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A Few Memories from the Beginning...

2005; Wolters Kluwer; Volume: 80; Issue: Supplement Linguagem: Inglês

10.1097/01.tp.0000186385.91735.5d

1534-6080

Hans W. Sollinger,

Biomedical Ethics and Regulation

It is a rare event for a clinical investigator to be involved in the development of a drug that ultimately finds a clinical application. In my case, I was fortunate enough to not only be involved in the clinical trials that led to the approval of this drug but also to have the opportunity to take the drug from the animal laboratory and guide it through phase I and II clinical trials. It was our laboratory at the University of Wisconsin that demonstrated mycophenolate mofetil (MMF) to be most effective when combined with a calcineurin inhibitor and/or prednisone in order to achieve significant prolongation of graft survival. My involvement in research in that compound (RS-61443, which ultimately became known as CellCept®) was more or less by luck. I believe it was Kevin Lafferty who mentioned to Tony C. Allison, then vice president for research at Syntex Laboratories, that our laboratory was performing kidney transplantation in dogs. I received a call from Tony in early 1988, and he later followed up with a visit here in Madison. Quite frankly, before that time I did not know too much about him. However, after studying his curriculum vitae, it became obvious that he was a preeminent scientist who had already done landmark work in the fields of malaria and hepatitis B and, in fact, was one of the first investigators to demonstrate the immunosuppressive capacity of cyclosporine. Over the years I had been approached by numerous individuals from various companies with promising new compounds of which none had ever found any use in the clinical arena; therefore, I was rather skeptical about Tony's proposal. We agreed to a $5,000 grant to perform a small series of dog experiments. The initial studies were carried out by Hennie Pienaar, a South African surgeon, and were later taken over by Klaus-Peter Platz, a surgeon from Germany who was responsible for successfully completing this series of dog experiments. In our initial experiments, we attempted to achieve graft prolongation by high-dose monotherapy with MMF 40 mg/kg; however, the animals experienced serious gastrointestinal problems that in the majority of cases necessitated euthanasia. What seemed a positive observation was that on autopsy the transplanted kidneys appeared normal and did not show any macroscopic or histological signs of rejection. We therefore proceeded and combined RS-61443 with low doses of prednisone and cyclosporine. This approach resulted in significant graft prolongation beyond 150 days in 50% of the dogs (1). Investigators who understand how difficult the canine model is will appreciate that this indeed represented significant graft prolongation; at this point, I became convinced that the drug might be clinically useful. It is of note that once we had identified the therapeutic dose for dogs at 20 mg/kg, very few other side effects were noted. In our initial manuscript reporting these findings (1), we stated that there was no hepatotoxicity, no nephrotoxicity, little effect on the hematological system, and no neurotoxicity. These predictions have turned out to be true not only in dogs but also in the many thousands of patients in whom MMF has now been used. But for a moment, let me step back in history. Mycophenolic acid (MPA), as Tony alludes to in his article "Mechanisms of Action of Mycophenolate Mofetil in Preventing Acute and Chronic Allograft Rejection" in this supplement, was discovered in 1893 and described in an Italian publication (2). The first time that its immunosuppressive effect was mentioned was in a paper by a Japanese group (3) that primarily was interested in the antibiotic effect of MPA. In the 1970s, the Eli Lilly Company was heavily involved in investigating MPA as therapy for psoriasis. Thomas Matthews, who later joined Syntex as a scientist on the MMF project, had worked with MPA during that time at Lilly and was aware of its immunosuppressive effects. Nevertheless, it seemed that the Lilly management considered the immunosuppressive effects of MPA a deterrent and later, for reasons that are not known in detail, abandoned the development of this drug. I am convinced that Tony, having extensive understanding of the purine salvage pathway, was the only individual who was intellectually prepared to take this drug and force it through preclinical testing since in his understanding and belief the drug represented a rather selective immunosuppressant that could have great benefits in transplantation. Now we know that he was absolutely correct, and in my personal view, despite the earlier mention of immunosuppressive properties of MPA by others, the credit for understanding the potential of this compound clearly must go to him. In addition, as detailed in their paper (4), much of the work describing the mechanisms by which this drug can exert its immunosuppressive effect was done in collaboration with his wife, Elsie Eugui. For me personally, the interaction with Tony and Elsie over many years was a most enjoyable one. I at all times recognized Tony's intellectual contributions and was very much aware that I was the lucky recipient of a gift that I then had the opportunity to push through many preclinical and clinical hurdles until U.S. Food and Drug Administration (FDA) approval in 1995. Needless to say, the road to drug approval was not without problems. First of all, in our initial experiments with monotherapy, the gastrointestinal toxicity was so serious that my former chief, Folkert O. Belzer, urged me to terminate these experiments. I only mention this because he later became one of the greatest advocates of MMF once the drug entered the clinical arena. I do remember having a conversation with Randy Morris at the 1988 Congress of the Transplantation Society in Sydney, Australia. Randy at that time already had completed a rather extensive series of transplants in rats, mostly using the ear-heart technique (5), and indicated to me that his enthusiasm for the drug was not too great. I must admit that at that time I agreed with him, and I wasn't sure that we would continue with