FDA Panel Rejects Novartis Corporation Transplant Drug; Advisory Committee Recommends Additional Study Data To Support Approval Of Certican(R) In Heart Transplant Recipients

ROCKVILLE, Md., Nov. 16 /PRNewswire/ -- Novartis announced today that the Cardiovascular and Renal Drugs Advisory Committee of the US Food and Drug Administration (FDA) recommended that more data be provided to substantiate the efficacy and safety of Certican(R) (everolimus) for use as prophylaxis against acute rejection in heart transplant recipients.

A majority of the Committee members agreed with the FDA and Novartis that Certican has demonstrated superior efficacy to a comparator in the prevention of acute rejection. Several members of the Committee also recognized the potential benefits Certican has demonstrated on the progression of cardiac allograft vasculopathy. However, the majority suggested that more prospective data on the Certican/cyclosporine combination regimen was needed to determine the optimal dosage regimen in order to further enhance renal safety. The Committee also suggested that therapeutic drug monitoring would be a useful approach to address these issues.

Novartis has initiated further clinical studies in heart transplantation using Certican in combination with reduced dose cyclosporine and therapeutic drug monitoring to supplement the existing clinical registration database from over 3,000 heart and kidney transplant recipients worldwide. Several Committee members suggested that data from one of these studies, an on-going European post-marketing study in heart transplantation which may be available for review in 2007, might address the committee's concerns.

"I believe that clinicians around the U.S. will be disappointed in this vote today," said Professor Howard Eisen of Drexel University Hospital in Philadelphia. "Preventing acute rejection and cardiac allograft vasculopathy (CAV) are the biggest challenges in heart transplantation today, and new effective treatment options are urgently needed. This vote may further delay patient access to this promising therapy."

Certican is the only drug in its class approved by most global heath authorities for the prevention of acute rejection in heart transplant recipients. It is currently approved in 48 countries for use in combination with Neoral® (cyclosporine, USP) MODIFIED.

"While today's vote by the committee is disappointing and represents a temporary setback, we are encouraged by the supportive statements that many of the Committee members made about the Certican program and we are still firmly committed to making Certican available to patients in the U.S.," said Giacomo Di Nepi, Head of the Transplant and Immunology Business Unit at Novartis Pharma AG. "The prevention of acute rejection and cardiac allograft vasculopathy (CAV) certainly remain among the biggest challenges in heart transplantation. We will continue to work with the FDA to gain approval of Certican in the U.S."

Heart transplant rejection

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.

This release contains certain forward-looking statements that can be identified by the use of forward-looking terminology, such as "will be," "expected," "opportunity," "will continue," "might address," or similar expressions, or by express or implied discussions regarding the potential approval of Certican® by the FDA. Such forward-looking statements reflect the current views of the Company regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause the actual results with Certican® be materially different from any future results, performance, or achievements expressed or implied by such statements. Furthermore, the FDA has not endorsed the potential benefits of reducing CAV and has raised issues relating to the appropriate dose of Neoral to be taken with Certican. There can be no guarantee that Certican® will be approved by the FDA, or that it will receive any additional marketing approvals in any other countries. Management's expectations regarding Certican® can be affected by, among other things, uncertainties relating to clinical trials, new clinical data, or additional analysis of existing clinical data, regulatory actions or delays or government regulation generally, the ability to obtain or maintain patent or other proprietary intellectual property protection, competition in general, government, industry, and general public pricing pressures, as well as factors discussed in the Company's Form 20-F filed with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those described herein as anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis

Novartis Pharmaceuticals Corporation researches, develops, manufacturers and markets leading innovative prescription drugs used to treat a number of diseases and conditions, including central nervous system disorders, organ transplantation, cardiovascular diseases, dermatological diseases, respiratory disorders, cancer and arthritis. The company's mission is to improve people's lives by pioneering novel healthcare solutions.

Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG (NYSE: NVS - News), a world leader in pharmaceuticals and consumer health. In 2004, the Group's businesses achieved sales of USD 28.2 billion and net income of USD 5.6 billion. The Group invested approximately USD 4.2 billion in R&D. Headquartered in Basel, Switzerland; Novartis Group companies employ approximately 81,400 people and operate in over 140 countries around the world.

For further information please consult http://www.novartis.com.


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


John Gilardi Novartis Global Media Relations + 41 61 324 3018 (direct) + 41 79 596 1408 (mobile) john.gilardi@novartis.com

Harry Rohme Novartis Pharma Communications +1 862 778 5151 (direct) +1 973 223 7717 (mobile) harry.rohme@novartis.com

Source: Novartis

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