East Hanover, N.J., August 6, 2012 — A Phase III study published in the American Journal of Transplantation found that patients who started treatment with RAD001 (everolimus) with reduced tacrolimus one month after liver transplant experienced non-inferior efficacy at month 12 compared to patients treated with standard tacrolimus.1 Significant differences in renal function were observed as early as one month after the introduction of RAD001, and were maintained throughout the study period.1 RAD001 is being investigated for the prevention of organ rejection in adult patients receiving a liver transplant.
Significant unmet medical needs remain in liver transplantation. Calcineurin inhibitors (CNI), 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
“In this study, patients treated with RAD001 plus reduced tacrolimus showed superior differences in renal function, compared to the tacrolimus control group, as early as one month after the introduction of RAD001, with no apparent decline over the one-year study period,” said John Fung, M.D., Ph.D., director, Transplantation Center, Cleveland Clinic Foundation, Cleveland, Ohio. “Despite early and reduced tacrolimus exposure, we did not see any compromise in the control of rejection, and that is very encouraging.”
This study includes two sets of endpoints. The original study protocol included two co-primary endpoints, which were composite efficacy failure (defined as graft loss, death or lost-to-follow-up) 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.4 The study protocol was amended when enrollment into the RAD001 with tacrolimus withdrawal arm was prematurely halted due to a higher incidence of treated biopsy-proven acute rejection (tBPAR) episodes and adverse events leading to treatment discontinuation (45 events), clustered around the time of tacrolimus elimination (at four months post randomization).1 When the protocol was amended, composite efficacy failure, defined as tBPAR, graft loss or death, became the primary efficacy endpoint and renal function became the key secondary endpoint.1
These published results are from the amended protocol and show that the study met the primary endpoint, which was the composite efficacy failure rate of treated biopsy-proven acute rejection (tBPAR), graft loss or death.1 The composite efficacy failure rate in the RAD001 plus reduced-exposure tacrolimus group was lower compared to the control group at month 12.1 The results showed non-inferiority (against the non-inferiority margin of 12%) for the RAD001 plus reduced-exposure tacrolimus group as compared to the tacrolimus control group.1 In addition, the study met the key secondary endpoint, demonstrating non-inferiority in change in renal function. Testing was done for superiority, measured by significant changes in renal function, one month after starting RAD001 plus reduced tacrolimus, with sustained improvement to month 12, compared to standard-exposure tacrolimus.1
“Novartis shaped the landscape of transplant medicines more than 25 years ago, and we continue to study innovative treatment approaches that reflect the evolving needs of transplant patients today,” said Usman Azam, M.D., Head of U.S. Medical & Chief Scientific Officer, Novartis Pharmaceuticals Corporation. “This Phase III study with RAD001 underscores our ongoing commitment, as results suggest a promising immunosuppressive strategy for patients who have had a liver transplant and are susceptible to the effects of immunosuppressive agents, including damage to the kidneys.”
Antigen-activated T cells play a key role in transplant rejection by recognizing foreign substances and multiplying in an attempt to protect the body. RAD001 acts as an immunosuppressant by binding to a protein called mammalian target of rapamycin (mTOR) and preventing the proliferation of these antigen-activated T cells. Immunosuppressants of the mTOR inhibitor class, including RAD001, act synergistically with CNIs, offering an opportunity to potentially lower CNI exposure.5
The U.S. Food and Drug Administration (FDA) has accepted the filing for RAD001 for the prevention of organ rejection in adult liver transplant patients, and a decision is expected by Q4 2012. This study was first presented as a scientific poster at the 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco, California in November 2011. The data were also presented earlier this year at the International Liver Transplantation Society (ILTS) 18th Annual International Congress in San Francisco in May, as well as the American Transplant Congress (ATC) 2012 Annual Meeting in Boston in June.
