Dose-response effects on HbA1c and bodyweight reduction of survodutide, a dual glucagon/GLP-1 receptor agonist, compared with placebo and open-label semaglutide in people with type 2 diabetes: a randomised clinical trial.

AIMS/HYPOTHESIS: The aim of this study was to assess the dose-response effects of the subcutaneous glucagon receptor/glucagon-like peptide-1 receptor dual agonist survodutide (BI 456906) on HbA1c levels and bodyweight reduction. METHODS: This Phase II, multicentre, randomised, double-blind, parallel-group, placebo-controlled study, conducted in clinical research centres, assessed survodutide in participants aged 18-75 years with type 2 diabetes, an HbA1c level of 53-86 mmol/mol (7.0-10.0%) and a BMI of 25-50 kg/m2 on a background of metformin therapy. Participants were randomised via interactive response technology to receive survodutide (up to 0.3, 0.9, 1.8 or 2.7 mg once weekly [qw; dose group (DG) 1-4, respectively] or 1.2 or 1.8 mg twice weekly [DG 5 and 6, respectively]), placebo or semaglutide (up to 1.0 mg qw). Participants and all those involved in the trial conduct/analysis were blinded; the semaglutide arm was open-label. The primary endpoint was absolute change from baseline in HbA1c after 16 weeks' treatment. The key secondary endpoint was relative change from baseline in bodyweight after 16 weeks' treatment. RESULTS: A total of 413 participants were randomised (DG1, n=50; DG2, n=50; DG3, n=52; DG4, n=50; DG5, n=51; DG6, n=50; semaglutide, n=50; placebo, n=60). The full analysis set comprised 411 treated participants (DG6, n=49; placebo, n=59). Adjusted mean (95% CI) HbA1c decreased from baseline (mean ± SD 64.7±9.2 mmol/mol [8.07±0.84%] after 16 weeks' treatment: DG1 (n=41), -9.92 mmol/mol (-12.27, -7.56; -0.91% [-1.12, -0.69]); DG2 (n=46), -15.95 mmol/mol (-18.27, -13.63; -1.46% [-1.67, -1.25]); DG3 (n=36), -18.72 mmol/mol (-21.15, -16.29; -1.71% [-1.94, -1.49]); DG4 (n=33), -17.01 mmol/mol (-19.59, -14.43; -1.56% [-1.79, -1.32]); DG5 (n=44), -17.84 mmol/mol (-20.18, -15.51; -1.63% [-1.85, -1.42]); DG6 (n=36), -18.38 mmol/mol (-20.90, -15.87; -1.68% [-1.91, -1.45]). The mean reduction in HbA1c was similar with low-dose survodutide (DG2: -15.95 mmol/mol [-1.46%]; n=46) and semaglutide (-16.07 mmol/mol [-1.47%]; n=45). Mean (95% CI) bodyweight decreased dose-dependently up to -8.7% (-10.1, -7.3; DG6, n=37); survodutide ≥1.8 mg qw produced greater bodyweight reductions than semaglutide (-5.3% [-6.6, -4.1]; n=45). Adverse events (AEs) were reported for 77.8% of survodutide-treated participants (mainly gastrointestinal), 52.5% receiving placebo and 52.0% receiving semaglutide. CONCLUSIONS/INTERPRETATION: Survodutide reduced HbA1c levels and bodyweight after 16 weeks' treatment in participants with type 2 diabetes. Dose-related gastrointestinal AEs could be mitigated with slower dose escalations. TRIAL REGISTRATION: ClinicalTrials.gov NCT04153929 and EudraCT 2019-002390-60. FUNDING: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.

Effects of Single and Multiple Ascending Doses of BI 1358894 in Healthy Male Volunteers on Safety, Tolerability and Pharmacokinetics: Two Phase I Partially Randomised Studies.

