Drugs of the Future 1999, 24(1): 22-29
`Copyright© 1999 PAOUS SCIENCE
`CCC: 0377-8282/99
`
`SDZ-RAD
`
`lmmunosuppressant
`
`[1 R,9S, 12S[1 'R(1 "S,3" R,4" R)], 15R, 18R, 19R,21 R,23S,30S,32S,35R]-1, 18-Dihydroxy-12-[2-[4-(2-hydroxyethoxy)-3-
`m ethoxycycloh exyl]-1 -methyl ethyl]-1 9, 30-d i m ethoxy-15, 1 7, 21, 23, 29, 35-hexam ethyl-11 , 36-d ioxa-4-
`azatricyclo[30.3.1 .04•9]hexatriaconta-16(E),24(E) ,26(E) ,28(E)-tetraene-2,3, 10, 14,20-pentaone
`40-0-(2-Hydroxyethyl)rapamycin
`
`growth factors (i.e., IL-2) which drive proliferation,
`rapamycin also suppresses proliferation at the late G1
`stage of the cell cycle. Thus, the proliferative signal pro(cid:173)
`vided by T cell growth factors is blocked and cells are
`unable to enter the S phase (4, 5). Furthermore, inhibition
`by rapamycin is not limited to IL-2-induced T cell prolifer(cid:173)
`ation since both hematopoietic and nonhematopoietic cell
`proliferation (e.g., mast cells, fibroblasts and vascular
`smooth muscle cells [VSMC]) has been successfully
`blocked by this agent (6-9).
`Rapamycin has been considered a potential candi(cid:173)
`date to prevent late graft loss resulting from graft vessel
`disease since the agent is capable of inhibiting prolifera(cid:173)
`tion of VSMC, thus avoiding intimal thickening responsi(cid:173)
`ble for vessel obstruction (10-12). Moreover, the nature of
`the differential modes of action described for cyclosporine
`and rapamycin has led to the discovery of synergistic
`interaction between the two agents, suggesting potential
`combination use of both for clinical transplantation
`(13-15). Although the efficacy of rapamycin has been
`
`H3C11"' Qyi
`
`0
`H
`~o
`.,CH3
`H3C
`0
`-
`,,
`
`7'
`CH3
`
`HaC-o''''
`
`H3C
`~ 8
`
`[I]
`
`OH
`
`0
`
`-
`CH3
`
`L.A. Sorbera, P.A. Leeson, J. Castaner. Prous Science, P.O. Box
`540, 08080 Barcelona, Spain.
`
`CH3
`
`CH3
`
`Mol wt: 958.2317
`
`CAS: 159351-69-6
`
`EN: 210424
`
`Synthesis
`
`Alkylation of rapamycin (I) with 2-(tert-butyldimethylsi(cid:173)
`lyloxy)ethyl triflate (II) by means of 2,6-lutidine in hot
`toluene gives the silylated target compound (111), which is
`deprotected by means of 1 N HCI
`in methanol (1 ).
`Scheme 1.
`
`Introduction
`
`The macrolide rapamycin (now designated sirolimus)
`[I]. a secondary metabolite of Streptomyces hygroscopi(cid:173)
`cus originally described as an antifungal agent in the mid
`1970s, was subsequently reported in 1989 to effectively
`suppress the rejection of transplanted allogenic solid
`organs in experimental animals (2, 3). In contrast to
`cyclosporine and FK-506, which act early after T cell acti(cid:173)
`vation by blocking transcriptional activation of early T cell(cid:173)
`specific genes thereby inhibiting synthesis of T cell
`
`West-Ward Exhibit 1017
`Sorbera 1999
`Page 001
`
`

`

`Drugs Fut 1999, 24(1)
`
`23
`
`Scheme 1: Synthesis of SDZ-RAD
`
`~I
`
`0
`
`HC~o
`3
`
`,CH3
`0
`
`,,
`
`7'
`CH3
`
`0
`
`CH3
`
`(I)
`
`F
`H3C CH3
`\ I
`1_,..F
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`..,.x;..._F
`8
`H C,..I
`O
`,:. ~
`3 CH3
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`
`{II)
`
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`
`Hc~
`3
`
`,,
`
`,CH3
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`7'
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`
`0
`
`CH3
`
`(Ill)
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`
`West-Ward Exhibit 1017
`Sorbera 1999
`Page 002
`
`

`

`24
`
`SDZ-RAD
`
`demonstrated after parenteral administration of the agent,
`difficulties have been encountered in the search for an
`effective oral formulation with good bioavailability and
`predictability (16-18). American Home Products is plan(cid:173)
`ning to submit an NDA for sirolimus as a treatment for
`immune-related anemia, using NanoCrystal technology
`from NanoSystems for delivery (19).
