Some thoughts:
(1) From a November 1997 XOMA release:
"Our two Phase II studies in trauma, with a total of 570 patients, plus our other Neuprex(tm) studies, gave us an ample database for designing the Phase III trial." said Jack Castello, chairman, president and CEO of XOMA. "Careful analysis of this data, and consultation with the FDA and clinical investigators, has enabled us to design a single Phase III trial that, if successful, is powered to produce data sufficient for product license application."
I wonder whether this statement of pivotal status for the trauma trials is still operative. Midpoint results are to be out next month, but if their recent handling of study results is any guide, mebbe just more confusion?
(2) Another XOMA PR:
Lancet Publication Details Positive Phase I/II Clinical Results for XOMA's Neuprex(tm) in Treatment of Meningococcemia
BERKELEY, CA -- November 13, 1997 -- XOMA Corporation (Nasdaq: XOMA) today announced the first peer-reviewed publication of clinical data from a Phase I/II trial of its investigational drug Neuprex(tm) (rBPI-21) in the treatment of severe pediatric meningococcemia. The article, authored by clinical investigators at hospitals collaborating in the trial with XOMA scientists and clinicians, will appear in the November 15, 1997 issue of the British medical journal, The Lancet.
* * * * * *
The specific aim of the open-label dose-escalating study, the first human clinical trial of Neuprex(tm), was to evaluate the safety and pharmacokinetics of the product in children with severe meningococcemia, and to conduct a preliminary assessment of clinical outcome. Of the 26 severely-ill patients enrolled in the trial from May 1995 to October 1996, only one died. This 3.8% case-fatality rate compares favorably to a recent historical mortality rate of 20% for children suffering the disease. In addition, compared with the historical controls, Neuprex(tm)-treated patients had a better overall outcome as measured by the Pediatric Overall Performance Category Scale. The study also confirmed that Neuprex(tm) is safe to administer to critically-ill children, and shows pharmacokinetics consistent with those seen in earlier adult volunteer studies.
They are citing mortality statistics in a study in which mortality was not an endpoint. Could these figures embody the same, possibly result-skewing or at least analysis-complicating problem that the Phase II study did, namely that the really sickest ones died before they could be enrolled, leaving the study population healthier than the norm from which the "historical mortality rate of 20%" was derived. Does the following shed any light on this question?
THE LANCET
Summary
Background: Meningococcal sepsis remains an important cause of morbidity and mortality. We hypothesised that children with severe meningococcaemia might benefit from inhibition of the inflammatory processes thought responsible for fulminant disease. rBPI21 is a recombinant, N-terminal fragment of human bactericidal/permeability-increasing protein, which kills meningococci and binds to and clears bacterial endotoxin, these being the primary inducers of the systemic inflammation. The aim of this study was to determine the safety and kinetics of rBPI21 in children with severe meningococcaemia and to make a preliminary assessment of clinical outcome.
Methods: In this open-label, dose-escalation, phase I/II trial in severe meningococcaemia (Glasgow meningococcal prognostic septicaemia score [GMSPS] >=8), 26 patients aged 1-18 years, who had received their first dose of antibiotics no more than 8 hours earlier were given rBPI21 by infusion at total doses of 1·0, 2·0, and 4·0 mg/kg.
Findings: The patients had significantly raised plasma concentrations of bacterial endotoxin and cytokines. Peak and steady state BPI concentrations were comparable with pharmacokinetic data in healthy adults. All complications were compatible with the expected pattern for severe meningococcal sepsis. Only one patient died. This outcome was found to compare favourably with a predicted mortality of >=30% by GMSPS, >=15% by plasma endotoxin values, >=28% by plasma interleukin-6 concentrations, 29-49% by severity of coagulopathy, and 20% (11/54) by comparison with recent historical patients consecutively treated in participating centres before this study.
Interpretation: This, the first clinical trial of rBPI21, shows that rBPI21 can be safely administered to children with severe meningococcaemia and that the pharmacokinetics are consistent with patterns seen in healthy adults. Predicted mortality, on the basis of GMSPS, laboratory indices of inflammation and coagulopathy, and historical controls, was for between four and eight deaths. These findings have prompted a phase III randomised trial.
I am still disgusted, but remain hopeful. |
