Antibody-Based Tissue Factor Antagonist in Acute Lung Injury
Antibody-Based Tissue Factor Antagonist in Acute Lung Injury
Baseline characteristics of the 18 patients enrolled in this Phase I clinical trial are shown in Table 1. Of these patients, one patient of the 0.08 mg/kg ALT-836 cohort died (acute hypoxia, unrelated to study drug) during the study, with the remaining patients completing the 28-day follow-up period.
Study drug-treated patients of the first two cohorts received 0.06 mg/kg or 0.1 mg/kg ALT-836 as a single bolus intravenous infusion over 15 minutes, whereas the third cohort received 0.08 mg/kg ALT-836 through a 2 hr infusion at 50 cc/hr. Pharmacokinetic analysis showed a dose dependent exposure to ALT-836 across the infusion range of 0.06 to 0.1 mg/kg (Table 2). Thus, increasing the duration of infusion to 2 hrs for the 0.08 mg/kg dose group did not decrease Cmax or overall exposure levels (AUCINF) as these values remained linear with dose. The terminal elimination half-life for ALT-836 was equivalent across dose levels with mean values ranging from 18.5 to 22.6 hrs. Volumes of distribution were about 50 ml/kg, consistent with plasma volume in the vasculature.
There was no detectable serum anti-ALT-836 antibody activity in any of the ALT-836-treated patients (n = 15).
Four patients encountered non-fatal serious adverse events (SAEs) during the study, including bilateral pulmonary embolism (0.06 mg/kg ALT-836-treated patient), hypoxic respiratory failure (0.1 mg/kg ALT-836-treated patient), worsening acute renal failure (placebo-treated patient), and worsening anemia and empyema (placebo-treated patient).
Of the 18 subjects enrolled in this trial, 16 subjects reported a total of 87 adverse events (AEs) during the study. Of these, 35 (40%) were mild in intensity, 48 (55%) were moderate in intensity, and 4 (5%) AEs were severe in intensity. The investigators attributed 16 of these AEs as "related to study treatment" (2 in placebo group, 3 in 0.06 mg/kg ALT-836; 6 in 0.08 mg/kg ALT-836, and 5 in 0.1 mg/kg ALT-836 groups). A summary of the incidence of treatment emergent AEs is presented Table 3 and a detailed listing of the AEs is provided in Additional file 2: Table A2.
The most frequent AE reported in patients treated with ALT-836 was hematuria or worsening hematuria (n = 9) (Table 3). These AEs were rated as mild to moderate and assessed by the clinical investigator as possibly or probably related to study drug in 8 of the 9 patients. On average, hematuria started 6.7 hours after study drug administration (range 3–19 hr), and resolved by 29.1 hours (range 6–53 hrs) post-onset without the need of medical intervention. No patient with hematuria became hemodynamically unstable and there was no decrease in platelet counts, prolongation of PT and aPTT time or increase in serum D-dimer and F1+2 levels. There was also no significant difference in markers of renal function (BUN, creatinine) between patients with or without hematuria and no signs of capillary fragility (petechiae, ecchymoses, conjunctival bleeding) were observed during the duration of hematuria. Besides hematuria, no major bleeding or other spontaneous minor bleeding events were observed in any patient receiving ALT-836.
Anemia was reported for 6 patients receiving ALT-836 as well as in two of three patients receiving placebo (Table 3). These adverse events were assessed as study drug related in 3 of 6 ALT-836-treated patients and in both of the placebo treated patients, one of which (as noted above) experienced anemia as a serious adverse event.
Aside from these events, there were no other adverse events or serious adverse events judged to be related to ALT-836 treatment by the clinical investigators.
There was no significant treatment effect on PT, platelet counts, aPTT, or plasma levels of D-dimer, prothrombin fragment F1 + 2 or fibrinogen at any ALT-836 dose. At the dose levels administered, the ALT-836 concentration observed in the patients' plasma were previously shown to be insufficient to prolong PT driven by the large excess of TF reagent added in the standard PT assay, though inhibition of clot formation and thrombin generation was observed in a whole blood assay. Additionally, treatment with high levels of a different TF antagonist reportedly did not alter levels of either coagulation factors or markers of thrombin generation in patients with ALI/ARDS. Thus, these laboratory parameters of coagulation may not be useful in assessing the pharmacodynamic effects of TF-targeted therapies.
As part of the safety assessment, evaluation of oxygenation index and patient outcomes was conducted. There was no significant treatment effect at any dose of ALT-836 on PO2/FIO2 ratio while patients were on mechanical ventilation. Assessment of hospital resource indices also did not reveal significant differences in ventilation free days or duration of hospital stay following ALT-836 treatment, though patients receiving 0.1 mg/kg ALT-836 showed an improvement in ICU-free days at day 28 when compared to placebo treated patients (mean ± SD: 8.7 ± 8.1 (placebo) vs. 20.0 ± 2.4 (ALT-836), P = 0.036) (Table 4). Although this result is encouraging, it should be noted that this study was not sufficiently powered to assess ALT-836 efficacy and that because of the large inherent variation in outcome parameters observed in this patient population, preliminary evaluation of efficacy end points will likely require a placebo-controlled Phase II trial with at least 45 subjects per treatment arm. The overall mortality rate observed in this study was lower than that reported in recently published studies in ALI/ARDS subjects. However, this also likely reflects the small number of subjects in this study since ongoing follow-up studies with larger numbers of the same subject population verified that placebo-treated subjects have a mortality rate consistent with historic values (H. Wong, personnel communication).