`During the last years, intensive research efforts have
`focused on the design of new rapamycin analogs.
`According to the Preus Science Ensemble database,
`Abbott, American Home Products, Merck & Co., Novartis,
`Pfizer and SmithKline Beecham have been involved in
`the search for this type of compounds (Table I). SDZ-RAD
`is one such rapamycin analog that maintains the immune(cid:173)
`suppressive activity and pharmacological properties of
`rapamycin. SDZ-RAD has been selected for further
`development for combination use with cyclosporine to
`prevent acute and chronic rejection following solid organ
`allotransplantation.
`
`Pharmacological Actions
`
`SDZ-RAD was shown to have a differential mode of
`action as compared to cyclosporine A and FK-506 in that
`it inhibited growth factor-stimulated proliferation of a lym(cid:173)
`phoid cell line and VSMC. When compared to rapamycin
`in vitro, results showed that SDZ-RAD inhibition of IL-6-
`stimulated proliferation of a IL-6-dependent hybridoma
`clone (B 12-29-15) was 2- to 3-fold less than that of
`rapamycin, with IC50 values of 0.2-1.4 nM and 0.07-0.5
`nM, respectively. However,
`inhibition of proliferation of
`fetal calf serum (FCS)-induced proliferation of VSMC was
`similar for both agents (IC50 = 0.4-3.6 nM). Similarly, the
`suppressive activity of SDZ-RAD was 2- to 5-fold lower
`than rapamycin in the two-way mixed lymphocyte reac(cid:173)
`tion using mouse spleen cells (BALB/c-CBA strain combi(cid:173)
`nation) (IC50 = 0.2-1.6 nM and 0.06-0.9 nM, respectively)
`and in studies using CD4-positive (helper type) human T
`cell clones specific for hemagglutinin peptide 307-319
`derived from peripheral blood mononuclear cells (PBMC)
`from a healthy volunteer (IC50 = 0.05-0.17 nM and 0.014-
`0.037 nM, respectively) (20). In addition, synergistic activ(cid:173)
`ity was demonstrated between SDZ-RAD and
`cyclosporine following isobologram analysis of results
`from in vitro experiments using the same two-way mixed
`mouse lymphocyte reaction; results indicated an absolute
`index of synergy ranging between 0.3 and 0.7, while IC70
`values of 21 and 0.3 nM were obtained for cyclosporine
`alone and SDZ-RAD alone, respectively (21 ). Synergism
`of SDZ-RAD (1 O nM) and cyclosporine A (100 ng/ml) was
`also demonstrated using T cells derived from human
`healthy volunteers. While SDZ-RAD (0.1-100 nM) alone
`dose-dependently decreased anti-CD3-driven T cell pro(cid:173)
`liferation, combination treatment produced an additive
`effect (22).
`The effects of SDZ-RAD on T cell proliferation were
`investigated using 9 human renal allograft recipients with
`stable graft function as PBMC donors. Patients receiving
`
`Table I: Recent patent literature on rapamycin analogs (from
`Prous Science Ensemble database).
