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Original article S W I S S M E D W K LY 2 0 0 1 ; 1 3 1 : 2 9 9 3 0 2 w w w . s m w .

c h 299
Peer reviewed article

The controversial early history of cyclosporin

Karl Heuslera, Alfred Pletscherb
Former Director of Pharma International Research and Development, Ciba-Geigy AG, Basel,
Former Director of International Research and Member of General Management,
Hoffmann-LaRoche Inc. Basel, Switzerland

The biological effects of cyclosporin, namely immunosuppression and absence of cytotoxicity, were discovered
in the course of a general screening program in which many scientists at Sandoz were involved. Contrary to
some statements in the literature both Dr J. Borel and Dr H. Sthelin markedly contributed to the discovery and
characterisation of the biological profile of the drug. In its subsequent exploitation Borel played the leading role.
The outstanding clinical importance and the extraordinary commercial success of cyclosporin explain the widespread
interest in the history of its discovery and development. It is also understandable that the recollection of the events
by the individuals involved in the early phases of this history is influenced by subjective impressions and inter-
pretations, which do not always reflect the historical facts. It is the purpose of this report to record and interpret
the facts as accurately and as completely as possible on the basis of the available records.1

The immunosuppressive drug cyclosporin was duction of cyclosporin led to one of the major
discovered in the 1970s in the laboratories of San- breakthroughs in medicine, e.g. in organ trans-
doz in Basel and later successfully marketed by this plantation, so that its history, especially its earlier
firm. Controversial reports about the discovery of part, is of general interest.
the unusual immunosuppressive profile of the drug Our presentation, which concentrates on the
have been published. In the scientific literature, J. discovery and early development phases within
F. Borel generally appears as the principal discov- Sandoz, is based on relevant publications, on in-
erer [110], but H. Sthelin has challenged this spection of internal documents from Sandoz (min-
view on various occasions [11, 12]. The manage- utes of meetings, reports etc. as far as still avail-
ment of Novartis, which as successor to Sandoz able), and patent documents. Finally, as a confir-
distributes cyclosporin, has asked us to re-examine matory element, peers and managers from the for-
the history of the immunosuppressive drug and ex- mer Sandoz company not directly involved in
press our opinion on the role of its principle pro- biological work with the drug were consulted.
ponents. We accepted this task because the intro-

An analysis of the available records

We gratefully ac- Discovery phase fungal metabolite with the desired activity spec-
knowledge the full
cooperation of the In the Sandoz company in Basel a screening trum, which was subsequently abandoned due to
Novartis organisa- system for antibiotics has existed since 1958. In unexpected toxicity in man [11, 14, 15].
tion, which gener- 1966 on the basis of a proposal from Dr A. Cerletti In 1970, on the initiative of Dr K. Saameli, a
ously made the rele-
vant documents
and Dr M. Tschler, an immunology laboratory general screening programme2 in which Sthelins
available to us and led by Dr S. Lazary was established within the Cell group participated came into operation [11]. Later
supported our en- Pharmacology group of Dr H. Sthelin. The aims that year, Dr Jean Borel joined Sandoz and took
deavour in every
possible way.
of this group included the search for an immuno- over the well-equipped immunology laboratory
i.e. a programme in suppressive agent without major cytotoxicity. For from Lazary, who was leaving the company. The
which compounds of this purpose Lazary and Sthelin had developed a haemagglutinin test was included in the various as-
synthetic or natural
mouse test in which immunosuppressive activity says of immunosuppressive activity [1, 11]. In late
origin are routinely
submitted to a bat- (by a haemagglutinin test) and cytostatic activity 1971, a fungal extract (24556) containing cy-
tery of biological (by inhibition of tumor growth) could be measured closporin as its main component was submitted to
tests in order to de- in the same animal after intraperitoneal (ip) ad- the general screening programme. A sample was
tect activities useful
for application in ministration of the test compound [1, 2, 11, 13]. also sent to Sthelins laboratory for testing of po-
medicine. In the late 1960s, this group discovered ovalicin, a tential immunosuppressive and cytostatic activity,
The controversial early history of cyclosporin 300

