In April 1980, after animal safety studies
had been performed,
Merck began clinical trials of lovastatin in healthy volunteers. Lovastatin was
shown to be dramatically effective for lowering LDL cholesterol in healthy
volunteers, with no obvious adverse effects18, 19.
However, this promising start was soon to be interrupted. Clinical trials with
compactin had been proceeding, but for reasons that have never been made public
(but which were believed to include serious animal toxicity) the trials were
stopped by Sankyo in September 1980. Because
of the close structural similarity between compactin and lovastatin, Merck
promptly suspended clinical studies with lovastatin, and initiated additional
animal safety studies. The future of the drug seemed extremely doubtful.
However, in 1982 some small-scale clinical investigations in very high-risk
patients resumed outside Merck. Bilheimer and Grundy in Dallas, Texas, and
Illingworth in Portland, Oregon asked Merck for lovastatin to test its effect
in selected small groups of patients with severe heterozygous FAMILIAL
HYPERCHOLESTEROLAEMIA (FH) (Box 1)
refractory to existing therapy. They observed dramatic reductions in LDL
with very few adverse effects. Later, Thompson in London found that lovastatin
considerably enhanced the hypolipidaemic effect of apheresis in patients with
hypercholesterolaemia [notice that
Merck is using the surrogate lowering cholesterol instead of the endpoints
prevent deaths and MI.]
After the additional animal safety studies
revealed no toxicity of the type believed to be associated with compactin,
Merck decided, in 1983, to re-initiate the clinical development programme,
initially in patients at very high risk of myocardial infarction. Because of
concerns about patient safety, this was a difficult decision, reached only
after prolonged internal debate. Not withstanding the excellent tolerability to
date in relatively small short-term studies, it was quite possible that more
experience in a large number of patients treated chronically, as well as
long-term animal toxicology studies, would yield a poor safety profile,
including potential carcinogenicity. This would prohibit the development of
lovastatin, or at best limit its use to a few ultra-high-risk patients — the 'ORPHAN
In randomized, double-blind Phase IIb
started in 1984 (TIMELINE),
lovastatin was as effective in patients with heterozygous FH23
and patients with CHD and non-familial hypercholesterolaemia24
as it had been in healthy volunteers19.
These effects were confirmed in larger Phase III studies, in which lovastatin
produced much greater reductions in LDL cholesterol than the control agents
with very few adverse effects. The effects of lovastatin in the Phase IIb
studies are shown in Fig. 2.
Effect of lovastatin by time and dose
on plasma cholesterol in
Phase IIb studies in patients with familial hypercholesterolaemia (FH), and
high-risk hypercholesterolaemic patients without FH. Bid, twice daily; qpm,
once daily in the evening. Lovastatin
produced a profound reduction of apolipoprotein-B-containing lipoproteins,
especially LDL cholesterol and, to a lesser extent, plasma triglycerides, and a
small increase in HDL cholesterol. Observed tolerability continued to be
excellent, with very few patients withdrawing from treatment due to adverse
effects. In November 1986, Merck applied for regulatory approval of lovastatin.
In February 1987, a US FDA advisory panel fully considered the various safety
issues arising out of the animal toxicology studies discussed below and the
clinical results summarized above. The panel voted unanimously for the approval
of the drug, and FDA approval was obtained on 31 August 1987 (TIMELINE).
Lovastatin had patent protection only in certain other countries, all of which
later granted approval.
EFFECTS ANIMALS: “Statins produce significant
toxicity at high
doses in a variety of animal species. These effects include increases in
hepatic transaminases, atypical focal hyperplasia of the liver, squamous
epithelial hyperplasia [ORGAN ENLARGEMENT] of the rat fore-stomach (an organ
not present in man), cataracts, vascular lesions in the central nervous system
(CNS), skeletal muscle toxicity, testicular degeneration and, although the
statins are clearly not genotoxic, tumours of the liver and other sites
(details can be found in the product circulars of the individual statins). It
has been shown, where it has been practical to conduct the experiment, that
these effects can be prevented by administering mevalonate 29,30, the product of the reaction catalysed
HMG-CoA reductase. This indicates that
these toxic effects are mostly, if not entirely, attributable to extreme
inhibition of the enzyme at high doses 29.
