Biotechnologie et société (5) - Jean-Paul Clozel (2006-2007)

Thank you, Jean-Paul. It is a real pleasure to be here and to present to this large audience the truly fascinating aspects of our work in biotechnology, in drug discovery of innovative medicines, and the fundamental role of this ongoing partnership between the university and the biotechnology, biopharmaceutical, or pharmaceutical company. Drug discovery... and actually my talk applies equally to research in innovative materials, biomaterials, vaccine research, and technical applications. But what is really important is that at all stages, from the idea that will lead to research towards a therapeutic application, through preclinical and clinical development, and up to clinical development and then market launch, the role of the university and the role of contact and interaction between universities and companies is fundamental. It is a bit like a rugby match where the team will pass the ball from one to another within the same team.

At the beginning of a drug, there is a starting point: a new idea that will be a hypothesis. Since at the beginning of innovative drug research, very often we are addressing a new target, a new molecular target. Sometimes it is about the demonstration of a new application of a system that existed before; sometimes it will be about a new concept, a new therapeutic tool. But each time, the pharmaceutical company must take the risk of saying: let's take this concept and try to make a drug out of it. The end goal is the fascinating one of trying to bring something new for the benefit of patients, particularly in diseases with significant therapeutic needs. But what we can hypothesize is that if we are talking about an idea that is, for example, a new molecular target, the probability is high that if the hypothesis is correct and we manage to find a molecule that actually targets, probably inhibits, this innovative approach, the drug will have a concept, will have effects and a profile different from what existed before, and will probably bring something superior, a true therapeutic advance. What is fundamental is that, as Jean-Paul Boulade-Site presented earlier in one of his talks, the origin almost always comes from the university, and I would like to illustrate this with examples.

When the starting point is a new molecular target, this is an approach we take at Actelion and Lyon very often. It involves a system described in a seminal publication, and the examples are numerous. It could be a new protein; endothelin was described in 1988 in a Nature paper. We will come back to the story of endothelin later, because I would like to give you two examples of the discovery and development of the first endothelin antagonists. But that was the starting point: a paper. And this paper suggested the existence of a new protein with a probably very important detrimental role in cardiovascular diseases. It could also be about a new system discovered, for example, something that is being done a lot at the moment: searching for the natural ligand of receptors, particularly G protein-coupled receptors that were discovered by the human genome but whose natural ligand is not yet known. So, university groups, generally, sometimes with financial support from pharmaceutical companies, try to aid research into understanding these systems. But there have been numerous examples of receptors that were called orphan receptors and which for a period had no known partner ligand, and university groups, particularly for the discovery of orexin and the orexin system, sought to understand what the ligand was, using tissue extracts, using small fractions of proteins, and went forward until they understood what the ligand present in the human organism was that would stimulate these previously orphan receptors.

It could also be the beginning of an idea for discovering a drug, the notion of a new system of attack, a new level of attack for a known therapeutic principle. And here too, the role of the university is fundamental in the long history of blockers of the renin-angiotensin system. And if we have in the room particularly fundamental experts in the discovery of the different aspects of these systems, in the renin-angiotensin system, the first drugs that resulted from this understanding were the angiotensin-converting enzyme inhibitors and the angiotensin II receptor blockers. But academics since Goldblatt, since Page, about 50 years ago, suggested that the preferential level of attack to prevent the formation of angiotensin II was to block renin, renin being the principal enzyme that allows the formation of angiotensin II from angiotensinogen. Renin is released by only a few cells in the kidney, the juxtaglomerular cells, an extremely regulated system. It is a rate-limiting enzyme in the formation of angiotensin II, so a fundamental role. And this university work, as well as all the tools that resulted from it, played a fundamental role in the first market introduction of a renin antagonist, a renin inhibitor, and the work we have been doing for years to try to find orally active molecules with very good bioavailability that block the system, probably better than an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker could.

It could also be about the description of a new role for a receptor, a system, or an enzyme that was already known before. We will come back later to the case of orexin, which was initially described as a protein playing a role in the regulation of appetite and which, a year and a half later, became a product described by the university as playing a fundamental role in the equilibrium between wakefulness and sleep. It could also involve drugs already on the market, like beta blockers, which were initially prescribed for arterial hypertension and which clinicians and researchers later realized played a probably important role, and indeed they are now also on the market for heart failure, a disease with also a very fundamental therapeutic need. University research thus allows us to take over from the first drugs and the first indication and continue to find new applications for known therapeutic principles. Thalidomide, which is sadly famous because in the 1950s and 1960s it caused teratogenic problems and 12,000 to 15,000 dramatic newborn cases, was initially prescribed as a sedative medication. But the high number of abnormal pregnancies was due to the fact that it was found to work as an antiemetic, so the initial indication was to prevent vomiting in the first trimester of pregnancy. Preclinical safety work at that time was very limited, unfortunately. Very quickly, because it was a drug that worked well, it had to be completely withdrawn from the market, I think in the 1960-61 period, following all these teratogenic accidents. But then an Israeli doctor realized that thalidomide actually had very important immunostimulant, antiproliferative, and anti-angiogenic effects, and that in very serious diseases, there could probably be a place for thalidomide, taking of course extreme precautions regarding the teratogenic risk, but these were much more serious diseases. This doctor initially treated a few patients himself with cutaneous manifestations of leprosy, erythema nodosum leprosum, and then pharmaceutical companies, particularly Celgene, took up the idea of developing it for cancers, starting with multiple myeloma, with very, very interesting efficacy. Then rapamycin, which was discovered and initially used and marketed in 1999 as an immunosuppressant, was thought to be a classical immunosuppressant similar to tacrolimus and FK506. But then researchers realized that rapamycin was actually very different from tacrolimus; it marketed like tacrolimus as an immunosuppressant but had other actions by blocking cell growth and multiplication and being an apoptotic agent. So the cancer applications of rapamycin came thanks to the university and were then taken up by Wyeth and Novartis to try to make it, beyond an immunosuppressant, an anticancer drug.