`us 5373014
`Abbott
`us 5378836
`WO 9425022
`WO 9514023
`WO 9514696
`WO 9514697
`American Home Products
`us 5385910
`EP 475577
`WO 9518133
`EP 470804
`us 5023264
`WO 9504738
`us 5391730
`EP 467606
`us 5100883
`WO 9534565
`us 5525610
`EP 512754
`WO 9616967
`EP 549727
`EP 515140
`WO 9617845
`EP 509795
`WO 9809970
`EP 516347
`WO 9809972
`us 5120727
`Merck & Co.
`EP 507556
`us 5258389
`us 5138051
`us 5310903
`us 5151413
`Novartis
`EP 514144
`WO 9409010
`WO 9305046
`us 5169851
`WO 9516691
`WO 9641807
`WO 9318043
`us 5194447
`Pfizer
`WO 9310122
`WO 9221341
`WO 9323422
`WO 9606847
`us 5233036
`SmithKline Beecham
`US 5260299
`WO 9214737
`WO 9404540
`WO 9311130
`WO 9411380
`WO 9402136
`WO 9410176
`WO 9402137
`EP 589703
`WO 9402485
`EP 593227
`WO 9410843
`US 5302600
`WO 9418206
`US 5344833
`WO 9418208
`WO 9528406
`WO 9522972
`WO 9425072
`WO 9504060
`WO 9425468
`a combination of cyclosporine (trough levels of 100-150
`ng/ml), methylprednisolone (< 12 mg/day) were adminis-
`
`tered SDZ-RAD (0.75, 2.5, 7.5 or 17.5 mg) or a placebo
`and blood was extracted at 0, 2, 6 and 10 h after treat(cid:173)
`ment. Results showed that T cell proliferation was signifi(cid:173)
`cantly decreased 2 and 6 h after SDZ-RAD administration
`with activity returning to normal after 10 h; a trend toward
`dose-dependent inhibition was observed although results
`were not statistically significant due to small sample size.
`No changes in T cell activity were observed in patients
`receiving the placebo (22).
`In contrast to in vitro results, SDZ-RAD was found to
`be as effective as an immunosuppressant as rapamycin
`in vivo when administered orally in several rat allograft
`models including localized graft-versus-host reaction,
`autoimmune glomerulonephritis induced by mercuric
`chloride and orthotopic kidney or heart allotransplanta(cid:173)
`tion; effective doses ranged from 1-5 mg/kg/day (20).
`Furthermore, the synergistic action of microemulsions of
`SDZ-RAD and cyclosporine was demonstrated in vivo in
`rats in which orthotopic kidney or heterotopic heart allo(cid:173)
`transplantation were performed. While the minimal effec(cid:173)
`tive oral dose for long-term allograft survival was 5
`mg/kg/day for cyclosporine and ~ 5 mg/kg/day for SDZ-
`
`West-Ward Exhibit 1017
`Sorbera 1999
`Page 003
`
`

`

`Drugs Fut 1999, 24(1)
`
`25
`
`RAD in the kidney and heart transplantations, respective(cid:173)
`ly, combination therapy reduced effective doses to 1-2
`mg/kg/day and 0.5-2.0 mg/kg/day for cyclosporine and
`SDZ-RAD, respectively (21).
`SDZ-RAD (2.5 mg/kg/day by gavage) was also shown
`to be effective in the rat model of transplant arteriosclero(cid:173)
`sis in which rats were orthotopically transplanted with
`abdominal aortas exposed to 1, 4, 16 or 24 h of cold
`ischemia (4 °C); aortas were retrieved and analyzed after
`2 months. The development of chronic rejection as indi(cid:173)
`cated by intimal thickening, which increased with
`increased ischemic exposure, was significantly reduced
`in SDZ-RAD-treated animals (23, 24). Cyclosporine (12
`mg/kg/day by gavage) administered alone was ineffective
`in reducing development of chronic rejection due to
`ischemic damage in similar experiments (25).
`SDZ-RAD (2.5 mg/kg/day) and cyclosporine (5
`mg/kg/day) administered independently for 60 days were
`both shown to significantly decrease the severity and
`incidence of transplant coronary artery disease in the
`genetically obese Zucker rat heart transplant model as
`compared to control rats. Results suggested that combi(cid:173)
`nation therapy may result in complete inhibition of trans(cid:173)
`plant coronary artery disease in this model (26).
