myfortic® enteric-coated mycophenolate sodium Preparing for the next step in MPA protection Author : Prof. Maurizio Salvadori Institution : Renal Unit Careggi University Hospital myfortic® – registered trademark of Novartis AG, Basel Switzerland

Mycophenolate mofetil (MMF) – a potent immunosuppressant A prodrug containing MPA as the active moiety Inhibitor of de novo purine nucleotide synthesis1 A potent and selective immunosuppressant: MMF (+ CsA and steroids) reduces incidence of acute rejection in renal transplantation by up to 50% compared with AZA2 Superior long-term efficacy compared with AZA3 Adverse event profile leading to the need for dose changes e.g. GI side effects4 GI side effects occurring in up to 45% of patients5 CsA, cyclosporine; AZA, azathioprine 1Eugui EM and Allison AC. Ann NY Acad Sci 1993; 309–329. 2Sollinger HW et al. Transplantation 1995; 60: 225–232. 3Ojo AO et al. Transplantation 2000; 69: 2405–2409. 4Pelletier RP et al. Clin Transplant 2003; 17: 200–205. 5European MMF Cooperative Study Group. Lancet 1995; 345: 1321–1325

MMF reduces late renal allograft loss Parameter MMF AZA RR Significance Acute rejection 15.5% 24.7% – < 0.001 in first 6 months Patient survival at 91.4% 89.8% 0.71 = 0.002 4 years (>6 months) Censored graft 85.6% 81.9% 0.73 < 0.001 survival at 4 years (CAF) CAF at 4 years – – 0.80 < 0.001 (acute rejection free) CAF, chronic allograft failure; RR, risk ratio Ojo AO et al. Transplantation 2000; 69: 2405–2409

MMF is associated with improved long-term outcome 100 MMF AZA 95 Censored graft survival1 90 p < 0.0001 85 12 24 36 48 The incidence of acute rejection during the first 6 months after transplantation was 24.7% in the AZA group compared with 15.5% in the MMF group (P <0.001). Four-year death-censored graft survival and 4-year patient survival were both significantly better for MMF than for AZA for patients started on MMF vs AZA (graft survival, MMF vs AZA: 85.6% vs 81.9%, P <0.0001; patient survival, MMF vs AZA: 91.4% vs 89.8%, P <0.002). Even in a subanalysis of patients who never had acute rejection, the risk of chronic allograft failure was 20% lower in the MMF group (P <0.001). This demonstrates that MMF is associated with improvements in both short-term and long-term results, possibly by different mechanisms. Reference 1. Ojo AO et al. Transplantation. 2000;69:2405-2409. Months Fewer late acute rejection: 65% risk reduction for late acute rejections compared to Aza (p<0.001) in long-term treatment2 1 Ojo AO et al. Transplantation 2000; 69: 2405–2409 2 Meier-Kriesche H-U et al. Am J Transplant 2003; 3: 68–73

MMF: GI intolerance limits therapeutic exposure Acute rejection Patient withdrawal Median MMF dose Low (0.9 g/day) Intermediate (2.3 g/day) High (4.1 g/day) 40 48 50 31 30 40 30 23 Acute rejection (%) Let’s see some background information on the trade off between MMF efficacy and tolerability: Hale and collaborators studied the relationship between mycophenolic acid (MPA) exposure shown on the horizontal axis and outcomes (acute rejection on the left, withdrawl on the right). They published data from a 6-month, double-blind, randomized, parallel-group, concentration- controlled trial. The study was designed to examine the relationship between mycophenolic acid (MPA) pharmacokinetics and outcomes. 156 renal transplant recipients were given twice-daily doses of MMF to achieve 3 predefined target MPA AUC values (low: 16 g•hr/mL; intermediate: 32 g•hr/mL; high: 61 g•hr/mL) Median daily doses of MMF at the end of the study were 0.9, 2.3, and 4.1 for the low-, intermediate-, and high-MPA target groups, respectively There was a direct correlation between MPA exposure and efficacy, the higher dose the better, and an inverse correlation between MPA exposure and tolerability, the smaller dose the better. In this study, an MPA level of 30 ug-h/mL was defined as the minimal exposure to ensure a good level of efficacy without too much withdrawal. But still there is some room for improvement especially in decreasing the withdrawal rate for an either identical or better efficacy. 20 Withdrawal (%) 13 20 11 12 10 10 16 32 61 16 32 61 MPA exposure: target AUC (µg•hr/ml) MPA exposure: target AUC (µg•hr/ml) Hale M et al. Clin Pharmacol Ther 1998; 64: 672–683