Results
Baseline characteristics of the 18 patients enrolled in this Phase I clinical trial are shown in Table 1. Of these patients, one patient of the 0.08 mg/kg ALT-836 cohort died (acute hypoxia, unrelated to study drug) during the study, with the remaining patients completing the 28-day follow-up period.
Pharmacokinetics and Immunogenicity
Study drug-treated patients of the first two cohorts received 0.06 mg/kg or 0.1 mg/kg ALT-836 as a single bolus intravenous infusion over 15 minutes, whereas the third cohort received 0.08 mg/kg ALT-836 through a 2 hr infusion at 50 cc/hr. Pharmacokinetic analysis showed a dose dependent exposure to ALT-836 across the infusion range of 0.06 to 0.1 mg/kg (Table 2). Thus, increasing the duration of infusion to 2 hrs for the 0.08 mg/kg dose group did not decrease Cmax or overall exposure levels (AUCINF) as these values remained linear with dose. The terminal elimination half-life for ALT-836 was equivalent across dose levels with mean values ranging from 18.5 to 22.6 hrs. Volumes of distribution were about 50 ml/kg, consistent with plasma volume in the vasculature.
There was no detectable serum anti-ALT-836 antibody activity in any of the ALT-836-treated patients (n = 15).
Adverse Events
Four patients encountered non-fatal serious adverse events (SAEs) during the study, including bilateral pulmonary embolism (0.06 mg/kg ALT-836-treated patient), hypoxic respiratory failure (0.1 mg/kg ALT-836-treated patient), worsening acute renal failure (placebo-treated patient), and worsening anemia and empyema (placebo-treated patient).
Of the 18 subjects enrolled in this trial, 16 subjects reported a total of 87 adverse events (AEs) during the study. Of these, 35 (40%) were mild in intensity, 48 (55%) were moderate in intensity, and 4 (5%) AEs were severe in intensity. The investigators attributed 16 of these AEs as "related to study treatment" (2 in placebo group, 3 in 0.06 mg/kg ALT-836; 6 in 0.08 mg/kg ALT-836, and 5 in 0.1 mg/kg ALT-836 groups). A summary of the incidence of treatment emergent AEs is presented Table 3 and a detailed listing of the AEs is provided in Additional file 2: Table A2.
The most frequent AE reported in patients treated with ALT-836 was hematuria or worsening hematuria (n = 9) (Table 3). These AEs were rated as mild to moderate and assessed by the clinical investigator as possibly or probably related to study drug in 8 of the 9 patients. On average, hematuria started 6.7 hours after study drug administration (range 3–19 hr), and resolved by 29.1 hours (range 6–53 hrs) post-onset without the need of medical intervention. No patient with hematuria became hemodynamically unstable and there was no decrease in platelet counts, prolongation of PT and aPTT time or increase in serum D-dimer and F1+2 levels. There was also no significant difference in markers of renal function (BUN, creatinine) between patients with or without hematuria and no signs of capillary fragility (petechiae, ecchymoses, conjunctival bleeding) were observed during the duration of hematuria. Besides hematuria, no major bleeding or other spontaneous minor bleeding events were observed in any patient receiving ALT-836.
Anemia was reported for 6 patients receiving ALT-836 as well as in two of three patients receiving placebo (Table 3). These adverse events were assessed as study drug related in 3 of 6 ALT-836-treated patients and in both of the placebo treated patients, one of which (as noted above) experienced anemia as a serious adverse event.
Aside from these events, there were no other adverse events or serious adverse events judged to be related to ALT-836 treatment by the clinical investigators.
Assessment of Clinical Laboratory Measurements and Patient Outcomes
There was no significant treatment effect on PT, platelet counts, aPTT, or plasma levels of D-dimer, prothrombin fragment F1 + 2 or fibrinogen at any ALT-836 dose. At the dose levels administered, the ALT-836 concentration observed in the patients' plasma were previously shown to be insufficient to prolong PT driven by the large excess of TF reagent added in the standard PT assay, though inhibition of clot formation and thrombin generation was observed in a whole blood assay. Additionally, treatment with high levels of a different TF antagonist reportedly did not alter levels of either coagulation factors or markers of thrombin generation in patients with ALI/ARDS. Thus, these laboratory parameters of coagulation may not be useful in assessing the pharmacodynamic effects of TF-targeted therapies.
As part of the safety assessment, evaluation of oxygenation index and patient outcomes was conducted. There was no significant treatment effect at any dose of ALT-836 on PO2/FIO2 ratio while patients were on mechanical ventilation. Assessment of hospital resource indices also did not reveal significant differences in ventilation free days or duration of hospital stay following ALT-836 treatment, though patients receiving 0.1 mg/kg ALT-836 showed an improvement in ICU-free days at day 28 when compared to placebo treated patients (mean ± SD: 8.7 ± 8.1 (placebo) vs. 20.0 ± 2.4 (ALT-836), P = 0.036) (Table 4). Although this result is encouraging, it should be noted that this study was not sufficiently powered to assess ALT-836 efficacy and that because of the large inherent variation in outcome parameters observed in this patient population, preliminary evaluation of efficacy end points will likely require a placebo-controlled Phase II trial with at least 45 subjects per treatment arm. The overall mortality rate observed in this study was lower than that reported in recently published studies in ALI/ARDS subjects. However, this also likely reflects the small number of subjects in this study since ongoing follow-up studies with larger numbers of the same subject population verified that placebo-treated subjects have a mortality rate consistent with historic values (H. Wong, personnel communication).
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