`Studies have also demonstrated that combination
`therapy with cyclosporine (1.5 mg/kg/day s.c.) and SDZ(cid:173)
`RAD (0.5 mg/kg/day p.o.) was effective in reducing chron(cid:173)
`ic kidney allograft rejection in rats 16 weeks after ortho(cid:173)
`topical transplantation (27). Moreover, rat lung allograft
`rejection indicated by opacification was further reduced
`significantly with combination therapy of cyclosporine (2.5
`or 7.5 mg/kg by gavage) and SDZ-RAD (2.5 mg/kg by
`gavage) as compared to transplanted animals receiving
`monotherapy with either of the agents (28).
`SDZ-RAD (1.5 mg/kg p.o.) in combination with
`methylprednisolone (20 g p.o.) and cyclosporine (10
`mg/kg p.o.) administered for 3 months was also shown to
`be effective in the porcine heterotopic bronchial allograft
`model. Luminal obstruction and complete epithelial recov(cid:173)
`ery was observed in treated pigs transplanted subcuta(cid:173)
`neously with segments of terminal bronchi (29).
`The efficacy of SDZ-RAD was also demonstrated in
`cynomolgus monkeys transplanted with lung or orthotopic
`kidney. In a dose-finding study in which contralaterally
`nephrectomized monkeys received orthotopic kidney allo(cid:173)
`transplants, SDZ-RAD (0.75, 1.5, 10 or 2.5 mg/kg/day
`p.o.) alone was found to be well tolerated and significant(cid:173)
`ly prolonged life; longer survival was observed when
`SDZ-RAD was administered together with cyclosporine
`(10 mg/kg p.o.) (30). Moreover, rejection was completely
`prevented by combination administration of SDZ-RAD
`(0.3 mg/kg) and cyclosporine (150 mg/kg/days 1-7, 100
`mg/kg/days 8-28) in animals with lung transplants; rejec(cid:173)
`tion continued in animals receiving monotherapy with
`either agent (31 ).
`
`Pharmacokinetics and Metabolism
`
`Pharmacokinetic studies using the rat model have
`reported similar ALIC values after oral administration of
`SDZ-RAD (435, 1468, 6076 ng/h/ml) and rapamycin
`(228, 1104, 4071 ng/h/ml) with doses of 1.5, 5 and 15
`mg/kg/day, respectively, for 28 days. The higher values
`obtained with SDZ-RAD were suggested to be due to
`increased bioavailability of the agent. In addition, there
`was no evidence of hydroxyethyl side chain cleavage of
`SDZ-RAD that would result in conversion to rapamycin
`(20).
`Studies in which absorption was examined using
`human intestinal cell line (Caco-2) monolayers and an in
`situ single-pass rat perfusion model have demonstrated a
`20-fold greater basolateral to apical transport of low µM
`concentrations of SDZ-RAD. Passive permeability for
`SDZ-RAD was found to be half that of rapamycin in both
`models (200 vs. 100 nm/sec in monolayers and 248 vs.
`126 nm/sec in the rat model) (32).
`Absorption and bioavailability of SDZ-RAD was also
`demonstrated in an intestinal first-pass metabolism study
`using rat jejunum. Following administration of 150 µg and
`1.5 mg SDZ-RAD to rats, 50 and 30% of the parent com(cid:173)
`pound, respectively, was concluded to be metabolized in
`the intestinal mucosa. Similar results were obtained with
`150 µg rapamycin, although the higher dose of 1.5 mg
`resulted in only 1-14% of rapamycin metabolized by the
`intestine. In addition, systemic clearances of 6.2 and 3.0
`ml/min were observed after intravenous administration of
`1 mg/kg SDZ-RAD and rapamycin, respectively. ALIC val(cid:173)
`ues for oral absorption of 1.5 mg/kg SDZ-RAD and
`rapamycin were 458 and 320 ng/ml/h, respectively, and
`oral absorption was determined to be 40% for SDZ-RAD
`as compared to 14% for rapamycin. Absolute bioavail(cid:173)
`ability was calculated to be 11 and 6%, respectively (33).
