HELPING HAND A nurse with Médecins Sans Frontières examines a patient at a tuberculosis hospital in the self-proclaimed Abkhaz Republic. SERGE SIBERT/MÉDECINS SANS FRONTIÈRES

Tuberculosis is one of the so-called neglected diseases--those for which drug development has been grossly inadequate, despite their prevalence and the human suffering and economic loss they cause. The reasons for neglect are primarily economic: These diseases are usually widespread in countries where patients are among the poorest in the world. The view has been that developing drugs for such populations is not profitable, and it is therefore undertaken only with great reluctance by for-profit entities.

However, new ways to develop drugs for neglected diseases have recently come to the fore. The existence of a company like Sequella, founded in 1997, is based on the premise that money can indeed be made from products aimed at diseases like tuberculosis. That premise is supported by a study showing that the global market for tuberculosis drugs could be as high as $700 million per year by 2010 (C&EN, March 25, page 42). The study was carried out by the Global Alliance for TB Drug Development, often shortened to TB Alliance.

TB Alliance, established in October 2000, is a nonprofit organization committed to delivering a new tuberculosis drug by 2010. It has a business model similar to that of a virtual drug company: It will use outside resources and services to move lead compounds through development. But as a nonprofit, it attracts philanthropic contributions instead of raising capital from investors.

TWO NONPROFIT drug development groups also have sprung up to combat other neglected diseases. The Institute for OneWorld Health, established in July 2000, is committed to finding new drugs to treat parasitic diseases. And early this year, Médecins Sans Frontières (Doctors Without Borders) launched the Drugs for Neglected Diseases Initiative (DNDI), an international effort to bridge R&D gaps in drug development.

Sequella exemplifies what a difference a start-up can make in addressing unmet public health needs. An example from its product pipeline is a patch that detects only active tuberculosis. At present, initial detection of tuberculosis infection is based on a skin test. However, the skin test does not differentiate between patients with active infection, who are infectious, and patients with latent infection, who are not infectious. Furthermore, individuals who have been inoculated with BCG vaccine, which is still being used in many developing countries to control tuberculosis, also test positive. On the other hand, definitive diagnosis of an active infection is resource-intensive and time-consuming (C&EN, May 17, 1999, page 60).

	Nacy	Freire
	PHOTOS BY MAUREEN ROUHI

Sequella's patch, when available, will solve this problem. The patch responds to a protein secreted only by mycobacteria that cause tuberculosis in humans. It won't pick up BCG vaccination or other mycobacteria, such as those that abound in soils in the southern U.S. And it won't respond to a previous tuberculosis infection that has been cured with drugs. Carol A. Nacy, Sequella's chief executive officer, estimates that the product may be available outside the U.S. in late 2003 and in the U.S. in 2004.

Patient compliance is another urgent need that another Sequella product is hoping to meet. In tuberculosis-endemic countries, compliance is monitored through DOTS--directly observed therapy, short course--which requires public health workers to personally observe and document patients taking medications daily.

Sequella is commercializing a wristwatch with a fluorescence detector on the back. The idea is to formulate tuberculosis drugs with indocyanine green, a fluorescent excipient that is approved by the Food & Drug Administration for human use. As the excipient circulates, the watch marks the time it crosses the path of the detector.

The device has been tested with rabbits. Human testing will be carried out on patients being examined for retinitis. According to Nacy, ophthalmologists routinely use indocyanine green to examine the retina. Sequella has reached an agreement with some ophthalmologists to put the wristwatch on patients to see if it can detect circulating excipient. The device may be on the market by late 2004.

Nacy has received enthusiastic inquiries about the device from doctors treating alcoholism and bipolar depression. "The tuberculosis people are the least interested," she tells C&EN. "They say, 'We know DOTS, and it works.' But the cost of one health worker monitoring six patients can pay for 500 of these monitors, which will be priced at less than $30 each." Besides, the device is a watch. If the patient makes it through the treatment, the reward is to keep the monitor. In developing countries, that's a good incentive.

"The best part of the company is that we have such fun products to play with," Nacy says. Another one is the Bronx box, invented by William R. Jacobs, a Howard Hughes Medical Institute investigator at Albert Einstein College of Medicine, Bronx, N.Y. It reduces the time and cost of determining the drug susceptibility profile of a tuberculosis infection.

Jacobs has engineered tuberculosis-invading viruses--or phages--that contain a firefly luciferase gene. When such a phage enters a live tuberculosis bacterium, it rapidly multiplies and emits light, indicating it has a living host. The emission pattern for bacterial isolates grown in the presence of different antibiotics, captured on film, will help doctors decide what drugs to prescribe. The Bronx box contains panels where, successively, phages invade bacteria, the phage-invaded bacteria are incubated in an antibiotic-containing medium, and a detector records light emissions. Results are available in two days.

