RS-61443 (Mycophenolate Mofetil)
`A Multicenter Study for Refractory Kidney Transplant Rejection
`
`HANS W. SOLLINGER, M.D., PH.D.,· FOLKERT O. BELZER, M.D.,· MARK H. DEIERHOI, M.D.,t
`ARNOLD G. DIETHELM, M.D.,t THOMAS A. GONWA, M.D.,:j: ROBERT S. KAUFFMAN, M.D., PH.D.,§
`GORAN B. KLiNTMALM, M.D., PH.D.:j:, SUE V. McDIARMID, M.D.,II JOHN ROBERTS, M.D.,lI
`J. THOMAS ROSENTHAL, M.D.,II and STEPHEN J. TOMLANOVICH, M.D.lI
`
`RS-61443 (mycophenolate mofetil) inhibits a key enzyme fo the
`de novo synthesis of purine nucleotides in T and B lymphocytes.
`The purpose of this study was to evaluate the efficacy of RS-
`61443 in patients with refractory renal allograft rejection. Pa(cid:173)
`tients eligible for the study had previously undergone anti-re(cid:173)
`jection therapy with high-dose steroids or OKT3 monoclonal
`antibody. All rejection episodes were proven by renal biopsy.
`Successful rescue was achieved in 52 (69%) patients. Rescue
`was more successful when patients were entered with a creatinine
`of 4 mg/dL or lower (79%), versus a 52% rescue rate in patients
`entered with a creatinine of 4 mg/dL or above. Major side effects
`were predominantly gastrointestinal, but there was no overt
`nephrotoxicity, hepatotoxicity, or bone marrow suppression. The
`overall infection rate was 40%, with the spectrum of infections
`characteristic for the highly immunocompromised patient. The
`conclude that this pilot study suggests that RS-61443 is effective
`in refractory kidney allograft rejection. Based on this study, pro(cid:173)
`spectively randomized multi-center trails have been planned and
`are in progress.
`
`R S-61443 (MYCOPHENOLATE MOFETIL), a mor(cid:173)
`
`pholinoethyl ester of mycophenolic acid (MPA),
`is a potent, noncompetitive, reversible inhibitor
`of eucariotic inosine monophosphate dehydrogenases.
`Because of the importance of guanosine and deoxygu(cid:173)
`anosine nucleotides in activating phosphoribosil pyro(cid:173)
`phosphate synthesis and ribonucleotide reductase, re(cid:173)
`spectively, it was postulated that depletion of guanosine
`monophosphate (and consequently, guanosine triphos(cid:173)
`phate and guanosine diphosphate) would have antipro(cid:173)
`liferative effects on lymphocytes. Furthermore, because
`lymphocytes rely on de novo purine synthesis, whereas
`
`Presented at the I 12th Annual Meeting of the American Surgical As(cid:173)
`sociation, April 6-8, 1992, Palm Desert, California.
`Address reprint requests to Hans W. Sollinger, M.D., University of
`Wisconsin Hospital, Department of Surgery, H4/780, 600 Highland Av(cid:173)
`enue, Madison, WI 53792.
`Accepted for publication April IS, 1992.
`
`From the University of Wisconsin Hospital, • Madison,
`Wisconsin; the University of Alabama, t Birmingham,
`Alabama; the Baylor University Medical Center,:j: Dallas,
`Texas; Syntex Research,§ Palo Alto, California; the UCLA
`Medical Center, II Los Angeles; and the University of
`California-San Francisco Medical Center, 11
`San Francisco, California
`
`other cell types do not, anti proliferative effects produced
`in this way are more selective for lymphocytes than other
`cell types. RS-61443 synthesized by Dr. Peter Nelson
`(Syntex Corporation, Palo Alto, CA) was found to have
`improved bioavailability as compared with mycophenolic
`acid. In vivo, the drug blocks proliferative responses ofT
`and B lymphocytes I and inhibits antibody formatipn2 and
`the generation of cytotoxic T -cells. 2 In vivo, monotherapy
`with RS-61443 was shown to prolong the survival of heart
`4
`allografts in rats and islet allograft survival in mice.3•
`When combined with low doses of cyclosporine A (5 mgt
`kg) and prednisone (0.1 mg/kg), RS-61443 significantly
`prolonged the survival of renal allografts in mongrel dogs. 5
`The first clinical trials with RS-61443 were conducted
`at the University of Wisconsin-Madison and the Univer(cid:173)
`sity of Alabama-Birmingham.!! The purpose of this study
`was to test the safety and tolerance in patients receiving
`primary cadaver kidneys. RS-61443 in doses from 100
`mg/day orally to 3500 mg/day orally was given to patients
`in combination with cyclosporine and prednisone. Forty(cid:173)
`eight patients were entered with six patients in each dose
`group. RS-61443 was well tolerated in all dose groups,
`with only one adverse event possibly related to the drug.