RAD001 Plus Reduced-Dose Tacrolimus: 12-Month Results
These are the analyses of the 12-month results from a 24-month, Phase III, multicenter, open-label, randomized study conducted in 719 de novo liver transplant patients.1 Following liver transplantation and a 30-day run-in period with tacrolimus and corticosteroids (with or without mycophenolate mofetil), patients were randomized to one of three groups: RAD001 (C0 3-8ng/mL) plus reduced-exposure tacrolimus (C0 3-5ng/mL) (n=245), RAD001 (C0 6-10ng/mL) with tacrolimus withdrawal at four months (n=231) or standard-exposure tacrolimus (C0 6-10ng/mL) only (control, n=243); all arms included corticosteroids for at least six months post-transplant.1 Enrollment into the RAD001 with tacrolimus withdrawal arm was prematurely halted due to a higher incidence of tBPAR episodes and adverse events leading to treatment discontinuation (45 events), clustered around the time of tacrolimus elimination (at four months post randomization).1
The study met the amended primary endpoint, which was the composite efficacy failure rate of tBPAR, graft loss or death.1 The composite efficacy failure rate in the RAD001 plus reduced-exposure tacrolimus group was lower compared to the control group at month 12 (6.7% vs. 9.7%, respectively).1 The results showed non-inferiority (against the non-inferiority margin of 12%) with -3.0% [97.5 CI (-8.7%, 2.6%)] in favor of the RAD001 plus reduced-exposure tacrolimus group (p<0.001 for non-inferiority).1 RAD001 plus reduced-exposure tacrolimus also demonstrated fewer episodes of tBPAR between day 30 and month 12 (excluding events that occurred prior to randomization).1 Episodes of tBPAR in the RAD001 plus reduced-exposure tacrolimus group were mild (graded =RAI 4-5) compared to nine episodes in the standard-exposure tacrolimus control group that were moderate (graded RAI 6-7) or severe (graded RAI 8-9).1 None of the graft losses in the RAD001 plus reduced-exposure tacrolimus group or the control group were related to rejection.1
In addition, the study met the key secondary endpoint, demonstrating non-inferiority in change in renal function. Testing was then done for superiority, with significant changes in renal function one month after starting RAD001 plus reduced tacrolimus and sustained improvement to month 12, compared to standard-exposure tacrolimus (adjusted mean difference in estimated glomerular filtration rate, or eGFR, change for RAD001 plus reduced tacrolimus versus tacrolimus control was +8.50mL/min/1.73m2 (97.5% CI 3.74, 13.27mL/min/1.73m2, p<0.001).1
The overall incidence of adverse events was comparable for both treatment arms (94.7% for the RAD001 plus reduced-exposure tacrolimus group and 95.0% for the tacrolimus control group). The most common adverse events for the RAD001 and tacrolimus groups (incidence =10%) reported by the study authors were: diarrhea, headache, peripheral edema, hypertension, nausea, abdominal pain, pyrexia (fever), leukopenia, hepatitis C, tremor and fatigue.1 There was a higher rate of patients in the RAD001 plus reduced-exposure tacrolimus group (25.7%) who discontinued the study due to adverse events compared to patients in the tacrolimus control group (14.1%).1 One case of hepatic artery thrombosis was reported in the RAD001 plus reduced-exposure tacrolimus group. The event was a second occurrence in a patient who experienced hepatic artery thrombosis during the run-in period prior to randomization.1 Interstitial lung disease was reported for one patient in each of the three treatment groups.1 The overall safety findings of RAD001 were comparable and consistent with previous RAD001 studies in solid organ transplantation.1
The study protocol was amended when enrollment into the RAD001 with tacrolimus withdrawal arm was discontinued.4 The results reported here are the data from the amended protocol. The original study protocol included two co-primary endpoints, which were composite efficacy failure and renal function measured by 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.4 The composite efficacy failure rate in the RAD001 plus reduced-exposure tacrolimus group was also lower compared to the control group at month 12, and showed non-inferiority [difference of -0.9%; 97.5% CI (-7.3% to 5.5%) against the non-inferiority margin of 10%].4 In the original study protocol, composite efficacy failure was defined as graft loss, death or lost-to-follow-up.4 In the amended protocol, the primary endpoint of composite efficacy failure at 12 months was defined as tBPAR, graft loss or death.1
About RAD001 (everolimus)
RAD001 (everolimus) is approved in the U.S. under the trade name Zortress®, and is indicated for use following kidney transplantation. Outside of the U.S., everolimus is approved in many countries under the trade name Certican® for use following heart and kidney transplantation.
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.
The foregoing release contains forward-looking statements that can be identified by terminology such as “is being investigated,” “commitment,” “promising,” “potentially,” “accepted the filing,” “expected,” “will,” or similar expressions, or by express or implied discussions regarding potential new indications or labeling for RAD001, or regarding potential future revenues from RAD001. 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 RAD001 to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that RAD001 will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that RAD001 will achieve any particular levels of revenue in the future. In particular, management’s expectations regarding RAD001 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.
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1. 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.
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. Saliba, F., De Simone, P., Nevens, F., et al. “Efficacy and safety of everolimus with early reduction or elimination of tacrolimus in 719 de novo liver transplant recipients: 12 month results of a phase III, randomized, controlled study.” Presented at the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 4-8, 2011; San Francisco, CA, USA. Poster LB-7.
5. Schuurman, HJ., Cottens, S., Fuchs, S., et al. SDZ RAD, A new rapamycin derivative: Synergism with cyclosporine. Trans, 1997;64,1;32-35.
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