ON THE DRUG development front, Sequella and TB Alliance are on complementary tracks. At the moment, Sequella's lead compounds are analogs of ethambutol that were discovered with combinatorial chemistry techniques by Clifton E. Barry III and coworkers at the National Institutes of Health. The company is also developing analogs of off-patent compounds with antituberculosis activity that were discovered by Lederle but not developed. "Lederle set aside these compounds because they would have competed with their ethambutol sales," Nacy tells C&EN. "In the 1960s, people thought that if you had a tuberculosis drug, that's it--not realizing that drug combinations would be needed."

TB Alliance is moving ahead with PA-824, a potent antituberculosis compound identified in industry (C&EN, June 26, 2000, page 14). TB Alliance has licensed the compound and has moved it further into preclinical development, says Maria C. Freire, the alliance's chief executive officer.

Existing drugs for tuberculosis have many shortcomings, Freire points out. Treatment lasts six to nine months and is complicated by the rapid development of drug-resistant strains; in addition, many drugs have terrible side effects. These factors, "compounded by the problem arising from the twin epidemics of HIV and tuberculosis, have made new medicines imperative for public health," she says.

To deliver on the promise of new drugs by 2010 on a modest budget of $300 million, TB Alliance focuses on late-discovery and preclinical-stage compounds, Freire says. "Our strategy includes novel compounds as well as analogs and derivatives of existing compounds that can be improved to match the required drug profile. There are also important opportunities in evaluating existing drugs that have not yet been used for tuberculosis."

THE ALLIANCE HAS set three goals for a new drug: It must shorten the treatment time or significantly reduce the number of doses needed to be taken under DOTS supervision; it must treat multiple-drug-resistant infections; and it must act against latent infection.

"There is no guarantee that every promising lead compound will deliver all three," Freire says. But in reviewing candidates for the portfolio, the alliance gives preference to compounds with potent bactericidal activity, to reduce the length of treatment; to those that belong to new compound families, to address the problem of drug resistance; and to compounds that demonstrate sterilizing activity, to deal with latent infection. "We are enthusiastic about PA-824 because it has a good chance of meeting all three objectives," she says.

To maximize the chance of registering a drug by 2010, the alliance needs to have five to seven projects in late-discovery or preclinical stage, and it needs to license two compounds for entry into Phase I clinical trials per year. Two deals are being negotiated, and several others are being evaluated. "We are on target, both in profile and timeline, in building our portfolio," Freire says.

"The alliance is an ally," Nacy says. "There's no competition if they come out with a drug and we have a drug. It is unlikely that our drugs will have the same mechanism of action. Besides, tuberculosis will never be treated with a single drug. A combination of drugs will always be needed because the bacteria quickly become resistant to single drugs.

WHEN SEQUELLA was born in 1997, it came with a twin, the Sequella Global Tuberculosis Foundation. Part of the solution to the tuberculosis problem, Nacy says, is to commercialize products, which is what Sequella Inc. is doing. The other need is to help researchers bridge the gap between basic research and product-oriented research, which is the foundation's role. The foundation attracts philanthropic money to fund proof-of-principle experiments that researchers need to do to assess the value of basic research projects. It focuses on early-phase development, where most products fail, Nacy says.

The two institutions are distinct and separate and have no obligations to each other, Nacy explains. At the moment, they share three attributes: a focus on tuberculosis; the name Sequella; and Nacy, who serves as the foundation's volunteer president. However, the foundation will soon have a new name and is searching for a CEO.

Tuberculosis vaccines have been a major beneficiary of the foundation. With support from the Bill & Melinda Gates Foundation, vaccine testing sites have been established, and three vaccines will soon go to human trials. One is a therapeutic DNA vaccine being commercialized by Sequella Inc., which had to compete with other organizations for Sequella Foundation funding in support of clinical testing. Another is a recombinant BCG vaccine strain that overexpresses a major protein found on cell walls of tuberculosis bacteria. This was developed by Marcus A. Horowitz and coworkers at the School of Medicine of the University of California, Los Angeles. The third is a synthetic peptide vaccine being commercialized by the Austrian company Intercell.

"We told the Gates Foundation that we would have one vaccine in clinical trials in five years," says Nacy, wearing the hat of Sequella Foundation president. The first clinical trials will begin in late 2002, and two more will be under way in 2003.

"We're going to meet and beat our five-year milestone in year four of the Gates grant," she says. That's an astonishing accomplishment, she points out, given the attitude of the tuberculosis vaccine community only a few years ago.

Nacy found that researchers were reluctant to test on humans. "I was blown away by the reason: They get grant support for studying vaccines," she says, and "a failure in humans could jeopardize future support." The anxiety is understandable, she adds.

Long treatment times, drug-resistant strains, and terrible side effects, "compounded by the problem arising from the twin epidemics of HIV and tuberculosis, have made new medicines imperative for public health."

FURTHERMORE, the tuberculosis vaccine community was setting its goals too high, it seemed to Nacy. "They thought their vaccine should be something that will be given at birth and would last a lifetime, that's inexpensive, and that would prevent both systemic disease in babies and pulmonary disease in adults."

