Trail-blazing rats at the University of Alabama,Birmingham, have become the first mammals to stomachand absorb antisense oligonucleotides by ingestion ratherthan injection.

The university's pharmacology and toxicology divisionhas an ongoing scientific collaboration with HybridonInc., of Worcester, Mass., which is developing antisense-based therapies, notably to fight the AIDS virus. Theprospect of delivering antisense molecules to patientsorally _ instead of by needle _ is the latest reportedinnovation in the company's elaboration of a second-generation therapeutic compound.

Its first-generation antisense preparation, trade-markedGEM91 (gene expression modulator), is halfway throughits second year of Phase Ib/II anti-HIV clinical trials inFrance and the U.S. (See BioWorld Today, Aug. 17,1994, p. 1.)

At five French medical centers and six U.S. teachinghospitals, 123 HIV-positive but asymptomatic AIDSpatients, (as of Monday, and still counting), are testingthe ability of GEM91's antisense oligonucleotides toclobber the crucial HIV gag gene.

As new cohorts of patients enroll in the trials, thecompany's senior vice-president for drug development,Paul Schechter, explained, "they get the next-higher doseof GEM91. The studies will end," he added, "when weget to dose-level intolerance. We have not yet seenintolerance that would make us stop."

The dose-escalating trials are double-blinded in the U.S.,but open-label in France, which permits Hybridon tomonitor its compound's efficacy. "We have not haddefinitive evidence of therapeutic effect," Schechterobserved. "Some evidence," he told BioWorld Today, "ispromising, but needs confirmation."

Two papers in this week's British journal, BiochemicalPharmacology, dated Aug. 7, report Hybridon's second-generation GEM antisense molecule. One describes itsoral bioavailability; the other, its enhanced stability in thebody. Both benefits derive from capping the originalDNA molecule at both ends with stretches of RNA, toprevent degradation, thus creating a hybrid nucleotide.

Prior to these two articles, the only open data onHybridon's hybrid antisense molecule was a EuropeanPatent Treaty Organization patent published two yearsago.

DNA/RNA Mixture Lengthens Half-Life

The company's chief scientific officer and senior vice-president, discovery, Sudhir Agrawal, explained toBioWorld Today, "Combining DNA and modified RNAin one oligo increased the half life of the compoundagainst breakdown by various enzymes, which are theproblem in in vivo situations. We also find," Agrawaladded, "that using DNA/RNA mixtures increases theaffinity of the drug for the HIV gag target."

To confirm the augmented duration of the hybrid overGEM91's straight DNA molecule, the Alabama co-authors injected the new compound intravenously intorats. Then, tracking its dissemination throughout theirbodies, they found, Agrawal said, "that even at 48 hours,we have the majority of the compound still in the intactform, still available for antisense activity."

By comparison, in the first-generation GEM91, he wenton, "we found that after 24 hours, we had very lowconcentration of the active compound left."

Parlaying this newfound stability, Agrawal and hi co-authors "tried a number of experiments to see if thecompound can be given orally."

As laboratory rats don't obligingly gulp down everysubstance put in their dish, the researchers fed theiranalog to the animals by a tube introduced into theirstomachs.

As reported in the journal, Agrawal said, "the papershows an oral absorption of that same hybrid compound.It shows for the first time that DNA can be given _ andabsorbed _ orally."

Two Second-Generation INDs Due Within A Year

"GEM91 is the only antisense therapeutic we have in theclinic so far," Schechter said, adding, "Hybridon isplanning to file at least two investigational new drug[IND] applications within the next year, to test oursecond-generation analog. These will include HIV as wellas other disease entities.

"The second generation," he observed, "gives us twoarrows in our quiver: One, prolonged duration of action;two, possibility of oral administration. We may not havethe optimal oral formulation yet," he observed; "we'reworking on it. I think it shows there is a secondgeneration."

Virologist Robert Gallo of the National Cancer Institutein Washington, an AIDS pioneer, told the 19thInternational Chemotherapy Congress last month inMontreal that anti-HIV antisense therapy confronts threechallenges: short half-life in vivo, need for oral deliveryand cost of manufacture.

Gallo has taken an active interest in the GEM91 trials.Tuesday after meeting with him at the National Institutesof Health in Bethesda, Md., Hybridon CEO AndrewGrinstead told BioWorld Today that "Gallo was pleasedto get our oral data, to say the least."

As for the manufacturing cost factor, Grinstead said:,"We have developed and tested the first two commercialmachines ever tested in the world. One is entirelydeveloped by Hybridon itself: a 100-millimole machinethat can produce 75 kilos of GEM91, or any othercomplex molecule, in a single shift in a year.

"The second, which has the same capacity" Grinsteadcontinued, "was developed and successfully tested, injoint venture with Pharmacia Biotech, Inc. [ofPiscataway, N.J.]" Hybridon owns the first, and will reaproyalties on the second.

"Just to validate it," Grinstead said, "we know that ourmajor clinical-antisense competitor, Isis PharmaceuticalsInc. [of Carlsbad, Calif.] has just put in an order for thesecond Pharmacia machine." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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