MMF: poor tolerability leads to sub-therapeutic dosing Dose reductions Non-compliance and drug discontinuation Sub-therapeutic drug exposure Impact on graft survival Impact on healthcare cost Lecture Note 6 Improved Delivery of Mycophenolic Acid (MPA) While MPA is an effective immunosuppressant, delivery of this therapeutic agent has presented tolerability issues Several studies have documented that MMF is a local irritant to the GI tract, resulting in a poorer tolerability Hence there was a need to develop an alternative form of delivery—an enteric-coated tablet with a bioequivalent systemic exposure and potential for improved GI tolerability

MMF: dosing and renal transplant outcome A retrospective analysis to describe patterns of dosing of MMF in the first year post-transplant and to determine whether these changes in MMF dosing were associated with altered outcomes In this study a cohort of 721 kidney transplant patients who received IS including MMF in combination with Cyclosporine were evaluated. Clinical outcomes were compared and contrasted between patients with and without MMF dose changes within the first year post transplantation. 70% of patients experienced at least one dose change during the first year post transplant. Pelletier RP et al. Clin Transplant 2003: 17: 200–205

MMF dose changes correlate with reduced graft survival This retrospective study assessed 721 renal transplant recipients Key findings: The majority of patients (70.3%) had at least one dose change during the first year post-transplant Early MMF dose reduction was associated with a very high incidence of acute rejection (34.4%) 21% of the dose changes were due to GI side-effects This similar study to the Pelletier et al. determined whether MMF dose reduction after renal transplantation was associated with subsequent risk of acute rejection. This retrospective cohort study assessed 213 renal transplant recipients. Cox regression was used to model MMF dose as a time-dependent variable, with time to first acute rejection as the primary outcome. One hundred twenty-six patients (59%) had a total of 176 MMF dose reductions during the study. MMF dose was reduced because of leukopenia (55.1%), gastrointestinal symptoms (22.2%), infection (7.4%), malignancy (1.1%), and unknown reasons (14.2%). The cumulative number of days with the MMF dose reduced below full dose was an independent predictor of acute rejection. The relative risk of rejection increased by 4% for every week that the MMF dose was reduced below full dose. No significant association was observed between the number of days with MMF dropped below full dose and allograft failure. The cumulative number of days with the MMF dose dropped below full dose is a significant predictor of acute rejection after renal transplantation. Clinicians need to be aware of the rejection risk when the MMF dose is reduced and maintain close The figure presents three items for each day of observation (time is on the horizontal axis). The shaded area represents the proportion of patients on full-dose MMF (left vertical axis). The black lines show how many patients had their MMF dose dropped below full dose on the day of observation (right vertical axis). The line gives the proportion of patients who were rejection-free (left vertical axis). The total number of observed patients is presented at the bottom Pelletier RP et al. Clin Transplant 2003: 17: 200–205

MMF dose changes lead to reduced graft protection No dose change (n = 214) 30 p  0.0001 p = 0.003 Dose change (n = 507) 25 23.7 23.3 20 Incidence of events (%) 15 11.7 10 21 % of dose changes occurred because of GI side effects (diarrhea, abdominal pain, intestinal bleeding). Other reasons were hematologic 37% (neutropenia and/or thrombocytopenia), 29% concurrent infections, CMV, HSV, fungal , UTI, and other) and others 11 % Patients who experienced a dose change during the first year post transplant (70%) experienced a significantly higher risk of acute rejection than the 30% of patients who did not have any dose change (3.7 vs 23.3%, p<0.0001) In addition dose reduction occurring during the first month post transplant was associated with an incidence of acute rejection of up to 34.4%. In addition, the significantly increased incidence of acute rejection in the dose change patients resulted in a significant difference for graft loss or death at 3 years 5 3.7 Acute rejection in first year Graft loss or death at 3 years Pelletier RP et al. Clin Transplant 2003: 17: 200–205

MMF: dose reduction and risk of acute rejection. A retrospective analysis to describe the impact of MMF dose decrease on occurrence of acute rejection This similar study to the Pelletier et al. determined whether MMF dose reduction after renal transplantation was associated with subsequent risk of acute rejection. This retrospective cohort study assessed 213 renal transplant recipients. Cox regression was used to model MMF dose as a time-dependent variable, with time to first acute rejection as the primary outcome. One hundred twenty-six patients (59%) had a total of 176 MMF dose reductions during the study. MMF dose was reduced because of leukopenia (55.1%), gastrointestinal symptoms (22.2%), infection (7.4%), malignancy (1.1%), and unknown reasons (14.2%). The cumulative number of days with the MMF dose reduced below full dose was an independent predictor of acute rejection. The relative risk of rejection increased by 4% for every week that the MMF dose was reduced below full dose. No significant association was observed between the number of days with MMF dropped below full dose and allograft failure. The cumulative number of days with the MMF dose dropped below full dose is a significant predictor of acute rejection after renal transplantation. Clinicians need to be aware of the rejection risk when the MMF dose is reduced and maintain close The figure presents three items for each day of observation (time is on the horizontal axis). The shaded area represents the proportion of patients on full-dose MMF (left vertical axis). The black lines show how many patients had their MMF dose dropped below full dose on the day of observation (right vertical axis). The line gives the proportion of patients who were rejection-free (left vertical axis). The total number of observed patients is presented at the bottom Knoll GA et al. J Am Soc Nephrol 2003; 14: 2381–2386