using the above mentioned methods [1, 11]. The resulting galenical difficulties. Scientists within
test for cytostatic activity was performed in Sthe- Sandoz, including Borel and Sthelin, contributed
lins personal laboratory using mice and a dosage to the solution of this problem. Borel and Sthelin
schedule modified3 earlier by Borel. The haem- even participated as volunteers in a comparative
agglutinin test, however, was performed in Borels study of the influence of various galenical forms on
laboratory using the serum of the same animals the bioavailability of cyclosporin organized by the
[15]. Considerable immunosuppressive activity in medical department of Sandoz [22]. In this context
the absence of major cytostatic activity was the ob- a method for the determination of cyclosporin
served outcome [1, 11, 16]. blood levels to which both Borel and Sthelin con-
Shortly thereafter, a new batch of 24556 was tributed was developed [1, 2, 11].
submitted directly to Borels laboratory by the co- In spite of occasional setbacks, the preclinical
ordinator of the general screening programme. development of cyclosporin was relatively
This time, no effect was seen in the haemagglu- straightforward. It took only four years from the
tinin assay in mice treated ip with the new batch. discovery of the immunological effects to the
It is not clear whether the same or a different green light for clinical testing. This indicates the
galenical form4 as in the first experiment was used interest of the research organisation in the drug,
[17]. A slight immunosuppressive effect was how- even though the sales estimates in 1976 were only
ever seen after oral administration [1]. In view of 25 million Swiss francs for 1989 [23].
the strikingly positive results in the first experi-
ment, research on the immunosuppressive poten- Clinical development
tial of 24556 was continued in spite of the disap- In April 1976 Borel gave a lecture at the spring
pointing findings in the second experiment. meeting of the British Society for Immunology in
London that was of major significance for the clin-
Preclinical development ical development of cyclosporin. This lecture,
In preclinical development pure cyclosporin which was based on the findings of Borel, Feurer,
(27400) was used. It was isolated in the Sandoz Gubler and Sthelin [20, 21], stimulated the inter-
laboratories, its chemical structure was deter- est of many scientists and clinicians, in particular
mined [18] and it was eventually synthesised [19]. the groups of Calne and White in Cambridge,
The biological investigations (general pharma- U.K. [2426] and Allison in London [27]. They
cology, pharmacokinetics, toxicology etc.) were subsequently started transplantation experiments
performed in specialized units of Sandoz. Borel with cyclosporin in animals and, impressed by the
carried the main responsibility for the character- dramatic results, then applied cyclosporin to pa-
isation of the immunological properties of cy- tients with kidney grafts. Additionally, Powles et
closporin. He could, however, base his work on al. carried out investigations with the drug in pa-
methods previously used by Lazary and Sthelin tients undergoing bone marrow transplantation.
[1, 11]. In these experiments, the immunosuppres- The impressive results from these groups were
sive effect of cyclosporin was confirmed in various published in the Lancet in December 1978 [28,
experimental models, including skin and bone 29]. These communications were of great signifi-
marrow transplantation studies in mice [17, 20]. cance for the development of cyclosporin in trans-
The first publications on the biological profile plantation medicine. Parallel to these efforts, ex-
of cyclosporin appeared in 1976, with Borel as the tensive clinical investigations were initiated and
first and Sthelin as the last author [20, 21]. The managed by Sandoz. A description of these efforts
preclinical and clinical research was complicated is, however, beyond the scope of this communica-
by the poor water solubility of cyclosporin and the tion.

The discovery of cyclosporin occurred in the and collaborators (especially Lazary) provided the
course of a general screening programme, which experimental system aimed at detecting an im-
Application of
included a large team of scientists, including mi- munosuppressant agent without major cytotoxic-
24556 on days 0, crobiologists, chemists, biologists, and pharmacol- ity and they also introduced the method (haemag-
1, 2, 3 instead of on ogists. The decision by the research management glutination) that made the discovery possible. Fur-
days 1, 4, 7 after
immunisation (Int.
of Sandoz to include testing for immunosuppres- thermore the first experiments on animals were
Document Sandoz sion in this screening programme was an impor- performed in Sthelins laboratory, and it was in
28.10.1970] tant precondition for the compounds subsequent this laboratory that the clinically important ab-
The publications of
discovery. The detection of the interesting biolog- sence of relevant cytotoxic activity was established.
Borel and Sthelin
[1, 2, 9] indicate two ical profile of cyclosporin (immunosuppression Borels laboratory performed the haemagglutinin
different formula- without cytotoxic activity) occurred in the very test, which demonstrated the immunosuppressive
tions, which is not first experiment carried out in the cell pharmacol- activity of cyclosporin. His modification of the ap-
in accordance with
internal Sandoz ogy group of Sandoz. Both Borel and Sthelin con- plication schedule may also have contributed to the
documents [15]. tributed towards this crucial experiment. Sthelin positive outcome of the experiment. Thus, in our
S W I S S M E D W K LY 2 0 0 1 ; 1 3 1 : 2 9 9 3 0 2 w w w . s m w . c h 301

