costs for approval of a single drug can amount to US$ 1.3 billion, with the majority of this budget being consumed by clinical trials. Also the process needs oversight and management by experienced clinical scientists to optimally set up the studies in order to ensure that a potential beneficial outcome will not be a victim of an underpowered study group or that the selection of the patient population was not optimal.
However, when the clinical trial starts, the selection process of the therapeutic moiety is already completed and the decision on target and approach is taken, from that point on it is the task of the clinicians to see if the generated hypothesis will hold true.
However, academics provide important contributions to drug discovery, using their specific strengths. These can be based on curiosity, expert knowledge in specific areas, exploitation of surprising findings, stimulating follow‐up research, and interdisciplinary research resulting from different academic laboratories teaming up, for instance. Different examples of how these specific strengths can lead to successful drug discovery will be discussed throughout this chapter.
1.2 Repurposing Drugs
One contribution ideally suited for academic research is the quest for new indications.
As approved drugs are openly commercially available, researchers, particularly scientists in clinical centers, can – based on patient derived data – generate hypotheses and probe them in a straightforward manner. In this context drug repurposing has attracted a lot of attention as the approach is very straightforward, and the resulting drug has already been demonstrated to be safe, bioavailable, and well tolerated in humans.
Often, this approach is guided by careful observation of disease‐accompanying factors and interpretation of the underlying pathology. In particular, changes of symptoms in patients suffering from more than one disease may provide interesting starting points for developing new hypotheses. An example is rituximab, which first was developed for the treatment of cancer. Its discovery will be discussed in more detail during the course of the chapter. Edwards et al. proposed that self‐perpetuating B‐lymphocytes may play a key role in driving progression of rheumatoid arthritis (RA) and autoimmune diseases [6]. They hypothesized that a CD20 (cluster of differentiation 20) targeted therapeutic, capable of specifically depleting this population of B‐cells, may represent an interesting therapeutic option. In 1999, a first case report of a patient suffering from non‐Hodgkin's lymphoma in association with inflammatory arthropathy appeared [7]. Within weeks of treatment with a monoclonal anti‐CD20 antibody, significant improvement of joint pain was observed, and three months later, the patient was virtually symptom‐free and capable of walking distances of 5 miles per day. In a following phase 2 study, positive results of rituximab in patients with RA were demonstrated, [8] followed by further trials. After being able to demonstrate convincing beneficial effects, rituximab was approved for treatment of RA in combination with methotrexate in 2006.
1.2.1 Thalidomide Derivatives
A second example is the utilization of thalidomide, lenalidomide, and pomalidomide for treatment of leprosy and various cancers. After the infamous and tragic history of thalidomide, it would be nearly impossible for any researcher in a big pharmaceutical venture to revive this drug. Being approved in Germany in 1957, thalidomide was frequently used for treatment of morning sickness. As the side effect profile seemed very favorable, it was frequently used by pregnant women. However, in 1961 reports on increased birth defects were reported, which were finally linked to thalidomide. These defects led to a significantly increased mortality at birth as well as to limb deformations, heart problems, and other side effects. It is estimated that more than 10 000 children were born with limb defects. The retraction of the drug from the European market led to introduction of a requirement for more stringent characterization of drug safety during the registration process. Teratogenicity is now one of the flags that will lead to exclusion of a drug from almost any optimization program, as it is difficult to rule out any erroneous use in women of child‐bearing age. However, by 1964, only three years after market withdrawal, Jacob Sheskin from Hadassah University in Jerusalem used thalidomide to treat patents in serious condition of leprosy [9]. In his original publication, Sheskin referred to administering thalidomide to six leprosy patients as a sedative drug; however, to his surprise the disease condition of all six patients improved. The initial study was followed by multiple comparative studies and the clinical benefit, in particular with respect to onset of action, and good tolerability became evident. Thalidomide was finally approved for treatment of leprosy in 1998.
Further research by Judah Folkman's laboratory at Children's Hospital at Harvard Medical School demonstrated that thalidomide effectively inhibited angiogenesis induced by fibroblast growth factor 2, offering a potential mechanistic explanation for the observed limb deformations [10]. Angiogenesis, however, is a hallmark of tumor growth, so in 1997 a trial was started [11] to examine the efficacy of treatment with thalidomide in patients with multiple myeloma, a hematological cancer that was not curable by conventional chemotherapy. A response rate of 32 % was observed. Actually, a first oncology clinical trial of thalidomide had already been performed as early as 1965. Olsen et al. [12] treated 21 patients suffering from various types of advanced cancers with thalidomide. Overall no inhibitory effect of tumor progression was observed in this study. The authors described subjective palliation in one third of patients. Albeit no tumor regression was observed, the authors noted a possible temporary slowing of rapidly progressing cancer in two patients. Interestingly, one of them was suffering from multiple myeloma.
1.2.2 Chemotherapy: Nitrogen Mustards
Another example of drug repurposing is the establishment of chemotherapy for treatment of cancer. Mustard gas was one of the deadliest and most detestable weapons used in World War I, leading to the death of hundreds of thousands of people. Stimulated by findings in medical records of soldiers exposed to mustard gas, which noted that significant changes in the blood composition were observed (notably a pronounced leucopenia), [13] Milton Winternitz, a chemist, teamed up with two pharmacologists at Yale University, Louis Goodman and Alfred Gilman. They decided to investigate potential therapeutic effects of chemical warfare agents for potential treatment of cancer (Figure 1.2). While sulfur lost (S‐lost) proved too volatile for therapeutic use, the corresponding nitrogen derivative (N‐lost) was more amendable to administration. The hydrochloride salt was significantly safer to handle and solutions for injections could be readily obtained before the anticipated use by dissolution in sterile saline. In a mouse model of lymphosarcoma, rapid tumor regression was observed, albeit the authors noted that required doses were close to toxic levels and tumor reoccurrence was inevitable [14]. However, a first human patient was treated on 27 August 1942, a date that can be regarded as the birth of chemotherapy. J.D. (only the initials of said patient are known today) suffered from advanced non‐Hodgkin's lymphoma [15]. He was already treated with radiation therapy, but the tumor still spread and left the patient in a very severe condition. He thus volunteered to participate in an exploratory study, and indeed daily injections of the drug were able to reverse the symptoms. Rapid tumor regression was observed and his overall condition improved significantly. Unfortunately, the effects were relatively short‐lived. A second series of injections was still able to provide some relief from tumor reoccurrence, but a third round of treatment could not improve the patient's condition any more, and J.D. died 96 days after the first injection. However, his lifespan was likely significantly prolonged, and these results spurred further clinical investigation [16]. Overall, beneficial effects have been observed for patients suffering from Hodgkin's disease or lymphosarcoma, albeit the effects were transient and the therapeutic window was narrow. These initial studies had already been performed during World War II, but as chemical warfare agents were the subject of investigation, they were regarded as classified information, which delayed publication until 1946. Publication of these results caused a wave of initial excitement, but the limited duration of treatment effects and the inability to ultimately cure cancer led to a change in mindset and to a widespread pessimism in the
