impaginato piccolo - Società Italiana di Parassitologia (SoIPa)

for each of these chemical entities. These presentations
covered the spectrum of necessary features of a successful
drug candidate, including chemistry, pharmacology,
toxicology, efficacy, and clinical parameters. In
what would later be viewed as a singular triumphant
moment for the Army’s drug development program, a
subtle shift started happening in the audience’s opinion
during the course of that day and before the team left
that day, the home town favorite had been voted down
unanimously in favor of continuing development of
artesunate over artelinic acid. Rather than bowing to
pressures to protect what was the team’s favored candidate,
the team courageously decided to develop the
drug that had the best chance of licensure and acceptance
at a time when a replacement for quinidine was so
urgently needed.
Within two years, the team completed the necessary
preclinical work for artesunate, and by November of
2004, an Investigational New Drug Application was
successfully filed with the U.S. Food and Drug
Administration (FDA). This paved the way for rapid
progress of this compound to be the first ever Good
Clinical Practices Phase 1 trial done with Good Clinical
Manufacturing (GMP) Practices Artesunate in both
single dose administration and multiple dose administrations.
The drug proved to be remarkably safe in
these trials with normal healthy volunteers, even at levels
that approached four times the anticipated dose to
treat severe malaria in critically ill malaria patients. The
drug was granted Orphan Drug Status due to the relatively
few cases that are seen in the U.S. as well as Fast
Track Status due to the pressing need to replace the
rapidly dwindling availability of quinidine. Phase 2
clinical trials in Kenya and Thailand were planned, executed,
and the first of these completed in Kenya confirmed
the remarkable efficacy of this drug in rapidly
treating malaria in sick malaria patients.
In August 2005, the South East Asian Quinine
Artesunate Malaria Trial (SEAQUAMAT) Group published
results of almost 1500 patients with severe
malaria showing that artesunate had superiority over
quinine using mortality as an endpoint for the trial.
This remarkable study added fuel to the fire that quinine,
and in the U.S., quinidine, should be replaced by
P. J. Weina - History of Artemisinins
29
artesunate in the treatment of severe malaria. This
study lead to the WHO’s guidelines at the end of 2005
and confirmed to the WRAIR development team that
they had indeed made the right choice of drug candidate
for development three years earlier. These results
also provided encouragement for the team to redouble
their efforts in getting this product to market as quickly
as possible. The problem to date had been that of getting
a commercial partner. This drug, as noted earlier,
had little commercial interest because it was not
patentable. Few pharmaceutical companies would be
knocking at the door to share co-development costs
with the Army in getting this product to market, much
less take the chance of providing this drug over a sustained
period after licensure. Luckily, there are new
pharmaceutical companies emerging that specialize in
niche markets such as orphan drugs. It was while the
Army’s program was within a year or two of approaching
its goal of filing a New Drug Application with the
FDA that WRAIR researchers met the Italian subsidiary
in the U.S., Sigma-Tau Pharmaceuticals, an
Italian subsidiary in the U.S. that specializes in rare diseases
and orphan drugs. This partnership was sealed in
early 2007 and should bring this critically needed product
not only to the U.S. market, but also hopefully to
the European and broader world market.
As noted in Table 1, there certainly are other agents
already on the market, bringing artemisinins to the people
who need them the most, saving lives, and several are
being made to International Commission on
Harmonization (ICH) standards for GMP. Most of these
other artemisinin preparations are produced for the larger
market out there, uncomplicated malaria, which by
some estimates affects several hundred million people in
the world each year. Most all of these drugs are oral formulations
that can be taken before patients with malaria
become so sick that they cannot tolerate oral medicines.
Among these include combinations of the artemisinins
and older antimalarial agents that follow the WHO’s
insistence that we combine the artemisinins with other
agents to preserve the efficacy of this class of compounds
and delay what some believe is the inevitability of resistance.
The history of the artemisinins is most certainly
still being written and likely will be as exciting as its long
and celebrated history to date.