`There was a statistically significant correlation between
`rejection episodes and dose, patients with rejection epi(cid:173)
`sodes versus dose, and number of OKT3/prednisone
`courses versus dose. There was no overt nephrotoxicity
`
`513
`
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`514
`of hepatotoxicity. Although the above-described experi(cid:173)
`ments, as well as the phase I clinical trial, seemed to in(cid:173)
`dicate the potential promise ofRS-61443 in maintenance
`therapy, animal experiments performed by Morris et al. 7
`and our own group8 suggested that the drug might also
`be efficacious for the treatment of acute allograft rejection.
`Morris et al.7 demonstrated complete reversal of histo(cid:173)
`logically established acute heart allograft rejection. The
`investigators delayed the administration of the drug until
`several days after transplantation. At a point when a heavy
`lymphocytic infiltrate was demonstrated in the myocar(cid:173)
`dium in control experiments, initiation of RS-61443
`therapy resulted in a reversal of the rejection process. Platz
`et al. 8 from our laboratory confirmed these experiments
`in a dog renal allograft model. Mongrel dogs receiving a
`renal allograft were treated with low-dose baseline im(cid:173)
`munosuppression consisting ofRS-61443 (10 mg/kg), cy(cid:173)
`closporine (5 mg/kg), and prednisone (0.1 mg/kg). After
`the animals started to reject their grafts as indicated by a
`significant rise in serum creatinine as well as biopsy-con(cid:173)
`firmed histologic diagnosis, anti-rejection therapy was in(cid:173)
`stituted. In one group, animals received a high-dose steroid
`bolus for 3 days, whereas in the other group, a 3-day bolus
`of80 mg/kg ofRS-61443 was administered orally. Steroid
`bolus therapy was only able to temporarily halt the rejec(cid:173)
`tion process, and ultimately, all animals lost their grafts
`within 20 days. In contrast, 14 of 16 dogs treated with a
`3-day RS-61443 bolus had reversal of the rejection process,
`and within 20 days, serum creatinine returned to pre(cid:173)
`rejection levels. These observations provided the stimulus
`to initiate this pilot rescue study.
`
`Materials and Methods
`
`This pilot study was designed as an open-label study
`of RS-61443 as an immunosuppressant for treatment of
`acute refractory cellular allograft rejection. By definition,
`the rejection must have been proven by biopsy and must
`have been refractory to treatment with at least one course
`of ALG/OKT3, whether or not the patient has received
`
`TABLE 1. Patient Characteristics (n = 75)
`
`Type of transplant
`LRD
`LURD
`CAD I
`CA02
`Sex
`Male
`Female
`Age (yr)
`Race
`White
`Black
`Hispanic
`Asian
`Filipino
`
`11 (15%)
`3 (4%)
`50 (66%)
`11 (15%)
`
`45 (60%)
`30 (40%)
`Mean 37 (range 8-68)
`
`41 (55%)
`26 (35%)
`5 (7%)
`2 (2%)
`1 (1%)
`
`SOLLINGER AND OTHERS
`
`Ann. Surg •• October 1992
`
`TABLE 2. Histocompatibility Data
`
`Total Mismatch
`
`PRA Pretransplant
`
`Mean
`
`Range
`
`Mean
`
`Range
`
`LRO
`LNR
`CAO 1
`CA02
`
`3 (50%)
`4.33 (72%)
`3.72 (62%)
`3.5 (58%)
`
`0-6
`3-6
`0-6
`0-6
`
`3
`1
`8.38
`14 .