New concepts are sometimes at the origin of the development of very important drugs, and again the idea comes from the university. Take the example of Gleevec, which was initially developed thanks to the ideas and the discovery that chromosome 22 had a too short arm, the Philadelphia chromosome. This was a discovery by researchers in Philadelphia that chromosome 22 is abnormal in chronic myeloid leukemia. Then researchers realized that this deletion and translocation onto another chromosome was linked to an abnormality of a fusion protein, BCR-ABL, which actually plays a role in chronically stimulating tyrosine kinase. So the idea of applying Gleevec first in chronic myeloid leukemia and then in solid tumors like stomach cancer initially came from the university, with researchers, particularly David Baltimore, communicating this information. And pharmaceutical companies, Novartis in particular, then went into the discovery, confirmed later in terms of therapeutic efficacy, of tyrosine kinase inhibitors. New therapeutic tools can also come from university ideas, like small interfering RNA, which destroy RNA transcription; antibodies; antisense, which prevent protein expression.

At the time of drug discovery, at the time of the research project, the interaction between universities and biotech or biopharmaceutical companies is also fundamental. The biopharmaceutical company has the tools to discover from this idea, from this suggestion of a new project. It has all the tools, but very often these tools come from discussions and work from the university. The preparation of small molecule libraries can come from interactions with university chemists. The development of screening tests, enzymes, the ideas for the concept of these tests very often come from interactions between universities and companies, as do the aspects of organic chemistry. And then when we arrive at the first molecules that inhibit, or less often activate, the molecular target we initially determined as playing a probable role in pathologies, we will need to confirm the hypothesis. Does blocking the endothelin system or blocking the orexin system actually have a profile that will allow the discovery of a new drug? This confirmation of the validity of the concept will very often be done in partnership between university and biopharmaceutical companies. It is also about the company accepting, after the first publication on this product, to give this molecule to universities so they can participate and play a complementary role to the biopharmaceutical company, trying to understand what the potential indications are, what the potential problems are with this molecule that hits a new system for the first time.

The choice of indication is fundamental. When we worked on endothelin, endothelin having been described as the most potent vasoconstrictor known, we hypothesized that endothelin probably played a role in diseases associated with vasoconstriction. But we then had to confirm this hypothesis and confirm in which indications associated with vasoconstriction the drug that blocked endothelin receptors would have the best possible applications. The choice of indication is aided by studying the role of the system in patients: measuring plasma concentrations, searching for expression in tissues, this is often in the hands of clinicians and will allow us to know if this system, if the protein, is increased in this pathology. We will ask the question of congruence: do the effects of endothelin — vasoconstriction, cell proliferation, fibrosis — correspond to the disease we want to treat? Which diseases are associated with vasoconstriction, with fibrosis? And then we will observe in animal or cellular models whether the first antagonists we discovered indeed confirm these initial hypotheses and allow us to think we may have a new concept in hand.

At the preclinical development level, there will also be interaction between specialists in pharmacokinetics, toxicology, and chemistry, between specialists at the biopharmaceutical company and the university, in order to arrive at the confirmation after one to one and a half years that the molecule we have selected to take into humans is indeed a molecule that does not pose major drug-drug interaction problems, does not pose exaggerated toxicity problems, or at least we understand how to judge and control them. At the time of clinical development, the interaction is fundamental between pharmaceutical researchers and clinicians. Clinicians in hospitals will play a role both as consultants and as actors: consultants to help define the patient population to be studied in Phase II and Phase III studies to prove that the drug brings a clinical benefit to patients and to perfectly know its profile; and they will be fundamental actors in defining the protocol of the study and in defining the endpoints, what we will define as important to judge, to show at the end of Phase III that the drug brings a fundamental clinical benefit compared to placebo.

