Gordana Kosutic

Ghrelin Agonist (TZP‐101): Safety, Pharmacokinetics and Pharmacodynamic Evaluation in Healthy Volunteers: A Phase I, First‐in‐Human Study

The authors evaluate the human safety, tolerability, pharmacokinetics, and pharmacodynamics of TZP‐101, an agonist of the hGHS‐R1a (ghrelin) receptor. Healthy subjects were randomized to either single‐dose TZP‐101 (20–600 μg/kg) or placebo by 30‐minute intravenous infusion. Subjects underwent continuous cardiac monitoring, 12‐lead electrocardiograms, and assessment for orthostatic hypotension, injection site tolerability, vital signs, and adverse events during the 24‐hour postdose period. Blood and urine samples were collected for pharmacokinetic/pharmacodynamic assessment for 24 hours. Forty‐eight subjects randomly received 1 of 6 TZP‐101 doses or placebo. TZP‐101 was well tolerated, with single episodes each of headache, lower abdominal pain, diarrhea, and dizziness. At the highest dose, 2 subjects experienced bradycardia. All events were self‐limited. Mean arterial blood pressure and heart rate decreased from baseline approximately 45 to 60 minutes after infusion start at higher doses. No other significant changes were observed. Pharmacokinetic analysis revealed less than dose‐proportional behavior of drug with low clearance (≅7 mL/h/kg), small volume of distribution (≅114 mL/kg), and half‐life values of ≅13 hours, which were independent of dose. Pharmacodynamic analyses suggested TZP‐101, at doses as low as 40 μg/kg, expressed activity at the receptor. TZP‐101 displayed a promising pharmacokinetic, pharmacodynamic, and safety profile for use in gastrointestinal motility disorders.

The ghrelin agonist TZP-101 for management of postoperative ileus after partial colectomy: A randomized, dose-ranging, placebo-controlled clinical trial

PURPOSE: Ghrelin agonist TZP-101 is a potent prokinetic. This phase 2b study evaluated TZP-101 safety and efficacy in postoperative ileus management. METHODS: Adults undergoing open partial colectomy were adaptively randomized to receive 20, 40, 80, 160, 320, 480 or 600 &mgr;g/kg TZP-101 (n = 168) or the placebo (n = 68) by 30-minute IV infusion within 1 hour of surgical closure and then daily for up to 7 days. The primary efficacy end point was the time to first bowel movement. Secondary end points included the percentage of patients with return of gastrointestinal function within 72 hours, and the time to readiness for discharge. RESULTS: TZP-101 accelerated the time to first bowel movement in all groups, with Cox proportional hazard ratios of 1.57 (P = .056) for the low-efficacious dose (80 &mgr;g/kg) and 1.67 (P = .03) for the most efficacious dose (480&mgr;g/kg). Using Kaplan-Meier analysis, the median time to first bowel movement was reduced in all TZP-101 groups by 10 to 22 hours vs. the placebo. A greater number of patients who received TZP-101 achieved recovery (P ≤ .001) by 72 hours postsurgery compared with the placebo. The median time to readiness for hospital discharge was significantly accelerated by 20.4 hours at the 480 &mgr;g/kg TZP-101 dose compared with the placebo (hazard ratio = 1.69; P = .03). The most common treatment-emergent adverse events were nausea and vomiting, which were reduced in the TZP-101 group compared with the placebo group. CONCLUSION: In patients undergoing major abdominal surgery, the first-in-class ghrelin agonist TZP-101 was well-tolerated and accelerated recovery of the upper and lower gastrointestinal tract, with a large proportion of subjects recovering within 72 hours compared with the placebo.

Clinical and demographic characteristics predictive of treatment outcomes for certolizumab pegol in moderate to severe Crohn's disease: analyses from the 7-year PRECiSE 3 study

Clinical factors were previously identified as predictors of short‐term treatment efficacy in Crohns disease (CD). The PRECiSE 3 (P3) 7‐year trial provides an opportunity to study predictors of short‐ and long‐term clinical remission among CD patients treated with certolizumab pegol (CZP).