`
`0-21
`0-3
`0-71
`0-63
`
`high-dose steroids. Also eligible were patients with re-re(cid:173)
`jection who were unable to tolerate further courses of
`OKT3 or ALG. Concomitant treatment with maintenance
`doses of cyclosporine and prednisone were permitted, but
`all other immunosuppressive drugs were prohibited during
`treatment with RS-61443. Dosing with RS-61443 was
`initiated within 48 hours of the kidney biopsy. Patients
`were treated with 1000 to 1500 mg of RS-61443 twice
`a day.
`Exclusion criteria included pregnant women, nursing
`mothers, patients with severe infections requiring anti(cid:173)
`microbial therapy at the time of entry into the study, and
`patients with a white blood count <2000/mm3, platelet
`count <SO,OOO/mm3, or hemoglobin <8 g/dL. Also ex(cid:173)
`cluded were patients with active peptic ulcer disease. Fur(cid:173)
`thermore, patients with severe diarrhea or ileus that might
`interfere with their ability to absorb oral medication were
`excluded.
`Five centers (University of Wisconsin, Madison, WI;
`University of Alabama-Birmingham, Birmingham, AL;
`UCSF Medical Center, San Francisco, CA; UCLA Med(cid:173)
`ical Center, Los Angeles, CA; Baylor University Medical
`Center, Dallas, TX) participated in the study after ap(cid:173)
`proval of the individual institutional review boards was
`obtained.
`Although the induction immunosuppressive protocol
`in the participating institutions differed, there was agree(cid:173)
`ment regarding the desired cyclosporine maintenance
`levels. All institutions attempted to achieve whole blood
`serum levels as monitored by TDX to be between 300
`and SOO ng/mL. First rejection episodes were generally
`treated with intravenous steroid boluses (250 to SOO mg
`IV/day) followed by tapering oral steroid doses. Depend(cid:173)
`ing on the severity of second or subsequent rejection ep(cid:173)
`isodes, repeat steroid boluses were used or OKT3 therapy
`was instituted. In all participating centers, OKT3 was used
`ifre-rejection occurred after completion of the initial ste(cid:173)
`roid regimen or if breakthrough rejection occurred during
`steroid tapering. Furthermore, the decision to use OKT3
`was also based on the severity of rejection determined by
`biopsy.
`A total of75 patients were enrolled between December
`10, 1990 and September 16, 1991. Patient characteristics
`are shown in Table 1. Degree of mismatch as well as pre(cid:173)
`transplant panel reactive antibodies is shown in Table 2.
`
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`
`REFRACTORY KIDNEY TRANSPLANT REJECTION
`
`515
`
`TABLE 3. Treatment of Rejection Before RS-61443 Therapy
`
`TABLE 5. Timing of Rescue
`
`No. of Prednisone
`Courses Prestudy
`
`OKT3/ALG Courses
`Prestudy
`
`Mean
`
`Range
`
`Mean
`
`Range
`
`Creatinine >4.0 mgfdL
`Creatinine s4.0 mgfdL
`
`Successful Rescue
`
`52%
`79%
`
`LRD
`LNR
`CAD 1
`CAD 2
`
`3
`2.33
`2.34
`1.64
`
`1-6
`0-5
`1-9
`0-4
`
`1.64
`1.0
`0.98
`1.1
`
`1-2
`1
`0-2
`1-2
`
`Results
`
`Among the 75 patients enrolled in the study who were
`qualified for entry into the rescue study, all but two had
`received both high-dose steroids and OKT3 before study
`entry. In all cases, a biopsy within 48 hours of initiation
`of RS-61443 rescue therapy demonstrated acute cellular
`rejection. The mean number of high-dose steroid courses,
`as well as OKT3 or ALG courses, is shown in Table 3.
`Successful long-term rescue was achieved in 52 (69%)
`of patients (Table 4). Successful rescue was defined as
`stabilization or improvement of renal function. Follow(cid:173)
`up time of successfully rescued patients now ranges from
`6 to 15 months. The success of rescue therapy was related
`to the quality of renal function at the time of the start of
`RS-61443 therapy. Patients enrolled with a serum creat(cid:173)
`inine of 4.0 mg/dL or less had a rescue rate of 79%,
`whereas patients enrolled with a serum creatinine' of 4
`mg/dL or greater had only a 52% rescue rate (Table 5).
`Successfully rescued patients who have remained on RS-
`61443 demonstrated continued improvement in renal
`function over the entire study period (Table 6).
