Steve Pakola

Monoclonal Antibody TB-403: A First-in-Human, Phase I, Double-Blind, Dose Escalation Study Directed Against Placental Growth Factor in Healthy Male Subjects

BACKGROUND TB-403 (RO5323441) is a humanized monoclonal antibody directed against placental growth factor (PlGF). Preclinical studies have demonstrated that targeting PlGF can result in significant inhibition of tumor growth and metastasis. OBJECTIVES The purpose of this study was to assess the safety profile, tolerability, and pharmacokinetics of TB-403, developed for the treatment of solid tumors. METHODS Healthy male subjects were exposed to a single intravenous infusion of TB-403 or placebo. Blood samples for hematology, clinical chemistry, coagulation factors, and urinalysis were collected; vital signs and ECGs were recorded; and serial blood samples were drawn for pharmacokinetic and immunogenicity measurements and circulating levels of pharmacodynamics markers PlGF and (VEGF) vascular endothelial growth factor. Sixteen subjects received either placebo or TB-403 at doses ranging from 0.3 to 5.0 mg/kg. RESULTS Mild (grade 1 or 2) nasopharyngitis, headache, neck pain, and joint pain were the most frequently reported adverse events (AEs). There were no serious AEs in the study, and none of the AEs led to withdrawal. None of the safety laboratory assessments was considered clinically significant, and none was reported as an AE. There were no apparent differences in terms of safety profiles among the 3 dose levels of active treatment compared with placebo. Clearance, volume of distribution, and terminal t(½) (mean values) for TB-403 in all 3 cohorts were in the range of 4.2 to 4.9 (mL/d/kg), 56 to 79 (mL/kg), and 8 to 13 (days), respectively. CONCLUSION The highest dose of TB-403 (5.0 mg/kg) was well tolerated in this study of a single intravenous infusion to healthy males. This result allowed a higher starting dose level in a subsequent Phase I study in cancer patients, the patient population for which this antibody is developed.

Tolerability and pharmacokinetics of TB-402 in healthy male volunteers

BACKGROUND TB-402, a human monoclonal antibody that partially inhibits Factor VIII activity (FVIII:C), is being developed as a long-acting antithrombotic agent. OBJECTIVES The primary goal of this study was to investigate the tolerability of TB-402 in healthy male volunteers. Secondary objectives were to determine the pharmacokinetics and pharmacodynamics of TB-402. METHODS In this ascending-dose study, healthy subjects aged 18 to 45 years were randomly assigned in a 2:1 ratio to receive TB-402 administered as a single intravenous bolus at 0.015, 0.1, 0.5, 2.5, 12.5, 37.5, 188, 620, or 1860 microg/kg or matching inactive vehicle (placebo). An older group (55-75 years) was also administered the highest dose that was well tolerated in the younger group (1860 microg/kg). Adverse events (AEs) were obtained from spontaneous reporting and from answers to nonleading questions asked by the principal investigator and study staff during follow-up visits on days 4, 7 (+/-1 day), 14 (+/-1 day), 21 (+/-2 days), 28 (+/-3 days), 42 (+/-3 days), and 56 (+/-3 days) after TB-402 administration. AEs were monitored up to the last study visit on day 56 after the administration of TB-402 or placebo, with special attention to bleeding events. The pharma-codynamic assessment of TB-402 included changes in FVIII:C, activated partial thromboplastin time (APTT), and prothrombin time (PT). RESULTS The study enrolled 56 subjects (mean ages: younger group, 28 years [range, 20-45 years]; older group, 65 years [range, 58-76 years]; weight, 79 kg [range, 60-104 kg] and 81 kg [range, 64-94 kg], re-spectively). Thirty-one of the 38 subjects who received TB-402 (82%) experienced a total of 85 treatment-emergent AEs (TEAEs), and 14 of 18 subjects who received placebo (78%) experienced 35 TEAEs. A total of 34 bleeding events were reported in 13 of 38 subjects (34%) who received TB-402 and 7 of 18 subjects (39%) who received placebo. Most common AEs reported in subjects who received TB-402 were headache (11 [29%]), vessel puncture-site hematoma (7 [18%]), and traumatic hematoma (5 [13%]); with placebo, these AEs were vessel puncture-site hematoma (4 [22%]), headache (3 [17%]), vasovagal reaction (3 [17%]), and hematuria (3 [17%]). No serious AEs considered to be related to TB-402 were reported, and no dose-dependent increases in bleeding events were observed. On pharmacokinetic analysis of TB-402, the t(1/2) values across doses were 22.9 days (age 18-45 years) and 19.5 days (age 55-75 years). TB-402 was associated with a reduction in FVIII:C over a period of approximately 48 hours in the d37.5-microg/kg dose groups. TB-402 was associated with a prolonged APTT at doses >or=2.5 microg/kg approximately 1.1-1.2-fold predose APTT). Administration of a higher dose of TB-402 was associated with an extended duration of APTT prolongation. No significant effect on PT was found. CONCLUSIONS In this study in healthy male volunteers, TB-402 was well tolerated in the population studied. Based on the findings from this study, the long t(1/2) of TB-402 may allow a pharmacodynamic effect over a prolonged period after single-dose administration. Further trials are needed to address the tolerability and efficacy of this agent in preventing thromboembolism. Clinicaltrials.gov identifier: NCT00612196.