`Biotransformation studies using liquid chromatogra(cid:173)
`phy coupled with mass-spectroscopic analysis of buffer
`samples from human liver microsomes incubated with
`[3H]-SD2-RAD (1, 10 and 20 µM) for 30 min revealed that
`the major metabolites of SDZ-RAD result from single
`hydroxylation and demethylation pathways. No conver(cid:173)
`sion of SDZ-RAD to rapamycin was detected and 39-0-
`demethyl-RAD was identified as a metabolite (34). Other
`studies have identified 34-hydroxy-RAD, 34-hydroxy(cid:173)
`RAD-dehydrate and 16-0-demethyl-RAD as metabolites
`of SDZ-RAD (35).
`The pharmacokinetics of SDZ-RAD were examined in
`a randomized, double-blind, crossover study involving
`patients with and without cystic fibrosis with stable lung
`transplants. Patients received a single oral dose of 0.035
`or 0.1 mg/kg SDZ-RAD followed by a 15 day washout
`period and a subsequent dose on day 16; patients were
`also receiving cyclosporine twice daily for a total daily
`dose of 225-800 mg and prednisone (up to 20 mg/day).
`There was a 3-fold difference in Cmax and ALIC values
`between high and low doses in patients without cystic
`fibrosis as compared to a 2-fold difference observed in
`patients with the disease. Cystic fibrosis patients also
`
`West-Ward Exhibit 1017
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`Page 004
`
`

`

`26
`
`SDZ-RAD
`
`Box 1: Safety and tolerability of single-dose SDZ-RAD in lung transplant recipients (39) [from Prous Science CSLine database].
`
`Box 2: Safety and tolerability of multiple-dose SDZ-RAD in stable renal transplant patients (40) [from Prous Science CSLine database].
`
`exhibited a delay in SDZ-RAD absorption and a reduction
`in systemic exposure. The pharmacokinetics of
`cyclosporine in patients without cystic fibrosis were unaf(cid:173)
`fected by the doses of SDZ-RAD used and SDZ-RAD
`was concluded to be well tolerated (36).
`Similar results were obtained in a double-blind study
`in which patients with stable renal transplants received
`ascending once-daily dosing of SDZ-RAD (0.75, 2.5 and
`7.5 mg p.o.) for 4 weeks; patients were also receiving
`cyclosporine twice daily (trough levels of 150-300 ng/ml).
`The pharmacokinetics of SDZ-RAD were dose propor(cid:173)
`tional with a slight potential for accumulation and steady
`state was achieved after 6-8 days. These results are in
`agreement with the 25 h reported half-life for SDZ-RAD
`(vs. 60 h for rapamycin). Slight reductions in cyclosporine
`Cmax and AUC values were noted in patients administered
`2.5 mg of SDZ-RAD (37).
`
`A method to simultaneously quantify plasma SDZ(cid:173)
`RAD and cyclosporine concentrations has been
`described which involves a combination of a solid-phase
`extraction step with an HPLC system coupled to an elec(cid:173)
`trospray mass spectrometer. The sensitivity of detection
`of each agent was 0.05 µg/1 with a range of recovery of
`84.3-102.3% obtained for SDZ-RAD and 81.7-92.2% for
`cyclosporine. A rate of analysis of 4 samples/min was
`maintained for more than 500 samples (38).
`
`Clinical Studies
`
`SDZ-RAD treatment was determined to be well toler(cid:173)
`ated in a randomized, double-blind trial in which 12 lung
`transplant recipients with and without cystic fibrosis
`
`West-Ward Exhibit 1017
`Sorbera 1999
`Page 005
`
`

`

`Drugs Fut 1999, 24(1)
`
`27
`
`receiving stable twice-daily cyclosporine were adminis(cid:173)
`tered a single dose of SDZ-RAD (0.035 or 0.1 mg/kg p.o.)