`A typical post-transplant course for one of the patients
`enrolled in the rescue study is shown in Figure 1. Patient
`CT, after receiving a first cadaver kidney transplant, had
`several rejection episodes treated with multiple steroid
`boluses and two courses ofOKT3. After the second course
`of OKT3, her renal function deteriorated again and RS-
`61443 rescue therapy was initiated. Over a follow-up pe(cid:173)
`riod of 1 year, her serum creatinine has improved to 1.2
`mg/dL, and she had no further rejection episodes. Renal
`biopsy the day before RS-61443 is shown in Figure 2.
`Protocol biopsy on day 28 after RS-61443 was started is
`shown in Figure 3.
`In 19 patients, the drug was discontinued for treatment
`failures. In these patients, allograft rejection could not be
`
`TABLE 4. Successful Long-term Rescue (n = 75)
`
`LRD
`LURD
`CAD 1
`CAD 2
`
`Total
`
`5 (45%)
`3 (100%)
`39 (78%)
`5 (45%)
`
`52 (69.0%)
`
`reversed, and the patients either had to return to dialysis
`or underwent transplant nephrectomy. In 11 patients, RS-
`61443 therapy was discontinued for other reasons than
`treatment failures (Table 7). Reasons that definitely are
`not associated with the use ofRS-61443 include one ure(cid:173)
`teral leak, one death, most likely due to a cardiac event,
`one cancer in the native kidney that was not recognized
`before transplantation, and two cases of recurrent glom(cid:173)
`erulopathy. Reasons for discontinuation probably related
`to the drug were one case of pancreatitis, one case of cy(cid:173)
`tomegalovirus colitis, and two cases of gastrointestinal
`complications.
`Infections during RS-61443 rescue therapy were com(cid:173)
`mon and represent the overall spectrum of infections in
`the highly immunocompromised patient (Table 8). No
`patient died of infectious complications.
`Side effects ofRS-61443 were predominantly gastroin(cid:173)
`testinal complaints (Table 9). Nausea and diarrhea were
`most commonly observed at the initiation of RS-61443,
`and in most instances were self-limiting or responded to
`dose reduction. In several patients, three times a day ad(cid:173)
`ministration was better tolerated than twice-daily admin(cid:173)
`istration. The only severe gastrointestinal side effects oc(cid:173)
`curred in one patient with pancreatitis, and in a second
`patient with hemorrhagic gastritis. In both patients, dis(cid:173)
`continuation of RS-61443 treatment resulted in a reso(cid:173)
`lution of symptoms. Leukopenia was frequently associated
`with cytomegalic virus infection or treatment with gan(cid:173)
`ciclovir. Allison and associates (personal communication)
`have postulated a drug interaction between RS-61443 and
`ganciclovir resulting in leukopenia. Leg pain, weakness,
`and myalgia, interestingly, were only observed' in one par(cid:173)
`ticipating center. Other side effects were nonspecific, and
`were not clearly related to RS-61443. During the study
`period, no evidence of significant nephrotoxicity, hepa(cid:173)
`totoxicity, or bone marrow suppression was observed.
`
`TABLE 6. Mean Creatinine Levels of Study Patients
`
`Creatinine Pre-
`RS-61443
`
`Creatinine Day Creatinine Day
`28
`56
`
`Current
`Creatinine
`
`Mean Range Mean Range Mean Range Mean Range
`
`4.65
`LRD
`LNR
`2.50
`CAD 1 3.74
`CAD 2
`5.35
`
`3.1-8.8
`1.7-3.6
`1.5-9.8
`2.1-11.3
`
`3.10
`2.10
`2.98
`2.50
`
`1.7-5.9
`1.6-2.7
`1.2-5.9
`1.3-4.3
`
`3.10
`2.03
`2.78
`2.78
`
`1.1-4.9
`1.5-2.3
`1.0-7.5
`1.4-5.6
`
`2.62
`1.83
`2.44
`2.22
`
`1.4-3.5
`1.4-2.1
`1.2-5.8
`1.6-2.4
`
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`516
`
`SOLLINGER AND OTHERS
`
`Ann. Surg.' October 1992
`
`PATIENT C.T., F., 36 YRS. 1st CADAVERIC KIDNEY TX., PRA %, CROSS MATCH NEG.