opinion, based on the available documented evi- and Sthelin [20]. Furthermore, Borel claimed in-
dence, both Borel and Sthelin played instrumen- correctly [32] that he himself had published the
tal roles in the discovery5 of the biological effects first paper mentioning cyclosporin in Immunol-
of cyclosporin, the contribution of Sthelin being ogy in 1976 [33]. In addition, Borel inferred that
at least equally as relevant as that of Borel. How- his persistence was important for the development
ever, as the discovery was made in the course of an of cyclosporin, since according to him, Sandoz had
established screening programme with clearly de- proposed to abandon the further development of
fined aims, earlier inputs from other scientists were the compound [1, 2]. We could find no evidence in
also important. the currently available Sandoz documents to sub-
During the preclinical development, Borel effi- stantiate this claim. In some publications with
ciently provided the necessary data that together Borel as author or co-author, the personal en-
with the results from other units (toxicology, drug gagement and continuous efforts of Borel in the
metabolism, galenics etc.) formed the basis for the research on cyclosporin are repeatedly emphasized
initiation of a clinical trials programme. Borel also whereas the role of others, especially of Sthelin,
established and maintained important contacts to is less apparent [1, 2]. On the other hand, in a table
outside investigators who at an early stage realized in a joint publication of Borel and Sthelin [13],
the importance of the potentially unique contri- Borel is noted as the discoverer of the immuno-
bution of cyclosporin to the development of trans- suppressive effects of the cyclosporin-containing
plantation medicine. The preclinical development extract, 24556. Later publications of Sthelin [11,
phase proceeded rapidly whereby Borel had the 12] are in contrast to this statement. On the whole,
support of his superiors in the research and devel- the presentation of the early history of cyclosporin
opment department. We conclude that a multidis- in the international literature was sometimes un-
ciplinary team of scientists was involved in the pre- balanced and distorted and Borels role overem-
clinical development of cyclosporin. The im- phasized [410].
munological data were mainly provided by Borel
and he also played a leading role in stimulating re-
search on cyclosporin by outside investigators. Correspondence:
The fact that in the scientific literature Borel Dr. Karl Heusler
often appears as the sole or main discoverer of the CH-4052 Basel
immunosuppressant effect of cyclosporin [110] Angensteinerstrasse 30
may be due to various reasons. Thus, Borel pub- E-mail
lished and lectured extensively and he maintained
numerous contacts with outside investigators, es- Prof. Dr. Alfred Pletscher
pecially in the later phases of cyclosporin develop- Am Hang 11
ment in which Sthelin was less involved. Also, in CH-4125 Riehen
some publications [2, 31] Borel did not quote the E-mail
original seminal paper by Borel, Feurer, Gubler

