Tissue plasminogen activator (t-PA) is widely known as a GenentechInc.'s clot-busting, blockbusting, budget-busting heart attack drug.Even at more than $2,000 per treatment, t-PA (trademarked Activase)holds two-thirds of the $300 million world market for reopeningblocked coronary arteries and restoring blood flow to a stricken heart.(See BioWorld Today, April 7, 1994, p. 1.)Now, seven years after the FDA approved t-PA for saving victims ofacute myocardial infarction, Genentech has a mutant variant of thegenetically engineered compound in animal trials. A team ofcardiovascular, cell-culture and process scientists at the companydescribe "A faster-acting and more potent form of tissue plasminogenactivator" in the current issue (April 26) of the Proceedings of theNational Academy of Sciences (PNAS).Activase, despite its clinical and commercial successes, has a numberof shortcomings, which the just-described analog purportedlyovercomes.Current t-PA treatment is by intravenous infusion lasting 90 or 180minutes, said biochemist William Bennett, the paper's principal author.This mutant version, he told BioWorld, counteracts the compound'sextremely short half-life; Activase clears the bloodstream in only sixminutes. The variant, TNK-tPA, hangs in there about eight timeslonger _ 1.9 milliliters per minute per kilogram of body weight in theblood plasma of rabbits, compared with 16.1 milliliters per minute perkilogram of body weight for t-PA. It would be administered in a singleshot, Bennett surmises, rather than by prolonged infusion.How TNK-tPA Outguns ActivaseA normal body makes its own plasminogen activator (PA), to preventunwanted clot formation, and it also makes an inhibitor to keep the PAfrom thinning the blood overmuch. In a blocked coronary artery, thisinhibitor is unwelcome; TNK-tPA is 80 times more resistant to it thanis Activase.In rabbits fitted with an external artificial coronary artery, plugged by areal fibrin clot, TNK-tPA, administered as an up-front bolus, dissolved50 percent of the clots in one-third the time required by standard t-PAinfusion. Because of its slower clearance and faster clot lysis, Bennettand his co-authors wrote, "TNK-tPA . . . is effective as a thrombolyticagent when given as a bolus at a relatively low dose." They add that thebolus dose of TNK-tPA "is likely to be more convenient and mightwell lead to shorter times to reperfusion."Will It Lead To A Lower Price?Bennett, who is directing Genentech's t-PA analog effort, said, "I don'thave any feel at all for what may happen to the price. A lot of it willdepend on what the dose will turn out to be, and that will depend onwhat will happen in the clinic."He expects the analog to be in the clinic "early next year" with Phase Itrials.Genentech's program of generating and testing mutant t-PA variants byoligonucleotide-directed mutagenesis has screened several hundredanalogs over the past five years or so. Half a dozen analogs showedmaximum potential in plasma clearance time, clot lysis, fibrin binding,activity in plasma and plasma clot, and resistance to plasminogenactivator inhibitor. Of these, TNK-tPA turned in the best overallrecord.His team, Bennett explained, developed its variants by switching aminoacids along Activase's 527-residue sequence. TNK, the front-runner,required changing a threonine for an asparagine, to create aglycosylation site (T), an asparagine for a glutamine at another site (N),and a cluster of four varied amino acids for four alanines in a row at athird (K).The Only Game In TownGenentech, based in South San Francisco, is the sole commercialplayer in the U.S. that is developing t-PA equivalents. The company'sEuropean partner, Boehringer-Ingelheim makes and markets theproduct everywhere else in the world.In Europe, Bennett said, several other companies are seeking togenerate alternative versions or products. Schering is working on avampire-bat-saliva molecule. And Boehringer-Mannheim is testing atruncated t-PA molecule.Frances Castellino, dean of Notre Dame University's College ofScience, has been working on the biochemistry of plasminogenactivator for 25 years. Anent Genentech's TNK-t PA variant, he toldBioWorld, "You're not talking to somebody who's hyper-excited abouta second-generation t-PA, because I don't know that Activase hasplayed itself out at this point, I don't know if we're not just tweaking."As for pricing," he added, "I can't see why it would be cheaper. Ipresume an enormous development cost, so I think that any pricingmiracle just isn't going to happen. But I'm not negative, justapprehensive." n

-- David N. Leff Science Editor

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