The incidence of MMF dose reductions is often underestimated This retrospective cohort study assessed 213 renal transplant recipients Key findings: 59% of patients experienced at least one MMF dose reduction The majority of dose reductions (58%) occurred within the first 3 months after transplantation 22% of dose reductions occurred because of GI adverse events This similar study to the Pelletier et al. determined whether MMF dose reduction after renal transplantation was associated with subsequent risk of acute rejection. This retrospective cohort study assessed 213 renal transplant recipients. Cox regression was used to model MMF dose as a time-dependent variable, with time to first acute rejection as the primary outcome. One hundred twenty-six patients (59%) had a total of 176 MMF dose reductions during the study. MMF dose was reduced because of leukopenia (55.1%), gastrointestinal symptoms (22.2%), infection (7.4%), malignancy (1.1%), and unknown reasons (14.2%). The cumulative number of days with the MMF dose reduced below full dose was an independent predictor of acute rejection. The relative risk of rejection increased by 4% for every week that the MMF dose was reduced below full dose. No significant association was observed between the number of days with MMF dropped below full dose and allograft failure. The cumulative number of days with the MMF dose dropped below full dose is a significant predictor of acute rejection after renal transplantation. Clinicians need to be aware of the rejection risk when the MMF dose is reduced and maintain close The figure presents three items for each day of observation (time is on the horizontal axis). The shaded area represents the proportion of patients on full-dose MMF (left vertical axis). The black lines show how many patients had their MMF dose dropped below full dose on the day of observation (right vertical axis). The line gives the proportion of patients who were rejection-free (left vertical axis). The total number of observed patients is presented at the bottom Knoll GA et al. J Am Soc Nephrol 2003; 14: 2381–2386

MMF dose reduction and risk of acute rejection. The relative risk of rejection increased by 4% for every week that the MMF dose was reduced below full dose (p = 0.02) Use of MMF below full dose is an independent predictor of acute rejection (p = 0.03) This similar study to the Pelletier et al. determined whether MMF dose reduction after renal transplantation was associated with subsequent risk of acute rejection. This retrospective cohort study assessed 213 renal transplant recipients. Cox regression was used to model MMF dose as a time-dependent variable, with time to first acute rejection as the primary outcome. One hundred twenty-six patients (59%) had a total of 176 MMF dose reductions during the study. MMF dose was reduced because of leukopenia (55.1%), gastrointestinal symptoms (22.2%), infection (7.4%), malignancy (1.1%), and unknown reasons (14.2%). The cumulative number of days with the MMF dose reduced below full dose was an independent predictor of acute rejection. The relative risk of rejection increased by 4% for every week that the MMF dose was reduced below full dose. No significant association was observed between the number of days with MMF dropped below full dose and allograft failure. The cumulative number of days with the MMF dose dropped below full dose is a significant predictor of acute rejection after renal transplantation. Clinicians need to be aware of the rejection risk when the MMF dose is reduced and maintain close The figure presents three items for each day of observation (time is on the horizontal axis). The shaded area represents the proportion of patients on full-dose MMF (left vertical axis). The black lines show how many patients had their MMF dose dropped below full dose on the day of observation (right vertical axis). The line gives the proportion of patients who were rejection-free (left vertical axis). The total number of observed patients is presented at the bottom Minimize the time that patients stay on a reduced dose of MPA therapy Knoll GA et al. J Am Soc Nephrol 2003; 14: 2381–2386

GI complications and long-term outcome in patients treated with MMF Graft survival and cost following gastrointestinal complications in renal transplant recipients treated with MMF An USRDS/Medicare retrospective analysis in patients with a functioning graft at 1 year Analysis of USRDS database on 6,400 MMF-treated patients receiving cadaveric renal transplants in 1995-1998 USDRS database was linked to Medicare database to identify costs for those patients Outcomes: 4 year post transplant graft survival and second year post transplant cost Inclusion criteria Medicare as primary payer of services Functioning graft at 1 year post-transplant Results GI side effects increased second year post transplant cost by $5,000 – 8,000. Cost included are: outpatient visits, outpatient medication, hospitalization We will see more details about the results in the following slides. Hardinger KL et al. Transplant Int 2004; 17: 609-616

