Bob, this is dedicated to Betty and others, like you, that insisted I learn to cut and paste. I am now trying to see if pictures can be transferred. This is a trial, only a trial, and I hope it does not lead to further trials. I believe everyone should buy subscriptions to things they want to read, as long as the price is below $100 per year. Above that price it is probably o.k. to cheat if one at least feels guilty. O. K. one last plug. Mike probably got at least two people to subscribe to Nature Biotechnology magazine last night. As a test, I am interested in seeing if one can cut and paste from a distant land like Englanterra. Let's try it now:
Business and Regulatory News
December 1998 Volume 16 Number 13 p 1303
Restored credibility for sepsis
therapeutics?
David Webber
David Webber is a freelance writer working in Dobbs Ferry, NY.
The pivotal phase III clinical trial of one of the last "surviving"
sepsis drugs—for the treatment of meningococcal sepsis—is nearing
completion. XOMA Corporation's (Berkeley, CA) Neuprex is
recombinant human bactericidal/permeability-increasing protein
(BPI), an endogenous neutralizer of endotoxin and, with lesser
potency, an antibiotic. Some experts are cautiously optimistic about
the outcome and hope that positive results will reinvigorate the
sepsis field. "This field needs some excitement," says Brett Giroir, of
Southwestern Medical Center in Dallas, TX, who is the principal
investigator of the Neuprex trial. "If positive, this study is going to
answer a lot of questions."
There is currently no approved therapeutic for sepsis, the systemic
inflammatory response syndrome that afflicts over 80,000 US
patients per year and has a mortality rate in excess of 25%.
Biotechnology and pharmaceutical companies rushed into that
commercial vacuum earlier this decade with inhibitors of a variety of
presumed mediators of the sepsis cascade such as endotoxin,
interleukin-1, tumor necrosis factor, and bradykinin. Following an
extraordinary series of major clinical trial failures by every one of
the novel drugs (Nat. Biotechnol. 15:601, 1997), leading clinicians
concluded that the biology of sepsis was too poorly understood for
anyone to develop a successful therapeutic, and shell-shocked
investors stopped funding most research. Ironically, XOMA was sent
into total eclipse for several years by the failure of its antiendotoxin
antibody, E5.
XOMA avoided calling Neuprex a sepsis drug for a long time, but has
begun doing so during the past year, reflecting its growing confidence
about the drug's chance of success. The reasons for optimism
regarding XOMA's phase III trial, experts say, are based on lessons
learned from past failures. All previous sepsis drugs showed activity
in at least some retrospectively defined patient subgroups. This
suggested that the heterogeneity of patients in "classical" sepsis
trials—representing a wide variety of serious, underlying diseases,
and probably, as a result, a broad range of serum levels of a drug's
biological targets—had confounded efforts to detect the efficacy of
the drugs.
In XOMA's phase III trial of Neuprex—expected to include around 300
participants—sepsis patients all have meningococcemia, a
bloodstream infection by Neisseria meningitidis that occurs in
several hundred patients per year. Patients are usually otherwise
healthy and all have high levels of endotoxin, Neuprex's target.
Moreover, Neuprex differs from previous drugs in that it is a potent
neutralizer of endotoxin, whereas the old agents, E5 and Centoxin,
were later shown to be relatively weak binders with limited ability
to prevent the binding to the next mediator in the cascade. (The
inflammatory response seen in many cases of sepsis is produced by
human cells when endotoxin, a component of the cell wall of
Gram-negative bacteria, is delivered to CD14 by
lipopolysaccharide-binding protein [LBP]. BPI works by binding the
same site on endotoxin as LBP, thereby inhibiting the endotoxin signal
to host cells.) "One hundred percent of patients with
meningococcemia are endotoxemic," points out Giroir, adding, "and
BPI is clearly the most effective neutralizing agent available."
"I am quite optimistic about this trial," adds Steven Opal, of Brown
University (Providence, RI), a leading sepsis researcher who is not
involved in the study. "Meningococcemia is perhaps the clinical
illness that is most like the endotoxin challenge experiments used in
animal labs. If a potent antiendotoxin agent is going to work
anywhere in human sepsis, it should work here."
Preliminary clinical data also support optimism. In an earlier
26-patient, open-label, phase I/II trial (Lancet 350:9089, 1997)
only one patient (4%) died, compared with 20% in a historical group.
In addition, no serious adverse events have been reported in over 700
patients who have received Neuprex in this and other trials.
Full patient enrollment of the phase III trial should be completed by
January 1999, and the results unblinded three months later. However,
an independent safety and efficacy monitoring committee intends to
look at whatever data are complete this month; if strongly positive,
the committee could stop the trial on compassionate grounds. Wary
Wall Street investors worry this could imply Neuprex's advantage
over placebo is marginal so far, and wonder why XOMA has not lined
up a large, pharmaceutical company partner for the drug. Skeptics
also note that the low incidence of meningococcemia is too small a
commercial opportunity to justify the risk of investing in a sepsis
drug. XOMA's stock price—near the bottom of its 52-week
range—reflects these concerns.
Although XOMA regards the meningococcemia study as proof of
concept for the majority of cases in which endotoxin levels are
clearly raised, "The utility of BPI as a general antisepsis agent is
more problematic, unless we come up with a better way of detecting
patients who have an endotoxin-driven illness than we have up to this
point," points out Opal.
Addressing the concerns about market size and the potential for more
general use, XOMA is currently conducting a 1650-patient, phase III
trial in hemorrhagic trauma, in which wounds facilitate the
migration of endotoxin-bearing bacteria from the intestinal tract
into the bloodstream. In addition, XOMA has developed an assay for
LBP—levels of which rise in response to endotoxin—as a rapid test for
endotoxin-driven sepsis.
"A positive study in meningococcemia would not just answer
questions regarding this disease, it would be the first wedge driven
in for doing something for sepsis in general," says Patrick Scannon,
XOMA's chief scientific officer.
Giroir: BPI is clearly the most effective endotoxin-neutralizing
agent available.
Bob, sorry, I still have not learned to cut and paste pictures. will try again, when and if appropriate.
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