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SANDOZ' SANDIMMUNE RECOMMENDED FOR APPROVAL IN RECALCITRANT PSORIASIS; IMMUNOSUPPRESSIVE WILL REQUIRE CREATININE MONITORING FOR RENAL DYSFUNCTION

Executive Summary

Sandoz' Sandimmune should be approved for the short-term treatment of recalcitrant psoriasis, FDA's Dermatologic Drugs Advisory Committee recommended at its Nov. 19 meeting. The committee voted unanimously in favor of approving the new indication. Sandimmune (cyclosporine) has been marketed since 1983 as an immunosuppressive to prevent organ rejection in patients undergoing kidney, liver and heart transplants. The committee emphasized that Sandimmune be considered for use only after patients have failed other psoriasis therapies, such as UVB light and tar (phototherapy), PUVA (photochemotherapy), methotrexate or etretinate. "It is clear that no one on the committee sees cyclosporine as first-line therapy for psoriasis, even severe psoriasis," committee Chairman Joseph McGuire, MD, Stanford University Medical Center, said. "We are trying to chip away at a definition that serves the patients and prevents the practicing physician from thinking that FDA has said: 'Here is a drug. Why don't ou give it a try,'" he remarked. "We see this as a second- or third-line modality." While the committee expressed few concerns about the efficacy of Sandimmune in the treatment of psoriasis in general, the committee voted to restrict use of the drug to patients with recalcitrant plaque-like psoriasis, excluding patients with more severe forms of psoriasis. Referring to patients with more severe forms of the disease, such as erythrodermic and pustular psoriasis, McGuire said: "I don't think we have the data in hand to say that the drug is efficacious in that subset." Sandoz consultant John Voorhees, MD, University of Michigan, countered that, in his experience, "it doesn't make any difference at all what kind of psoriasis it is." Voorhees remarked that the committee, if it recommended Sandimmune only for patients with plaque-like psoriasis, would "disenfranchise the group of individuals who in fact need it the most." McGuire responded that the committee's vote to restrict the use of Sandimmune "may be excluding patients who truly need the drug; however...if the drug is approved for plaque-like psoriasis, other patients with severe psoriasis will be treated [on an unapproved basis] and perhaps there will eventually be enough data so that one can come back" to the committee. Sandoz estimates that about 6 mil. patients a year require systemic treatments for psoriasis. Approximately 200,000 people in the U.S. have received Sandimmune for transplant rejection prevention. The NDAs submitted by Sandoz (50-695 and 50-696) for oral solution and capsule forms of Sandimmune contain efficacy data from three U.S. Phase III trials with a total of 311 psoriasis patients, six foreign controlled trials and 11 foreign uncontrolled trials. Sandimmune's safety database in psoriasis includes 770 patients. Data from the three U.S. trials were presented by Sandoz Clinical Research Executive Director Jay Birnbaum, PhD. In the first study (protocol 299), 85 patients who previously had failed other psoriasis treatments were initially dosed with 0, 3 mg/kg, 5 mg/kg or 7.5 mg/kg per day of Sandimmune oral solution for eight weeks. Patients were entered subsequently into an eight-week titration phase of doses ranging from 3 mg/kg to 12.5 mg/kg per day. Those patients who responded to therapy were put on maintenance doses of either 0, 1.5, or 3 mg/kg per day for 16 weeks. The second U.S. study (protocol 501) treated 181 recalcitrant psoriasis patients with a twice-daily dose of Sandimmune oral solution for a total of 3-6 mg/kg/day for 16 weeks. Patients then entered a double-blind, placebo-controlled maintenance phase of 0 or 3 mg/kg per day for 24 weeks. In the third study (protocol 502), 69 patients received placebo or 4 mg/kg per day of Sandimmune capsules for 12 weeks. Birnbaum reported that 60% of patients treated with the 3 mg/kg oral solution dose in studies 299 and 501 demonstrated significant improvements in their psoriasis condition. The response rate increased to 80% for patients treated with 5 mg/kg Sandimmune and 100% for patient receiving the 7.5 mg/kg/day dose. In the Sandimmune capsule study 502, 80% percent of patients treated with 4 mg/kg/day showed significant improvement. In addition, 80%-90% of patients receiving the 5 mg/kg/day dose showed a greater than 75% reduction