Blessed by a trans-Atlantic constellation of AIDS research stars,the first test of an antisense compound aimed at HIV got underway last week in France.
In a randomized Phase I safety study at Cochon and Salpetrireteaching hospitals in Paris, six HIV-positive patients receivedinitial intravenous or subcutaneous doses of GEM 91, anantisense oligonucleotide developed by Hybridon Inc. ofWorcester, Mass. Another 18 subjects are being recruited forthe clinical study, which is designed to test the novel drug'stolerability at ascending dosage levels. All 24 volunteers willbe adult men or women who are infected with the AIDS virusbut do not yet have symptoms of the disease.
This initial clinical trial of GEM (gene expression modulation)91 is being co-sponsored by Hybridon and France's NationalAgency for AIDS Research. "Antisense represents a completelynovel approach to anti-viral therapeutics,S said Jean-Paul Levy,director of the French agency. The question is to determine thesafety and tolerance in humans, and this will be the objectiveof this clinical trial we are now undertaking."
Hybridon's chairman and chief executive officer, E. AndrewsGrinstead III, told BioWorld that the French government ispaying for the entire study, which he estimated will saveHybridon "definitely in the millions of dollars and enable us tomove boldly on two continents."
A parallel Phase I study will soon commence in the U.S.,Grinstead said. GEM 91 is a clinical candidate at the AIDSClinical Trials Group (ACTG). Last month, the companysubmitted the final data requested by the FDA before itapproves Hybridon's investigational new drug application(IND), which has been pending since last November. "We expectto hear from the FDA shortly," Grinstead said. "A major U.S.teaching hospital involved in drug and AIDS research inanimals has already obtained approval from its internal reviewboard and is standing by, ready and enthusiastic to go," headded.
Unlike conventional Phase I safety and pharmacokinetic drugstudies, the trial just begun in France and pending in the U.S.divides the protocol into three progressive stages: Phases I-A,I-B and I-C. Hybridon's newly appointed senior vice presidentfor drug development, Paul Schechter, explained that thesesteps, promulgated by the ACTG, "designate various stages ofdrug development for treatment of AIDS."
In general, he told BioWorld, I-A involves first-timeadministration of a single dose to humans. "The endpointobjective of a I-A study is to define tolerability. You escalatethe drug until you reach intolerance, at which point I-A isover."
Schechter expects that the French study will move to thesecond dose level of this I-A framework within the next month.
I-B indicates multiple dosing and I-C, he explained, "issomewhat different than with other kinds of drugs. We takethose people who are apparently responding to the compoundin Phase I-B and allow them to continue treatment underobservation in I-C." He noted that "this is very dicey because inPhase I you're really not looking for an efficacy response. It's adesignation somewhat specific for this AIDS indication."
GEM 91 is a 25-mer antisense oligodeoxynucleotidephosphorothioate molecule targeted to the gag gene in the HIVgenome. It prevents gag from encoding a protein vital to HIVreplication. The rationale for its use in AIDS therapy is theability of an antisense sequence to specifically inhibit theexpression of HIV-1 viral or messenger RNA.
This mechanism of action should override HIV's shifty abilityto mutate and thus evade the mechanisms of action deployedby current therapies, such as AZT and ddI.
"We have not seen a strain of this virus or a patient samplethat GEM has not been able to inhibit," Grinstead told BioWorld.
Last July, Hybridon's chief scientific officer and vice presidentof drug discovery, Sudhir Agrawal, reported to the NationalCooperative Drug Development Group-HIV in Washington, D.C.,that GEM 91 "was effective in inhibiting 10 primary HIV-1isolates." Two of the 10, he added, were AZT-resistant and oneddI-resistant.
On this score, Roger Monier, director of France's prestigiousGustave Roussy cancer institute, has said, "Antisenseoligonucleotides are much less likely than conventional anti-viral drugs to induce the development of resistant virusstrains."
Robert Gallo, who heads the National Cancer Institute's tumor-cell biology laboratory, lauded the GEM 91 trials in HIV-infected people "(as beginning) a new and important chapter ofclinical research and therapy of AIDS."
Paul Zamecnik, principal scientist at the Worcester Foundation,is credited with demonstrating in the 1970s that antisensetechnology was more than a concept. He founded Hybridon in1990 expressly to exploit antisense for medical purposes.
When Zamecnik synthesized his first batch of antisensemolecules in 1978, Grinstead related, "it took a senior scientisthalf a year to make material like GEM 91, and the nominal costwas $16 million per gram."
By the mid-1980s, thanks to advances in solid-state chemistry,the price tag on a gram was down to $100,000, and by 1990 to$10,000.
"Two years ago," Grinstead pointed out, "nobody made morethan a few grams; now we are approaching a kilo of material,and cost is $1,500 per gram, without economies of scale or allthe technologies we've developed to put into the manufacturingprocess."
With at least one eye on the changing health-care system'seffect on drug pricing, he concluded, "We have the ability to gobelow $1,000 a gram." While ultimate dosages PP in themicrogram range PP will only emerge in months to come fromthe just-started Phase I trials in France, Grinstead surmised,"one gram of GEM will go a long way."
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.