Vitreomacular interface diseases: pathophysiology, diagnosis and future treatment options

Over the past two decades, the role of vitreomacular adhesion in vitreomacular interface pathologies, such as vitreomacular traction syndrome, epiretinal membrane and macular hole, has been increasingly recognized. Abnormalities of the vitreoretinal interface may contribute to important retinal pathologies such as diabetic retinopathy, diabetic macular edema and age-related macular degeneration. The prevalence of many of these serious disorders is rising. Eyes with vitreomacular adhesion-related disorders can experience rapid deterioration of vision and function if not managed in a timely and effective manner. The only treatment option currently available is vitrectomy. Pharmacologic treatment options have advanced over the past decade, and the current strategy of ‘watchful waiting’ until symptoms worsen may not be acceptable in the future. This article reviews vitreomacular interface disorders, and explores the evidence of experimental agents that can potentially treat these conditions.

Abstract A111: A phase I, dose escalation study of TB‐403, a monoclonal antibody directed against PlGF, in patients with solid tumors

Rationale and Objectives: TB‐403 is a humanised recombinant immunoglobulin G isotype 1 monoclonal antibody expressed in Chinese hamster ovary cells and directed to the receptor‐binding site of placental growth factor (PlGF). The antibody is highly specific and does not cross‐react with vascular endothelial growth factor A (VEGFA). PlGF levels are low in normal tissues, but up‐regulated in several pathological conditions, including several types of cancer. TB‐403 has been shown to significantly inhibit tumor growth in xenograft tumor models. The primary objective of the phase 1 study was to determine the maximum tolerated dose (if Methods: In this multi‐center study, cohorts of 3 patients were treated with 8 weekly doses of 1.25, 5, or 10 mg/kg or 3 doses of 20 and 30 mg/kg once every three weeks (q3w). Six additional patients were treated with 30 mg/kg q3W. Patients showing objective tumor response or stable disease (SD) after 8 weeks were offered extended therapy. Main eligible criteria were: solid tumor with no other treatment options, ECOG performance status 0–1, normal organ function, and no prior anticancer therapy within 30 days (bevacizumab within 60 days). Results: A total of 23 patients were accrued. No DLT, changes in ECG, laboratory findings or urine analysis were seen, except for one patient with an unrelated biliary stenoses. Of related or possibly related grade III or IV adverse events only one episode of pulmonary embolism, one case of dyspnoea and a case of dry skin were observed. Related or possibly related grade I and II adverse events included skin rash (1 patient), fatigue (5 patients), fever (1 patient), diarrhoea (1 patient), and hypertension (1 patient). No objective responses according to RECIST criteria were observed but five patients had SD ≥ 8 weeks, including 2 patients (pancreatic adenocarcinoma and esophageal squamous carcinoma) treated with weekly 5 mg/kg TB‐403 with SD > 10 months. Conclusion: TB‐403 was well tolerated. MTD was not established due to lack of dose‐limiting toxicity up to a dose of 10 mg/kg weekly and 30 mg/kg q3w. Prolonged SD (> 10 months) was seen in two patients treated with 5 mg/kg weekly TB‐403. Pharmacokinetic and molecular pharmacodynamic data will be presented. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A111.

Neutralization of α2-antiplasmin by microplasmin: A randomized, double-blind, placebo-controlled, ascending-dose study in healthy male volunteers

