvement versus placebo on the DAS-A total change score (last-observation carried forward method; LOCF, endpoint). On the DAS-A total change score (observed cases analysis), lorazepam produced statistically significant improvement versus placebo at weeks 1, 2, and 4 (P < 0.05; no week 3 visit), whereas paroxetine, separated from placebo at weeks 2 and 4 (P < 0.05). Both active drugs produced results on the Hamilton Anxiety Rating Scale (HAM-A) at weeks 1 through 4 that were similar to those found on the DAS-A. CONCLUSIONS: These data indicate that the DAS-A can detect symptomatic improvement in GAD patients treated with lorazepam during the first week of treatment, and, in a secondary analysis, as early as 24 h.

How modeling and simulation have enhanced decision making in new drug development.

The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer's disease (AD). The issue was how to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression, and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning experiences as well as extensive financial savings. The motivation for this case in point was the "Learn-Confirm" paradigm described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug Application was applied to confirm the evidence of efficacy across these dose levels. Modeling and simulation analyses showed that the two studies corroborate each other with respect to the pain relief profiles. The use of PK/PD information confirmed evidence of efficacy across the three studied doses, eliminating the need for additional clinical trials and thus supporting the approval of the product. It can be speculated that the work by Lewis Sheiner reflected in the FDA document titled "Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products" made this scientific approach to the drug approval process possible.

Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam.

BACKGROUND: Pregabalin inhibits release of excess excitatory neurotransmitters, presumably by binding to the alpha2-delta subunit protein of widely distributed voltage-dependent calcium channels in the brain and spinal cord. OBJECTIVE: To assess the anxiolytic efficacy of pregabalin in patients with generalized anxiety disorder. DESIGN: Double-blind, placebo-controlled, active-comparator trial. Patients were randomized to 4 weeks of treatment with pregabalin, 300 mg/d (n = 91), 450 mg/d (n = 90), or 600 mg/d (n = 89); alprazolam, 1.5 mg/d (n = 93); or placebo (n = 91). SETTING: Psychiatry research and clinic settings. PATIENTS: Outpatients meeting the DSM-IV criteria for generalized anxiety disorder, with a baseline Hamilton Anxiety Rating Scale (HAM-A) total score of 20 or greater. MAIN OUTCOME MEASURES: Change from baseline to end point in total HAM-A score in the pregabalin and alprazolam groups compared with the placebo group. The end point response criterion was 50% or greater reduction in the HAM-A total score. RESULTS: Pregabalin and alprazolam produced a significantly greater reduction in mean +/- SE HAM-A total score at last-observation-carried-forward end point compared with placebo (-8.4 +/- 0.8): pregabalin, 300 mg (-12.2 +/- 0.8, P<.001), 450 mg (-11.0 +/- 0.8, P = .02), and 600 mg (-11.8 +/- 0.8, P = .002), and alprazolam (-10.9 +/- 0.8, P = .02). By week 1 and at last-observation-carried-forward end point, the 3 pregabalin groups and the alprazolam group had significantly (P<.01) improved HAM-A psychic anxiety symptoms compared with the placebo group. Compared with the placebo group, HAM-A somatic anxiety symptoms were also significantly (P<.02) improved by the 300- and 600-mg pregabalin groups, but not by the 450-mg pregabalin (week 1, P = .06; week 4, P = .32) and the alprazolam groups (week 1, P = .21; week 4, P = .15). Of the 5 treatment groups, the 300-mg pregabalin group was the only medication group that differed statistically in global improvement at treatment end point not only from the placebo group but also from the alprazolam group. CONCLUSION: Pregabalin was significantly more efficacious than placebo for the treatment of psychic and somatic symptoms of generalized anxiety disorder and was well tolerated by most study patients.

Efficacy of pregabalin in the treatment of generalized anxiety disorder: double-blind, placebo-controlled comparison of BID versus TID dosing.

Pregabalin is a new anxiolytic that acts as a presynaptic inhibitor of the release of excessive levels of excitatory neurotransmitters by selectively binding to the alpha2-delta subunit of voltage-gated calcium channels. The current study evaluated the anxiolytic efficacy of BID versus TID dosing of pregabalin in patients with generalized anxiety disorder. Outpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition generalized anxiety disorder and having baseline Hamilton Anxiety (HAM-A) total scores > or =20 were randomized to 6 weeks of double-blind treatment with pregabalin 200 mg/d (BID; N = 78), 400 mg/d (BID; N = 89), or 450 mg/d (TID; N = 88) or placebo (N = 86). Mean improvement in HAM-A total score at last observation carried forward end point was significantly greater on pregabalin 200 (P = 0.006), 400 (P = 0.001), and 450 mg/d (P = 0.005) compared with placebo. Pairwise comparisons of BID versus TID dosing found no difference in HAM-A change score at end point. All 3 pregabalin dosage groups showed significantly greater efficacy versus placebo at end point on the HAM-A psychic and somatic anxiety factor scores. Improvement on both factors was rapid: significance versus placebo was achieved as early as the first assessment at week 1, with > or =30% reduction in HAM-A severity and equal or greater improvement for every subsequent visit in > or =38% of patients in all 3 pregabalin dosage groups (P < or = 0.001). Pregabalin was well tolerated, and despite the fixed-dose study design, discontinuations caused by adverse events ranged from 9% to 13%--comparable with that observed with placebo (8%). This study demonstrates that pregabalin is an effective treatment of generalized anxiety disorder, with BID dosing showing similar efficacy and comparable tolerability with TID dosing.