INTRODUCTION: The transient receptor potential canonical (TRPC) ion channels have been implicated in the pathophysiology of major depressive disorder (MDD), and TRPC inhibition has been shown to reduce depressive-like behaviour in rodent models of depression. BI 1358894, a small-molecule inhibitor of TRPC ion channels, is currently being developed for the treatment of MDD. OBJECTIVE: Two phase I studies assessed the safety, tolerability, and pharmacokinetics (PK) of oral BI 1358894 in fed and fasted states following a single ascending dose (SAD) [NCT03210272/1402-0001] and multiple ascending doses (MAD) [NCT03754959/1402-0002] in healthy male volunteers. In addition, any potential food effect was evaluated after a single dose. METHODS: In both studies, eligible healthy male volunteers (aged 18-45 years; body mass index of 18.5-29.9 kg/m2) were allocated to receive BI 1358894 or placebo. In the SAD study (1402-0001), volunteers were randomised 3:1 to receive BI 1358894 or placebo in fasted (3, 6, 10, 25, 50, 100, or 200 mg) and fed states (200 mg). The food effect part was conducted as an open-label, randomised, two-way crossover study at doses of 50 and 100 mg in fasted and fed states (high-calorie, high-fat breakfast). For the MAD study (1402-0002), volunteers were randomised 4:1 to receive BI 1358894 (10, 25, 50, 100, or 200 mg) or placebo once daily for 14 days under fed conditions. Primary endpoint (both studies): number of volunteers with drug-related adverse events (DRAEs). Secondary PK endpoints for study 1402-0001: area under the concentration-time curve (AUC) from time zero extrapolated to infinity (AUC∞), maximum plasma concentration (Cmax), and AUC from time zero to the last quantifiable data time point (AUC0-tz). Secondary PK endpoints for study 1402-0002: AUC over 0-24 h (AUC0-24), Cmax after the first dose, and steady-state AUC and Cmax over a uniform dosing interval (AUCτ,ss and Cmax,ss, respectively) after the last dose. RESULTS: BI 1358894 was well tolerated at doses ≤ 200 mg under all tested conditions and no dose dependency was observed in DRAE frequency for either study. In the SAD study, BI 1358894 exposure increased dose proportionally across 3-50 mg in the fasted state and across 50-200 mg in the fed state. A positive food effect was observed at the tested doses. In the MAD study, BI 1358894 exposure increased less than dose proportionally across 10-200 mg. CONCLUSIONS: These studies demonstrate that BI 1358894 is well tolerated in healthy male volunteers following single and multiple doses, with no dose dependency observed in DRAE frequency. BI 1358894 exposure increased dose dependently in both the SAD and MAD studies, with higher exposure of BI 1358894 observed in the fed state. CLINICALTRIALS REGISTRATION: These trials have been registered on ClinicalTrials.gov: NCT03210272/1402-0001 (registered on 6 July 2017) and NCT03754959/1402-0002 (registered on 27 November 2018).

Bioequivalence of Intravenous Alteplase from Two Different Manufacturing Processes in Healthy Male Volunteers: Results from a Two-Stage, Adaptive-Design Study.

OBJECTIVE: Alteplase is a recombinant tissue plasminogen activator used for thrombolytic treatment in several indications and is currently approved in Europe under the brand name Actilyse®. The current manufacturing process for alteplase was recently modified to meet increasing global demands. The aim of this randomized, open-label, adaptive two-stage design, two-way crossover study was to establish bioequivalence of alteplase derived from the two manufacturing processes (modified versus current). METHODS: The two alteplase formulations (modified and current, 0.2 mg/kg body weight) were compared in healthy male volunteers after intravenous infusion over a period of 30 min. The trial was put on hold after treatment of 12 subjects (Part A) and restarted as Part B (n = 18) with design adaptations, including a heparin bolus. RESULTS: Pharmacokinetic parameters of alteplase were determined from plasma concentration-time profiles. The pharmacokinetic parameters tested (AUC0-tz, Cmax, and AUC0-∞) for alteplase after single intravenous infusion demonstrated no differences between alteplase obtained from the modified and current processes. An analysis of variance (ANOVA) model was applied to test for bioequivalence. The geometric means ratio and the respective 92.83% confidence intervals (CIs) for all primary and secondary pharmacokinetic endpoints were well within the prespecified equivalence boundaries of 80-125%. The CIs also included unity, suggesting no statistically significant differences between the two treatments. CONCLUSIONS: The results show that alteplase exposure was virtually identical for the formulations tested, and statistical evaluation demonstrated bioequivalence of the formulations. Both formulations of alteplase were well tolerated by the subjects at the single intravenous doses in the trial. TRIAL REGISTRATION: Trial registration number: NCT04419493, 2019-004932-40 (EudraCT Number).