BACKGROUND Microplasmin is the isolated proteinase domain of plasmin. Administration of microplasmin has been found to neutralize alpha(2)-antiplasmin (alpha(2)-AP) activity, which has been associated with reduced infarct size in various preclinical models of stroke. OBJECTIVES The goals of this first-in-man study were to investigate the ability of microplasmin to neutralize alpha(2)-AP activity and to monitor its tolerability in healthy male volunteers. METHODS This Phase I, double-blind, placebo-controlled, ascending-dose study included 10 groups, each containing 6 subjects who were randomized to receive microplasmin or placebo in a 2:1 ratio. The study had 3 parts. In part 1, subjects received a single intravenous bolus of microplasmin 0.1, 0.5, 1, 1.5, or 2 mg/kg or placebo over 15 minutes. In part 2, subjects received a bolus of microplasmin 1 mg/kg or placebo, followed by an infusion of 1, 2, 3, or 4 mg/kg or placebo over 60 minutes. In part 3, subjects, all of whom were aged >55 years, received a bolus of mi-croplasmin 1 mg/kg or placebo, followed by an infusion of 1 mg/kg or placebo. The primary pharmaco-dynamic end point was the change in alpha(2)-AP activity, measured at different time points up to 4 days after dosing using a chromogenic assay. All adverse events were monitored based on spontaneous reports and nondirected questioning at study visits up to the post-study visit 21 days after administration of study drug. RESULTS The mean (SD) age of subjects in parts 1, 2, and 3 was 30 (8), 30 (8), and 64 (8) years, respectively. All groups receiving microplasmin had a dose-dependent decrease in alpha(2)-AP activity. In part 1, the mean maximal inhibition of alpha(2)-AP was 11.8% (6.0%), 27.7% (4.3%), 53.0% (4.8%), 65.3% (4.3%), and 84.0% (6.0%) after bolus administration of microplasmin 0.1, 0.5, 1, 1.5, and 2 mg/kg, respectively, and 7.4% (6.9%) after administration of placebo. In part 2, the mean maximal inhibition of alpha(2)-AP was 74.6% (11.2%), 95.5% (3.3%), 99.0% (1.0%), and 88.0% (12.5%) after bolus administration of microplasmin 1 mg/kg followed by an infusion of 1, 2, 3, and 4 mg/kg, respectively, compared with 12.9% (6.8%) after administration of placebo. In part 3, the mean maximal inhibition was 69.7% (3.4%) after bolus administration of microplasmin 1 mg/kg followed by an infusion of 1 mg/kg, compared with 8.8% (4.1%) with placebo. One subject in the highest dose group in part 1 (2 mg/kg) and 2 subjects in the highest dose group in part 2 (1 + 4 mg/kg) had an urticarial reaction. All 3 subjects also had a decrease in total hemolytic complement and an increase in complement 5a. CONCLUSIONS Neutralization of alpha(2)-AP activity by microplasmin was feasible in these healthy male volunteers. The urticarial reactions observed in the highest dose groups were considered dose-limiting adverse events. Further trials are needed to investigate the tolerability of this therapy and whether it is neuroprotective in patients with acute ischemic stroke.

Abstract A3: A first‐in‐man, phase I, dose escalation study of TB‐403, a monoclonal antibody directed against PlGF, in healthy male subjects

Rationale and Objectives: TB‐403 is a humanised recombinant immunoglobulin G isotype 1 (IgG1) monoclonal antibody expressed in Chinese hamster ovary (CHO) cells and directed to the receptor‐binding site of placental growth factor (PlGF). The antibody is highly specific and does not cross‐react with vascular endothelial growth factor (VEGF). Whilst VEGF is involved both in physiological and pathological angiogenesis, the levels of PlGF are low in normal tissues, but up‐regulated in several pathological conditions, including several types of cancer. TB‐403 has been shown to significantly inhibit tumor growth in xenograft tumor models. In all preclinical studies performed with TB‐403 there were no drug‐related findings up to and including the maximum feasible doses tested (300 mg/kg/wk IV in the cynomolgus monkey for 13 weeks). This first‐in‐man (FIM) study was designed to investigate the safety and tolerability of a single dose of TB‐403 in healthy male subjects. A secondary objective included the investigation of the single dose pharmacokinetics of TB‐403. Methods: This FIM study was a phase 1, double‐blind, randomized, placebo‐controlled, single‐dose escalation study in healthy male subjects. Sixteen male subjects in 3 dose groups were exposed to a single, intravenous infusion of TB‐403 or placebo over 60 minutes at dose levels of 0.3, 1.25 or 5.0 mg/kg with 2+2, 4+2 and 4+2 subjects per group, respectively. The starting dose was selected as 1/10th of the Minimum Anticipated Biological Effect Level (MABEL) determined in a xenograft tumor model. TB‐403 was given at escalating doses and safety was closely monitored up to Day 56. Review of adverse events, safety laboratory results, electrocardiogram and vital sign measurements up to and including Day 7 was performed by a Data Monitoring Committee before dose escalation. Results: All 16 subjects were Caucasians with the age, body weight, and body mass index range of 22–46 years, 63.1–114.5 kg and 20.4–31.4 kg/m2, respectively. The most frequently reported adverse events were nasopharyngitis, headache, neck pain and joint pain with no significant difference in frequency or severity between TB‐403 and placebo for these or other reported adverse events. The adverse events were either not related or unlikely related to TB‐403 and 16 were mild, 8 moderate and 3 severe in intensity. There were no serious adverse events, and none of the events led to withdrawal. Pharmacokinetic properties of TB‐403 were investigated and showed a terminal half‐life of TB‐403 ranging from 8 to 13 days and a dose-proportional exposure in terms of both Cmax and AUC. Conclusion: TB‐403 was safely administered to healthy males in this study without dose‐limiting toxicity after an intravenous infusion in the dose range of 0.3 mg/kg to 5.0 mg/kg. The safe administration of TB‐403 to healthy male subjects allowed a higher initial safe start dose level in a subsequent study in cancer patients. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A3.