Malaria drug muddle

Research community questioning legitimacy of Canadian drug approved for market in Africa

With one million deaths and 300 million new cases of malaria each year, the quest for a successful malaria treatment is urgent. But one new drug, touted by its manufacturer as safe and exceptionally effective, and already approved for sale by five African nations, is provoking suspicion in the malaria research community. At best, some researchers claim, the Canadian drug Malarex has not been adequately tested for safety or efficacy, at worst, others say, it may be a fraud.

“Malarex is a natural extract, which is a bunch of alkaloids, and the one that is most active is voacamine,” explains Leonard Stella, the chief operating officer of Millenia Hope, a small biotech company based in Montreal. “Our goal is to get the product to the people because we know it’s not harmful and we know that it works.” And since it’s a herbal remedy that’s been used by “witch doctors” in Brazil for many years, Stella adds, “we haven’t done tests yet to find out how it works.”

Though Millenia Hope may not understand the drug’s mechanism of action, the company does claim to have demonstrated, in vitro as well as in animals and humans, the drug’s ability to kill the malaria parasite Plasmodium falciparum, and to do so safely. But even the researchers said to have performed the tests do not corroborate all the company’s claims.

Founded in 1997, Millenia Hope obtained an Italian patent four years ago for a natural compound called voacamine, derived from the roots and bark of the Brazilian plant Peschiera fuchsiaefolia, and developed the extract into its premier product, Malarex. In one press release dated February 7, 2001, Millenia Hope states that in vitro tests by McGill University malaria researchers Erwin Schurr and Celestino DeFlumeri of the Center for the Study of Host Resistance, “confirmed that, even at extremely low doses, Malarex was able to cause a substantial decrease in malarial parasite.”

Schurr, says that his lab did receive a compound from Millenia Hope identified as Malarex, and was asked to test it for anti-malarial activity. With the help of another lab, Schurr confirmed that the compound did contain voacamine, though not in pure form, but rather was a mixture of several crude extracts. Still, Schurr tested the compound on his Plasmodium cultures and found that it could kill the parasite. The results were given in a confidential report to Millenia Hope, says Schurr but “The selective quotation of results contained in the report prior to publication are upsetting and have prompted us to cease further work with Millenia Hope.”

Schurr adds, “the in-vitro experiments in my lab were repeated on numerous occasions and the results were quite impressive in that we detected significant anti-plasmodial activity. But what we showed was that under artificial laboratory conditions a compound identified to us as Malarex can efficiently kill Plasmodium parasites, but so can bleach, to be the devil’s advocate.” There is a long way to go, Shurr says, “to determine if and to what extent such in vitro activity can be maintained in an in vivo system. Obviously, a huge amount of additional investigation is needed to make any inferences about the possible utility of this compound for treatment of malaria in people.”

In a quarterly report published October 15, 2001, Millenia Hope stated that it is “running a new series of animal tests, under the auspices of Dr. Mary Stevenson of McGill University.” Mary Stevenson is an immunologist at McGill and indeed working on malaria, but could not offer any comments on the effectiveness of Malarex on blood-stage malaria. “Millenia Hope and McGill University negotiated and signed a contract for me to carry out toxicity and efficacy studies on Malarex in a mouse model of malaria. The company reneged and did not provide the agreed upon funds for the work. Thus, the studies were never performed despite my interest,” she says.

In yet another press release dated June 10, 2000, the company stated: “tests on Malarex had produced no mortality or significant side effects in pre-clinical animal laboratory studies. The toxicity tests, carried out at FDA-approved facilities in Montreal, Canada, used doses as high as 100 times the usual dose without producing significant clinical side-effects in the laboratory animals used for the study.” According to Stella, these tests were performed at a contracted lab and conducted by Millenia Hope’s chairman, George Tsoukas, a physician and professor at McGill and Montreal General Hospital.

Tsoukas did not return The Scientist’s calls seeking information about Millenia Hope’s scientific claims. One of those is that human trials of the drug have been performed and more are planned. The company’s web site states, “Our medical research program has always foreseen the need for continuing clinical human trials to confirm Malarex’s safety and efficacy in humans. Dr. Knox van Dyke, a pharmacology professor at West Virginia University and a renowned malaria researcher, will head a new trial.”

Van Dyke, who believes that Malarex has antimalarial activity, told The Scientist that negotiations are ongoing but no trial is yet scheduled. “If you find a capsule of the drug, you will ascertain that the material inside the capsule is a crude extract of the drug rather than the pure voacamine whose structure is known. This is all the information I have at present,” says van Dyke.

The only human clinical trial of Malarex that could be confirmed by The Scientist involved 30 patients and was conducted by Albert Same Ekobo, former national coordinator of Cameroon’s Anti-Malarial Programme in Yaounde. Millenia Hope stated in January 2002 that all patients were cured of their malarial symptoms within four days, results that “are consistent with our other studies of Malarex.”

Reinhard Krippner, with the German Embassy in Yaounde, has inquired at Cameroon’s Ministry of Health about testing of Malarex in that country and discovered that Same Ekobo did do a study in 1999 after being asked by his Minister of Health “to do a ’little’ trial because [the Minister] was close to the company.” Same Ekobo’s results have not been published.

Of only nine publications on voacamine in peer-reviewed scientific journals dating back to 1967, none mentions either Malarex or Millenia Hope. The most recent study, published last year in Phytotherapy Research, confirms that the alkaloid has some effect on malarial parasites both in cell cultures and mice but concludes that “further work is needed to clarify the mechanism of action.”

Confusing matters further, another malaria drug called Malarex, containing the well-established malaria treatment chloroquine diphosphate, is manufactured by the Danish company Alpharma. Millenia Hope’s Stella says that the company is “aware of their competition.” In the countries where Alpharma is selling its Malarex which, according to Stella, include the same Central African countries where Millenia Hope is marketing its drug Millenia Hope has changed its drug’s name to MMH Malarex.

Millenia Hope also claims a strategic partnership with Malaria Foundation International (MFI), however Mary Galinski, president and founder of MFI, told The Scientist that the foundation has never been involved with Millenia Hope or any projects pertaining to Malarex.

Despite the apparent lack of evidence that Millenia Hope’s Malarex is safe for humans, the company says it has received approval for sale of the drug in five Central African countries and is awaiting word from six more nations. Millenia Hope is expecting to ship upward of 25 million doses to those 11 countries, but it could be a while, explains Stella. “We worked our tails off to get the product approved, then we worked to get the right distributor and then it turns out that these African governments can’t afford it,” he says. “So now we are trying to get the Canadian government to subsidize the African governments so they can afford to buy Malarex.”

“In my opinion this is a crock,” one Canadian malaria expert familiar with Millenia Hope and their research on Malarex told The Scientist. Another malaria researcher suggests that the explanation for the inconsistencies surrounding Millenia Hope’s claims could be that the company, which is listed on the Berlin stock exchange and the NASDAQ, may not have a real drug to sell.

“This seems like a financial scam which probably works very well on unsuspecting stock market gamblers,” says Marcel Hommel, editor of Malaria Journal (an open access journal published by The Scientist’s partner BioMed Central) and professor at the Liverpool School of Tropical Medicine. “If, for the sake of argument, we believe that the drug does not actually exist, the whole thing makes complete sense!”