Zortress

Treatment for Organ Transplant -- Rejection Prophylaxis

Update: Zortress (everolimus) Now FDA Approved - April 20, 2010

FDA Advisory Committee Recommends Additional Study Data to Support Approval of Certican in Heart Transplant Recipients

Acute rejection and cardiac allograft vasculopathy (CAV), a rapid thickening of coronary arteries, are two major risk factors for mortality in cardiac transplant recipients. Acute rejection events result in a 30% increase in death within five years after cardiac transplantation, while CAV is estimated to affect up to 80% of heart transplant recipients within the first five years after transplant surgery. The occurrence of CAV in patients one - year after heart transplantation nearly tripled their risk of major adverse cardiovascular events or death.

Filing data

Data from the Phase III, multicenter, international, randomized study submitted to the FDA, demonstrated that patients treated with Certican in combination with cyclosporine experienced a greater than 25% reduction in the incidence of treated acute rejection compared to those receiving conventional therapy. In a substudy, patients demonstrated a highly significant reduction in the incidence and severity of CAV. Certican 1.5 mg reduced progression of internal coronary artery wall thickening (a measure of presence and severity of CAV) by 60% (p=0.014). This large prospective trial is the first successful superiority trial in heart transplant recipients, validating the significant impact of Certican on progression of CAV in these high-risk patients.

About Certican

Certican is an orally administered investigational immunosuppressant described as a "proliferation signal inhibitor (also known as an mTOR inhibitor)," which is currently being evaluated for co-administration with Neoral (cyclosporine, USP) MODIFIED, and appears to target many of the underlying causes of chronic allograft dysfunction or late graft loss.

An NDA originally submitted to the FDA for indications in both kidney and heart transplantation in 2002 resulted in an approvable letter from the FDA in October of 2003. Further analysis, and additional data submitted by Novartis in February 2004 led to a second approvable letter from the FDA in August of that year. In compliance with this approvable letter, two new prospective studies (one in each indication) using Certican in combination with reduced doses of cyclosporine were initiated this year. A global, multicenter clinical trial (including US sites), aimed at further refining the use of Certican in heart transplantation, began enrolling patients this month and was discussed during the Advisory Committee meeting. Another study, a Phase IV commitment in Europe comparing Certican with MMF in heart transplant recipients, was initiated in December 2004.

The Novartis Transplantation and Immunology Business Unit is committed to developing an innovative range of therapeutic products for the prevention of organ rejection, in order to provide an extensive choice of drugs to the transplant community and to maintain Novartis' role as a global market leader in this field of medicine.

Product safety: Neoral

Neoral Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIED have increased bioavailability in comparison to Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Sandimmune Oral Solution (cyclosporine oral solution, USP). Neoral and Sandimmune are not bioequivalent and cannot be used interchangeably without physician supervision. For a given trough concentration, cyclosporine exposure will be greater with Neoral than with Sandimmune. If a patient who is receiving exceptionally high doses of Sandimmune is converted to Neoral, particular caution should be exercised. Cyclosporine blood concentrations should be monitored in transplant and rheumatoid arthritis patients taking Neoral to avoid toxicity due to high concentrations. Dose adjustments should be made in transplant patients to minimize possible organ rejection due to low concentrations. Comparison of blood concentrations in the published literature with blood concentrations obtained using current assays must be done with detailed knowledge of the assay methods employed. Neoral and Sandimmune are systemic immunosuppressants and may increase the susceptibility to infections and the development of neoplasia.

Source: Novartis Pharmaceuticals Corporation

References
Eisen H, Tuzcu M, Dorent R et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. New Engl J Med 2003; 349: 847-58.
Kobashigawa JA, Tobis JM, Starling RC et al. Multicenter intravascular ultrasound validation study among heart transplant recipients: outcomes after five years. J Am Coll Cardiol: 2005; 45: 1532 - 37

Posted: November 2005

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