`
`Bx
`
`Bx
`
`Bx
`
`Bx
`
`A5-61443
`
`I
`
`4
`
`3
`
`2
`
`1
`
`I\) c:
`'2
`:;:;
`IV
`I\) ...
`0
`en
`
`OKT31
`MAL6
`
`3000
`
`RS
`
`1000
`
`CsA
`1000
`Steroids
`(J.v.)
`100
`Pred.
`P.O.
`
`8/269/1
`
`10/6
`
`11/13
`
`12/1
`
`FiG. I. Typical course for a patient enrolled in RS·61443 rescue study.
`
`'90
`
`1/5
`
`'91
`
`Discussion
`
`Based on animal experiments from our own laboratory8
`and the report of Morris et al.,7 we felt encouraged to test
`the potential of RS-61443 in reversing acute allograft re(cid:173)
`jection. Because other agents such as high-dose steroids
`and OKT3 are extremely useful in the treatment of acute
`
`allograft rejection, the investigators believed that a pro(cid:173)
`tocol that addresses refractory renal allograft rejection after
`extensive treatment with high-dose steroids and OKT3
`would be the appropriate pilot study to gain some initial
`information about this drug's potency. The study was de(cid:173)
`signed with the intent to use RS-61443 for rescue therapy
`after conventional anti-rejectio~ therapy had failed. With
`
`FIG. 2. Biopsy before initiation of RS·61443 rescue therapy. The inter(cid:173)
`stitium shows moderate to severe infiltration by lymphocytes. Tubules
`show focal injury.
`
`FIG. 3. Biopsy 28 days after initiation ofRS·61443 therapy. The interstitial
`lymphocytic infiltrate is significantly decreased. Mild chronic tubular
`interstitial nephritis remains.
`
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`
`REFRACTORY KIDNEY TRANSPLANT REJECTION
`
`517
`
`TABLE 7. Patients Terminated From Study
`for Nontreatment Failure (n = 11)
`
`Recurrent disease
`Lymphoma
`Pancreatitis
`Death (unknown cause)
`Ureteral leak
`CMV colitis
`GI bleed
`GI side effects
`CA native kidney
`
`2
`2
`I
`I
`I
`1
`1
`1
`1
`
`the exception of two patients in this study, all patients
`had received both high-dose steroid therapy and OKT3.
`Despite the rather advanced state of rejection in some
`patients with serum creatinine levels above 9 mg/dL, we
`were able to reverse rejection in 69% of patients. It was
`also shown that earlier intervention with RS-61443 re(cid:173)
`sulted in a higher rescue rate (79%). Clearly, in some of
`our patients, renal damage was so extensive that even a
`reversal of the immunological event left us with an organ
`beyond repair. Patients undergoing mUltiple rejection ep(cid:173)
`isodes and treatment with mUltiple doses of high-dose ste(cid:173)
`roids and OKT3 represent a group that is highly suscep(cid:173)
`tible to complications of immunosuppressive therapy,
`particularly infections. Therefore, the infection rate of 40%
`in our group is within expectation. Clearly, a high inci(cid:173)
`dence of cytomegalovirus infection, as well as herpes in(cid:173)
`fections, must be expected. It is encouraging, however,
`that none of the patients in this rescue group died from
`the complications of infection.
`Side effects, as expected, were mainly gastrointestinal
`in nature. In most patients, mild nausea, occasional vom(cid:173)
`iting, and diarrhea was observed. These side effects were
`either self-limiting or responded to dose reduction. The
`two most severe gastrointestinal complications included
`pancreatitis and hemorrhagic gastritis. In both cases,
`symptoms resolved after drug discontinuation. Other side
`effects observed were listed for the sake of completeness;
`however, no clear-cut relationship to RS-61443 was dem(cid:173)
`onstrated. This view is' supported by the fact that in more
`than 350 patients receiving RS-61443 for the treatment
`
`TABLE 8. Infections
`
`CMV
`Oral/GI candida
`Herpes zoster
`Herpes simplex'
`C. difficile
`E. coli (systemic)
`Listeria
`Pneumocystis
`Bacterial pneumonia
`
`Overall infection rate
`
`13 (17%)
`7 (9%)
`3 (4%)
`2 (3%)
`1 (1%)
`1 (1%)
`1 (1%)
`1 (1%)
`1 (1%)
`
`30/75 (40%)
`
`TABLE 9. Side Effects
`
`Moderate GI
`Mild 01
`Leukopenia
`Increased liver enzymes
`Skin rash
`Leg pain/bone pain/weakness/myalgias
`Headaches
`Fevers
`Severe 01
`Neutropenia
`Hand/leg cramps
`Leukocytosis
`Thrombocytopenia
`Photosensitivity
`Tremors
`
`17
`13
`8
`5
`5
`5
`3
`3
`2
`2
`2
`1
`1
`1
`1
`
`oftherapy-resistant rheumatoid arthritis, none developed
`infectious complications.
