Contemporary drug discovery case studies

CONTEMPORARY DRUG DISCOVERY CASE STUDIES

Drug discovery often happens through an unpredictable path that depends on the deep expertise and close collaboration among various disciplines. This section highlights some contemporary examples of drug discovery that led to significant advancements in human health outcomes.

Statins

The pathway1 to the discovery of this class of cholesterol-lowering drugs—a subject of 13 nobel prizes—exemplifies not only the concurrent cross-disciplinary progress but also the magnitude of effort required for such a breakthrough. Lovastatin, the first compound in this series, was com-mercialized by Merck in 1987 and was followed by the commercialization of semisynthetic (simvastatin and pravastatin) and synthetic (fluvastatin, atorvastatin, rosuvastatin, and pitavastatin) statins.

The intertwined pathway to the discovery of these drugs starts with the discovery of cholesterol in 1784 from gallstones by the French chemist Francois Poulletier. The proof of structure of cholesterol was established in the early twentieth century. Cholesterol was linked to atherosclerosis in 1910 by an investigation that showed significantly higher (~20-fold) cholesterol lev-els in human atherosclerotic plaques. This was followed by an experimental production of atherosclerosis in rabbits by the consumption of cholesterol-rich diet. A Norwegian clinician first proposed the link between cholesterol and heart attacks in several large families in 1939. A genetic understanding of this phenomenon, now known as familial hypercholesterolemia, was established in 1960s. Further, epidemiological studies carried out in 1950s and 1960s established a link between cholesterol and coronary artery disease.

Meanwhile, the complex 30-enzyme biochemistry of cholesterol’s synthesis and regulation of metabolism was elucidated in 1950s. With the cholesterol synthetic pathway known and the connection to human disease fairly plausible, several companies invested in research on molecules that would block one or more of these steps through synthesis of analogs of natural substrates. Some of these drugs, such as triparanol, commercialized in 1959 and withdrawn from the market in 1960s, were effective in reduc-ing cholesterol level but had serious side effects due to the accumulation of other sterols in the synthetic pathway. Cholesterol-lowering drugs such as nicotinic acid, clofibrate, and cholestyramine started becoming available in late 1950s to early 1960s. The first molecule that inhibited HMG CoA reductase enzyme, citrinin, a key enzyme in the cholesterol synthetic and metabolic regulatory pathway, was isolated from mold in 1971, and the second compound, compactin, was isolated in 1972. The preclinical and clinical results with compactin in the 1970s inspired compactin was also isolated from mold Penicillium citrinum chemists from Merck to discover lovastatin in 1978–1979, whose development was a bit delayed due to the initial suspicion of carcinogenicity of this class of compounds based on observations in dogs at high doses. Nevertheless, promising clinical results with low side effect profile resulted in full development of lovastatin, with new drug application (NDA) filing in 1986 and commercialization in 1987.

Immuno-oncology

Immuno-oncology drugs started transforming clinical treatment of cancer for a wide spectrum of patients with the regulatory approval and commer-cialization of the following humanized recombinant monoclonal antibodies (mAbs): ipilimumab (Yervoy®) by Medarex, Inc., and Bristol-Myers Squibb, Co. (BMS), targeting the CD28-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) receptor, in 2011; and pembrolizumab (Keytruda®) by Merck and nivolumab (Opdivo®) by BMS, both targeting the programmed cell death 1 (PD-1) receptor, in 2014–2015. The discovery of these revolution-ary medicines exemplifies not only cross-functional development, but also the necessity of continuous evolution of drug discovery and development paradigms. These shifting paradigms are exemplified by the following2:

·           Immunotherapy agents are unique in that they do not directly attack the tumor but rather mobilize the body’s innate and adaptive immu-nity. The contemporary clinical new cancer drug development par-adigm was based on the historical experience with chemotherapy drugs, whereby reduction in tumor size was a measured endpoint, and clinical success was measured in terms of progression-free sur-vival (PFS). Increase in tumor size during clinical trial over a relatively short period of time, about 2 months, would typically lead to cessation of dosing with the experimental drug. In the clinic, the immunother-apy drugs take longer to reach time-to-event endpoint, with delayed separation of survival curves. They also produced unique immune-related adverse effects that were reversible and clinically manageable. Clinical success of ipilimumab was a result of modification of phase III clinical trial endpoint during the study to overall survival (OS) and prolonged dosing, with clinical management of immune-specific side effects. A previous clinical trial of another immunotherapy agent, the anti-CTLA4 mAb tremelimumab, which operated with the chemo-therapy paradigm of clinical development, failed to demarcate itself in the clinic to gain regulatory approval.

·           Host immunity being consequential to tumor treatment had been observed and experimented with for a long time. German pathologist Rudolf Virchow observed immune infiltration of human tumors in the nineteenth century. American surgeon William Coley observed clearance of cancer on intratumoral injection of bacterial broth in some cases. The discovery of immune checkpoints to tumor progres-sion in the twentieth century, cloning of the CTLA4 gene in 1987, and demonstration of the value of immune checkpoint inhibitors in cancer treatment in mouse models in 1990s provided impetus to the discovery of immune-checkpoint modifying drugs.

·           Antibodies for human use long suffered from immune rejection, until progressive development from polyclonality to monoclonality and humanization through recombinant DNA technologies made possible the development of therapeutic antibodies that would not elicit an immune response.

·           Development of antibodies as drugs went through a long journey, with the difficulty of exact characterization of physicochemical properties and structural features. The number, type, and quantity of size and charge variants of these large-molecule drugs are often used for purity assessment instead of exact chemical structures of compounds. The development paradigms deviate from the conventional small-molecule drugs in utilizing comparability among clinical batches, instead of absolute chemical purity, as a benchmark during drug development.

The development of immuno-oncology drugs exemplifies the value of concur-rent significant advancements in different fields and their interplay in facilitat-ing the discovery and commercialization of an entirely new class of drugs.