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FUJISAWA PROGRAF ONE-YEAR SURVIVAL RATE IS 88% IN U.S. PIVOTAL TRIAL DATA; ANTI-REJECTION DRUG NOT MORE EFFECTIVE THAN CYCLOSPORINE -- FDA ADVISORY CMTE.

Executive Summary

The one-year survival rate for Fujisawa USA's Prograf is 88% in liver allograft recipients, Phase III U.S. data presented to FDA's Antiviral Drugs Advisory Subcommittee on Immunosuppressants Nov. 22 shows. Prograf (FK-506, tacrolimus) as an anti-rejection therapy in liver transplantation was shown to be comparable Sandoz' Sandimmune (cyclosporine). In the U.S. trial of 555 patients at 12 centers, the same percentage of cyclosporine patients survived to the one-year mark as Prograf patients, Fujisawa USA Associate Director of R&D, William Fitzsimmons, told the subcommittee. Graft survival rates were also similar: 82% for the FK-506 group against 79% for the cyclosporine group. Fujisawa USA also presented data from its Phase III European trials of FK-506. Together, the open-label, comparative trials took place at 20 sites and involved over 1,000 patients, about 20% of the entire liver transplant population in the U.S. and Europe in 1990 and 1991. Patients were randomized before transplant to regimens based on either FK-506 or Sandimmune. Primary efficacy endpoints were one-year patient survival and one-year graft survival, with graft loss defined as death or retransplant. Voicing the consensus of the subcommittee, Chairwoman Deborah Cotton, MD, Harvard Medical School, said Prograf "has been shown to be effective in terms of the primary endpoints." Based on the clinical trial data, the committee voted unanimously that Prograf's safety and efficacy were demonstrated for the prophylaxis of organ rejection in adult patients receiving allogeneic liver transplants. The secondary efficacy endpoint was rejection, which was determined by "biopsy and pathologic review," Fitzsimmons said. Acute rejection rates for the first year favored FK-506 (68%) over cyclosporine (76%), and the one-year Kaplan-Meier estimate of refractory rejection was 3% for FK-506 compared with 15% for cyclosporine. Fujisawa USA consultant Ronald Busutill, MD/PhD, the director of the University of California at Los Angeles-Dumont Liver Transplant Program, called the Kaplan-Meier result of "crucial importance." However, subcommittee member Donald Hricik, MD, University Hospitals of Cleveland, doubted the result's significance because "the open-label design is most likely to introduce bias in terms of the interpretation of biopsies." Lawrence Hunsicker, MD, University of Iowa, concurred: "I don't think I have much confidence that FK-506 is superior to cyclosporine with respect to the incidence of rejections." The committee voted unanimously that Prograf has not "been demonstrated to be superior to current standard therapy" in the secondary efficacy endpoints. Company consultant Russell Wiesner, MD, the medical director of Liver Transplant at the Mayo Clinic, said Prograf's "toxicity profile is very similar to that seen with cyclosporine." He remarked that the events occur "usually within the first five days" and "are generally manageable with the reduction of dose." Sixty-one Prograf patients and 16 Sandimmune patients had to discontinue treatment because of adverse events. However, these figures were probably affected by the intent-to-treat protocol design, which allowed cross-over. "The threshold for discontinuation...may have been lower in FK-506 patients since these patients could be readily switched to an established cyclosporine-based regimen," Wiesner suggested. The main reasons for discontinuation of FK-506 therapy were neurotoxicity and nephrotoxicity. No statistically significant difference was reported in major neurological events, but FK-506 patients had a higher incidence of headache, paresthesias, tremor and confusion. Renal events were more common in FK-506 (58%) than in cyclosporine (36%), but there was no significant difference in the incidence of "serious" renal events, defined as causing death, life-threatening complications, hospitalization, neoplasm or permanent disability. Renal adverse effects generally occurred "within the first four days...when patients were on I.V.," Wiesner said. He added that "long-term renal function seems to be similar [between the groups]," and that "no patient required long-term chronic dialysis in the FK-506 group." The original FK-506 dose of .15 mg/kg/day I.V. given as a four-hour infusion twice a day had to be modified to .1 mg/kg/day I.V. given as a continuous 24-hour infusion because of "early renal dysfunction," Fitzsimmons noted. In the original protocol, dosing began in the operating room, but the final protocol allowed for "post-operative establishment of urine output and delaying the initiation to six to 24 hours after reperfusion of the liver," Fitzsimmons said. The oral dose in both protocols was .3 mg/kg/day in two divided daily doses. The proposed labeling dose is .05 to .1 mg/kg/day in a continuous I.V. infusion and .15 to .3 mg/kg/day post-operative in two divided daily oral doses. Hunsicker said "the ability to give this drug orally shortly after transplantation...is a substantial advantage." Closely related to dosing was the issue of therapeutic drug monitoring (TDM). Fujisawa USA VP-R&D Operations James Shook, PhD, said, "We recommend on-site blood-level monitoring during hospitalization." Wiesner also emphasized "the importance of blood-level monitoring to maintain blood-levels of FK-506 in an acceptable therapeutic range to avoid excesses of rejection... and toxicity." The subcommittee was of several minds on this issue. Barry Kahan, MD/PhD, University of Texas, Houston, said "TDM is needed for safe use." Hricik was "convinced that monitoring is necessary." Hunsicker pointed out that in the trials, "blood level was only a secondary criterion for dose-adjustment after the primary question of whether the patient was rejecting or whether the patient had toxicity." He proposed that labeling could say "management may be facilitated by the use of levels." In the U.S. study, 51 of the patients were 12 years old or younger, with a mean age of three. The one-year survival rate in the 30 Prograf pediatric patients was 80%, versus 81% in the 21 Sandimmune patients. Graft survival rates were also nearly identical: 70% for Prograf against 71% for Sandimmune in the pediatric population. Fujisawa consultant Sue McDermott, MD, UCLA-Dumont, said "the toxicity profile of FK-506 in children appears to be very similar to that seen in adults, with the caveat that known risk for the development of lymphoproliferative disease in the immunosuppressed child...must be appreciated." She also stressed that "it would be unwise to underestimate the disfigurement that hirsutism causes a child." Hirsutism has been seen as a side effect of cyclosporine but not of FK-506. McDermott added that "children require dosing... on the high end of the recommended range." Committee members, when asked to recommend postmarketing studies, put forth the need to learn more about Prograf in children. Hunsicker said, "We have...zero information about this in children," and recommended special pediatric labeling. Other suggested areas of Phase IV research included drug interactions, metabolic pathways and further study of dosing. Thomas Starzl, MD, director of the Transplant Institute at the University of Pittsburgh, commented in the open public hearing about the competition between cyclosporine and Prograf. The surgeon, who used FK-506 at Pittsburgh, called Prograf "the first major immunosuppressant drug to come down the pike in 10 years.... I don't think anybody in their right mind is talking about throwing any drug overboard; what is at stake here is adding to the armamentarium." Fujisawa USA filed NDAs 50-708 and 50-709 for I.V. and capsule Prograf in early September. FK-506 will be manufactured at Fujisawa's plant in Killorglin, Ireland, and the raw materials for the drug will be made in Toyama, Japan.
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