Contribution of Protein Binding to the Pharmacokinetics of the Ghrelin Receptor Agonist TZP-101 in Healthy Volunteers and Adults with Symptomatic Gastroparesis Two Randomized, Double-Blind Studies and a Binding Profile Study

AbstractBackground and objective: TZP-101 is a selective, small molecule ghrelin receptor agonist in clinical development for the treatment of gastric motility disorders. The objectives of this study was to assess pharmacokinetic parameters of TZP-101 after multiple- and single-dose administration to healthy subjects and patients with gastroparesis, respectively, and to determine the contribution of protein binding to its pharmacokinetic behaviour. Methods: Pharmacokinetics following 30-minute intravenous infusions of single (160–600 µg/kg) doses of TZP-101 in patients with gastroparesis and multiple (80–600 µg/kg/day) doses of TZP-101 in healthy subjects were characterized. TZP-101 protein binding was measured in human, dog, rat, rabbit and monkey plasma using equilibrium dialysis. Results: TZP-101 pharmacokinetic profiles were less than dose proportional in both healthy subjects and patients, most likely because of concentrationdependent protein binding. A small volume of distribution (99–180 µL/kg following single doses) and long half-life (10–20 hours) were concentration independent in both healthy subjects and patients. Systemic clearance increased with increasing dose. Incidence of adverse events was not related to dose or treatment (active vs placebo). TZP-101 binding to human plasma proteins (primarily α1-acid glycoprotein) was ≥99% between 5 and 15 µmol/L (2.7 and 8.1 µg/mL) and was significantly higher than in other species. Conclusions: The pharmacokinetic parameters of TZP-101 in patients with gastroparesis and healthy subjects are comparable and display a similar trend toward increased clearance at higher dose levels resulting in little accumulation of TZP-101 at high dose levels and after multiple dosing. Significant protein binding indicates that the fraction of free drug rather than the total plasma concentration should be taken into consideration for human risk assessment based on animal safety data. Furthermore, the concentration of unbound drug should be considered when optimizing the clinical dose.

Pharmacokinetics of modified oral calcitonin product in healthy volunteers.

Study Objective. To assess the preliminary pharmacokinetics, pharmacodynamics, safety, and tolerability of single oral doses of a chemically modified salmon calcitonin product, CT‐025, in healthy volunteers.

Reinduction with Certolizumab Pegol in Patients with Crohn's Disease Experiencing Disease Exacerbation: 7-year Data from the Precise 4 Study

Background:Patients with Crohns disease in whom tumor necrosis factor antagonist therapy fails have limited treatment options, and the benefit of reintroducing the same therapy remains unclear. Here, we report results from PRECiSE 4 (NCT00160706), an open-label extension study of certolizumab pegol in patients who withdrew from the placebo-controlled studies PRECiSE 1 or 2. Methods:Patients eligible for PRECiSE 4 had Crohns disease exacerbation on placebo or primary or secondary failure to certolizumab pegol in PRECiSE 1 or 2, and received 400 mg certolizumab pegol subcutaneously at weeks 0, 2, and 4 and every 4 weeks thereafter up to 360 weeks. We assessed safety (adverse events) and efficacy (clinical remission) of extended certolizumab pegol therapy. Results:Patients enrolled in PRECiSE 4 (N = 310; mean age, 37 yr; 58% female; 95% white) had a mean Crohns disease duration of 8.5 years before entering the qualifying studies. At weeks 52, 104, and 156, remission rates were 28.5%, 17.5%, and 12.6% by nonremitter imputation, and 63.8%, 60.0%, and 63.5% by observed cases, with 47.4%, 31.9%, and 23.2% of patients, respectively, remaining on therapy. By study end (7.5 yr), 92.3% of patients discontinued therapy, 49% on account of adverse events. No new safety signals emerged. Incidence rate (new cases)/100 patient-years was 6.11 for serious infections and 1.29 for malignancies. Conclusions:Certolizumab pegol was effective in many patients who previously discontinued certolizumab pegol for lack or loss of response. Thus, discontinuation of therapy may not always be necessary. Safety was consistent with previous findings.

Exposure-response relationship of certolizumab pegol induction and maintenance therapy in patients with Crohn's disease

Therapeutic drug monitoring may optimize therapy for Crohns disease (CD).

TZP-102, Ghrelin Agonist Phase 2 Data: The Improvement in Symptoms of Gastroparesis (Nausea, Early Satiety, Bloating and Abdominal Pain) Significantly Correlated With Patient Rating of Overall Treatment Effect

* Percentage of patients with a score ≥ 1 **Where 0=none,1=very mild, 2=mild, 3=moderate, 4=severe, and 5=very severe for individual symptoms. TZP-102, Ghrelin Agonist, Phase 2 Data: The Improvement in Symptoms of Gastroparesis (Nausea, Early Satiety, Bloating and Abdominal Pain) Significantly Correlated with Patient Rating of Overall Treatment Effect R McCallum1, J Wo2, R Venuti3, T Esfandyari4, M Jamal5, G Dimcevski6, L Tarnow7, R Malik8, PM Hellstom9, L Shaughnessy3, P Charlton3, G Kosutic3, N Ejskjaer10 1Texas Tech Univ Health Sci Ctr El Paso TX, 2Univ Louisville, Louisville KY, 3Tranzyme, Inc., Durham NC, 4Univ Kansas Med Ctr, Kansas City KS; 5Long Beach VA Med Ctr, Long Beach CA, 6Haukeland Univ Hosp, Bergen NO, 7Steno Diabetes Ctr, Gentofte DK, 8Univ Manchester, Manchester UK, 9Uppsala Univ Hosp, Uppsala SE, 10Aarhus Univ Hosp, Aarhus DK