GI complications and long-term outcome in patients treated with MMF The total incidence of GI complications in the first 12 months post-transplant is 27.4% GI complications and MMF discontinuation results in significantly lower graft survival (70% vs 87% in patients without GI complications who continue MMF, p < 0.0001) Even patients with GI complications who continue MMF have lower graft survival versus those without GI side effects (83% vs 87%, p = 0.001) GI side effects increase post-transplant costs by $4,600–6,900 (p < 0.001) Analysis of USRDS database on 6,400 MMF-treated patients receiving cadaveric renal transplants in 1995-1998 USDRS database was linked to Medicare database to identify costs for those patients Outcomes: 4 year post transplant graft survival and second year post transplant cost Inclusion criteria Medicare as primary payer of services Functioning graft at 1 year post-transplant Results GI side effects increased second year post transplant cost by $5,000 – 8,000. Cost included are: outpatient visits, outpatient medication, hospitalization We will see more details about the results in the following slides. GI complications significantly increase risk of graft loss and healthcare cost Hardinger KL et al. Transplant Int 2004; 17: 609-616

GI complications increase risk and frequency of MMF discontinuations 25 p  0.001 21.3 20 16.0 15 Incidence of MMF discontinuation (%) 10 5 27.3% of patients experienced GI side effects and 17% discontinued MMF. This 17% differs between GI/No GI groups as 16% discontinued in the No GI complications group and 21.3% discontinued MMF in the GI complications group. No GI complications GI complications Multivariate analysis: GI complications in the first 12 months post-transplant increase the risk of MMF discontinuation by 19% Hardinger KL et al. Transplant Int 2004; 17: 609-616

GI complications significantly increase risk of graft loss 35 29.8 30 25 p = 0.001 20 4-year graft loss (%) 17.7 17.0 15 12.9 10 This figure shows directly the impact on graft loss instead o surviving graft. 5 No GI, MMF continued GI, MMF continued No GI, MMF discontinued GI, MMF discontinued Hardinger KL et al. Transplant Int 2004; 17: 609-616

GI complications increase healthcare costs 25,000 22,694 p  0.0001 20,000 19,400 16,178 14,799 15,000 2nd year average Medicare Payments Costs in the US (US$) 10,000 Patients with GI side effects that discontinued MMF had 53% higher cost than no GI MMF continuation patients, even if the cost of MMF was now subtracted from the MMF discontinuation group ($22,694 vs. $14,799, p=0.0042) Patients with GI side effects that continued on MMF also had 31.1% significantly higher cost than no GI MMF continuation patients ($19,400 vs. $14,799, p<0.0001) 5000 No GI, MMF continued GI, MMF continued No GI, MMF discontinued GI, MMF discontinued Hardinger KL et al. Transplant Int 2004; 17: 609-616

Summary The introduction of MMF was associated with better short-term and long-term outcomes MMF dose changes increase the risk of graft loss GI complications significantly increase risk of graft loss and healthcare costs This similar study to the Pelletier et al. determined whether MMF dose reduction after renal transplantation was associated with subsequent risk of acute rejection. This retrospective cohort study assessed 213 renal transplant recipients. Cox regression was used to model MMF dose as a time-dependent variable, with time to first acute rejection as the primary outcome. One hundred twenty-six patients (59%) had a total of 176 MMF dose reductions during the study. MMF dose was reduced because of leukopenia (55.1%), gastrointestinal symptoms (22.2%), infection (7.4%), malignancy (1.1%), and unknown reasons (14.2%). The cumulative number of days with the MMF dose reduced below full dose was an independent predictor of acute rejection. The relative risk of rejection increased by 4% for every week that the MMF dose was reduced below full dose. No significant association was observed between the number of days with MMF dropped below full dose and allograft failure. The cumulative number of days with the MMF dose dropped below full dose is a significant predictor of acute rejection after renal transplantation. Clinicians need to be aware of the rejection risk when the MMF dose is reduced and maintain close The figure presents three items for each day of observation (time is on the horizontal axis). The shaded area represents the proportion of patients on full-dose MMF (left vertical axis). The black lines show how many patients had their MMF dose dropped below full dose on the day of observation (right vertical axis). The line gives the proportion of patients who were rejection-free (left vertical axis). The total number of observed patients is presented at the bottom

Enteric-coating in NSAIDs: a track record Aspirin Reduced acute gastric mucosal injury to placebo levels1 Naproxen Reduced premature discontinuations due to upper GI complaints by 39%2 Piroxicam Reduced gastric damage by 40%3 1 Cole AT et al. Aliment Pharmacol Ther 1999; 13: 187 2 Caldwell JR et al. J Rheumatol 1994; 21: 689 3 Aabakken L er al. Scan J Gastroenterol 1992; 27: 1049

