Sometime between last Friday evening and Monday morning,at a burn-injury center somewhere in the U.S. [precise locationwithheld to protect patient confidentiality], a badly burnedadult (or a placebo-control case) received an intravenous in-jection of the first therapeutic drug designed to shut down thehuman complement system.
Developed by T Cell Sciences, Inc. of Cambridge, Mass., the re-combinant protein, sCR1, is being tested in this initial double-blind, placebo-controlled clinical trial by T Cell's partner,SmithKline Beecham (SKB) of Philadelphia.
sCR1 stands for "soluble complement-receptor-1." T Cell engi-neered it to block one of the earliest of the 16 or more proteinsthat activate the complement cascade, as the body's firstcounterattack against infection or tissue injury (see box onPage 3).
In burn-injury or smoke-inhalation victims, complementrenders the lungs permeable, causing potentially fatal anduntreatable hemorrhage and inflammation. It's first suffocatingeffect is known as adult respiratory distress syndrome (ARDS)a principal cause of burn-injury death. sCR1 aims to prevent ormitigate ARDS by cutting the complement cascade off at thepass.
"In the therapeutic area, this complement inhibitor will takeour company from the research-only stage into a development-phase pharmaceutical firm," said Alfred R. Rudolph, T Cell'ssenior vice-president.
Burn injuries account for only 15 percent of the ARDS market.Life-threatening trauma and sepsis make up the remaining 85percent, for a total of 300,000 ARDS patients. "Our jointsteering committee with SKB agreed that we'd concentrate onthe burn market first," Rudolph explained. "It's a very defined,homogeneous patient population in geographically concentratedburn centers, with well-defined statistical outcomes oftherapy."
Preclinical studies of sCR1 in three animal species G rats, mini-pigs and primates G showed uniformly significant reduction inthe ravages of complement against lung and other organs.Based on these results, T Cell and SKB filed investigational newdrug applications with the FDA last August. It has taken sincethen to line up the first patient that meets their trial criteria.
"All told,we anticipate enrolling fewer than 50 patients tocomplete the trial," Alan W. Tuck, T Cell's president and chiefexecutive officer told BioWorld. He believes that, in addition togathering safety and dose-escalation data, the trial should giveindications of efficacy, as only burn victims may benefit fromthe drug.
Tuck estimates the total complement inhibitor-market in theU.S. alone at half a billion dollars, numbering 1,890,000patients. Its therapeutic potential, besides ARDS, includes organtransplantation, renal dialysis, cardiopulmonary bypass,glomerulonephritis, lupus, and post-heart-attack reperfusioninjury. All of these entities involve insult to healthy tissuescaused by inappropriate overactivity of the complementcascade.
Because T Cell's complement inhibitor functions enzymatically,and gets its licks in early in the cascade, Tuck points out, "ittakes only a relatively small quantity to act therapeutically.This should give us a good safety profile, and also help when itcomes to pricing the commercial product." As for competition,he said, "Nobody else is working on anything that deals withthe heart of the complement system."
SKB will manufacture the soluble receptor blocker, underlicense from T Cell, Tuck said, and will also exercise exclusiveworldwide marketing rights, shared with YamanouchiPharmaceutical Co. of Tokyo for the Japanese market. Forcertain segments of North America, the Philadelphiapharmaceutical firm and T Cell will co-market, once certainsales levels are reached.
T Cell Sciences closed Monday at $7.38, up 25 cents a share.
Sidebar Story: COMPLEMENT CASCADE 101
Like airborne Special Forces that jump in ahead of the groundtroops, the human complement cascade attacks invadingpathogens well before the immune system organizes itshumoral and cellular countermeasures.
That's the good news. The bad news is that complement alsorecognizes damaged and neighboring healthy tissues as foreign,and deploys its cell-lysing proteins to destroy them, too.
Less understood than the antibodies and T cells of the immunesystem, the score or so of serum proteins that populate thecomplement cascade go into action one after the other, eachtriggering the next factor. But it's not a linear domino effect;the "C" factors and sub-factors operate in two separate butintertwined pathways, which all but defy two-dimensionaldiagramming.
To begin its onslaught, complement factor C3 lands on a targetcell on which a complex of two connected antibodies havealready perched, preparatory to unfolding the immune defenseprocess. C3 is thus activated, and it's at this early point that TCell's sCR1 receptor nips the cascade in the bud by latching onto the C3 molecule.
Otherwise, activated C3 then activates C5 and a host of other Cfactors. C5 mobilizes a membrane attack complex for directlykilling the target cell. Along the way, the cascade punishestissues in various ways, such as increasing vascularpermeability, and causing acute inflammation.121592SCR1
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.