BETHESDA _ An FDA advisory panel recommended two versionsof recombinant human growth hormone (HGH) for approval to treatTurner's syndrome _ a rare disorder that affects only girls. Bypooling their data from clinical trials, Genentech Inc. and Eli Lillyand Co. convinced the panel to vote 6-to-1 in favor of using Nutropinand Humatrope to treat the very short stature associated withTurner's.
"This has been a 13-year process," said Sandra Blethen, seniorendocrinologist at Genentech. "We are tremendously pleased that thepanel recommended this drug for Turner's. This is the only treatmentwe have to help these patients gain the height that will afford them abetter quality of life."
Turner's syndrome affects approximately 50,000 American womenand girls and represents one in 2,000 to one in 5,000 live femalebirths in the U.S. The condition is cause by deletions in one of thetwo X chromosomes. Turner's syndrome may cause a variety ofproblems including ovarian failure, webbing of the neck andsusceptibility to ear infections. However, the most salient feature ofTurner's is extremely short stature: the Turner's female attains anadult height of 4 feet 8 inches on average.
In stark contrast to the patent battle the two companies engaged inover recombinant HGH, Genentech, of South San Francisco, andLilly, of Indianapolis, teamed up to jointly present the results fromfour clinical trials of their drugs in Turner's sufferers in order toobtain orphan drug approvals for recombinant HGH. Genentechpresented data from two clinical studies of Nutropin in 188participants while Lilly presented the interim results of two clinicaltrials of Humatrope comprised of 378 participants. Overall, Nutropinand Humatrope resulted in an average 5 centimeter or 2 inch increasein adult height.
Because Turner's often causes ovarian failure, all of the trialparticipants were also given estrogen near the time of normalpuberty_ anywhere between the age of 12 and 16. In one of theGenentech studies, the subset of girls who had the greatest increase _about 4 inches _ had started recombinant HGH before age 11 anddidn't take the feminizing doses of estrogen until after age 14 or 15.
"The timing of estrogen appears to determine the height that thesegirls will attain," said Genentech's Kenneth Attie.
Growth hormone showed few side effects, although girls taking thedrug were more likely to suffer ear infections and exhibit glucoseintolerance than those who weren't taking the drug.
The panel, however, questioned the design of the studies. In 1987, anFDA advisory panel detailed the requirements for a clinical trials toshow growth hormone's efficacy. The panel decided that efficacycould only be shown with concurrently controlled studies thatmonitored patients until they had achieved adult height. While bothcompanies monitored their patients until they reached adult height,Genentech used "historical controls" or documented cases ofTurner's that had reached adulthood, and only one of Lilly's trialsused a placebo control.
Panel member Jose Francisco Cara, of the Henry Ford Hospital,pointed out that historical controls could bias the results in favor oftreatment simply because people have been getting taller over thepast few decades. Panel member D. Roger Illingsworth, of theOregon Health Sciences Center, noted that the companies had notestablished the optimal dose for the drug. Robert Sherwin, of YaleUniversity School of Medicine, raised concerns that increases inglucose intolerance could ultimately increase these women's risks forcardiovascular disease.
Nonetheless, the panel voted 6-to-1 to recommend both Nutropin andHumatrope for approval in Turner's syndrome with the condition thatpost-marketing studies establish the appropriate dose and monitorside effects.
Panel chair Henry Bone III, of the Henry Ford Hospital in Detroit,disagreed with the rest of the panel. "I don't think any drug that wedon't know how it is working, we don't know the long term effectsand we don't know the optimal dosage, should get a unanimousrecommendation."
The FDA ordinarily follows the advice of its advisory panels, but isunder no obligation to do so. n
-- Lisa Seachrist Washington Editor
(c) 1997 American Health Consultants. All rights reserved.