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Novartis new two-year data with Certican shows positive outcomes at 24 months in largest liver transplant trial to date

• Study's endpoints met; Certican with reduced exposure tacrolimus provided comparable efficacy with superior renal function maintained from month one to 24 versus control arm [1]

 

• Calcineurin inhibitors like tacrolimus are part of the standard immunosuppression regimen after a liver transplant but may contribute to a decline in renal function over time [2],[3]

 

• Certican was approved by European Health Authorities for use in adult liver transplant patients in October 2012

Basel, November 12, 2012 - Novartis today announced new two-year results from the largest Phase III study ever in liver transplantation that confirmed comparable efficacy to control and superior renal function results previously seen at 12 months [1]. The trial evaluated the introduction of Certican (everolimus) with reduced exposure tacrolimus administered twice-daily starting one month after liver transplantation versus standard-exposure tacrolimus [1].

"Novartis has a longstanding commitment to the transplant community and to research into potential treatment options to help improve patient outcomes," said Tim Wright, Global Head of Development, Novartis Pharma. "The promising renal function results seen in this study represent yet another potential advance for patients and build upon the recent approval of Certican for adult liver transplant patients by the European Health Authorities."

The data were presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, MA, USA.

"These results showed that treatment with Certican with reduced tacrolimus led to a clinically relevant retention of renal function compared to standard tacrolimus, with no compromise in rejection," said John Fung, M.D., Ph.D., Director, Transplantation Center, Cleveland Clinic Foundation, Cleveland, OH. "The two-year results suggest that a treatment regimen of Certican with reduced tacrolimus is not only possible, but also sustainable, and that's exciting news for patients and their healthcare providers who are concerned about the impact of CNIs on renal function."

A large, independent registry study of nearly 70,000 patients who received a non-renal solid organ transplant between 1990 and 2000 showed that the incidence of chronic renal failure was greater in liver transplant recipients than in recipients of all other solid organ transplants, except intestinal transplants [4]. Calcineurin inhibitors (CNIs), such as tacrolimus, are part of the standard-of-care treatment regimen for immunosuppression in liver transplantation, but they can contribute to complications, including impaired renal function [2],[3]. Certican works by binding to a protein called mammalian target of rapamycin (mTOR), and acts synergistically with CNIs, offering an opportunity to lower CNI exposure [5],[6].

In October 2012, European Health Authorities approved Certican (RAD001/everolimus) for the prophylaxis of organ rejection in adult patients receiving a liver transplant. In the US, RAD001 is an investigational agent for the prevention of organ rejection in adult patients receiving a liver transplant and a decision by the US Food and Drug Administration is expected by the end of 2012.

Study Details: Certican with Reduced-Dose Tacrolimus: New 24-Month Results

The 24-month results are from a Phase III, multicenter, open-label, randomized, controlled study conducted in 719 de novo liver transplant patients.Four weeks following liver transplantation, patients treated with tacrolimus and corticosteroids (with or without mycophenolate mofetil) were randomized to one of three groups: Certican (C0 3-8ng/mL) in combination with reduced-exposure tacrolimus (C0 3-5ng/mL) (n=245), Certican (C0 6-10ng/mL) followed by tacrolimus withdrawal at four months (n=231) or standard-exposure tacrolimus (C0 6-10ng/mL) only (control, n=243). All three study arms included twice-daily treatment. Additionally, all arms included corticosteroids for at least six months post-transplant.Enrollment into the tacrolimus withdrawal arm was prematurely halted due to a higher incidence of acute rejection episodes and adverse events leading to treatment discontinuation, clustered around the time of tacrolimus elimination at four months post randomization[1]. The study protocol was amended at that time.

The original study protocol included two co-primary endpoints, which were composite efficacy failure and renal function measured by estimated glomerular filtration rate (eGFR) based on the four-variable Modification of Diet in Renal Disease (MDRD4) equation at 12 months after liver transplantation. Both co-primary endpoints were met. In the original study protocol, composite efficacy failure was defined as graft loss, death or lost-to-follow-up [7].

The amended endpoints assessed at 24 months included the composite efficacy failure rate (treated biopsy proven acute rejection [tBPAR], graft loss, or death) and its individual components, and change in renal function. Key safety endpoints included the incidence of adverse events (AEs) and serious AEs (SAEs) [1].