So Merck, and the regulatory agencies
considering the marketing application submitted by Merck, were faced with a wide range of animal
toxicological effects, as well
as the history of compactin and the known central role of the cholesterol
biosynthesis pathway in many physiological processes, including the production
of steroids and cell membranes. [Since
the toxicity of the very similar in structure compactin, whose toxicity in
animal studies resulted from it not being tested clinically, that the same
occurred for Lovastin, but Merck went forward. Compactin was withdrawn from the
market for ] … Fortunately,
except for rare cases of myopathy and marked but
asymptomatic increases in hepatic transaminases, none of the adverse effects
found in animals occur at human therapeutic doses.” Nature Reviews Drug Discovery
2, 517-526 (July 2003) | doi:10.1038/nrd1112
Author’s affiliations: A. Tolbert,
Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Top of page
- Studies in
the 1950s and 1960s led to the formulation of the lipid hypothesis, which
proposed that elevated low-density lipoprotein (LDL) cholesterol was
causally related to coronary heart disease (CHD) and that reducing it
would reduce the risk of myocardial infarction and other coronary events.
(HMG-CoA) reductase, the rate-limiting enzyme in the cholesterol
biosynthetic pathway, was an attractive target in the search for drugs to
reduce plasma cholesterol concentrations.
and lovastatin, natural products with a powerful inhibitory effect on
HMG-CoA reductase, were discovered in the 1970s, and taken into clinical
development as potential drugs for lowering LDL cholesterol.
in 1980, trials with compactin were suspended for undisclosed reasons
(rumoured to be related to serious animal toxicity). Because of the close
structural similarity between compactin and lovastatin, clinical studies
with lovastatin were also suspended, and additional animal safety studies
- In 1982
some small-scale clinical investigations of lovastatin in very high-risk
patients were undertaken, in which dramatic reductions in LDL cholesterol
were observed, with very few adverse effects. After the additional animal
safety studies with lovastatin revealed no toxicity of the type thought to
be associated with compactin, clinical studies resumed.
trials confirmed the effectiveness of lovastatin. Observed tolerability
continued to be excellent, and lovastatin was approved by the US FDA in
at its maximal recommended dose of 80 mg daily produced a mean reduction
in LDL cholesterol of 40%, a far greater reduction than could be obtained
with any of the treatments available at the time. Equally important, the
drug produced very few adverse effects, was easy for patients to take, and
so was rapidly accepted by prescribers and patients. The only important
adverse effect is myopathy/rhabdomyolysis. This is rare and occurs with
all HMG-CoA reductase inhibitors.
other HMG-CoA reductase inhibitors, now widely known as statins,
subsequently became available for prescription: simvastatin, pravastatin,
fluvastatin, atorvastatin, cerivastatin and rosuvastatin.
mechanism of the reduction in LDL cholesterol by statins is now known not
to be simply reduction in cholesterol biosynthesis. Induction of the LDL
receptor is crucial to their effectiveness.
the basic lipid hypothesis had been validated by the late 1980s, the
movement towards treating hypercholesterolaemia was questioned because
overviews of trials of treatments from the pre-statin era suggested that
although CHD events might be reduced, survival was not improved.
large-scale, long-term trials published during the last decade, such as
the Scandinavian Simvastatin Survival Study (4S, 1994), The Long-Term
Intervention With Pravastatin in Ischaemic Disease (LIPID, 1998) and the
Heart Protection Study (HPS, 2002) with simvastatin, have now provided
unequivocal evidence of a reduction in all-cause mortality.
- In 2001,
cerivastatin was withdrawn by its manufacturer due to an excessive risk of
- In HPS the
risk of serious cardiovascular events was reduced by simvastatin
regardless of LDL-cholesterol level.