Assessment of immunogenicity from galcanezumab phase 3 trials in patients with episodic or chronic migraine.

BACKGROUND: This analysis characterizes the immunogenicity profile of galcanezumab, a humanized monoclonal antibody that selectively binds calcitonin gene-related peptide and inhibits its activity, in phase 3 migraine trials. METHODS: Immunogenicity data were analyzed from baseline and double-blind, placebo-controlled phases of the 3-month chronic migraine study REGAIN, the 6-month episodic migraine studies EVOLVE-1 and EVOLVE-2, and from baseline and open-label phases of the 12-month chronic and episodic migraine Study CGAJ. The incidence of baseline antidrug antibodies, treatment-emergent antidrug antibodies, neutralizing antidrug antibodies, and the effect of antidrug antibody titer on pharmacokinetics and pharmacodynamics were assessed. The relationship between antidrug antibody status and efficacy was explored using average change in monthly migraine headache days. Safety analyses assessed the potential relationship between treatment-emergent antidrug antibodies and hypersensitivity events or adverse events related to injection sites. FINDINGS: Across studies, 5.9-11.2% of patients had baseline antidrug antibodies. The incidence of treatment-emergent antidrug antibodies was 2.6-12.4% in the galcanezumab group and 0.5-1.7% in the placebo group. The majority of treatment-emergent antidrug antibodies were detected approximately 3-6 months after first study drug dose. Overall, the observed antidrug antibody titer did not impact galcanezumab concentrations, calcitonin gene-related peptide concentrations, or galcanezumab efficacy. There was no evidence that hypersensitivity events or adverse events related to injection sites were mediated by treatment-emergent antidrug antibodies. INTERPRETATION: These data showed that immunogenicity did not impact galcanezumab concentrations, calcitonin gene-related peptide concentrations, or the efficacy and hypersensitivity profile of galcanezumab in patients with migraine.

Effects of once-weekly dulaglutide on kidney function in patients with type 2 diabetes in phase II and III clinical trials.

Dulaglutide is a once-weekly glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes (T2D). Integrated data from 9 phase II and III trials in people with T2D (N = 6005) were used to evaluate the effects of dulaglutide on estimated glomerular filtration rate (eGFR [Chronic Kidney Disease Epidemiology Collaboration]), urine albumin-to-creatinine ratio (UACR) and kidney adverse events (AEs). No significant differences in eGFR were observed during treatment for dulaglutide vs placebo, active comparators or insulin glargine (mean ± standard deviation values: dulaglutide vs placebo: 87.8 ± 17.7 vs 88.2 ± 17.9 mL/min/1.73 m2 , P = .075; dulaglutide vs active comparators: 89.9 ± 16.7 vs 88.8 ± 16.3 mL/min/1.73 m2 , P = .223; and dulaglutide vs insulin glargine: 85.9 ± 18.2 vs 83.9 ± 18.6 mL/min/1.73 m2 , P = .423). Lower UACR values were observed for dulaglutide vs placebo, active comparators and insulin glargine (at 26 weeks, median [Q1-Q3] values were: dulaglutide vs placebo: 8.0 [4.4-20.4] vs 8.0 [4.4-23.9] mg/g, P = .023; dulaglutide vs active comparators: 8.0 [4.4-21.2] vs 8.9 [4.4-27.4] mg/g, P = .013; and dulaglutide vs insulin glargine: 8.9 [4.4-29.2] vs 12.4 [5.3-50.5] mg/g, P = .029). AEs reflecting potential acute renal failure were 3.4, 1.7 and 7.0 events/1000 patient-years for dulaglutide, active comparators and placebo, respectively. In conclusion, dulaglutide treatment of clinical trial participants with T2D did not affect eGFR and slightly decreased albuminuria.

Tirzepatide Immunogenicity on Pharmacokinetics, Efficacy, and Safety: Analysis of Data From Phase 3 Studies.