1 Borel JF, Kis ZL, Beveridge T. The history of the discovery and 12 Sthelin HF. Irrefhrung in der Forschung: Beispiel: Sandim-
development of Cyclosporin (Sandimmune). In: Meluzzi VJ, mun. Vortrag in der naturforschenden Gesellschaft Basel,
Adams J, eds. The search for anti-inflammatory drugs. Boston: 27.11.1996.
Birkhuser; 1995;2763. 13 Borel JF, Sthelin H. Cyclosporin A The history and signifi-
2 Borel JF: The history of cyclosporin-A and its significance. In: cance of its discovery. Sandorama 1983/ II:59.
White DJG, Cambridge, eds. Cyclosporin-A. Proceedings of an 14 Lazary S, Sthelin H. Immunosuppressive and specific antimi-
international conference on Cyclosporin-A. Cambridge, Sep- totic effects of Ovalicin. Experientia 1968;24:11713.
tember 1981. Amsterdam, New York, Oxford: Elsevier Bio- 15 Lazary S, Sthelin H. Immunosuppressive effect of a new an-
medical Press; 1982;617. tibiotic: Ovalicin. Antibiotica et Chemotherapeutica 1969;15:
3 Borel JF, Kis ZL. The discovery and development of Cy- 17781.
closporin (Sandimmune). Transplant Proc 1991;23:186774. 16 Int. document Sandoz 29.12.1971.
4 Kolata G. Drug transforms transplant medicine. Science 1983; 17 Int. document Sandoz 20.4.1972.
221:402. 18 Regger A, Kuhn M, Lichti H, Loosli HR, Huguenin R, Qui-
5 Cyclosporin turns five. Random samples. Science 1988;242: querez C, von Wartburg A. Cyclosporin A, ein immunsuppres-
198. siv wirksamer Peptidmetabolit aus Trichoderma polysporum,
6 Bernard J. Cyclosporin. Progress Allergy 1986;38:18. Helv Chim Acta 1976;59:1075.
7 Woodruff M. Cyclosporin A. Proceedings of the International 19 Wenger RM. Total synthesis of Cyclosporin A and Cy-
Neither Borel nor Conference on Cyclosporin A.: Elsevier; 1982;569. closporin H. Two fungal metabolites isolated from the species
Sthelin appear as 8 Alagille D. Jean-Franois Borel: le dcouvreur de la ciclo- Tolypocladium Inflatum GAMS. Helv Chim Acta 1984;67:
inventors on the sporine. Arch Pdiatr 1994;I:2302. 50225.
cyclosporin patents 9 Berde B. The experimental biologist and the medical scientist 20 Borel JF, Feurer C, Gubler HU, Sthelin H. Biological effects
[28]. This, in accor- in the pharmaceutical industry. Progress Drug Res 1980;24: of Cyclosporin A: A new antilymphocytic agent; Agents and Ac-
dance with the legal 83100. tions 1976;6/4:45875 (received 20.1.1976; published July
requirements, is be- 10 Berde B. Biologen und Mediziner in der Forschung der phar- 1976).
cause the patents mazeutischen Industrie. Sandoz Bulletin 1980;54:414. 21 Borel JF, Regger A, Sthelin H. Cyclosporin A. A new anti-
relate to cyclosporin 11 Sthelin HF. The History of cyclosporin A (Sandimmun) re- lymphocytic agent (abstract). Experientia 1976;32:777.
as such. visited: another point of view. Experientia 1996;52:513. 22 Int. document Sandoz 19.4.1977.
The controversial early history of cyclosporin 302

23 Int. document Sandoz 4.8.1976. 29 Powles RL, Barrett AJ, Clink H, Kay HEM, Sloane J, McEl-
24 Calne RY, White DJG, Rolles K, Smith DP, Herbertson BM. wainTJ. Cyclosporin A for the treatment of graft-versus-host
Prolonged survival of pig orthotopic heart grafts treated with disease in man. The Lancet 1978/II:132731.
Cyclosporin A. Lancet 1978/I:1183. 30 Swiss Patent Application 17/11/73, December 6, 1973.Cf. also
25 Calne RY, White DJG. Cyclosporin A A powerful immuno- US Patents 4,117,118 (Sept. 26, 1978) and 4,215,199 (Jul. 29,
suppressant in dogs with renal allographs. IRCS Med Sci 1980).
1977;5:595. 31 Borel JF. Entwicklung und Bedeutung des Cyclosporins
26 Kostakis AJ, White DJG, Calne RY. Prolongation of the rat (Sandimmun). Foundation Dr. Max Cloetta 1984, report No.
heart allograft survival by Cyclosporin A. ICRS Med Sci 12, 31-530.
1977;5:280. 32 Borel JF, Baumann G, Chapman I, Donatsch P, Fahr A, Mueller
27 Green CJ, Allison AC. Extensive prolongation of rabbit kidney EA, Vigouret JM. In vivo pharmacological effects of Cy-
allograft survival after short-term cyclosporin-A treatment. closporin and some analogues. Adv Pharmacol 1996;35:
Lancet 1978/I:11823. 115246.
28 Calne RY, White DJG, Thiru S, Evans DB, McMaster P, Dunn 33 Borel JF: Comparative study of in vitro and in vivo drug
DC, et al. Cyclosporin A in patients receiving renal allografts effects on cell mediated cytotoxicity. Immunology 1976;31:
from cadaver donors. The Lancet 1978/II:1323-1327. 63141(submitted 1.3.1976; published October 1976).
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