NIH, WHO SEEK INDUSTRY PARTNERS TO DEVELOP LONG-ACTING MALE HORMONES

By David N. LeffScience Editor

An internationally patented androgenic-hormone analog is lookingfor a few good licensees to share in its development andcommercialization.

The testosterone-based, slow-release, injectable compound wasjointly invented and patented by scientists at the World HealthOrganization (WHO) and the National Institute of Child Health andHuman Development (NICHHD).

Last week, the National Institutes of Health Office of TechnologyTransfer submitted a notice to the Federal Register invitingapplications to license the product, testosterone bucylate, and/or entera Cooperative Research and Development Agreement (CRADA) forbringing it to market.

The U.S. patent, No. 4,948,790 issued Aug. 14, 1990 to eightinventors, from the NIH and WHO, to which agencies it is jointlyassigned.

Chemically, testosterone bucylate is testosterone 17b-(trans-4-n-butyl) cyclohexyl carboxylate.

Trials in animals and humans show that this analog of the malehormone has prolonged activity, up to three months so far, wheninjected intramuscularly. NICHHD's Contraceptive DevelopmentBranch tested the compound in rodents and primates; WHOconducted the first clinical studies in hypogonadal and normal men.

Endocrinologist Richard Blye, one of the eight inventors in thatpatent, is a pharmacologist at the Branch.

"WHO, a co-patent holder," he told BioWorld Today, "is interestedin looking at this drug as a male contraceptive; we, initially as anandrogen replacement drug. While testosterone bucylate will work asa contraceptive," Blye explained, "it's really unacceptable to us atthis point because the dose levels required are super-physiological."

Too Much Testosterone Fuels Aggression

He added that "high dose levels are associated with some side-effects, one of which is aggression. We've seen that in weight-liftersand body-builders who take these huge doses of anabolic steroids."

Blye pointed out that because users of contraception "are otherwisehealthy, normal people," FDA regulates contraceptives morestringently than it does most other drugs.

"But as a replacement androgen for hypogonadism," he emphasized,"testosterone bucylate is superb." Also its market seems to beexpanding, he observed. "There's considerable interest in raisingandrogen levels in the aging male. With the increased attention to ouraging population, right now the big thrust is for post-menopausalwomen.

"But men suffer certain sequellae of age too," Blye observed, "andthe beauty of this drug is that it is so much longer-acting than thecurrently available testosterones, enanthate and cypionate. These areinjected every one to three weeks; ours can probably be given everytwo to three months."

What gynecologists are to female problems, andrologists are to male.Endocrinologist Alvin Paulsen is past president of the AmericanSociety of Andrology, and professor emeritus of medicine at theUniversity of Washington, Seattle.

"There is a renewed interest in treating older men," Paulsen toldBioWorld Today, not for sexuality but to improve bone and muscle,by maintaining normal male hormone levels."

He added that in therapy for hypogonadism, "testosterone essentiallyinduces puberty." As the major share of this potential market fortestosterone bucylate, he cites "Klinefelter's syndrome, which afflictsone in every 500 to 600 people in the world, and is probably thebiggest hypogonadal population."

Describing its mode of action, Blye observed that testosteronebucylate "is really like giving a prodrug, with the active drug beingthe natural hormone." The compound," he said, "is given as anaqueous crystal suspension, slowly released from the injection site,and hydrolyzed in the blood to testosterone."

"Testosterone," the Contraceptive Development Branch's director,physiologist Nancy Alexander, explained to BioWorld Today,"works as a male contraceptive by stopping spermatogenesis. It doesthis by getting the brain to prevent or reduce the secretion ofluteinizing hormone, plus some follicle-stimulating hormone, by thepituitary gland.

"We are applying to the FDA for an investigational new drug [IND]to use it first as replacement therapy, at lower doses," she added, "totreat hypogonadal men, who either have a hormone signalingproblem in the brain, or because somehow their testes do not respondto the hormonal message and produce testosterone."

In such patients, she said, injection of supplemental testosterone"causes their body shape to change. They get more muscle. Theirvoice would deepen. They become masculinized."

After Hypogonadism, On to Contraception

"Second," Alexander continued, "for male contraception, asreplacement therapy when other hormonal male contraceptives, nowbeing developed, are employed."

Blye surmises that WHO "will probably wait to try it for malecontraception until we file an IND. Once we are free to go ahead inthe U.S., that will be of enormous value to them in seeking approvalfor clinical studies overseas, even if to be used alone forcontraception."

He made the point that "Our IND contains the toxicity studies we did,five to 10 times any human dose proposed for contraception."

Conversely, Alexander said, "We hope the FDA will accept theforeign data from WHO's clinical work, and allow us to skip some ofthe early-phase clinical trials, and move on to some more excitingones."

Meanwhile, her branch is "moving ahead with designing Phase I andII human trials," Blye said. "Obviously we need an industrial partner.The federal government is not in the business of selling drugs. If wecan take this compound through early clinical studies, and show it'sefficacious without toxicity, this would be a real incentive for somecompany to grab it."

Editor's note: For CRADA information, consult Gordon Guroff,deputy scientific director, NICHD (301) 496-4751; for patentlicensing, Carol Lavrich, NIH Office of Technology Transfer, (301)496-7735, extension 287; for technical questions concerning thisinvention, Nancy Alexander, Contraceptive Development Branch,NICHD, (301) 496-1661. n

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

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