our experiments for too long. Randy also indicated to me later that it was difficult to use this drug in monkeys. Besides these technical difficulties, there were, of course, a lot of internal discussions within Syntex, and the decision to go ahead with the development of this drug was by no means a unanimous one. I remember with great amusement that two leaders with vice president titles who were involved in the major decisions about the development of these drugs both had the first name Bob. We jokingly referred to their controversy as "the Battle of the Bobs." Once the dog experiments were completed, we agreed it was time to begin discussions with the FDA. By this time, the team had grown in size, and in particular I remember that Tom Matthews, Bernadette DeArmond, Karen Campbell, and Robert S. Kauffman joined us. The discussions with the FDA were rather straightforward. I pushed for the simplest, clinically most relevant trial, a concept that they seemed to embrace as we had few difficulties getting approval for our phase I study. This study was primarily designed to be as safe as possible for the transplant recipient. Having as a backdrop the already existing experience of Syntex in several hundred patients who had received MMF for rheumatoid arthritis, I felt very comfortable entering the clinical arena. In the first phase I trial, we added to our already existing immunosuppressive regimen ascending doses of MMF (6). The initial problem was to find a collaborating center, for then, and now, I thought relying on the experience of a single center a rather unacceptable way to introduce a drug into the clinical arena. The University of Wisconsin was well known for its work in organ preservation but not for studies in drug development. In my search, the first call was to Gilbert Diethelm, the chair of the Department of Surgery at the University of Alabama at Birmingham (UAB). Gil was not only a highly experienced kidney transplant surgeon but was well known for his straightforward personality. I knew I would get an honest opinion from him regardless of how the drug performed. One of my former fellows, Mark H. Deierhoi, had recently moved to UAB, and Gil appointed him to be the lead investigator for this study. It was a great pleasure for me to see that both centers had identical results, and our first joint publication appeared shortly afterward in Transplantation (6). We also collaborated in a study that demonstrated MMF to reverse an already ongoing rejection episode (7). Based on the positive outcomes of the phase I trial, three large-scale, pivotal trials of MMF in de novo renal allograft recipients were initiated in 1992 (8). Great credit has to go to Bob Kauffman, who was the driving force not only in the study design but in the execution of all the necessary logistics and paperwork, which was a monumental task. The MMF team by that time had grown to more than a dozen individuals, with Rob Dow, Betsey Aden, Karen Campbell, and Bob Kauffman playing key roles. Even while these studies were ongoing, and despite the fact that they were double-blinded, there was already a good indication of significant efficacy. Centers enrolled in the trial experienced a noticeable decline in the use of Orthoclone® OKT3, for the treatment of severe refractory rejections. Although I had this knowledge, I did not share it with anybody since I did not want to introduce bias into the trials or to whomever might ultimately acquire the drug. This was of particular significance because we had heard rumors that Syntex might be bought by a large drug company. One of the reasons there were financial problems at Syntex was that there was a significant delay in the initiation of the clinical trials because of the inability of Syntex to produce enough of the drug. A major management decision not to produce the drug at Ajinomoto cost the program 18 to 24 months on the development of the timeline and might well have been a contributing factor to the sale of Syntex. It is rumored that the chief executive officer of Roche Laboratories, Inc., Fritz Gerber, made the decision to offer more than $5 billion to acquire Syntex (and, particularly, MMF) based on a dream. He knew that if the clinical trial results for CellCept were positive, Syntex would most likely be acquired by Sandoz. I do not recall exactly the time point when the name CellCept was coined, but it was a combination of the words "accept" and "select." "Select" was the name preferred by Syntex management, but that name was unavailable. Jennifer Lorenzen combined the two names, and CellCept was born. Most people at the time wanted the name to be "RS" or "Myco." I also was asked to submit my favorite name, and I still have the letter in my file that indicated that I suggested "Mycofortic" (what an irony). The abbreviation "MMF" was created by Maria Koretz. The debate was whether or not to use "MPM," which would parse with "MPA" and reinforce the similarity between mycophenolic acid and mycophenolate mofetil. However, the decision was made to create a unique abbreviation that would focus on the mofetil difference. The day the CellCept launch plan was introduced to key advisers in the La Jolla Hilton Hotel in California, May 4, 1994, was the day that Roche announced its tender offer to purchase Syntex. Finally, CellCept was launched 100 years after MPA was first identified. In summary, a great story, a great drug, and great people I had the honor and privilege to work with. Nevertheless, despite the multiple advantages that MMF has brought to literally hundreds of thousands of transplant patients, and perhaps in the future to patients with autoimmune diseases, the drug is not perfect. We, the basic and clinical investigators, look forward to further improvements in the development of more highly selective and more potent inhibitors of DNA metabolism that can be utilized to the advantage of our patients. With some comfort, I will predict that work is already on its way to achieving these goals.FIGURE 1.: Original MMF investigator group (Palo Alto, California, 1995). Front row (L-R): Gabriel Danovitch, John Neylan, Hans Sollinger, Mark Deierhoi, Stephen Tomlanovich, Samuel Weinstein. Back row (L-R): Sang Cho, Joshua Miller, Mark Pescovitz, Mark Tortoritis, Ronald Ferguson, Thomas Gonwa, Ernest Hodge.