Strategy  EC-MPS (myfortic®) Develop alternative delivery form – an enteric-coated tablet that provides: Therapeutic equivalence to MMF (CellCept®) Smaller tablet might improve compliance Potential for improved GI tolerability and fewer dose reductions

myfortic®: comparison with MMF 720 mg b.i.d. (2 x 360 mg tablets) Mycophenolate sodium – salt Active moiety: mycophenolate Delayed release, enteric-coated Release in small intestine MMF 1000 mg b.i.d. (2 x 500 mg tablets) Mofetil ester – prodrug Active moiety: mycophenolate Immediate release Comparison of myfortic® formulation with MMF: myfortic® contains the active component (MPA), whereas MMF is a prodrug : ester of MPA myfortic® is an advanced enteric-coated formulation delaying MPA release until it reaches the small intestine. Myfortic® are smaller sized tablets than MMF

myfortic®: enteric-coating for GI protection and direct MPA delivery Enteric-coated tablets remain intact in the harsh acid environment of the stomach Enteric coating delays the release of MPA until it reaches the small intestine Designed to improve upper GI tolerability Potential of limiting the number of dose reductions Provide effective MPA protection Impact of enteric coating: The advanced enteric-coated formulation of myfortic® delays MPA release in the small intestine. The reason for the delayed absorption of myfortic® is its enteric coating which remains intact in the acidic environment of the stomach and only dissolves once it reaches the pH neutral environment of the small intestine. myfortic® can potentially improve the upper GI tolerability of MPA treatment

myfortic®: enteric-coating for GI protection and direct MPA delivery myfortic® 180mg enteric-coated tablet myfortic ® 360mg enteric-coated tablet 30 60 90 120 150 180 210 240 270 300 20 40 80 100 time [min] X409 1299, 360 mg pH 5.0 pH 5.5 pH 6.0 pH 6.8 30 60 90 120 150 180 210 240 270 300 20 40 80 100 Drug release (%) time [min] Batch X049 0100, 180 mg pH 5.0 pH 5.5 pH 6.0 pH 6.8 Drug release (%) The choice of ERL080 release at approximately pH 6.0 was based on the following considerations. The first and primary concern was that ERL080 would release in the small intestine and not in the stomach. Given the high tendency for renal transplant patients to develop gastritis due to multiple factors including uremia, steroids, calcineurin inhibitors, stress, etc., a principle goal of the ERL080 program was to assure that MPA release from Myfortic would consistently occur in the small intestine. (Abou-Saif, et al, 2000 ; Ravelli, 1995 ; Piamela, et al, 1990) In addition, a number of renal transplant patients are treated prophylactically with low dose proton pump inhibitors (PPI), for example in the pivotal ERLB301 study the rate of PPI use was 40%. Continuous gastric pH monitoring has shown that in the context of chronic PPI therapy (omeprazole 20 mg q day) with a concomitant meal, maximal median gastric pH is approximately 5.5 to 5.0 [Williams, et al, 1998]. Thus, in the context of renal transplant patients on PPIs, the choice of a release pH of 5.0 to 5.5 would have increased the probability of early release of MPA in stomach. However, with the pH release features of the current ERL080 formulation, we estimate that even in renal transplant patients on prophylactic PPI therapy with concommitant meal, the majority of MPS release, >70-80%, will occur in the small intestine. Enteric coating remains intact whilst passing through the stomach, allowing for direct systemic MPA delivery via the small intestine Novartis, data on file

myfortic®: clinical program Early phases: 10 trials, 172 renal transplant patients Similar MPA after administration of myfortic® 720 mg or MMF 1000 mg  dose for phase III Phase III: Two trials to confirm similar safety and efficacy 68 centers world-wide 745 renal transplant patients (de novo and maintenance) Comparator = MMF In combination with cyclosporine and steroids Clinical development program A comprehensive program of clinical studies. Early stages designed to demonstrate the bioequivalence of myfortic® versus MMF. First phase III trial to show efficacy and safety of myfortic® in de novo transplant patients. Second phase III trial to show that maintenance transplant patients can be safely switched to myfortic® from MMF. Ongoing and future studies to further demonstrate the excellent safety and tolerability profile of myfortic®. None of the trials were designed to show meaningful difference in terms of GI tolerability This clinical program is not a program of a generic

