GENENTECH NUTROPIN HGH APPROVED FDR CHRONIC RENAL INSUFFICIENCY

GENENTECH NUTROPIN HGH APPROVED FDR CHRONIC RENAL INSUFFICIENCY that causes short stature in children who are awaiting kidney transplantation on Nov. 17. FDA designated Nutropin (recombinant somatropin for injection) as a "5S" drug, meaning a new version of an already marketed product given standard review by the agency. Nutropin is the first recombinant human growth hormone approved for a condition other than human growth hormone deficiency. Lilly markets Humatrope and Genentech markets Protropin for GHD deficiency. There are an estimated 3,000 U.S. children with short stature secondary to chronic renal insufficiency condition (CRI). Approximately 120 patients are currently receiving Nutropin in an ongoing Phase III trial. There were a total of 195 children in the clinical trials. Clinical trial results showed that height in the normal range was achieved by 65% of the Nutropin-treated children within two years and 91% within three years. Genentech expects to have Nutropin available before year-end through pediatric nephrologists and endocrinologists. FDA's approval letter notes that methods validation by FDA labs of the recombinant DNA production methodology "soon will be initiated." Nutropin is supplied as 5 mg or 10 mg vials of somatropin. The recommended daily dose is 0.05 mg/kg administered via subcutaneous injection. Genentech is not disclosing the price for Nutropin. The average wholesale price of Protropin is $420 per 5 mg vial, or approximately $15,272 per year. In clinical trials, children with CRI have been on Nutropin for about three years. Nutropin "has the same amino acid sequence as hGH produced naturally in the human body," Genentech pointed out, which would make the product equivalent to Humatrope. A 1993 introduction puts Nutropin on the market prior to the March 1994 expiration of Humatrope's orphan exclusivity for use in GH-deficient children. Nutropin has a pending application for that indication as well, and expects to market the product for that indication next year. The approval of Nutropin comes less than a month after FDA's Endocrinologic & Metabolic Drugs Advisory Committee unanimously agreed that the product could be approved without waiting to see results on final adult height of treated children ("The Pink Sheet" Nov. 1, p. 17). Genentech originally submitted the NDA for Nutropin on March 5, 1991 but withdrew the application to collect additional data on two years of treatment and patients followed for one year post-transplant. The company resubmitted the NDA (20- 168) on July 9. Amendments to the NDA were filed by the company on July 27, Aug. 17, Oct. 8, 14 and 29, and on Nov. 8, FDA's approval letter notes. The company also has committed to Phase IV tracking studies. Approved draft labeling states that Nutropin is indicated for "the treatment of children who have growth failure associated with chronic renal insufficiency up to the time of renal transplantation. Nutropin therapy should be used in conjunction with optimal management of chronic renal insufficiency." The drug is contraindicated in children with active neoplasia. Labeling cautions that patients should be monitored for evidence of glucose intolerance since hGH "may induce a state of insulin resistance." Children also should be "examined periodically for evidence of progression of renal osteodystrophy," labeling cautions, due to the possibility of slipped capital femoral epiphysis or avascular necrosis of the femoral head. Adverse reactions include the development of antibodies to the protein and, rarely, intracranial hypertension, which was resolved after stopping therapy or reducing the dose, draft labeling notes. At the FDA advisory committee meeting, FDA said 22 cases of intracranial hypertension in people taking hGH have been uncovered, including eight in children receiving hGH for CRI. As submitted by Genentech to the committee, labeling notes that leukemia has been reported in a small number of hGH patients "but the risk, if any, remains to be established." Genentech has agreed to modify its draft language about post- transplant growth in the clinical pharmacology section of labeling after discussions between the company and FDA's Division of Metabolism and Endocrine Drug Products. In the revision, a new subsection called "Post-Transplant Growth" will be added after the subsection "Effects of Nutropin on Growth Failure Due to Chronic Renal Insufficiency (CRI)." The agency approval letter states that the new subsection will read: "The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) has reported data for growth post-transplant in children who did not receive growth hormone. The average change in height SD [standard deviation] score during the initial two years post- transplant was 0.18 (n = 300, J. Ped 1993; 122:397-402)." The subsection will go on to read: "Controlled studies of growth hormone treatment for the short stature associated with CRI were not designed to compare the growth of treated or untreated patients after they received renal transplants, however, growth data are available from a small number of patients who have been followed for at least 11 months. Of the seven control patients, four increased their height SD score and three had either no significant change or a decrease in height SD score." The new subsection continues: "The 13 patients treated with Nutropin prior to transplant with Nutropin had either no significant change or an increase in height SD score after transplantation, indicating that the individual gains achieved with growth hormone therapy prior to transplant were maintained after transplantation. The differences in the height deficit narrowed between the treated and untreated groups in the post- transplant period."