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Like the Wings of Icarus, Treatment Hype Sweeps Its prey Upward to the Heavens, Then Plucks Them Down Into icey Waters

Dividends from Desperation

While all the Western world beats its chest, proudly promoting the renewed, if disputatious, promise of (3TC) nucleoside combinations furiously FAXed around the world late last month; with nightly news teams hunting down salacious, headline-making whimsy like Hank Heimlich’s malaria therapy (apparently it works equally well for chronic fatigue syndrome and cancer); and with those most willing to dispel disbelief launching private pilgrimages in search of una de gato (Uncaria tomentosa, or “cat’s claw”) found principally in the Peruvian jungles. (Those returning from the journey report the wholesale clearing of coca fields in order to make room for this burgeoning new cash crop.) or Chinese chi cong therapy (an allegedly Taoist approach being promoted by a Taiwanese mid-Manhattan restauranteur as a cure for AIDS which requires of its devotees a minimum six month’s celibacy), it would seem prudent to examine a bit of the less-highly-hyped work that is simmering along out there, but lacks the public relations muscle of Glaxo and Wellcome or the Hard Copy/Primer Impacto sensationalistic appeal of leaches, tropical diseases and the second coming of Christ. When even the staid, stand-way-back-and-take-a-long-hard-look-before-being-sucked-in Economist appears to have tipped headlong into the pit of orgiastic euphoria (“Slowly, and surprisingly silently, progress is being made in the treatment of AIDS;” see “Step by step,” November 26), it’s high time for a brief brush with sobriety.

Late last year, on the heels of yet another UK-based meeting, passive immune therapy (PIT) re-appeared on the world stage to make its belabored renaissance (“Mr. DeMille, my close-up …”). Only the most perspicacious few realized that the UK-released PIT results had already been presented at the June 1993 International Conference in Berlin and the December 1993 National Retrovirus Meeting in D.C. Nonetheless, as one of the many press-release-rewriting news corps, the French weekly L’Express ran a full page on the miraculous promise of other people’s antibodies, quoting California researchers’ claims that the benefits of PIT had added “2-5 years” to their patients’ lives!

Thankfully, London’s AIDS Treatment Update editor Edward King, feet ever so squarely on the ground, saw it fit to emblazon the cover of his November issue with the stern caveat, “It is clear that passive immunotherapy does not represent a dramatic breakthrough,” adding that, “Two people who received plasma in one of the British PIT studies are believed to have been infected with hepatitis C from the treatment.” In light of the deafening din of disinformation deluging desperate denizens out there, is it any wonder that these self-proclaimed near-the-end-of-their-rope-ers are frantically boarding rickety ATRs and shuttling here and there in order to boil their blood or endure the ravages of physician-inflicted Amazonial rigors and fever (actually FDA recently granted approval for expansion of a hyperthermia study in Pittsburgh)?

Even last month’s headline making 3TC/AZT combination results, although admittedly intriguing, are based solely on short-term surrogate marker changes: the same surrogate marker changes that brought us those all-powerful antiretrovirals AZT, ddI, ddC (a real winner) and d4T. In a trenchant early analysis (unfortunately, her editor chose to top off the report with the unduly dramatic headline, “New Drug Combo Knocks Wind Out of AIDS”), New York Newsday science reporter Laurie Garrett put the 3TC/AZT wind-knocking combination into perspective like this: AZT pushed viral levels down 100-fold for a few days, but then the virus crept back up to baseline. AZT+3TC pushed viral levels down 1000-fold for a few days, and then plateaued at a level about 10-fold below baseline. In two of the four studies, this 10-fold reduction in viral load was sustained throughout the 52 weeks of follow-up. (With one billion new viral particles being produced daily, a mere 10-fold reduction in levels of circulating virus… well, you can do the math.) And while the substance of these headline-making stories clearly varies in degree of merit, they often serve only to distract attention away from equally (or more) worthwhile developments less prone to basking in the radiant glow of the fickle miracle cures limelight.

