The best magazine
Discussion
The effect of talactoferrin alfa on 28-day all-cause mortality in patients with severe sepsis was evaluated in a randomized, double-blind, placebo-controlled phase 2 study. The trial achieved its primary endpoint of a reduction in 28-day all-cause mortality, from 26.9% in the placebo group to 14.4% in the talactoferrin group. This represents a 12.5% absolute and a 46.5% relative reduction in mortality. Furthermore, the effect of talactoferrin on reducing mortality was sustained at 6 months.
Lactoferrin is a naturally occurring 78 kDa iron-binding protein present in mucosal surfaces and at the sites of inflammation. It is expressed throughout the body in immune cells and body surfaces exposed to the external environment. Although it is present in tears, saliva, and respiratory secretions, the highest concentrations are found in colostrum. Maternal milk plays a central role in helping to establish the immune system, including the GALT—the largest immune system in the body. In breast fed infants, enhancing the gut barrier to infection has been attributed at least in part to lactoferrin. Interestingly, the milk of mothers of premature infants has a much higher concentration of lactoferrin (> 5g/L) than that of the mothers of mature term infants (~ 1–5g/L). One recent study in very low birth weight and extremely low birth weight newborns showed that enteral administration of bovine lactoferrin decreased the occurrence of neonatal sepsis.
Lactoferrin binds to epithelial cells and modulates intracellular signaling pathways impacting cytokine secretion (e.g., nuclear factor-kB), increases levels of key chemokines (e.g., CCL20) and cytokines (e.g., interferon-γ) derived from the GI tract, and decreases production of Th2-mediated cytokines (interleukin [IL]-4, IL-6, and IL-10). The biologic effects include a decrease in GI tract–induced systemic surges of proinflammatory cytokines that may contribute to the multiorgan dysfunction in sepsis. Lactoferrin appears to normalize gut permeability, decrease bacterial translocation across the gut, dampen the hyperimmune response to inflammatory stimuli, and potentially also impact the immunosuppressed state that follows the proinflammatory surge. Sepsis is a severe clinical syndrome characterized by cytokine release, increased expression of adhesion molecules, release of reactive oxygen species, and expression of acute-phase proteins. These pathophysiological aspects of sepsis impact the gut, and this may be one area where talactoferrin acts. In 15 healthy human volunteers, talactoferrin reduced the indomethacin-mediated increase in gut permeability. In animal models of sepsis induced by bacteria and endotoxin administration (Agennix data on file), enterally administered lactoferrin decreased mortality. The gut has been considered a "motor of multiorgan failure" in sepsis. The sepsis-induced increase in gut permeability results in increased bacterial translocation, which can further exacerbate the septic state. Both local and systemic sequelae are observed following the ischemia-reperfusion injury to the gut that is observed in sepsis. Oral talactoferrin, which acts locally on intestinal enterocytes and the GALT, may help stabilize the gut and interrupt this sequence of noxious events. Given the potential action of TLF in the gut, it is interesting to note that patients with abdominal infections tended to fair worse with TLF compared to placebo. This finding requires further evaluation. Direct infectious, ischemic or surgical insults to the gut may impact potentially protective mechanisms in the otherwise normal gut during sepsis. It is also possible that this outcome from a small subgroup in a small trial may be misleading.
The reduction in mortality from TLF administration in this phase 2 study is large compared to other sepsis trials. However, the use of concomitant medications (steroids, drotrecogin alfa) and the baseline characteristics, including the numbers of organ failure, sites of infection, types of organism, incidence of positive blood cultures, and APACHE II scores, were similar to other recently reported interventional sepsis studies. The Kaplan–Meier survival curves begin to separate in the first few days, and their separation becomes more pronounced in the second and third week. Thereafter, the effect seems to be relatively constant. The reason behind this pattern of effect is unknown and will require additional investigation on the mechanism of action that may include effects on excessive inflammation as well as later hypoimmune phases of sepsis. A recent analysis of several immunomodulating therapies studied in severe sepsis has suggested a treatment-by-severity interaction, with greater benefit observed with increasing severity. Perhaps consistent with this observation, we observed that the greatest mortality reduction in the TLF-treated patients occurred in those with higher APACHE II scores.
The results of this study were scrutinized for sources of bias that could have occurred because of the study drug labeling error. An analysis of efficacy data performed only on patients without randomization errors provided results similar to those for the overall MITT population. In addition, results from analysis of the sensitivity population that excluded the 22 patients who received both TLF and placebo were also similar to those for the MITT population. Another analysis, which excluded the 45 patients who received study drug to which they were not randomized (sensitivity analysis 2), is the most conservative and in that sense, it could be argued, the most reliable. These sensitivity analyses provide further evidence that the errors in labeling of the study medication vials did not introduce bias nor impact the study outcome.
The findings from this phase 2 study, and the need for new therapies in severe sepsis, warrant further studies with talactoferrin. Recently, talactoferrin was evaluated globally in another phase 2/3 sepsis trial. The primary endpoint of this latter study was to determine the effect of oral talactoferrin alfa on 28-day all-cause mortality in patients with severe sepsis. Based on the review of available data, the DSMB for this second study recommended that patient enrolment and treatment be stopped. The data from the phase 2/3 will be unblinded to better understand the results.
Source: ...