Drug discovery often happens through an unpredictable path that depends on the deep expertise and close collaboration among various disciplines.
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.
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as triparanol, commercialized in 1959 and withdrawn from the market in 1960s,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
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.
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