CONTEXT: Antidrug antibodies (ADA) can potentially affect drug pharmacokinetics, safety, and efficacy. OBJECTIVE: This work aimed to evaluate treatment-emergent (TE) ADA in tirzepatide (TZP)-treated participants across 7 phase 3 trials and their potential effect on pharmacokinetics, efficacy, and safety. METHODS: ADA were assessed at baseline and throughout the study until end point, defined as week 40 (SURPASS-1, -2, and -5) or week 52 (SURPASS-3, -4, Japan-Mono, and Japan-Combo). Samples for ADA characterization were collected at SURPASS trial sites. Participants included ADA-evaluable TZP-treated patients with type 2 diabetes (N = 5025). Interventions included TZP 5, 10, or 15 mg. ADA were detected and characterized for their ability to cross-react with native glucose-dependent insulinotropic polypeptide (nGIP) and glucagon-like peptide-1 (nGLP-1), neutralize tirzepatide activity on GIP and GLP-1 receptors, and neutralize nGIP and nGLP-1. RESULTS: TE ADA developed in 51.1% of tirzepatide-treated patients. Proportions were similar across dose groups. Maximum ADA titers ranged from 1:20 to 1: 81 920 among TE ADA+ patients. Neutralizing antibodies (NAb) against TZP activity on GIP and GLP-1 receptors were observed in 1.9% and 2.1% of patients, respectively. Less than 1.0% of patients had cross-reactive NAb against nGIP or nGLP-1. TE ADA status, ADA titer, and NAb status had no effect on the pharmacokinetics or efficacy of TZP. More TE ADA+ patients experienced hypersensitivity reactions or injection site reactions than TE ADA- patients. The majority of hypersensitivity and injection site reactions were nonserious and nonsevere, and most events occurred and/or resolved irrespective of TE ADA status or titer. CONCLUSION: Immunogenicity did not affect TZP pharmacokinetics or efficacy. The majority of hypersensitivity or injection site reactions experienced by TE ADA+ patients were mild to moderate in severity.

Clinical Trial Drug Safety Assessment for Studies and Submissions Impacted by COVID-19.

Abstract-In this article, we provide guidance on how safety analyses and reporting of clinical trial safety data may need to be modified, given potential impact from the COVID-19 pandemic. Impact could include missed visits, alternative methods for assessments (such as virtual visits), alternative locations for assessments (such as local labs), and study drug interruptions. Starting from the safety analyses typically included in Clinical Study Reports for Phase 2-4 clinical trials and integrated submission documents, we assess what modifications might be needed. If the impact from COVID-19 affects treatment arms equally, analyses of adverse events from controlled data can, to a large extent, remain unchanged. However, interpretation of summaries from uncontrolled data (summaries that include open-label extension data) will require even more caution than usual. Special consideration will be needed for safety topics of interest, especially events expected to have a higher incidence due to a COVID-19 infection or due to quarantine or travel restrictions (e.g., depression). Analyses of laboratory measurements may need to be modified to account for the combination of measurements from local and central laboratories.

Effective Partnering in Conducting Benefit-Risk Patient Preference Studies: Perspectives From a Patient Advocacy Organization, a Pharmaceutical Company, and Academic Stated-Preference Researchers.

BACKGROUND: Formal incorporation of patients' perspectives is becoming increasingly important in medical product development and decision making. This article shares practical advice regarding how patient advocacy organizations, the pharmaceutical industry, and academic experts in stated-preference research can effectively partner on benefit-risk patient preference studies. METHODS: The authors partnered on a benefit-risk patient preference study related to the treatment of psoriasis. The authors from Duke Clinical Research Institute also share their experiences in collaborating with numerous other organizations in conducting benefit-risk patient preference studies. RESULTS: Upon initiation of the study partnership with appropriate experts, training is important to ensure all collaborators have a common understanding of the methodology, what objectives stated-preference methods can support, and expectations for the project. To the extent possible, partners should align on and document relevant clinical and logistical details prior to study implementation. During study implementation, partners should use good communication practices and document and maintain a record of any changes to the original plan. Presentation of the study results should be tailored to the particular audience, with the appropriate partner leading the presentation based on its format and audience. CONCLUSION: Partners from patient advocacy organizations, the pharmaceutical industry, and academia can effectively collaborate on benefit-risk patient preference studies with sufficient planning and ongoing communication. This article is a call for action for other organizations to engage in sharing of experiences regarding effective partnering in quantifying patient preferences in medical product development.

What is clearance worth? Patients' stated risk tolerance for psoriasis treatments.

