Transcript 3rd Lecture
PHL 616 Drug Discovery & Development Third Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212 Email: [email protected] Creation of a new drug, contd. Creation of a new drug, Case histories Five drugs, namely paclitaxel (Taxol), flecainide (Tambocor), omeprazol (Losec), imatinib (Gleevec/Glivec) and trastuzumab (Herceptin) were successful case histories in drug discovery projects Each represents a highly innovative ‘breakthrough’ project rather than an incremental development based on an existing therapy, and they illustrate the variety of different approaches taken by successful projects over the past 35 years Only about 1 in 50 drug discovery projects begun is successful in terms of bringing a compound to market Only at the point when official approval for trials in man is granted does the project become visible to the outside world, so data on success rates, timelines, etc., are much more accessible for the minority of projects that progress to Phase I or beyond than for the majority that never get that far Analyzing the success factors for early-stage drug discovery projects is therefore difficult Creation of a new drug, Case histories Paclitaxel (Taxol) It is an interesting example of a project based on the development of a natural product The sample of bark from the Pacific Yew was collected in 1962 and found to have modest activity against various tumor cell lines The active substance was isolated in 1969 and joined a collection of moderately active, but not particularly interesting, lead compounds In 1975, when this collection was tested on a new assay, a melanoma cell line, paclitaxel stood out as highly active. Its activity was confirmed in animal models, and it was soon chosen as a development candidate Interest was further stimulated when its novel mechanism of action, the promotion of microtubule polymerization, was very elegantly demonstrated Creation of a new drug, Case histories, Paclitaxel, contd. Development was difficult, for two main reasons: 1. Paclitaxel is insoluble in water, and the early formulations for injection used in Phase I trials contained a high proportion of the solubilizing agent Cremophor EL, causing frequent severe allergic reactions when given as a bolus I.V. injection After considerable delay, the problem was overcome by the use of slow infusions & development was resumed 2. The second problem was the supply of material for clinical trials, and the uncertainty that it could ever be produced on a commercial basis Pacific Yew grows slowly & has a restricted habitat, & conservationists were opposed to commercial harvesting. As a result, there was only enough material for limited Phase II studies, on patients with ovarian cancer 3. The improvement in these patients was dramatic, but continuation of the project, now in collaboration with Bristol Myers Squibb, was seriously hindered by the limited supplies of yew tree bark Creation of a new drug, Case histories, Paclitaxel, contd. 4. The conservation concerns were overcome when an official survey showed that the tree population was not in fact threatened, and industrial supplies of bark were collected to support the trials program right through to 1992, when the drug was officially approved The obstacles to progress in this case were: a. The failure of the primary screen to reveal the compound as anything out of the ordinary b. The appearance of serious side effects resulting from the properties of the excipient c. The supply issue Creation of a new drug, Case histories Flecainide (Tambocor) In the early 1960s, the drugs used to treat cardiac arrhythmias were mainly quinidine, procainamide, digoxin and lidocaine The first three had many troublesome side effects, whereas lidocaine use was largely confined to intensive care settings In 1964, the 3M company tried to develop better antiarrhythmic drugs, by introducing –CF3 groups to fluorinated derivatives of known local anaesthetic and antiarrhythmic drugs The primary screening assay was based on the ability of compounds to prevent ventricular fibrillation induced by chloroform inhalation in mice Secondary assays on selected compounds were carried out on anaesthetized dogs A potential development compound was synthesized in 1969, but abandoned because of its CNS side effects Creation of a new drug, Case histories Flecainide, contd. After 5 years (1974) of careful chemistry, during which many different structural classes were tested, flecainide was synthesized and found to have a much improved therapeutic window compared to its predecessors The first clinical studies were performed in 1976, and development proceeded quite smoothly until the compound was registered in 1984 The drug is now accepted as the standard Class 1c antiarrhythmic agent The main delaying factor in the flecainide project was simply slow chemistry After encountering side-effect problems with the lead compound, it took 5 years to find the solution