RESTON, VA _ Like most biotechnology ventures, TherionBiologics Corp. is a small company attempting to tackle a bigproblem. Its cutting edge research on AIDS vaccines represents oneof the most sophisticated, complex and riskiest approaches in thefield while its financial future is by no means guaranteed.
Although the work of the company and its main academiccollaborator, Harvard University professor Ronald Desrosiers, ishigh on the agenda at scientific gatherings like the four-dayConference on Advances in AIDS Vaccine Development here, it islow on that of venture capitalists and other investors.
"AIDS research is perceived as very, very high risk by investors,"explains Therion's CEO and founder, Dennis Panicali. "We're 10years into vaccine development in this country and the results havebeen uniformly disappointing in the clinic. Investors see it'simportant and it's a potentially huge market, but it's just too long-term an investment."
Therion, of Cambridge, Mass., has tried and failed to go public twicesince its inception in 1991. It attempted its last initial public offeringin mid-1992. It has relied upon $7.5 million from venture capitalistsand federal government grants to fund its work. In April, the firmwas awarded continuation of a $5 million, five-year grant from theNational Institute of Allergy and Infectious Diseases (NIAID) tofurther its AIDS vaccine.
Therion's Approach Is Riskier
Compounding the financing, development and regulatory problemsthat face any small biotechnology company working on AIDS isTherion's technology _ an approach that is deemed riskier and morecomplex than most. The company is testing a live recombinantvaccinia virus engineered to express multiple HIV antigens while itscollaborator, Desrosiers, is testing a live attenuated virus. (Therionhas exclusive rights to commercialize Desrosiers' work.) Desrosiersis also receiving NIAID support to the tune of $6 million over fouryears.
Therion's vaccine is considered the safer of the two approaches sinceit uses the same benign virus used in the smallpox vaccine andmerely adds to it genes that encode for expression of nine HIVantigens. Desrosiers' vaccine is the genuine article _ be it SIV(simian immunodeficiency virus) or HIV _ genetically snipped andtucked, but still intact.
"Only small companies would take these kinds of risks but we takethe large risks in hopes of large rewards," said Panicali. "We have atechnology here that could solve some of the major scientificchallenges of AIDS vaccines."
Needless to say, the words "live attenuated virus" in the context ofAIDS is alarming. South San Francisco-based Genentech Inc.'sAIDS vaccine project leader Donald Francis said, "Nopharmaceutical company will go near it." Yet Desrosiers' resultstesting a live attenuated SIV in Rhesus macaques have the scientificcommunity buzzing. The live SIV, modified by deleting the so-called "nef" gene which may affect the replication-competency andvirulence of the virus, has provided 100 percent protection againstinfection in macaques for up to five years so far. The results havebeen independently reproduced by others, according to Panicali.
Significant problems for a live attenuated virus loom, among themconcerns about their potential to cause cancer (as retroviruses areknown to do), concerns about sexual transmission from vaccinated tonon-vaccinated individuals and, most important, fear that the vaccinemight just slow the progression from infection to AIDS, rather thanstopping it. In addition, Desrosiers found that 100 percent protectionwas achieved only in macaques that had been vaccinated for a fullyear. Macaques that were challenged with SIV after less than a yearof vaccination did not fare as well. "That tells us that protectiveimmunity takes awhile to develop," explained Panicali.
Uncertainty Surrounds Use Of Live Vaccine
Panicali points out that historically, the use of live viruses has solvedsome of medicine's most difficult viral problems: measles, mumpsand polio are all examples of infections cured by live vaccines.Nevertheless, people are understandably queasy about a live vaccinefor AIDS.
"The live attenuated virus is the ultimate vaccine in terms ofcomplexity, as well as the ultimate in terms of mimicking the virus,"Panicali told BioWorld. "The nature of this vaccine frightens peopleyet it is perhaps the only vaccine that really works. At some point,we're going to have to solve that conundrum."
In the meantime, Therion is attempting to learn from Desrosiers'work how it might modify its own vaccine to boost effectiveness. Sofar, at least in macaques, Therion's viral vaccinia vector product(called TBC-3B) has not proved as effective as Desrosiers' liveattenuated virus. In the best studies, it protected one in threemacaques from SIV infection. TBC-3B is currently being evaluatedin a Phase I immunogenicity and safety study sponsored by theNational Institutes of Health.
As opposed to HIV envelope vaccine strategies that try to spark aprotective immune system response by introducing one HIV antigen(such as glycoprotein 120), Therion is hoping that nine antigens willbetter mimic the real virus. Panicali likes to say that gp120 vaccines,such as those developed by Genentech Inc. and Biocine (a jointventure of Chiron Corp. and Ciba-Geigy Ltd.), are "first generation"products. "The next generation of vaccines will be more complex,"he said.
Panicali is quick to point out that his company's success or failuredoes not hinge on its AIDS program _ he said Therion's cancerimmunotherapy program is more crucial _ but concedes that the 32-employee firm spends "about 40 percent" of its efforts on AIDS.Therion's annual burn rate of $3.5 to $4 million will necessitateanother round of venture financing by "early next year," saidPanicali. n
-- Lisa Piercey Washington Editor
(c) 1997 American Health Consultants. All rights reserved.