Contrary to what may be the heard-on-the-street prevailing sentiment, quite a bit is being done in little labs across the land. Although it may be true that the big household names like Merck, Bristol, Pfizer, Roche, Glaxo, Smithkline, Schering and even Wellcome itself appear loathe to make any big investments in HIV therapeutics (preferring the “me-too” posture that has lavished upon us questionable AZT knock-offs like ddC, d4T, 3TC and a whole slew of fine-tuned rennin inhibitors rebirthed for the burgeoning AIDS market), it is not the mega-drug houses, by-and-large, where the creative, risk-taking brain power is – or ever has been, to a large degree. Rather, it is the tiny biotech start-ups, the academic-based venture capitalist teams from which the new ideas and out-on-a-limb approaches flow.

Take Allelix Pharmaceuticals, for example. A $25M-cap venture in Ontario, Canada which is about to begin Phase II studies of its tat antagonist; a compound which has also shown preliminary activity against CMV. Or Receptagen, a $78M-cap boutique (also in Canada), which is soon to launch a clinical study of a specially formulated co-enzyme Q-10, a proposed anti-apoptotic therapeutic.

Then there are the antisense companies: Hybridon, Gilead and Isis, among others. Hybridon’s phase II trial of GEM-91 is now underway in New York, Birmingham and Paris, after a successful phase I. Gilead is busy at work on both anti-CMV and anti-HIV antisense therapeutics (GS504 and GS840, respectively) and expects to present results from a 48-patient phase II/III study of GS504 (cidofovir) later this year. Gilead’s phase I/II study of the orally administered GS840 (a pro-drug of its initial GS393) was expanded from one site (Johns Hopkins) to six late last month. Also in California there is Isis, whose compound 2922 has shown modest activity against CMV and is being tested in combination with standard-of-care therapies for CMV, ganciclovir and foscarnet. Isis recently announced the beginning of a phase III which will enroll 200 patients, and is in the process of filing an IND for its anti-HIV compound ISIS 5320.

In yet another scientific frontier, the first potential gene therapy product entered Phase II studies a month or so ago. San Diego-based Viagene is forging ahead with its fibroblast transplanted env-expressing vector (HIV-IT). Initial results reported that the product induced increased expression of cytotoxic T-lymphocytes (CTLs), believed to be crucial to controlling HIV’s spread in the body (or, according to your pathogenetic model of choice, unwittingly responsible for the savage obliteration of HIV-infected CD4+ T-cells).

Other gene therapy approaches are steadily progressing at Phil Greenberg’s lab in Seattle, Flossie Wong-Staal’s lab at University of California at San Diego, Gary Nabel’s lab in Ann Arbor and Robert Walker’s lab at NIH. In collaboration with Dr. Walker, Cell Genesys has recently announced results from its work with HIV-specific cytotoxic T-lymphocytes (CTLs). For ill or for good, the science of therapeutic genetic manipulation has burst its way out of the gate and is speeding its way around the track faster than anyone had ever anticipated. Sandoz, which has made a big bet in the gene therapy arena with its recently upgraded 72% stake in Systemix, is also the place where SDZ NIM 811, a cyclophilin-A inhibitor will first get its first therapeutic workout.

In the area of cytokine therapy (IL-2 and alpha interferon aside), Genetics Institute has begun phase I studies of its enhancer of cell-mediated immunity IL-12, first proposed by Dr. Gene Shearer and others as a way to maintain a cellular (as opposed to antibody dominated) immune response to HIV (though recent research out of Dr. Fauci’s lab, which suggests that IL-12 may preferentially boost the development of CD4+ but not CD8+ T-lymphocytes, raises red flags for those who believe in the crucial infection-fighting role for CD8s).

Finally, of course, there is the renewed interest surrounding Bristol’s hydroxyurea (an old cancer, and new sickle cell, drug), in combination with ddI. While nothing earth-shattering has been seen with the combo to date, the idea of altering the “micro-environment” of the cell in order to produce therapeutic benefit represents a novel approach to therapy which might pay off, if not with this present candidate, with future compounds down the road. Progress is being made in the research, if not the treatment, of AIDS, but one must be very careful where s/he looks.

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