in the Psoriasis Area and Severity Index (PASI) score, which is measured on a 0-72 point scale with a high score indicating worsening psoriasis. While Sandimmune appears to be highly effective in resolving psoriasis, some patients relapsed on maintenance therapy. With relapse defined as a two-point worsening on a seven-point global evaluation score, 38% of Sandimmune-treated patients relapsed with a median time to relapse of greater than 16 weeks in one study and greater than 24 weeks in another study. Patients receiving placebo relapsed at rates of 73%-90% by week six of the studies. Birnbaum presented data showing that patients taken off Sandimmune therapy experienced an increase of psoriatic body surface area from 5% to 18%; however, the degree of psoriasis remained about the same one year after discontinuing of therapy. Summarizing the findings, Birnbaum said that with an initial dose of 3-5 mg/kg Sandimmune per day "most patients will achieve at least a moderate improvement and 60% or so will clear, or near clear, within three to four months treatment." Based on the data, Birnbaum noted that Sandoz is recommending patients be treated with 3-5 mg/kg/day for four months initially. Patients responding to therapy should be continued on Sandimmune for another two to four weeks. "Only at that time, if the effect is judged to be insufficient, should the dose be increased, but under no circumstances should it be increased above a dose of 5 mg/kg per day," Birnbaum said. The committee's major concerns about the use of Sandimmune in patients with psoriasis involved the drug's demonstrated renal toxicity and potential for inducing malignancies. Sandoz consultant William Bennett, MD, Oregon Health Services University, presented data showing that 25% of Sandimmune-treated patients had serum creatinine levels 50% above their baseline values. In the U.S. trials, 37 patients, or 11% of total patients treated, were discontinued from drug therapy because of renal dysfunction, Bennett reported. Other adverse events experienced by patients receiving Sandimmune in the trials included headache (23%), nausea/vomiting (18%), hypertension (14%), hirsutism/hypertrichosis (11%), cold/flu (11%) and musculoskeletal pain (9%). Sandimmune also increased triglyceride levels and decreased hemoglobin levels of patients in the studies. Because renal dysfunction is a major toxicity of Sandimmune, the drug's labeling will recommend that physicians measure serum creatinine levels every two weeks for the first three months and once every month thereafter, Sandoz VP Regulatory Affairs Marion Finkel, MD, noted. She added that continuous use of Sandimmune in psoriasis patients will be limited to one year "to avoid renal problems down the pike." Finkel reported that Sandoz has an ongoing trial in Europe that is monitoring renal function in patients treated for up to four years with Sandimmune. Sandoz is planning another study to "look at non-invasive methods for following renal changes, including [Magnetic Resonance Imaging] and ultrasound." In addition to renal toxicity, Sandimmune therapy has been associated with an increase in malignancies in patients treated for long periods of time at high doses. "There was slightly more than a doubling of overall cancer risk in patients who received cyclosporine" for prevention of transplant rejection, Sandoz consultant Kenneth Rothman, MD, Boston University School of Medicine, reported. In the psoriasis studies, 19 patients developed cancer, nine of which were skin cancers. "We know that immunosuppression in general increases cancer incidence, particularly skin cancer and lymphoma," Rothman noted. Finkel told the committee that Sandoz is planning a Phase IV postmarketing trial that will follow 2,500 psoriasis patients for five years. The malignancies recorded in the trial will be compared to a historical control of patients treated with PUVA therapy. A case control group will be included in the study to allow the sponsor to identify certain risk factors for developing malignancies, Finkel said. Committee member Mary Massa, MD, Loyola University, Chicago, emphasized that Sandimmune will be used by "dermatologists who will need to have updated education on how to handle and monitor this drug." Finkel said Sandoz realizes this and "is planning to work with the American Academy of Dermatology as well as the National Psoriasis Foundation to develop an educational program for physicians and patients."
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