A Phase 1 Study of mTORC1/2 Inhibitor BI 860585 as a Single Agent or with Exemestane or Paclitaxel in Patients with Advanced Solid Tumors.

This phase 1 trial (NCT01938846) determined the maximum tolerated dose (MTD) of the mTOR serine/threonine kinase inhibitor, BI 860585, as monotherapy and with exemestane or paclitaxel in patients with advanced solid tumors. This 3+3 dose-escalation study assessed BI 860585 monotherapy (5-300 mg/day; Arm A), BI 860585 (40-220 mg/day; Arm B) with 25 mg/day exemestane, and BI 860585 (80-220 mg/day; Arm C) with 60-80 mg/m2/week paclitaxel, in 28-day cycles. Primary endpoints were the number of patients with dose-limiting toxicities (DLTs) in cycle 1 and the MTD. Forty-one, 25, and 24 patients were treated (Arms A, B, and C). DLTs were observed in four (rash (n = 2), elevated alanine aminotransferase/aspartate aminotransferase, diarrhea), four (rash (n = 3), stomatitis, and increased gamma-glutamyl transferase), and two (diarrhea, increased blood creatine phosphokinase) patients in cycle 1. The BI 860585 MTD was 220 mg/day (Arm A) and 160 mg/day (Arms B and C). Nine patients achieved an objective response (Arm B: Four partial responses (PRs); Arm C: Four PRs; one complete response). The disease control rate was 20%, 28%, and 58% (Arms A, B, and C). The most frequent treatment-related adverse events (AEs) were hyperglycemia (54%) and diarrhea (39%) (Arm A); diarrhea (40%) and stomatitis (40%) (Arm B); fatigue (58%) and diarrhea (58%) (Arm C). The MTD was determined in all arms. Antitumor activity was observed with BI 860585 monotherapy and in combination with exemestane or paclitaxel.

A case control study of sarcosine as an early prostate cancer detection biomarker.

BACKGROUND: Sarcosine has been investigated as a prostate cancer biomarker with mixed results concerning its predictive power. We performed a case-control evaluation of the predictive value of serum sarcosine for early detection in a population-based cohort of men undergoing prostate-specific antigen (PSA) screening. METHODS: For analysis we used 251 cancer cases and 246 age-matched non-cancer cases from the San Antonio Biomarkers Of Risk (SABOR) screening study. For cancer cases, pre-diagnostic serum was utilized for sarcosine measurement. Controls were defined as men who had been followed at least for 5 years on study with no prostate cancer diagnosis; sarcosine was measured on the initial baseline serum. HPLC-electrospray ionization mass spectrometry was used for serum sarcosine quantification. The association of sarcosine with prostate cancer was assessed using area underneath the receiver-operating characteristic curve (AUC), and logistic regression adjusting for PSA, digital rectal exam, family history, age, race, and history of a prior negative biopsy. Among cancer cases, nominal logistic regression was used for the association of sarcosine with Gleason grade. RESULTS: Sarcosine levels were overlapping between the prostate cancer cases (median 15.8 uM, range 6.2 to 42.5 uM) and controls (median 16.2 uM, range 6.4 to 53.6 uM). The AUC of sarcosine was not statistically different from random chance either for participants with any PSA value (52.2 %) or those with PSA values in the range of 2 to 10 ng/mL (54.3 %). Sarcosine was not predictive of Gleason score and added no independent predictive power to standard prostate cancer risk factors for detection of prostate cancer (all p-values > 0.05). CONCLUSIONS: Serum sarcosine should not be pursued further as a marker for the early detection of prostate cancer.