Plasma MPA concentration (g/ml) myfortic®: delayed Tmax consistent with MPA release in the small intestine myfortic® 720 mg 10 MMF 1000 mg Plasma MPA concentration (g/ml) 1 Comparison of concentration versus time profiles of MPA for myfortic® and MMF: Maximal achieved concentration (CMax) for myfortic® is lower than for MMF and occurs at a later time (Tmax) which is consistent with an enteric formulation (delayed release) . Myfortic administered at a dose of 720 mg provide similar MPA exposure than MMF administered at a dose of 1000 mg 0.1 2 4 6 8 10 Time (hours) Schmouder R et al. Presented at the American Society of Transplantation 18th Annual Meeting 1999, Chicago, IL, USA; Abstract 787

myfortic® demonstrates equivalent efficacy to MMF – study B301 Pivotal trial B301 Multicentre, double-blind, randomized, parallel-group, 12-month study de novo renal transplant patients Designed to show therapeutic equivalence of myfortic® to MMF endpoint: treatment failure at 6 months (biopsy-proven acute rejection [BPAR], graft loss, death or loss to follow-up) Patients randomized to myfortic® 720 mg b.i.d. (n=213) or MMF 1000 mg b.i.d. (n=210) in combination with Neoral® and prednisolone Phase III pivotal trial - ERLB301 This phase III pivotal trial was designed to confirm the therapeutic equivalence of myfortic® and MMF in de novo renal transplant patients. The primary efficacy endpoint was the assessment of efficacy failure at 6 months defined as the incidence of BPAR, graft loss, death or loss to follow-up. The secondary efficacy endpoints were incidence of biopsy proven acute rejection, graft loss, death, clinically diagnosed rejection, incidence of rejection requiring antibody therapy and incidence of biopsy proven chronic rejection at 6 and 12 months Study size determination : The sample size was based on the following assumptions: the probability of treatment failure within 6 months was 20% for both groups; EC-MPS is clinically equivalent to MMF when the 95% CI lies entirely within the pre-determined interval [–12,+12], and the power for claiming clinical equivalence is 0.85. Patients received either MMF 1000 mg b.i.d. or EC-MPS 720 mg b.i.d. plus matching placebo. The concomitant immunosuppressive regimen consisted of ME-CsA and corticosteroids. ME-CsA treatment was initiated within 24 hours pre- or post-transplant at 10 mg/kg/day and adjusted to maintain a 12-hour whole blood cyclosporine concentration (C0) in the following target ranges: 200–400 ng/ml for days 1–7, 200–300 ng/ml for weeks 1–4, 150–250 ng/ml for months 2–6 and 100–200 ng/ml for months 7–12. Prednisone (or equivalent) dose was tapered according to local practice, but not to less than 5 mg/day for at least 6 months. Use of antibody therapy as an induction treatment was equivalent in both treatment groups: 39.4% and 42.9% of patients in the EC-MPS and MMF groups, respectively. The most common therapies were basiliximab (22.1% EC-MPS patients; 23.8% MMF patients) and anti-lymphocyte or anti-thymocyte antibodies (16.4% EC-MPS patients; 17.1% MMF patients) Salvadori M et al. Am J Transplant 2003; 4: 231-236

Incidence of events (%) myfortic® effective in de novo patients Pivotal trial B301 Biopsy-proven acute rejection, graft loss or death* 26.3 28.1 Biopsy-proven acute rejection 22.5 24.3 Biopsy-proven chronic rejection (3–12 months) 2.8 myfortic® (n = 213) 6.2 MMF (n = 210) 5.2 Graft loss or death 6.7 Within the first 6 months post-transplant, on the basis of ITT analysis, the incidence of efficacy failure, defined as the incidence of BPAR, graft loss, death or loss to follow-up, was similar for EC-MPS and MMF (25.8% and 26.2%, respectively). The 95% CI for efficacy failure was [–8.7,+8.0], indicating clinical equivalence between the two study treatments. At 12 months as described on this slide, the incidence of BPAR, graft loss or death was similar between the 2 treatment groups. The incidence of biopsy proven chronic rejection diagnosed between 3 and 12 months tended to be lower in the myfortic group 5 10 15 20 25 30 35 Incidence of events (%) *BPAR, graft loss, death or loss to follow-up: myfortic® 28.6% and MMF 28.1% (95% CI: [–8.0,+9.1]) (0–12 months; ITT population). myfortic® group had more grafts with a cold ischemia time >24 hours (p=0.051) Salvadori M et al. Am J Transplant 2003; 4: 231-236

myfortic®: comparable overall safety and tolerability Pivotal trial B301 myfortic® (n = 213) MMF (n = 210) Safety and tolerability of myfortic® and MMF The overall incidence of adverse events (AEs), severe and serious adverse events was similar for both the myfortic® and MMF treatment groups, The incidence of infections was also similar for both treatment groups but there were differences in the incidence of serious infections as shown on the next slide. 12 months analysis Salvadori M et al. Am J Transplant 2003; 4: 231-236