`The most encouraging observation in this study was
`that renal function in patients rescued continued to im(cid:173)
`prove over the observation time. Steele (personal com(cid:173)
`munication) has recently made the observation that RS-
`61443 prevents vasculopathy associated with allograft re(cid:173)
`jection. If these findings can be confirmed in human renal
`allografts, the decrease in arteriopathy would explain the
`continued improvement in creatinine levels. Clearly, one
`criticism of this pilot study is that one cannot be certain
`that in a number of patients, an additional course of high(cid:173)
`dose steroids or OKT3/ALG would not have resulted in
`allograft rejection reversal. Therefore, a prospective ran(cid:173)
`domized study was designed to address this question. This
`study is now in progress in several transplant centers in
`the United States, and will allow us to analyze the effect
`of RS-61443 in this setting with greater precision.
`One of the most exciting aspects of this study as well
`8
`as the previously mentioned experimental observations7
`•
`is the ability of RS-61443 to reverse rejection. From a
`theoretical view, an antimetabolite should not be very
`effective once clonal proliferation has taken place and ac(cid:173)
`tivated effector cells have been generated~ Therefore, a
`second mechanism of action for RS-61443 has to be pos(cid:173)
`tulated. Allison and Eugui (personal communication)
`have recently suggested that RS-61443 downregulates
`expression of adhesion molecules. It was demonstrated
`that MPA-mediated depletion of guanosine triphosphate
`decreases the transfer of mannose and fucose to glyco(cid:173)
`proteins, some of which are adhesion molecule~, facili(cid:173)
`tating the attachment of leukocytes to endothehal cells
`and to target cells. By this mechanism, MPA could de(cid:173)
`crease the recruitment of lymphocytes, monocytes, and
`neutrophils into sites ofinflammation. Muller et al.9 have
`shown that in activated human peripheral blood lympho(cid:173)
`cytes, treatment with MPA significantly decreases the
`transfer of mannose to dolycol phosphate and to mem(cid:173)
`brane glycoprotein. If these findings can be extrapolated
`
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`
`518
`to the in vivo situation, the observed reversal of allograft
`rejection with RS-61443 could be explained by the de(cid:173)
`creased recruitment of activated lymphocytes to the graft
`site.
`
`References
`1. Eugui EM, Mirkovich A, Allison AC. Lymphocyte-selective anti(cid:173)
`proliferative and immunosuppressive effects of my co phenolic acid
`in mice. Scand J Immunol 1991; 33: 175.
`2. Eugui AM, Almquist S, Muller CD, Allison AC. Lymphocyte-se(cid:173)
`lective cytostatic and immunosuppressive effects of my co phenolic
`acid in vitro: role of deoxyguanosine nucleotide depletion. Scand
`J Immunol 1991; 33:161.
`3. Morris RE, Hoyt EG, Murphy MP, et al. Mycophenolic acid mor(cid:173)
`pholinoethy1ester (RS-61443) is a new immunosuppressant that
`prevents and halts heart allograft rejection by selective inhibition
`ofT and B cell purine synthesis. Transplant Proc 1990; 22: 1659.
`
`SOLLINGER AND OTHERS
`
`Ann. Surg .• October 1992
`
`4. Hao L, Lafferty JU, Allison AC, Eugui EM. RS-61443 allows islet
`allografting and specific tolerance induction in adult mice.
`Transplant Proc 1990; 22:876.
`5. Platz KP, Sollinger HW, Hullett DA, et al. RS-61443: a new, potent
`immunosuppressive agent. Transplantation 1991; 51:27.