At 24 months, the incidence of composite efficacy failure (Kaplan-Meier estimates) was numerically lower with Certican with reduced tacrolimus compared to the tacrolimus control group (10.3% vs. 12.5%; risk difference -2.2%; [97.5% CI: -8.8%, 4.4%]; p=0.452). The incidence of BPAR was significantly lower with Certican with reduced tacrolimus compared to the tacrolimus control group (6.1% vs. 13.3%; risk difference: -7.2% [95% CI: -13.5%, -0.9%]; p=0.010). The incidence rates of graft loss, death, and tBPAR were comparable between the two groups. Superior renal function was maintained at month 24 with Certican with reduced tacrolimus compared with standard tacrolimus (mean difference in eGFR change: 6.7 mL/min/1.73m2 [97.5% CI: 1.9, 11.42]; p=0.0018) (ITT population). For on-treatment patients, the difference in eGFR at month 24 was 11.5 mL/min in favor of Certican with reduced tacrolimus [1],[8].

At month 24, the incidence rates for Certican with reduced tacrolimus vs. the tacrolimus control group for any AEs (96.3% vs. 97.9%) and any SAEs (56.3% vs. 54.1%) were comparable.The most common AEs reported in either Certican with reduced tacrolimus or the tacrolimus control groups were: headache, hypertension, diarrhea, peripheral edema, pyrexia, abdominal pain, nausea, hepatitis C, leukopenia, fatigue, hypercholesterolemia, tremor, renal failure, nasopharyngitis, back pain, abnormal liver function tests. There was a numerical difference in the incidence of malignant tumors in the Certican with reduced tacrolimus group (11) compared to the tacrolimus control group (16)[1].

The 12-month results from this study were first presented as a scientific poster at the 62nd AASLD Annual Meeting in November 2011, as well as at the International Liver Transplantation Society (ILTS) 18th Annual International Congress in May 2012 and the American Transplant Congress (ATC) 2012 Annual Meeting in June 2012. In August 2012, the 12-month study results were published in the American Journal of Transplantation (AJT).

About Certican (everolimus)

Everolimus is the most-extensively studied immunosuppressant in solid organ transplantation with more than 10,000 transplant recipients enrolled in Novartis-sponsored clinical trials worldwide[9].Under the trade name Certican®, it is approved in more than 90 countries to prevent organ rejection for renal and heart transplant patients, and in addition, is approved in the EU, Chile and Philippines to prevent organ rejection for liver transplant patients. In the US, under the trade name Zortress®, the drug is approved for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant.

Everolimus is also available from Novartis in different dosage strengths and for different uses in non-transplant patient populations under the brand names Afinitor® and Votubia®. It is also exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Not all indications are available in every country. As an investigational compound, the safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywhere else in the world.

Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such as "may," "commitment," "potential," "promising," "suggest," "can," "expected," or similar expressions, or by express or implied discussions regarding potential new indications or labeling for everolimus, potential additional marketing approvals for everolimus, or regarding potential future revenues from everolimus. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with everolimus to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that everolimus will be submitted or approved for sale, or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that everolimus will achieve any particular levels of revenue in the future. In particular, management's expectations regarding everolimus could be affected by, among other things, unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry and general public pricing pressures; unexpected manufacturing issues; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file 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 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 provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2011, the Group's continuing operations achieved net sales of USD 58.6 billion, while approximately USD 9.6 billion (USD 9.2 billion excluding impairment and amortization charges) was invested in R&D throughout the Group. Novartis Group companies employ approximately 127,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com.

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References

1. Saliba, F., De Simone, P., Nevens, F., et al. Everolimus-Facilitated Reduction of Tacrolimus Provides Comparable Efficacy and Superior Renal Function Versus Standard Tacrolimus In de novo Liver Transplant Recipients: 24-Month Results of a Randomized Trial. To be presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9-13, 2012; Boston, MA, USA.

2. McGuire B.M., Rosenthal P., Brown C.C., et al. Long-term Management of the Liver Transplant Patient: Recommendations for the Primary Care Doctor. American Journal of Transplantation 2009; 9: 1988-2003.

3. Venkataramanan, R., Shaw, L.M., Sarkozi, L., et al. Clinical Utility of Monitoring Tacrolimus Blood Concentrations in Liver Transplant Patients. J Clin Pharmacol, 2001; 41:542-551.

4. Ojo, A., Held, P., Port, F., et al. Chronic Renal Failure after Transplantation of a Nonrenal Organ. New Eng J Med, 2003;349:931-940.

5. Certican® Prescribing Information.

6. Schuurman, HJ., Cottens, S., Fuchs, S., et al. SDZ RAD, A new rapamycin derivative: Synergism with cyclosporine. Trans, 1997;64,1;32-35.

7. De Simone, P., Nevens, F., De Carlis, L., et al. Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial. American Journal of Transplantation. 2012.

8. Saliba, F., De Simone, P., Nevens, F., et al. Everolimus-Facilitated Reduction of Tacrolimus Provides Comparable Efficacy and Superior Renal Function Versus Standard Tacrolimus In de novo Liver Transplant Recipients: 24-Month Results of a Randomized Trial. Abstract.

9. Novartis Data on File: DSUR. July 2012.

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Posted: November 2012

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