myfortic®: trend to fewer serious infections Pivotal trial B301 myfortic® (n = 213) MMF (n = 210) p = 0.22 p = 0.01 Serious infections were recorded less frequently in patients receiving EC-MPS than MMF (22.1% versus 27.1%, respectively; p = ns) (Figure 2). The incidence of serious pneumonia was statistically significantly lower in patients receiving EC-MPS than those receiving MMF (0.5% versus 4.3%; p = 0.01). The incidence of CMV infection and CMV disease observed during the study was similar between the two groups. 12 months analysis Salvadori M et al. Am J Transplant 2003; 4: 231-236

myfortic®: trend to fewer dose changes due to GI AEs Pivotal trial B301 myfortic® (n = 213) MMF (n = 210) p = 0.20 p = 0.22 Gastrointestinal adverse events: The requirement for fewer dose reductions or dose discontinuations in response to GI AEs in the EC-MPS group compared with the MMF group as described on this slide may suggest that EC-MPS has a positive effect on the severity of GI AEs. No difference in the overall incidence of GI AEs was observed between EC-MPS and MMF in the context of this double-blind, double-dummy, randomized trial, which was not designed to statistically detect differences between treatment groups in terms of GI tolerability. 12 months analysis Incidence of GI AEs similar for myfortic® and MMF Dose changes include interruptions, discontinuations or dose decrease Salvadori M et al. Am J Transplant 2003; 4: 231-236

Conclusions: de novo renal transplant patients Pivotal trial B301 Therapeutic equivalence demonstrated between myfortic® 720 mg b.i.d. and MMF 1000 mg b.i.d. Safety comparable for myfortic® and MMF myfortic® therapy resulted in a trend to fewer dose changes due to GI AEs And therefore may improve long term graft survival

MMF-treated patients can be safely converted to myfortic® – study B302 Pivotal trial B302 Multicentre, double-dummy, randomized, parallel-group 12-month study maintenance renal transplant patients 6 months post-transplant Designed to investigate if MMF-treated patients could be safely converted to myfortic® Primary endpoint: incidence/ severity of GI AEs at 3 months, neutropenia at 3 months vs MMF Patients receiving MMF 1000 mg b.i.d. for 6 weeks were randomized to myfortic® 720 mg b.i.d. (n = 159) or MMF 1000 mg b.i.d. (n = 163) in combination with Neoral® ± prednisolone Phase III pivotal trial - ERLB302 This phase III trial was designed to investigate if stable maintenance renal transplant patients receiving MMF could be safely converted to myfortic® Primary assessment was based on the incidence and severity of GI AEs at 3 months and occurrence of neutropenia within 3 months. To be eligible for this study, patients were to be at least 6 months post transplant and were to receive MMF at a dose level of 2000mg per day in combination with Neoral +/- steroids Patients were randomised to receive myfortic 720 mg twice-daily dose or MMF 1000 mg twice-daily Patients were demographically similar and also received concomitant immunosuppressive treatment with cyclosporine (Neoral®) +/- corticosteroids Budde K et al. Am J Transplant 2003; 4: 237-243

No Loss in efficacy in MMF patients converted to myfortic® Pivotal trial B302 myfortic® (n = 159) MMF (n = 163) p = ns Efficacy was assessed as a secondary objective in patients converted to myfortic® Incidences of BPAR, acute rejection, BPCR and graft loss or death were comparable for myfortic® and MMF with a trend to be less frequent with myfortic. 12 month analysis Budde K et al. Am J Transplant 2003; 4: 237-243

Mean GI severity score – change from baseline Severity of GI adverse events: myfortic® vs MMF Pivotal trial B302 0.23 12 months 0.47 0.19 myfortic® (n = 159) 6 months 0.27 MMF (n = 163) p = NS 0.15 3 months 0.20 A similar number of patients experienced GI AEs in both treatment groups. Nevertheless the increase in GI severity score from baseline adjusted for duration was less in the EC-MPS group than in the MMF group. These data suggest once again that Myfortic may offer a benefit to transplant patient by decreasing the severity of adverse GI symptoms associated with MPA therapy. 0.1 0.2 0.3 0.4 0.5 Mean GI severity score – change from baseline Severity scores for all GI AEs were recorded, including: 0 (no event), 1 (mild), 2 (moderate) and 3 (severe). For each patient, the individual scores from post hoc analysis, weighted by duration, were summarized to obtain a total severity score. Mean severity score and changes from baseline were recorded. Budde K et al. Am J Transplant 2003; 4: 237-243