`6. Sollinger HW, Deierhoi MH, Belzer FO, et aI. RS-61443: a phase I
`clinical trial and pilot rescue study. Transplantation 1992; 53:
`428.
`7. Morris RE, Hoyt""EG, Murphy MP, et al. Mycophenolic acid mor(cid:173)
`pholinoethylester (RS-61443) is a new immunosuppressant that
`prevents and halts heart allograft rejection by selective inhibition
`ofT- and B-cell purine synthesis. Transplant Proc 1990; 22: 1659.
`8. Platz KP, Bechstein WO, Eckhoff DE, et al. RS-61443 reverses acute
`allograft rejection in dogs. Surgery 1991; 110:736.
`9. Muller CD, Kowalski WJ, Eugui EM, Allison AC. Inhibition by
`mycophenolic acid of the transfer of man nose to lymphocytic
`cell membrane glycoproteins and cell adhesion. Eur J Cell Bioi
`1991 (submitted for publication).
`
`DISCUSSION
`
`DR. G. KLINTMALM (Dallas, Texas): Mr. President, members and
`guests: I am not really discussing the paper because I am one of the co(cid:173)
`authors; I am here to give you a little update on where we stand with
`the drug in other organs. The same institutions have a multicenter study
`going for liver transplant rescue.
`At this time we have enrolled 23 patients with acute unresponsive
`liver allograft rejection with the same definition and criteria for entry as
`in the kidney trial. The patients have had previous steroid therapy and
`OKT3 therapy without response. Of those, we have had 21 responses,
`14 of those being complete responses and seven improved. Two failed,
`one of a chronic rejection and one of an acute rejection. One patient
`died of overimmunosuppression, a cytomegalovirus, and Candida in(cid:173)
`fection. In the heart trial that is going on, involving a few other additional
`institutions, nine patients have been treated, and as you see, we have
`seen a response in all nine, complete or partial, and all nine patients are
`retaining the graft.
`Of importance is also to say that the infectious complications have
`been few in the liver group; we have had eight patients with 14 infections.
`Of those 14, only four were of significant nature. And as far as side
`effects, they were the same as reported by Dr. Sollinger, very small indeed.
`For recipients of livers and hearts, we believe this drug is interesting. We
`believe the drug should be explored in further trials, which are planned
`to commence later this year.
`
`DR. CLYDE F. BARKER (Philadelphia, Pennsylvania): The search goes
`on for the ideal immunosuppressive agent. And I do not think we have
`it yet, but I believe that RS-61443 is one of the most promising and most
`exciting. The thoughtfulness with which Dr. Sollinger and his colleagues
`have approached the use of this and the logical sequence of their studies
`is to be commended. We know from his work and from the basic ex(cid:173)
`perimental work of others much more about the mechanism of action
`of RS and about the potential for its use than is the case in many of the
`new agents that have been brought forth with more publicity.
`This paper addresses an additional factor that is very interesting, in
`transplantation biology, and Dr. Sollinger has already mentioned it. He
`has selected a stage in the sequence of post-transplant care at which
`rejection is the very difficult to deal with. Not only has clonal expansion
`occurred and the clinical symptoms of rejection manifested themselves,
`but in fact these have failed to respond to conventional therapy. For an
`immunosuppressive agent, this is the most rigorous test of all. The success
`of RS in this setting is what makes this work particularly exciting.
`With most immunosuppressive agents, as Dr. Sollinger indicated, the
`optimal time to introduce them is at the time of the transplant, or, if
`possible, even before the transplant. Conversely, certain agents have had
`particular success when used at the time of rejection, for example, potent
`
`cytotoxic agents such as anti-lymphocyte serum and the monoclonal
`antibodies directed against lymphocytes. And RS looks as though it may
`share that capability with these agents. One wonders whether RS would
`be even more effective if used earlier in the course of a transplant.
`The results are so good that one wonders, in fact, what the catch is to
`the use of this agent. All immunosuppressive agents have their limitations.
`Therapy was withheld in patients who had serious infection apparently
`because RS shares with all immunosuppressive agents risk in the face of
`infection. I wonder whether the agent is dangerous in the setting of viral
`infections.
`Finally, I would like to know what the bottom line is in terms of the
`eventual outcome of the treatment of these patients. Because this was
`not a controlled series in which other forms of rescue therapy were em(cid:173)
`ployed instead of RS, would those patients in fact have simply had no
`other recourse or would there have been persistence with other forms of
`anti-rejection therapy? In other words, could some of these patients in
`the absence of the availability of RS have been rescued?
