The Catechol O‑Methyltransferase Inhibitor Entacapone in the Treatment of Parkinson’s Disease: Personal Reflections on a First‑in‑Class Drug Development Programme 40 Years On

In the 1980s, Orion Pharma, then a mid-ranking
Nordic area pharmaceutical company, established
a drug development programme on the
inhibition of catechol O-methyltransferase
(COMT). This enzyme, which plays an important
role in the inactivation of catecholamine neurotransmitters
and drugs with a catechol structure,
thus came under consideration as a target in the
innovative translational and clinical programme
we describe in this historical review. The starting
point was the conjecture that a peripherally acting
COMT inhibitor might improve entry of
levodopa into the brain. This had potentially
significant implications for the medical treatment
of Parkinson’s disease (PD). The rationale
was that more efficient delivery of levodopa to
the brain might allow the high therapeutic doses
of levodopa to be reduced and the dose interval
to be extended. Elucidation of structure–activity
relations paved the way for the discovery and
development of entacapone, a 5-nitrocatechol
that was a potent and highly specific inhibitor
of COMT. Experience in phase III clinical trials
established that entacapone, used as an adjunct
to regular or controlled-release levodopa preparations
(also including a peripherally acting
dopa-decarboxylase inhibitor), increased ONtime
and reduced OFF-time and improved clinical
condition in patients with PD experiencing
wearing-off, often with a reduced daily levodopa
dose. Several of these studies also identified that
entacapone improved patients’ quality of life
and was cost-effective. Subsequently, entacapone
has been amalgamated into a triple-combination
preparation (Stalevo®) with levodopa
and carbidopa to create a flexible and convenient
drug therapy for patients with PD who have
end-of-dose motor fluctuations not stabilised on
levodopa/dopa-decarboxylase inhibitor treatment.
This review offers a historical perspective
on a successful programme of drug development
by researchers who played central roles in the progress from
exploratory hypothesis to registered pharmaceutical products.
pharmaceutical product.