Conversion to myfortic®: no compromise on safety Pivotal trial B302 myfortic® (n = 159) MMF (n = 163) Incidence of Events (%) Overall safety outcome: The overall incidence of AEs was similar for myfortic® and MMF. The incidence of drug-related AEs was similar for both treatment groups. The incidence of infection was similar for both treatment groups. myfortic® and MMF dispay a similar safety profile 12 month analysis Budde K et al. Am J Transplant 2003; 4: 237-243

myfortic®: significantly fewer serious infections Pivotal trial B302 myfortic® (n = 159) MMF (n = 163) p  0.05 Incidence of events (%) Patients receiving Myfortic experienced less serious adverse events. As already observed in the de novo study as a trend, maintenance patients treated with Myfortic experienced significantly less serious infection. The incidence of serious pneumonia was also lower in patients treated with Myfortic. 12 month analysis Budde K et al. Am J Transplant 2003; 4: 237-243

Stable renal transplant patients can be safely converted to myfortic® Conclusions: maintenance renal transplant patients Pivotal trial B302 myfortic® has a similar efficacy profile to MMF Safety profile is comparable, with some trends in favor of myfortic® Severity of gastro-intestinal events Efficacy failures Significantly fewer serious infections Stable renal transplant patients can be safely converted to myfortic®

myfortic®: summary (1) myfortic® is an effective and well-tolerated immunosuppressant for: de novo renal transplant patients, who need to achieve sustained therapeutic MPA protection to prevent acute rejection renal transplant patients taking MMF, who may often be considered for dose adjustments or withdrawal due to GI intolerability

myfortic®: summary (2) myfortic® is an advanced, enteric-coated formulation delivering MPA, designed to protect the upper GI tract from MPA-related upper GI side effects myfortic® potentially improves GI tolerability leading to fewer dose reductions or discontinuations Patients taking MMF can be safely converted to myfortic®

BACK-UP SLIDES

Association of MMF with improved long-term outcome 85 90 95 100 1 2 3 4 years after Transplantation % patients with late acute rejection MMF AZA 99,1% 98,9% p<0.001 93,9% Patients continued on MMF or AZA 90,7% The incidence of acute rejection during the first 6 months after transplantation was 24.7% in the AZA group compared with 15.5% in the MMF group (P <0.001). Four-year death-censored graft survival and 4-year patient survival were both significantly better for MMF than for AZA for patients started on MMF vs AZA (graft survival, MMF vs AZA: 85.6% vs 81.9%, P <0.0001; patient survival, MMF vs AZA: 91.4% vs 89.8%, P <0.002). Even in a subanalysis of patients who never had acute rejection, the risk of chronic allograft failure was 20% lower in the MMF group (P <0.001). This demonstrates that MMF is associated with improvements in both short-term and long-term results, possibly by different mechanisms. Reference 1. Ojo AO et al. Transplantation. 2000;69:2405-2409. Fewer late acute rejection: 35% RR in long-term treatment Meier Kriesche et al. Am J Transplant 2003; 3: 68–73

Patient demographics: no significant differences Pivotal trial B301 myfortic® MMF (n = 213) (n = 210) Cadaveric donor 85.0% 82.4% Living donor 15.0% 17.6% HLA mismatch 0-3 62.0% 60.0% 4-6 37.1% 38.6% Donor CMV positive / Recipient CMV negative 16.9% 12.4% Cold ischemia time 20.7% 13.3%  24 hrs* *p = 0.051 Salvadori M et al. Am J Transplant 2003; in press

myfortic®: probability of efficacy failure reduced by 1/3 Pivotal trial B302 10 8 myfortic® 6 MMF probability of efficacy failure (%) Kaplan–Meier estimates of 4 2 The Kaplan Meier point estimates of the probability of experiencing BPAR, graft loss or death within 12 month of the initial dose of study medication suggested that a MMF patient was three times more likely to experience such an efficacy event failure than an EC-MPS patient: 2.7 for EC-MPS vs 8.7% for MMF 90 180 270 360 Time post-transplantation (days) Probability of BPAR, graft loss or death at 12 months: EC-MPS 2.7% vs MMF 8.7%; 95% CI [-13, +1.1] Budde K et al. Am J Transplant 2003; in press

Patient demographics: no significant differences Pivotal trial B302 *ITT/safety populations Budde K et al. Am J Transplant 2003; in press

myfortic® in maintenance patients: no compromise on safety Pivotal trial B302 * Neutrophils < 1,500/mm3 † No significant difference between the study groups ‡ Primary Endpoint: GI AE at 3 months; neutropenia within 3 months Budde K et al. Am J Transplant 2003; in press

myfortic® in maintenance patients: upper GI AEs Pivotal trial B302 Budde K et al. Am J Transplant 2003; in press

myfortic® in maintenance patients: non-upper GI AEs Pivotal trial B302 Neumayer H-H et al. Presented at the XIX International Congress of the Transplantation Society, Miami, FL, USA; Abstract 2129 Budde K et al. Am J Transplant 2003; in press