`What was the bottom line in terms of the outcome of graft survival
`and patient survival overall at I year? In other words, do you know the
`outcome of the transplant in addition to the outcome of the rescue
`therapy?
`
`DR. DAVID E. R. SUTHERLAND (Minneapolis, Minnesota): Dr. Sol(cid:173)
`linger, what effect does RS-61443 have on rejection of other organs, such
`as the heart, in which chronic rejection is a very serious problem? Also,
`why is RS-61443 better than other drugs that inhibit purine synthesis?
`You alluded to an effect on adhesion molecules as one possible mech(cid:173)
`anism that allows an effect on clones that have already expanded. Are
`there drugs that are specific inhibitors or antagonists of adhesion molecules
`that do not affect purine synthesis? Their use would allow you to test
`the hypothesis, and such agents might even be superior to a drug that
`does affect purine synthesis.
`With regard to the choice of patients to randomize, why wait until
`rejection is refractory? Why not randomize patients at the onset of re(cid:173)
`jection to standard therapy such as OKT-3 versus RS-61443, and then
`see find the incidence of refractory rejection. I also do not see any draw(cid:173)
`backs to using RS-61443 as prophylaxis. You did a pilot trial using the
`drug prophylactically. Why not randomize?
`Finally, Dr. Sollinger alluded to a possible effect on chronic rejection,
`and this is most intriguing. The patients he has treated had their rejection
`episodes at a time where chronic rejection is usually not the dominant
`lesion.
`Why not administer the drug to patients with proven chronic rejection,
`such as patients who have a gradual elevation in creatinine a few years
`after the transplant, and in whom a biopsy shows histologic features
`typical of chronic rejection? Usually we do not treat this condition because
`it is inexorably progressive in spite of everything we have tried. It seems
`
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`REFRACTORY KIDNEY TRANSPLANT REJECTION
`
`that such patients would be perfect to include in a randomized trial
`testing the hypothesis.
`
`DR. HANS WERNER SOLLINGER (Closing discussion): Dr. Klintmalm,
`certainly your experience in liver transplantation is very encouraging,
`.
`and confirms the experience in our center.
`The question of whether the agent should be given at the very beginning
`is very important. Preliminary experience with RS-61443 suggests that
`the drug is most effective when given for the prevention of rejection. In
`a phase I trial with kidneys we did not lose any grafts secondary to
`rejection. Randomized trails are currently under way in at least 10 centers
`in the United States using RS-61443 right from the beginning; the control
`group will receive azathioprine and the treatment group will receive RS-
`61443.
`Also, there is a randomized trial for the treatment of refractory rejection
`and there is a randomized trial for the treatment of first rejection. All of
`these trials are in place, and multiple centers in the United States and
`in Europe are planning to participate.
`Dr. Barker, what is the disadvantage of this drug? Clearly the drug is
`an immunosuppressive agent, but as far as specific side effects are con-
`
`519
`cerned, it is extremely well-tolerated and, to the best of my knowledge,
`with the exception of nausea and diarrhea, we have not seen side effects
`that can be clearly attributed to RS-61443.
`Is there a danger of administering the drug in the setting of a viral
`infection? Of course, the drug is an immunosuppressive agent; and all
`immunosuppressive drugs might suppress antiviral immune responses:
`There was one death in this study. The cause was not known. Overall
`the rescue rate was 70%, but I cannot give you the actuarial I-year graft
`survival at this time.
`Finally, I would like to address the question of chronic rejection. We
`have used the aortic allograft model, which allows the classical signs of
`chronic rejection to be detected as early as 3 to 6 months after trans(cid:173)
`plantation. We could demonstrate that RS-61443 is the only immuno(cid:173)
`suppressive drug tested that could prevent chronic vasculitis.
`What is unique as far as the mechanism of action of RS-61443 is
`concerned? As I pointed out, one possible mechanism is the downre(cid:173)
`gulation of adhesion molecules. One also has to remember that the drug
`interferes with a number of G-protein-mediated signals that are GOP
`dependent, and it is quite likely that we understand only little at this
`moment ho'v this drug really works.
`
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