E-drug: Visceral leishmaniasis treatment news 3
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From NEJM vol 347 November 28, 2002, Number 22
Copied as fair use
Valeria Frighi
An Oral Drug for Leishmaniasis
Encouraging results are reported in this issue of the Journal for an
oral drug for use in the battle against visceral leishmaniasis in
India (pages 1739-1746). Given the hurdles that typically stymie the
development of drugs for diseases endemic primarily to impoverished
regions, the story of miltefosine may offer a model for future
successes.
In Bihar, in northeastern India, with 83 million residents who are among
the poorest and least educated people in the country, as many as
200,000 deaths from visceral leishmaniasis occur each year. Nearly
everyone in this region of India has watched a neighbor or family
member waste away and die from complications of this infectious
disease, which is transmitted by the bite of a sandfly. For decades,
treatment with injected pentavalent antimony was effective, but the
parasite in Bihar has developed resistance, rendering this approach
nearly useless there. The second-line medication, conventional
amphotericin B, can require a month of intravenous infusions and carries
a risk of renal toxicity. Short-course treatment with lipid
formulations of amphotericin B are highly effective but are
financially out of reach in Bihar.
In the mid-1990s, miltefosine was shown to have activity against
leishmania in vitro and in animal models. Researchers in Bihar began
working with a company that had developed miltefosine as an
anticancer drug. But no one was certain whether adequate support
would be available to develop this drug for use almost exclusively in
impoverished populations. In 1995, Tropical Disease Research (TDR), a
program sponsored by the World Health Organization and other
international groups, and the company now known as Asta
Medica-Zentaris entered into an agreement to develop miltefosine for
visceral leishmaniasis in India.
"We're dealing with a drug that would not make a lot of money," said
Juntra Karbwang, M.D., clinical coordinator for product research and
development at TDR. "Convincing people to contribute to this kind of
development is hard." TDR officials wanted to ensure that research
was of adequate quality that the drug, if effective and well
tolerated, could be registered
quickly in India and elsewhere. Adherence to the Guidelines for Good
Clinical Practice (GCP), as defined by the World Medical Assembly in
the 1989 Declaration of Helsinki, would be crucial - although such a
goal was daunting in a region of poverty and limited medical
resources.
TDR assembled a task force that included not only scientists from the
drug company and three clinical investigators from India, but also an
American physician and a British physician with experience in drug
development and with the disease. "We went to Bihar to convince
investigators there that we wanted not just a paper in a journal, but
an end product that could be used," Karbwang said. "Some scientists
don't think that far ahead. They would have to comply with Good
Clinical Practice."
The Bihar investigators were on board immediately, which was crucial
to the success of the study. "When one is initially introduced to
GCP, it seems irritating and a lot of unnecessary paperwork," said
Shyam Sundar, M.D., one of the Indian investigators. "The greatest
challenge is to get used to the idea that
someone will verify every word or finding that you wrote or the lab
report, and you will be questioned umpteen times. There is huge
amount of paperwork. It is absolutely different from what you did
earlier. But once you know [how to do it], it flows like a silk."
As part of the effort to comply with the guidelines, TDR introduced
clinical monitors into the study. These physicians and scientists
provided oversight and direction for the study, from the writing of
the protocol to the verification of the data. Two clinical monitors
from India, one from Thailand, and one from Vietnam visited the study
site monthly. Investigators typically are not eager to see monitors,
said Karbwang, but "in this case, they asked `When will the monitors
come?' This [cooperation] contributed greatly to the success" of the
study.
In the phase 3 trial reported in this issue of the Journal, patients
were randomly assigned to receive either oral miltefosine for 28 days
or intravenously administered conventional amphotericin B every other
day for a total of 15 infusions. All patients were hospitalized so
that the oral therapy could be observed and patients could be
monitored. Recruitment was not a problem, even though many patients
were not yet so sick that they would have been hospitalized
otherwise. Most patients in the study were illiterate. If no literate
family member was present, a social worker read an information sheet
to the patient in the local Hindi dialect, and consent was given
orally.
The patients, noted Sundar, "have seen someone next door suffering
and dying from visceral leishmaniasis, and they are dead scared. In
90 percent of cases, patients agreed to be admitted without
difficulty. Some, however, chose not to take this treatment.
Unfortunately, in Bihar, the only drug for them is
amphotericin B, which needs to be infused in the hospital, so [the
study conditions were] not much different."
The results with miltefosine, at each stage of research, surprised
even the investigators. At the doses that are needed to be effective
against visceral leishmaniasis, oral miltefosine had less general
toxicity than it did when used in patients with cancer and did not
have the toxic effects on the eyes and the male reproductive system
that have been seen in studies in animals. The reasons for this lower
toxicity are not clear, but they may be related to the specific
population of patients involved in the study.
Planning is under way for a phase 4 trial, supported by the Indian
government, to learn more about outpatient use of miltefosine, which
is now registered for use in India. The price for the drug in India
has not yet been set. However, the involvement of the Indian
government early in the development of the drug suggests that it may
reach patients more quickly than many new drugs do.
In practice, with an outpatient drug, compliance with the full
four-week regimen is likely to be the biggest challenge. Given the
rapid clinical improvement induced by miltefosine, there will be a
great temptation to discontinue treatment prematurely. Underdosing
will be common, predicts Sundar, which will result in a risk of
increased tolerance and, ultimately, failure. "There is a great need
to educate the physicians [who will be] using this drug, and in turn,
patients need to be warned and educated," he said. Staff training has
begun in 20 centers in Bihar and Nepal.
Meanwhile, other countries have asked to use the drug, even though
its effectiveness against other variants of visceral leishmaniasis is
uncertain. Miltefosine is imperfect: it cannot be used in pregnant
women. And the sickest patients were excluded from the current study.
Yet its success to date has been cause for great hope. "The story of
miltefosine is extraordinary on three fronts," says Barbara Herwaldt,
M.D., M.P.H., of the Division of Parasitic Diseases at the Centers
for Disease Control and Prevention. "It's extraordinary that it is an
oral drug, that it went through the development phases specifically
for leishmaniasis, and that it cleared so many toxicity, efficacy,
and logistic hurdles. This drug has the potential to revolutionize
treatment of visceral and perhaps other leishmanial syndromes,
especially in the impoverished regions where leishmaniasis typically
occurs."
Sandra Jacobs
--
Dr. Valeria Frighi
Diabetes Trials Unit
Radcliffe Infirmary
Woodstock Road
Oxford OX2 6HE
UK
tel. -44-1865-228422
fax -44-1865-224584
e-mail valeria.frighi@dtu.ox.ac.uk
--
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