`and a subsequent dose 16 days later. Plasma samples
`obtained on days 1-6 and 15-21 were found to have dose
`proportional concentrations of SDZ-RAD. Mild to moder(cid:173)
`ate adverse effects were reported by 42% of the patients,
`with headache being the only side effect experienced by
`more than 1 patient (17%). Anemia, granulocytopenia
`and pneumonia were reported for 1 patient each (8%).
`Although mean creatinine, cholesterol and platelet counts
`were not significantly different from baseline, mean
`triglyceride levels were slightly elevated and leukocytes
`reduced (39) (Box 1 ).
`The safety and tolerability of SDZ-RAD treatment was
`also demonstrated in stable renal transplant patients in a
`28-day, randomized, double-blind, placebo-controlled
`trial. Eight transplant recipients receiving prednisone (5-
`10 mg) and twice-daily cyclosporine (trough concentra(cid:173)
`tion range ot' 150-300 ng/ml) were administered either
`SDZ-RAD (0.75, 2.5 or 7.5 mg/day p.o.) or a placebo for
`4 weeks. All but 1 patient who suffered from pneumonia
`completed the study; this patient was replaced. Serious
`side effects were experienced by 3 patients receiving 7.5
`mg which included pneumonia, multiple herpetic lesions
`and left leg pain. Mild or moderate adverse effects were
`reported in 67, 100 and 100% of patients treated with
`0.75, 2.5 and 7.5 mg SDZ-RAD, respectively. No differ(cid:173)
`ences in leukocyte and platelet counts were observed
`between drug-treated and placebo-treated patients.
`Dose-concentration linearity was observed in treated
`patients. It was concluded that longer term studies are
`necessary to evaluate the effect of SDZ-RAD on lipid pro(cid:173)
`files (40) (Box 2).
`SDZ-RAD is currently in advanced phase 11/111 clinical
`trials (41 ).
`
`Manufacturer
`
`Novartis AG (CH).
`
`References
`
`1. Cottens, S., Sedrani, R. (Sandoz-Refindungen VmbH;
`Sandoz-Patent GmbH; Sandoz Ltd.). 0-Alkylated rapamycin
`derivatives and their use, particularly as immunosuppressants.
`EP 663916, EP 867438, JP 96502266, US 5665772, WO
`9409010.
`2. Caine, R.Y., Collier, D.S., Lim, S. et al. Rapamycin for
`immunosuppression in organ allografting. Lancet 1989, 2: 227.
`3. Morris, R.E., Meiser, B.M. Identification of a new pharmaco(cid:173)
`logic action for an old compound. Med Sci Res 1989, 17: 609.
`4. Morris, R.E. Rapamycins: Antifungal, antitumor, antiprolifera(cid:173)
`tive, and immunosuppressive macro/ides. Transplant Rev 1992,
`6: 39.
`5. Sehgal, S.N. Rapamune (sirolimus, rapamycin): An overview
`and mechanism of action. Ther drug Monit 1995, 17: 660.
`
`6. Hatfield, S.M., Mynderse, J.S., Roehm, N.W. Rapamycin and
`FK506 differentially inhibit mast cell cytokine production and
`cytokine-induced proliferation and act as reciprocal antagonists.
`J Pharmacol Exp Ther 1992, 261: 970.
`7. Hultsch, T., Martin, R. Hohman, R.J. The effects of the
`immunophilin ligands rapamycin and FK506 on proliferation of
`mast cells and other hematopoietic cell lines. Mo! Biol Cell 1992,
`3: 981.
`8. Akselband, Y, Harding, M.W., Nelson, P.A. Rapamycin inhibits
`spontaneous and fibroblast growth factor /3-stimulated prolifera(cid:173)
`tion of endothelial cells and fibroblasts. Transplant Proc 1991,
`23: 2833.
`9. Cao, W., Mohacsi, P., Shorthouse, R., Pratt, R., Morris, R.E.