PURPOSE: The purpose of this study was to provide quantitative evidence of patients' tolerance for therapeutic risks associated with psoriasis treatments that could offer psoriasis improvements beyond the PASI 75 benchmark. MATERIALS AND METHODS: We used a discrete-choice experiment in which respondents chose between competing psoriasis treatments characterized by benefits (i.e. reduced plaque severity, reduced plaque area), risks (i.e. 10-year risk of tuberculosis, 10-year risk of death from infection), and treatment regimen. We analyzed choice data using random-parameters logit models for psoriasis affecting the body, face, or hands. RESULTS: Of 927 eligible members of the National Psoriasis Foundation who completed the survey, 28% were unwilling to accept any greater risk of treatment-related infection mortality. Among the remaining 72%, respondents were willing to accept higher risks of infection-related mortality associated with treatment to completely remove plaques covering only 1% of the body, compared to reducing lesions from 10 to 1% of the affected area. This finding was more pronounced for lesions on the face. CONCLUSIONS: Most patients placed greater value on eliminating even very small plaques compared to avoiding treatment-related risks. The perceived importance of complete versus near-complete clearance was stronger than previously documented.

Assessment of Pancreas Safety in the Development Program of Once-Weekly GLP-1 Receptor Agonist Dulaglutide.

OBJECTIVE: To assess the risk of acute pancreatitis during treatment with glucagon-like peptide 1 receptor agonist dulaglutide, placebo, and active comparators across phase 2/3 dulaglutide trials. RESEARCH DESIGN AND METHODS: A total of 6,005 patients with type 2 diabetes participated (dulaglutide group N = 4,006 [dose range 0.1-3.0 mg]; active comparator group [metformin, sitagliptin, exenatide twice daily, insulin glargine] N = 1,541; placebo group N = 703; 245 placebo-treated patients subsequently received dulaglutide or sitagliptin and were also included in these groups) for up to 104 weeks. The following events were adjudicated: investigator-reported pancreatitis, adverse events (AEs) of severe or serious abdominal pain of unknown etiology, and confirmed asymptomatic increases in pancreatic enzymes ≥3× the upper limit of normal range. RESULTS: Overall, 203 events from 151 patients underwent adjudication (dulaglutide group n = 108; comparator group including placebo n = 43). Acute pancreatitis was confirmed by adjudication in seven patients (dulaglutide n = 3, placebo n = 1, sitagliptin n = 3). Exposure-adjusted incidence rates were as follows: dulaglutide group 0.85 patients/1,000 patient-years, placebo group 3.52 patients/1,000 patient-years, sitagliptin group 4.71 patients/1,000 patient-years. No events of pancreatitis were confirmed by adjudication in patients treated with exenatide twice daily, metformin, or glargine. Increases in median values of lipase and pancreatic amylase within the normal range were observed with all treatments except glargine. These changes were not associated with AEs. CONCLUSIONS: The exposure-adjusted incidence rate of acute pancreatitis in dulaglutide-treated patients was similar to the rates with placebo, with few reported cases during the entire program.

Genomic imprinting in Turner syndrome: effects on response to growth hormone and on risk of sensorineural hearing loss.

CONTEXT: Evidence exists for X-linked parent-of-origin effects in Turner syndrome, because phenotypic and cognitive profiles differ between 45,X(maternal) and 45,X(paternal) individuals. OBJECTIVE AND DESIGN: We evaluated the parent-of-origin effect of the intact X chromosome on spontaneous growth, GH-stimulated height gain, and frequency of sensorineural hearing loss in 54 subjects with Turner syndrome recruited from a Canadian randomized, controlled trial of GH supplementation to adult height. METHODS AND RESULTS: Microsatellite analyses revealed that 72% of nonmosaic 45,X subjects retained an X(maternal), whereas 86% of nonmosaic 46,X,i(Xq) subjects carried an intact X(paternal). No significant differences were noted between X(maternal) and X(paternal) subjects for parents' heights, birth weight and length, and height, age, or bone age at study entry. In all subjects, and in those with X(maternal), baseline height sd score correlated with midparental height (all: r = 0.511, P < 0.001; X(maternal): r = 0.535, P = 0.001) and with mother's height (all: r = 0.510, P < 0.001; X(maternal): r = 0.574, P < 0.001) but only weakly with father's height (all: r = 0.334, P = 0.015; X(maternal): r = 0.292, P = 0.094). Using a linear model including age and height at GH initiation, subjects with X(maternal) had a greater mean height gain than those with X(paternal) (sd score difference and 95% confidence interval for all karyotypes was +0.43 and 0.04-0.82, P = 0.030, and for 45,X was +0.64 and 0.06-1.21, P = 0.031); X-linked imprinting explained 36-53% of the GH response. After pure tone audiometry testing, X(maternal) subjects were also less likely (P = 0.040) to have sensorineural hearing loss than X(paternal) subjects. CONCLUSION: This study provides evidence of an X-linked imprinting effect on GH response and on sensorineural hearing loss in Turner syndrome and should fuel the search for candidate genes.