Effects of Transient and Persistent Anti-drug Antibodies to Certolizumab Pegol: Longitudinal Data from a 7-Year Study in Crohn's Disease

Background: Anti-drug antibodies (ADAbs) may decrease the efficacy of biologics and increase the risk of adverse events. A single positive test may not preclude further treatment because of variations in assays used, test timing, and patient variables. We evaluated the longitudinal patterns of immunogenicity during 7 years of antitumor necrosis factor-alpha drug certolizumab pegol (CZP) treatment for moderate-to-severe Crohns disease. Methods: PRECiSE 3 patients (n = 595) received open-label CZP 400 mg every 4 weeks up to 7 years. CZP–ADAb expression, plasma CZP concentration, Harvey-Bradshaw Index, C-reactive protein, and fecal calprotectin concentrations were measured multiple times. Longitudinal data, examined for CZP–ADAb positivity and categorized as transient (with temporary/no effect on CZP concentration), persistent, or negative, were correlated with clinical and biological variables. Results: Of the CZP–ADAb–positive patients, 40 (22.6%) had transient CZP–ADAbs and 94 (77.4%) had persistent CZP–ADAbs. Demographic characteristics were similar between groups. Median C-reactive protein and fecal calprotectin were higher (P < 0.05 at some visits) and plasma CZP concentrations were significantly lower (P < 0.0001 at all visits) in the persistent CZP–ADAb–positive group relative to the CZP–ADAb–negative group. Transient CZP–ADAb–positive and CZP–ADAb–negative patients had similar plasma CZP, C-reactive protein, and fecal calprotectin concentrations. Median Harvey-Bradshaw Index scores and rates of adverse events were similar among groups. Conclusions: This analysis demonstrates that persistent CZP–ADAb has negative effects on drug levels and efficacy, whereas transient expression may not. Serial measurements may be needed to characterize ADAb positivity. www.clinicaltrials.gov, Number NCT00160524.

Sa1139 Safety of Certolizumab Pegol in 2570 Crohn's Disease Patients With 4378 Patients Years at Risk: Integrated Data From the Global Clinical Program

Back ground: The calcineurin inhibitor (CNI) tacrolimus (TAC) has been reported to be effective for induction and maintenance of remission in patients with refractory ulcerative colitis (UC). However, CNI has nephrotoxic potential leading to acute and chronic renal damage in some cases. To date, little is known about the influence of long term administration of oral TAC on renal function in patients with UC. Aim: The aim of our study was to evaluate the incidence and the severity of renal function impairment in UC patient who received TAC treatment. Methods: In this retrospective study, the medical charts of 71 adult patients with steroid-refractory UC treated with TAC between 2012 and 2014 in a single Japanese center were analyzed. In principle, TAC was orally administrated as a 2 week-induction (target trough levels 10-15ng/ml) followed by a maintenance therapy (target trough levels 5-10ng/ml). Estimated glomerular filtration rate (eGFR) was evaluated during the treatment. Acute kidney injury (AKI) was defined by the RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure of function, Loss of function and End-stage kidney disease) consensus criteria using the maximal change in serum creatinine (Scr) and eGFR during the TAC treatment compared with baseline value before treatment. Results: The mean duration of TAC administration was 210 days. At 12weeks, TAC produced a clinical response in 54 patients (76.1%) and remission was achieved in 29 of those 54 (40.8%). The AKI rate during TAC treatment was 46.5% (33 of 71 patients). RIFLE class R (Scr increase > 1.5 times or eGFR decrease > 25%) accounted for 27 patients (38.0%), and RIFLE class I (Scr increase > 2 times or eGFR decrease > 50%) for six (8.5%). The AKI rate was 76.8% (10/13) in patients who had been administrated TAC for more than 1 year and 37.5% (18/48) in patients with TAC treatment within 6 months (p=0.006). After withdrawal of TAC, renal function impairment (eGFR decrease > 25%) was still observed in 10 patients (14.1%). Conclusions: Oral TAC therapy appears to be effective for patients with refractory UC. However, renal function impairment was frequently observed during this treatment. Thus, careful monitoring of renal function must be required to avoid irreversible chronic renal damage during long-term administration of TAC.