`Effects of rapamycin on growth factor-stimulated vascular
`smooth muscle cell DNA synthesis. Transplantation 1995, 59:
`390.
`10. Hayry, P., lsoniemi, H., Yilmaz, S. et al. Chronic allograft
`rejection. lmmunol Rev 1993, 134: 39.
`11. Gregory, C.R., Huie, P., Billingham, M.E., Morris, R.E.
`Rapamycin inhibits arterial intimal thickening caused by both
`alloimmune and mechanical injury. Transplantation 1993, 55:
`1409.
`12. Gregory, C.R., Huang, X., Pratt, R.E. et al. Treatment with
`rapamycin and mycophenolic acid reduces arterial intimal thick(cid:173)
`ening produced by mechanical injury and allows endothelial
`replacement. Transplantation 1995, 59: 655.
`13. Morris, R.E., Meiser, B.M., Wu, J., Shorthouse, R., Wang, J.
`Use of rapamycin for suppression of alloimmune reactions in
`vivo: Schedule dependence, tolerance induction synergy with
`cyclosporine and FK506, and effect on host-versus-graft and
`graft-versus-host reactions. Transplant Proc 1991, 23: 521.
`14. Tu, Y., Stepkowsky, S.M., Chou, T.-C., Kahan, B.D. The syn(cid:173)
`ergistic effects of cyclosporine, sirolimus, and brequinar on heart
`allograft survival in mice. Transplantation 1995, 59: 177.
`15. Martin, D.F., DeBarge, LR., Nussenblatt, R.B., Chan, C.C.,
`Roberge, F.G. Synergistic effect of rapamycin and cyclosporine
`A in the treatment of experimental autoimmune uveoretinitis. J
`lmmunol 1995, 154: 922.
`16. Granger, D.K., Cromwell, J.W., Chen, S.C. et al. Prolongation
`of renal allograft survival in a large animal model by oral
`rapamycin monotherapy. Transplantation 1995, 59: 183.
`:17. DiJoseph, J.F., Fluhler, E., Armstrong, J., Sharr, M. Sehgal,
`S.N. Therapeutic blood levels of sirolimus (rapamycin) in the
`allografted rat. Transplantation 1996, 62: 1109.
`18. Kahan, B.D. Murgia, M.G., Slaton, J., Napoli, K. Potential
`applications of therapeutic drug monitoring of sirolimus immuno(cid:173)
`suppression in clinical renal transplantation. Ther Drug Monit
`1995, 17: 672.
`19. Elan updates nicotine patch studies and its late-stage devel(cid:173)
`opment pipeline. Prous Science Daily Essentials Dec 7, 1998.
`20. Schuler, W., Sedrani, R., Cottens, S., Haberlln, B., Schulz,
`M., Schuurman, H.-J., Zenke, G., Zerwes, H.-G., Schreier, M.H.
`SDZ RAD, a new rapamycin derivative. Pharmacological proper(cid:173)
`ties in vitro and in vivo. Transplantation 1997, 64: 36-42.
`21. Schuurman, H.-J., Cottens, S., Fuchs, S., Joergensen, J.,
`Meerloo, T., Sedrani, R., Tanner, M., Zenke, G., Schuler, w. SDZ
`RAD, a new rapamycin derivative. Synergism with cyclosporine.
`Transplantation 1997, 64: 32-5.
`
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`Sorbera 1999
`Page 006
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`

`28
`
`SDZ-RAD
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`30. Schuurman, H.-J., Schuler, W., Ringers, J., Jonker, M. The
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`33. Crowe, A., Bruelisauer, A., Duerr, L., Guntz, P., Lemaire, M.
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`34. Dannecker, R., Vickers, A.E.M., Ubeaud, G., Hauck, C. In
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`36. Dingemanse, S.A., Wong, R., Dou, L., Smith, T., Newmark,
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`
`37. Dingemanse, S.A., Wong, R., Dou, L., Smith, T., Wilkie, M.,
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`38. Vidal, C., Kirchner, G.I., Wunsch, G., Sewing, K.-F.
