SATURDAY

November 8

SESSION 3

2:30 – 2:45

RETINOIDS IN DERMATOLOGY: AN INTERESTING PAST AND A BRIGHT FUTURE

Ulf Wiegand

The daily use of retinoids for the treatment of dermatological diseases has been common practice for about 20 years. Prior to the introduction of oral retinoids (e.g. Accutane® and Neotigason®/Soriatane®) treatment of acne and psoriasis posed a difficult challenge for every physician. Both medicines have revolutionized the treatment of skin diseases. I have been privileged to work for nearly two decades as clinical pharmacologist at Roche Headquarters in Switzerland. Before joining Roche my areas of expertise were cardiovascular medicine, blood substitutes and anesthesiology. I was assigned to the team conducting clinical trials with isotretinoin. At that time I had no experience in dermatology and did not realize how interesting this part of medicine is and how fascinating retinoids could be. This presentation tries to summarize very briefly a few aspects of the clinical development of retinoids. I will also highlight how vital and beneficial interactions are between physicians treating patients and those whose goals are to provide them with new, improved and innovative medicines. The closer we work together the better it is for our patients.

Oral isotretinoin (13-cis-retinoic acid, Accutane®) was first tested in 1969 in animals in the Swiss laboratories of Hoffmann - La Roche for its anti-acne activity. Proof of concept trials were conducted in Europe since 1971 with very encouraging results. Daily oral doses of 5 – 20 mg isotretinoin resulted in a clearance of acne in 80% of the patients with severe forms of the disease. The side effects observed were considered moderate compared to the dramatic improvement of the disease.

Animal experiments had documented, however, that isotretinoin is teratogenic in several species. Based on this fact it was considered by scientists at Roche headquarters inconceivable to develop a medicine with teratogenic properties for the treatment of a non-life threatening disease such as acne. Despite the great success of trials in patients the development of isotretinoin was therefore discontinued in 1973. In 1978 Peck and Yoder as well as Strauss published remarkable results on the treatment of cystic acne with isotretinoin. Based on these new data the clinical development of isotretinoin was again initiated. In 1982 the US FDA approved as first Health Authority oral isotretinoin for the treatment of severe recalcitrant cystic acne with prominent warnings about its teratogenicity. Following this, isotretinoin was approved in many other countries, such as Canada in 1983, Australia (1985), and in Europe. The warning for female patients regarding its teratogenicity have been continuously strengthened and improved over the last two decades to assure an appropriate management of the risk for female patients.

Following the initial success thousands of new retinoids were synthesized and tested in several biological models in our laboratories. Two aromatic retinoids, which showed promising results in the mouse papilloma test, were etretinate (Tigason®/Tegison® and acitretin (Neotigason®/Soriatane®) . The first encouraging results in patients with psoriasis were published as early as 1975 by Ott and Bollag. In this study etretinate showed marked activity in severe generalized psoriasis vulgaris. Subsequently patients with other cutaneous disorders such as Darier’s disease, lichen planus and other disorders of keratinisation showed very good response when treated with etretinate. In subsequent trials it was documented that etretinate has an extremely long terminal elimination half-life (more than 150 days). This unusual value was later on explained by the very high lipophilicity of etretinate. The long half-life was specifically critical for the post-therapy contraceptive period of this compound. Etretinate was first approved in Europe starting in the UK in 1981 and subsequently in other countries around the world including Canada in September 1984.

Studies assessing the mechanism of action of etretinate showed that the free acid acitretin and not etretinate is the pharmacologically active molecule. Etretinate has first to be hydrolyzed to acitretin to cause any therapeutic effect. Acitretin also has the advantage of a much shorter half-life of approx. 2 days, which is extremely important for the post-therapy contraceptive period in women of childbearing age. Therefore additional studies were conducted with acitretin and submitted to health authorities around the world. Acitretin was first approved in Europe in 1989 with a post-therapy contraceptive period of 2 months. Later on another unexpected observation was made in psoriasis patients in a clinical trial in Finland. In patients, who consumed larger amounts of alcohol, it was noted that etretinate can be formed from acitretin. This metabolic pathway, which initially was considered impossible, could be confirmed in animals as well as in healthy volunteers. As a consequence the post therapy contraceptive period for acitretin was extended to at least 2 (or 3) years.

Vesanoid® (all-trans retinoic acid) is another important and very interesting retinoid that I accompanied through major parts of its clinical development. Its indication is outside the field of dermatology, since it is used for the treatment of acute promyelocytic leukemia. This molecule and its oncological indication are particularly interesting, since isotretinoin is formed in major concentrations the blood of patients treated with Vesanoid, but it still has no anti-acne effect at all. Vesanoid was approved in Canada in 1995 and subsequently in the US and other countries around the world. This molecule is a very clear proof for the importance of local metabolite concentrations at the receptor site.

Every month I see publications about new pharmacological activities and biochemical effects of retinoids, which one would not have expected at all. I am convinced that the future of retinoids as therapeutic agents will not only be bright in dermatology but most surprisingly also in other areas of medicine e.g. for the treatment of cancer and also for currently more unexpected diseases such as emphysema or renal dysfunction.