Part 1: Compound WR 142,490
The information contained in this story, as well as in all previous and future writings on mefloquine, has been obtained from a variety of academic journals, papers, and other publications. I have access to a vast body of academic work which has allowed me to conduct the research that I have been doing on this particular topic. Any opinions I may express are based upon this information, and are not speculation or conjecture on my part.
The Walter Reed Army Institute of Research (WRAIR) began the task of finding a new anti-malarial treatment during the war in Vietnam. The standard medication at the time, chloroquine, was no longer effective as the most dangerous variant of the tropical disease had developed a resistance to the drug.
Between 250,000 and 300,000 compounds were tested as part of its malaria drug programme over a period of about 10 years. One of these was a compound that was known as WR 142,490. It isn’t clear when the compound was first synthesized, but the information I’ve found so far puts it somewhere between 1968 and 1971.
The United States military is prohibited by congress from marketing a drug directly to the public, so it turned to Swiss pharmaceutical giant F.Hoffmann-La Roche AG (Roche) for this. Anti-malarial prophylaxis is a necessity for anyone travelling into a malaria zone, so there was a definite market for the drug commercially, as well as militarily. More importantly, it would be available to the millions of people who live in malaria zones who didn’t have a genetic resistance to malaria.
The WRAIR turned over the results of their phase I and phase II trials to Roche free of charge, and it wouldn’t be long before Roche was conducting clinical trials of its own. Roche would gain approval for the drug in Switzerland and would begin marketing it there in 1985, and in France shortly after, under the brand name Lariam.
The Clinical Trials
The earliest mention in the literature of clinical trials for WR 142,490 that I was able to locate is from 1973, in a paper titled “Human Malaria Infections in the Owl Monkey”. The paper refers to a number of compounds that were tested as part of the study, among them WR 142,490. It notes that the compound performed well in the trial, and there is a sense of optimism in the potential for it’s development.
The paper also makes reference to a study being conducted contemporaneously in Chicago by Rieckmann and Carson at the Rush-Presbyterian-St.Luke’s Medical Centre in Chicago. The results of the study appear in the journal “Science”, on November 21st, 1975. The study was conducted by the Malaria Unit of the Army Medical Research Project, out of Rush-Presbyterian-St.Luke’s Hospital in Chicago, and the Stateville Penitentiary in Joliet, Illinois.
The military often used inmates in correctional facilities as participants in drug trials. From all indications the participants of these trials were all volunteers, however this does not negate the ethical implications of scientific testing on prisoners. For reasons that are purely scientific, it is logical, but this is but one occasion among many where science and ethics have clashed over the centuries and is for someone else to debate right now.
According to the paper, the trial was performed on 47 male volunteers who were infected with malaria. Again, the results were promising. It was successful in treating malaria, with cure rates similar to those seen in the current treatments, and most importantly, there were very few serious side effects associated with it. There is no mention of an psychological adverse effects.
A number of phase II and even phase III trials are performed during the next decade, usually in areas that lie within malaria zones. The studies were done with the number of participants ranging from less than a dozen to no higher than 1,000, but most seem to be in the range of between 50 and 400 participants. There was some mention of psychological side effects, hallucinations, bad dreams, etc., but the seem to have been give little credence. Often, such reactions were attributed to an un-diagnosed mental illness, or substance abuse.
The World Health Organization
Part of the mandate of the WHO is to monitor disease levels across the globe, including malaria, and to help formulate a plan to prevent their spread and find treatments for them. For years, malaria had been a major concern of the organization as chloroquine resistance was rendering contemporary medicine useless. A new treatment was an absolute imperative, and WR 149,490 grabbed their attention in 1974.
In an article of the World Health Organization Bulletin in 1974, the compound enters WHO literature for the first time, where the findings of a clinical trial involving 47 volunteers are published. Again, despite the low number of participants, the paper’s authors seem optimistic that they fave found the next generation of anti-malarial treatment and prophylaxis.
Early on, a new variable had become a part of the equation, and that variable was drug resistance. Researchers were expressing a concern early on about the time it would take before a strain of malaria resistant to the new drug would be. There were even reports as early as the 1970’s of strains of malaria that were showing a resistance to the drug now called mefloquine. There are a number of studies conducted in the 1970’s and 80’s which were conducted to test mefloquine’s efficacy when when used in combination with a variety of other prophylaxis. The hope was to slow the rate at which resistance would develop, in order to give them time to develop the next generation anti-malarial.
Then, in 1983, the World Health Organization would make a statement that would forever change the lives of thousands of people around the world. In an Update article entitled “Development of mefloquine as an anti-malarial drug.”, the WHO announces that phase I trials of the drug have started in the United States. It further goes on to state that phase II and Phase III clinical trials had been COMPLETED, and that it was hoped that the drug would be registered in the very new future.
They make reference to a single phase III trial in Zambia that was done with 99 male volunteers. They were given a single 1000 mg dose which was reported to be “well tolerated, effective, and safe”, and had a cure rate of 98%.
At the end of the article was the following statement:
Thus it can be concluded from the extensive clinical trials conducted predominantly in male subjects that mefloquine may be safe and effective as a treatment.
Two years later, in 1985, mefloquine was approved for sale in Switzerland, followed shortly after that by France. By then an FDA medical officer in Washington D.C. named Dr. Celia Maxwell was recommending mefloquine for approval in the United States. In 1989, it was approved for use by the FDA, and in Europe the first reports of adverse events pertaining to mefloquine begin to appear in the literature.
The world was about to find out that mefloquine wasn’t as well tolerated or as safe as they were lead to believe. The results would be deadly.