The life of a child stunted by growth-hormone deficiency is not ahappy one. Parents too suffer from empathy with their offspring'smisery at school, and concern for their short-stature child's success inlater life.

Fortunately, relief is at hand, in the form of recombinant humangrowth hormone (rhGH). Daily injections of rhGH over time _ along time _ can often, but not always, add inches to a youngster'sheight.

And there's the rub, or rather the sting.

Young children tend to dread the pain of the daily needle, especiallythat it's inflicted by their own mother or father.

"Clearly, a very difficult parent-child interaction," observed ScottPutney, vice president, molecular biology, at Alkermes Inc., ofCambridge, Mass. "And it obviously presents some social problems,"he added, "if the kid can't get away to camp, for example."

Parents and pediatric endocrinologists yearn for a delayed-releasesystem of administering rhGH, like the Norplant contraceptivesubcutaneous implant, which doles out its daily hormone dosage overa five-year period.

"Slow release works for that contraceptive," Putney told BioWorldToday, "because it's a small molecule. Growth hormone," hecontinued, "is a single-chain polypeptide of 191 amino acids. For aprotein that large, current sustained-release technologies don't work."

He explained: "Proteins are much less stable than peptides, so it'smuch harder to make a sustained release by formulating microspherecarriers." This poses two problems, he pointed out: "The proteinsmust retain their stability first, during fabrication of the microspheres;second, in the body, once they are injected in solution at bodytemperature."

A paper in the July 1, 1996, Nature Medicine describes howAlkermes, in partnership with Genentech Inc., of South SanFrancisco, created and tested "A month-long effect from a singleinjection of microencapsulated human growth hormone." Putney isthe article's principal author.

It reports successful preclinical studies in primates, but in February,Alkermes began FDA-approved Phase I human trials, injecting asingle dose of its proprietary rhGH-laden microspheres into adultpatients with subnormal growth hormone secretion.

"This current trial has enrolled 13 patients, divided between NewYork University and the University of Virginia, [Charlottesville],"Alkermes' chief financial officer, Michael Landine, told BioWorldToday. He added, "We wouldn't expect results until early Septemberof this year."

In the primate studies, four young rhesus monkeys received singlesubcutaneous injections of the rhGH-charged carriers, while fourcontrols got conventional daily shots of the hormone. A month later,both groups had elevated levels of rhGH, but the four sustained-release-treated animals displayed higher titers of the hormone'seffector end-product, insulin-like growth factor, than did the fourcontrols.

Three innovations account for these results, Putney said _ design ofthe microspheres, stabilization of the rhGH and its cryogenicincapsulation into the carrier spheres:

Microspheres _ Zinc Stabilization _ Cryo-Loading

Specially formulated polymers of lactic and glycolic acids _common industrial chemicals _ make up the protein-dispensingmicrospheres, trademarked by Alkermes as ProLease. "Thesepolymers have been around for years, used in surgical sutures,bandages and artificial bone plates," Landine explained.

As to how they work in sustained release of large molecules, headded, "Imagine a sponge cut in half. They're not hollow spheres, butsolid pockets of protein mixed with the polymer. Each solid sphere,about 50 nanometers in diameter, has maybe 100 units of lactic andglycolic acids that just break down randomly and float away. As thatmaterial degrades, it allows release of the drug."

Landine pointed out that "We can control its rate of degradation froma couple of days out to months. We can design it based on what ourclient company wants their compound to do."

To load the fragile rhGH hormone into this polymer carrier, theAlkermes team complexed the protein with zinc, which stabilizes themolecule by dimerizing it. Finally, the formulation takes place in awater-free, cryogenic environment, provided by liquid nitrogen.

Right now, Putney said, "We have a corporate collaboration withSchering-Plough Corp. [of Madison, N.J.] for a ProLease formulationof their alpha interferon, Intron-A. That's still in the preclinicalstages; we would expect that the first half of 1997 it should be in theclinic, as determined by the partner."

Alkermes, Landine said, "has an agreement with Genentech for rhGHand one other unnamed molecule, in which they provided us fundingto do the formulation work and the trial we've done. They have anoption for a license for those two particular compounds, andmilestones and royalties associated with them."

"Protein-based drugs," the Nature Medicine paper observed, "arebecoming an increasingly important part of the pharmacopeia.Because of . . . short in vivo half-lives, proteins are typicallyadministered by frequent injection, and their instability has greatlylimited . . . sustained-release formulations."

Other Candidate Proteins Await Nomination

Alkermes sees many other applications for its slow-release system."For example," Landine suggested, "erythropoietin would be a goodcandidate. So would vaccines, where you'd like to deliver antigensover periods of time and other interferons, such as interferon-beta formultiple sclerosis.

"Gene therapy," he went on, "is something we could do verystraightforwardly, as well as antisense administration. This is a veryuniversal process."

One exception is insulin, the hormone diabetics inject at least once aday. Sustained release, Landine surmised, "probably would not work,because there's such a huge intra-patient variability in their need forinsulin."

But on the plus side, he continued, "If you have a compound or aprotein with a very fast half-life, which to be effective would requirefive or six or seven injections a day, if you can get it to even a once-a-week formulation, that would make it a practical, marketableproduct. So with that technology, we can begin to think about otherproteins that would never otherwise be developed, that you'd neverhear about." n

-- David N. Leff Science Editor

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

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