I would now like to come to examples, the example of endothelin in particular. In August 1987, a first paper was published by the University of Denver in Colorado. This paper described a new substance that seemed to be produced by bovine endothelial cells and had not been described before. But what this paper described was that this substance caused a very significant vasoconstriction. Based on this paper, a Japanese group and ourselves, at Roche, sought to understand the nature of this factor, which seemed to be a very potent vasoconstrictor product, indeed something new. We started culturing human cells, endothelial cells. As you know, endothelial cells are the innermost layer of the vascular wall, in contact with blood but also in contact with tissue, thus capable of sensing changes in the blood and reflecting them to the entire organism. We realized that human endothelial cells, similar to what was written in the paper for bovine cells, produced an extremely significant vasoconstriction with a very, very long duration of action, more impressive than almost anything known before. Based on this observation, we started trying to purify what would be called human endothelin, but at that time, after the description of the first paper, it was called "endothelium-derived constricting factor." The Japanese group of Masashi Yanagisawa at the University of Tsukuba beat us in the search for the nature, description, and purification of this new factor, endothelin, and published on March 31, 1988, in Nature the structure and the gene of this potent vasoconstrictor, the most potent vasoconstrictor ever described. He actually described the structure of the porcine substance, and we continued to search, but they very quickly then described human endothelin, and we were able to be the first to show that human endothelial cells produced this same substance, endothelin. This university paper, for us at the pharmaceutical company Hoffmann-La Roche, only reinforced our determination to work on this peptide, which seemed to be such a potent vasoconstrictor. We hypothesized that it played a role in cardiovascular or other diseases linked to endothelial dysfunction, which could be explained by the abnormal production of this very potent vasoconstrictor. So, we set out in search of molecules that block its action, and at the same time we tried to understand the other effects of endothelin and what the therapeutic applications could be. Thanks to the discovery of molecules that inhibit and antagonize specifically the endothelin receptors, we were able to show in a Nature paper in 1993 for the first time the revelation of the pathophysiological role of endothelin. And then, thanks to very important chemical work, we were able to describe and study as tools products that blocked either one or the other of the two receptors described by the university, ETA and ETB, and this allowed us to advance greatly in understanding the role of each of the two endothelin receptors. Currently, three of these molecules are either: registered for the treatment of a first disease, pulmonary arterial hypertension, which is the case of bosentan, and now indicated and recommended for the prevention of digital ulcers in patients with systemic sclerosis; or in clinical development in Phase III currently, with tezosentan and clazosentan.

The role of animal experiments to confirm the potential, to judge whether the drug actually has a role in certain diseases before going to humans, is fundamental. Here, we gave bosentan as a research molecule to more than 800 university groups to help us understand the profile of this product, its advantages and disadvantages, in which model it would work and in which model it might not. And here I just wanted to show you an example of the sharing of responsibilities and discoveries that we were able to make at Hoffmann-La Roche and that the university could make. At Hoffmann-La Roche, we showed that endothelin and bosentan might play a role in migraine, particularly in the mechanisms of neurogenic inflammation. In these rat models, bosentan completely prevented neurogenic inflammation, which was one of the hypotheses for the cause of migraine attacks. We also showed the efficacy of bosentan in heart failure, acute renal failure, and in vasospasm following subarachnoid hemorrhage. University groups, for their part, were able to show the efficacy of bosentan, thanks to the provision of this molecule, in chronic pulmonary hypertension, pulmonary fibrosis and other fibrotic processes, and, bottom right, in melanoma, because endothelin and the ETB receptor in particular play a very important role in the physiology and pathology of cutaneous melanocyte cells and in pathology in melanomas. Bosentan was able in vitro, in cellular systems, to inhibit the proliferation of melanocytic cells. All of this guided the choices we were able to make regarding in which indications to develop bosentan. You do not succeed every time; the risk is high since we start from hypotheses. Bosentan did not show efficacy in migraine attacks in a clinical study, suggesting that neurogenic inflammation does not play a fundamental role. On the other hand, it showed very significant efficacy in the treatment of symptoms and prevention of disease progression in pulmonary arterial hypertension, and it is currently being studied in Phase III in idiopathic pulmonary fibrosis and in Phase II in malignant melanoma. Tezosentan is in Phase III for the prevention of pulmonary hypertension after surgery and cardiopulmonary bypass, and clazosentan for the prevention of vasospasm after subarachnoid hemorrhage.

Another small illustration, and I will finish very quickly, is orexin. It was initially described as regulating appetite, and it interested us as a project because it was produced by only about a thousand cells in the human brain, in the lateral hypothalamus. We started working on this system, but it was the university that showed, a year and a half after the first description, that orexin was actually a wakefulness hormone, a wakefulness peptide. We were then able to verify that indeed our first molecules played a role in inducing sleep, with a much more physiological sleep than that allowed by other drugs then available for the treatment of sleep, with an increase not only of non-REM sleep but also, for the first time, of REM sleep. We published this in Nature Medicine, and the product is now in Phase 2, with confirmation of its efficacy in the treatment of primary insomnia. So there you go. The interactions are multiple; partnership is fundamental. It is driven by pragmatism and by the passion to try to discover new drugs. For the university, I believe it is fascinating to know that fundamental discoveries and the discovery of tools may allow industrial applications, and for the industry, it is absolutely fascinating to be able to work in partnership with the university and maintain this spirit of innovative projects of discovery to try to find new drugs. I thank you.