Precision Medicine in Active Surveillance for Prostate Cancer: Development of the Canary-Early Detection Research Network Active Surveillance Biopsy Risk Calculator.

BACKGROUND: Men on active surveillance (AS) face repeated biopsies. Most biopsy specimens will not show disease progression or change management. Such biopsies do not contribute to patient management and are potentially morbid and costly. OBJECTIVE: To use a contemporary AS prospective trial to develop a tool to predict AS biopsy outcomes. DESIGN, SETTING, AND PARTICIPANTS: Biopsy samples (median: 2; range: 2-9 per patient) from 859 men participating in the Canary Prostate Active Surveillance Study and with Gleason 6 prostate cancer (median follow-up: 35.8 mo; range: 3.0-148.7 mo) were analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Logistic regression was used to predict progression, defined as an increase in Gleason score from ≤6 to ≥7 or increase in percentage of cores positive for cancer from <34% to ≥34%. Fivefold internal cross-validation was performed to evaluate the area under the receiver operating characteristic curve (AUC). RESULTS AND LIMITATIONS: Statistically significant risk factors for progression on biopsy were prostate-specific antigen (odds ratio [OR]: 1.045; 95% confidence interval [CI], 1.028-1.063), percentage of cores positive for cancer on most recent biopsy (OR: 1.401; 95% CI, 1.301-1.508), and history of at least one prior negative biopsy (OR: 0.524; 95% CI, 0.417-0.659). A multivariable predictive model incorporating these factors plus age and number of months since last biopsy achieved an AUC of 72.4%. CONCLUSIONS: A combination of readily available clinical measures can stratify patients considering AS prostate biopsy. Risk of progression or upgrade can be estimated and incorporated into clinical practice. PATIENT SUMMARY: The Canary-Early Detection Research Network Active Surveillance Biopsy Risk Calculator, an online tool, can be used to guide patient decision making regarding follow-up prostate biopsy.

Prostate Cancer Prevention Trial risk calculator 2.0 for the prediction of low- vs high-grade prostate cancer.

OBJECTIVE: To modify the Prostate Cancer Prevention Trial risk calculator (PCPTRC) to predict low- vs high-grade (Gleason grade≥7) prostate cancer and incorporate percent free-prostate-specific antigen (PSA). METHODS: Data from 6664 Prostate Cancer Prevention Trial placebo arm biopsies (5826 individuals), where prostate-specific antigen and digital rectal examination results were available within 1 year before the biopsy and PSA was ≤10 ng/mL, were used to develop a nominal logistic regression model to predict the risk of no vs low-grade (Gleason grade<7) vs high-grade cancer (Gleason grade≥7). Percent free-PSA was incorporated into the model based on likelihood ratio analysis of a San Antonio Biomarkers of Risk cohort. Models were externally validated on 10 Prostate Biopsy Collaborative Group cohorts and 1 Early Detection Research Network reference set. RESULTS: Of all the Prostate Cancer Prevention Trial biopsies, 5468 (82.1%) were negative for prostate cancer, 942 (14.1%) detected low-grade, and 254 (3.8%) detected high-grade disease. Significant predictors were (log base 2) PSA (odds ratio for low-grade vs no cancer, 1.29*; high-grade vs no cancer, 2.02*; high-grade vs low-grade cancer, 1.57*), digital rectal examination (0.96, 1.49*, 1.55*, respectively), age (1.02*, 1.05*, 1.03*, respectively), African American race (1.13, 2.83*, 2.51*, respectively), prior biopsy (0.63*, 0.81, 1.27, respectively), and family history (1.31*, 1.25, 0.95, respectively), where * indicates P value<.05. The new PCPTRC 2.0 either with or without percent free-PSA (also significant by the likelihood ratio method) validated well externally. CONCLUSION: By differentiating the risk of low- vs high-grade disease on biopsy, PCPTRC 2.0 better enables physician-patient counseling concerning whether to proceed to biopsy.