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`39. Doyle, R., Wong, R., Newmark, R., Dingemanse, A., Lin, T.,
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`Additional References
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`Appel., S., Paradis, K., Korn, A., Jean, C., Winkler, M., Kliem, V.,
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`Sci Sess Bus Meet Amer Soc Transplant Physicians (May 10-14,
`Chicago) 1997, Abst 359.
`Cole, O.J., Stubington, S.R., Shehata, M., Rigg, K.M. The effect
`of different immunosuppressants on the development of chronic
`rejection in the rat aortic model. 3rd Int Con! New Trends Clin
`Exp lmmunosuppr (Feb 12-15, Geneva) 1998, 19.
`Viklicky, 0., Zhou, H., MOiier, V., Szab6, A., Heemann, U. SDZ
`RAD prevents early manifestation of chronic rejection in rat renal
`allografts. Nephrol Dial Transplant 1998, 13(6): A255.
`Kirchner, G.I., Vidal, C., Mueller, L., Winkler, M., Sewing, K.-F.
`Hepatic metabolism of concomitantly administered cyclosporin
`and SDZ RAD [40-0-(2-hydroxy-ethyl)rapamycin] can be ana(cid:173)
`lyzed by automated online extraction combined with LC/ES I-MS.
`Gastroenterology 1998, 114(4, Part 2): Abst L0319.
`Kirchner, G.I., Vidal, C., Sewing, K.-F. Hepatic metabolism of
`SDZ RAD: Structural identification of three metabolites.
`Gastroenterology 1998, 114(4, Part 2): Abst L0320.
`Hausen, B., lkonen, T., Brilla, N., Berry, G.J., Christians, U.,
`Robbins, R.C., Sherwood, S., Schuler, W., Morris, R.E.
`Successful suppression of lung allograft rejection in non-human
`primates by combined treatment using the new rapamycin deriv(cid:173)
`ative, SDZ RAD, plus microemulsion cyclosporine. J Heart Lung
`Transplant 1998, 17(1 ): Abst 1.
`Salminen, U.S., Maasilta, P.K., Taskinen, E.I., Alho, H.S., lkonen,
`T.S., Harjula, A.L.J. Effect of immunosuppression on develop(cid:173)
`ment of obliterative lesions in a porcine heterotopic bronchial
`allograft model. J Heart Lung Transplant 1998, 17(1 ): Abs! 129.
`Hausen, B., Boeke, K., Berry, G.J., Christians, U., Morris, R.E.
`SDZ RAD, a new rapamycin analogue, effectively suppresses rat
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`.
`Hausen, B., Boeke, K., Berry, G.J., Christians, U., Segarra, I.,
`Benet, L.Z., Morris, R.E. Coadministration of Neoral and the
`novel rapamycin analog, SDZ RAD, to lung allograft recipients:
`
`West-Ward Exhibit 1017
`Sorbera 1999
`Page 007
`
`

`

`Drugs Fut 1999, 24(1)
`
`29
`
`Potentiation of immunosuppressive efficacy and reduction of tox(cid:173)
`icity by staggered vs. simultaneous treatment. Transplantation
`1998, 65(8, Suppl.): Abs! 518.
`Hausen, B., lkonen, T., Berry, G.J., Christians, U., Robbins, R.C.,
`Hook, L., Benet, L.Z., Schuler, W., Morris, R.E. Coadministered
`Neoral and the new rapamycin derivative, SDZ RAD, for nonhu(cid:173)
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`based trials to maximize efficacy and tolerability. Transplantation
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`
`Dingemanse, S.A., Wong, R., Carter, C., Kahan, B. Multiple-dose
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`1644.
`
`Dingemanse, S.A., Wong, R., Doyle, R., Brazelton, T., Morris, R.
`First pharmacokinetic study with SDZ RAD in lung transplanta(cid:173)
`tion. 17th World Cong Transplant Soc (July 12-17, Montreal)
`1998, Abs! 1645.
`
`West-Ward Exhibit 1017
`Sorbera 1999
`Page 008
`
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