Implementation of Structured Benefit-Risk Assessments in Marketing Authorization Applications: Lessons Learned.

BACKGROUND: A recent publication from Eli Lilly and Company provided guidance on incorporation of a structured benefit-risk assessment framework into Section 2.5.6 of the Clinical Overview of marketing authorization applications. Because a template alone cannot deliver a judicious benefit-risk evaluation, the purpose of this manuscript is to present lessons learned and practical approaches that pharmaceutical companies (sponsors) can apply in developing holistic benefit risk assessments of medicinal products for their marketing authorization applications. METHODS: Benefit-risk scientists at Eli Lilly and Company facilitated use of a structured benefit-risk assessment in Section 2.5.6 of the Clinical Overview for a number of marketing authorization applications submitted to regulators between 2013 and the 2016. Based on our experiences in implementing the approach described in the publication by Wolka et al, we have identified commonalities that contributed to successful implementation. RESULTS: The 3 key learnings from the authors' experience are to (1) use a cross-functional team approach; (2) employ a process that lends to the objectivity and efficiency of benefit-risk assessments; and (3) leverage data visualizations for clear and concise communication of benefit-risk information. CONCLUSIONS: Sponsors can apply these approaches to incorporate benefit-risk assessments into their marketing authorization applications. Further shared learnings and benchmarking among the pharmaceutical industry will be necessary to further advance the science and practice of benefit-risk assessment.

Effects of tadalafil on erectile dysfunction in men with diabetes.

OBJECTIVE: To evaluate the efficacy and safety of tadalafil taken as needed before sexual activity by men with diabetes and erectile dysfunction (ED). RESEARCH DESIGN AND METHODS: Men with type 1 or type 2 diabetes and a minimum 3-month history of ED were randomly allocated to one of three groups: placebo (n = 71), tadalafil 10 mg (n = 73), or tadalafil 20 mg (n = 72) taken up to once daily for 12 weeks. Changes from baseline in mean scores on the erectile function domain of the International Index of Erectile Function (IIEF) and changes from baseline in the proportion of "yes" responses to question 2, "Were you able to penetrate?," and 3, "Were you able to complete intercourse?," of the Sexual Encounter Profile were coprimary outcome measures. RESULTS: A total of 191 (88%) of 216 patients completed the study. Treatment with tadalafil significantly improved all primary efficacy variables, regardless of baseline HbA(1c) level. Therapy with tadalafil also significantly improved a number of secondary outcome measures, including changes in other IIEF domains, individual IIEF questions, and percentage of positive responses to a global assessment question measuring erection improvement. Treatment with tadalafil did not alter mean HbA(1c) levels. Tadalafil was well tolerated, with headache and dyspepsia being the most frequent adverse events with active treatment. CONCLUSIONS: Tadalafil therapy significantly enhanced erectile function and was well tolerated by men with diabetes and ED.

Efficacy and safety of oral tadalafil in the treatment of men in Canada with erectile dysfunction: a randomized, double-blind, parallel, placebo-controlled clinical trial.

INTRODUCTION: Erectile dysfunction (ED) is a highly prevalent, often undertreated condition. AIM: This 12-week, double-blind, parallel, placebo-controlled study was conducted at 25 sites in Canada to evaluate the efficacy and safety of oral tadalafil, a phosphodiesterase type 5 inhibitor, for the treatment of ED. METHODS: Men with ED of organic, psychogenic, or mixed etiology were stratified by baseline ED severity then randomly assigned to placebo (N = 50), tadalafil 10 mg (N = 103), or tadalafil 20 mg (N = 100), taken as needed (maximum, once daily). MAIN OUTCOME MEASURES: Efficacy was assessed by the International Index of Erectile Function (IIEF), a Sexual Encounter Profile diary, and a global assessment question (GAQ). RESULTS: Tadalafil 10 mg and tadalafil 20 mg significantly improved erectile function compared with placebo (P < 0.001, all measures). At end point, the mean IIEF erectile function (EF) domain scores were 14.5, 21.2, and 23.3 of a possible score of 30 for placebo, tadalafil 10 mg, and tadalafil 20 mg, respectively. Patients treated with tadalafil reported greater change from baseline on the IIEF EF domain score compared with placebo, regardless of baseline ED severity. During treatment, the mean per-patient proportion of successful intercourse attempts was higher for tadalafil 10 mg and 20 mg than for placebo (placebo, 31.9%; tadalafil 10 mg, 56.7%; and tadalafil 20 mg, 61.5%), and a greater proportion of patients reported improved erections with tadalafil (GAQ; placebo, 22.0%; tadalafil 10 mg, 67.0%; tadalafil 20 mg, 79.0%). Fifty percent and 62% of patients treated with tadalafil 10 mg and 20 mg, respectively, achieved successful sexual intercourse after their first dose, compared with 31% with placebo. Treatment-emergent adverse events were generally mild or moderate. CONCLUSION: Tadalafil was an effective, well-tolerated therapy for ED of broad-spectrum etiology and severity.

Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial.

OBJECTIVES: To examine the therapeutic effects of tadalafil on erectile dysfunction (ED) at 24 and 36 hours after dosing. METHODS: A multicenter, randomized, double-blind, placebo-controlled, parallel-group study of 348 men (mean age 57 years) with ED was conducted in Europe and the United States. Patients were stratified by baseline severity of ED using the Erectile Function domain score of the International Index of Erectile Function and then randomly allocated within the severity group to receive tadalafil 20 mg (n = 175) or placebo (n = 173). Subsequently, participants were randomly assigned to two 4-week treatment intervals, during which they were requested to attempt sexual intercourse approximately 24 or 36 hours after tadalafil or placebo dosing. The primary outcome measure was the proportion of successful sexual intercourse attempts (completed to ejaculation) according to patient self-report using the Sexual Encounter Profile diary. RESULTS: Of the 348 patients, 327 (94%) completed the trial (163 of 175 in the tadalafil group and 164 of 173 in the placebo group). Thirty-six hours after tadalafil dosing, 59.2% of intercourse attempts were successful versus 28.3% in the placebo group (P <0.001). The proportion of successful intercourse attempts at approximately 24 hours after treatment was also significantly greater with tadalafil (52.9%) than with placebo (29.1%; P <0.001). Tadalafil was well tolerated. The incidences of four treatment-emergent adverse events were significantly greater in the tadalafil group than in the placebo group (all P <0.05): headache, flushing, dyspepsia, and myalgia. CONCLUSIONS: Tadalafil 20 mg is an effective and well-tolerated treatment for ED that has a period of responsiveness of up to 36 hours.

Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses.

PURPOSE: We conducted integrated analyses of the efficacy and safety of tadalafil, a potent, selective phosphodiesterase 5 inhibitor, for the treatment of erectile dysfunction. MATERIALS AND METHODS: A total of 1,112 men with a mean age of 59 years (range 22 to 82) and mild to severe erectile dysfunction of various etiologies were randomized to placebo or tadalafil, taken as needed without food or alcohol restrictions, at fixed daily doses of 2.5 mg, 5 mg, 10 mg, or 20 mg up to a maximum of once daily [DOSAGE ERROR CORRECTED] in 5 randomized, double-blind, placebo controlled trials lasting 12 weeks. The 3 co-primary outcomes were changes from baseline in the erectile function domain of the International Index of Erectile Function and the proportion of "yes" responses to questions 2 and 3 of the Sexual Encounter Profile. Additional efficacy instruments included a Global Assessment Question. RESULTS: Compared with placebo, tadalafil significantly enhanced all efficacy outcomes. Patients receiving 20 mg. tadalafil experienced a significant mean improvement of 7.9 in International Index of Erectile Function erectile function domain score from baseline (p <0.001 versus placebo), 75% of intercourse attempts (Sexual Encounter Profile question 3, a secondary efficacy outcome) were successfully completed (p <0.001 versus placebo) and 81% reported improved erections at end point compared with 35% in the control group (p <0.001). Tadalafil was consistently efficacious across disease severities and etiologies, as well as in patients of all ages. Tadalafil was well tolerated, and headache and dyspepsia were the most frequent adverse events. CONCLUSIONS: Tadalafil was effective and well tolerated in this patient population.