The Sequella Foundation persuaded the community not to worry about a gold standard and just start somewhere, Nacy says. "By getting into clinical trials now, we can see what works under what situations, we can build a body of information based on humans, and researchers then can go back and reengineer their vaccines. The foundation has persuaded the community that it's okay even if their vaccine is just a bit better than what's available. It still will make a big difference."

Patients with tuberculosis have much reason to hope for new remedies. Help is also on the way for people suffering from other neglected diseases.

OneWorld Health, which was founded by Victoria Hale, a pharmaceutical scientist and an expert in drug development, is targeting parasitic diseases. "Drugs for tropical diseases are often very old, some dating back to the 1920s," she points out. "New drug therapy for infectious diseases has received little attention among large pharmaceutical companies, and the situation is even worse for tropical diseases."

However, the inattention is not for lack of interest. "Many pharmaceutical scientists I speak with are eager to contribute to research on tropical diseases," Hale says. "It is simply a matter of creating opportunities to engage their talents. OneWorld Health is one of several new paths for scientists to make a bold impact on global health."

With support from the Gates Foundation and NIH, OneWorld Health is developing new treatments for Chagas disease and visceral leishmaniasis, which are caused by protozoan parasites. It is in the process of acquiring an exclusive license from the U.S. Army to complete development of a new product for cutaneous leishmaniasis. And it will soon explore the safety of antimalarial combination therapies for pregnant women.

With the World Health Organization (WHO) as partner, OneWorld Health is initiating a Phase III clinical trial of paromomycin in India. Paromomycin is an off-patent antibiotic, first used 45 years ago, but abandoned, Hale says. It has since been shown to have significant promise in fighting visceral leishmaniasis infection. The clinical trial, performed to international standards, will be the basis for approval and registration of paromomycin in India and around the world, she tells C&EN.

DNDI IS THE latest to join the ranks of nonprofit, virtual drug development organizations. It is so new that its founder, Médecins Sans Frontières, is still identifying cofounder institutions to help create the new legal entity. Nevertheless, DNDI already has several immediate drug development pilot projects under way.

"We have identified projects that we believe can, in the very short term, make a difference--for example, by making a product available in two years," says Els Torreele, cochair of Médecins Sans Frontières' Drugs for Neglected Diseases Working Group, which recommended the creation of DNDI. "From these projects, we can learn how to make DNDI's vision of an international virtual drug development network work in a systematic way."

Two projects involve developing fixed-dose drug combinations to treat chloroquine-resistant malaria. "It is widely accepted that drug combinations are the best way to slow or prevent the development of resistance to drugs," Torreele points out. In these projects, eight partners worldwide are working on one-pill combinations of artesunate with mefloquine and with amodiaquine.

Artesunate is hailed as the new drug for malaria. It is rapid-acting, and malaria-causing parasites have not yet developed resistance to it. Mefloquine and amodiaquine are older drugs. They are slow-acting, and in some malaria-endemic countries they are no longer effective. DNDI believes, as does WHO, that combining artesunate with mefloquine or amodiaquine will yield a drug with better efficacy, Torreele says. She expects these projects to have something that can go to clinical trials by 2003.

One project--to reexamine a candidate drug to treat sleeping sickness and Chagas disease--has been concluded. Megazol is an old anti-infective drug that fights the parasites causing these diseases but was abandoned because it is mutagenic. "It had never been studied carefully to see if it could be used in doses low enough to be effective for sleeping disease and not cause mutagenesis," Torreele says. "We examined everything known about this compound and did additional toxicological experiments to determine if it could still be a candidate." Last month, their data showed that the toxicity is too problematic, and the project has been terminated.

	WAITING A Honduran boy waits to be screened for Chagas disease. Treatment can be administered only to children 12 years old and younger because the drug is too dangerous for older patients. SERGE SIBERT/MÉDECINS SANS FRONTIÈRES

AND IN THE PLANNING stages is a project that complements one of OneWorld Health's--to register paromomycin in countries where leishmaniasis is prevalent. "We are discussing with registration authorities in different countries what needs to be done and identifying the partners who will do it," she says.

OneWorld Health and DNDI are both tackling diseases that no one else would, Hale says. But their approaches are different. OneWorld Health is a nonprofit company employing researchers who work full time. "The complexity and uncertainty of drug development demand that we have full-time scientists on-site to give daily attention to every aspect of the drug development endeavor," Hale says. By contrast, DNDI will manage drug development virtually, relying on partnerships among institutions, especially in developing countries, to bring new drugs to where they are most needed.

Back at Sequella Inc., Nacy is bursting with excitement. "I have just signed my lead investor," she tells C&EN. "We are ready to do the first venture financing of a tuberculosis-focused company ever." Although the business is viewed as high risk, Sequella's pipeline seems to have convinced investors that it's on to something.

RALLY Nonprofit groups target parasitic diseases DISEASE, CAUSATIVE AGENT,AND MODE OF TRANSMISSION DISTRIBUTION AND ANNUAL DEATHS PROJECTS Malaria 100 countries: tropical Africa, Asia, and Latin America OneWorld Health and Drugs for Neglected Diseases Initiative (DNDI) are developing combination therapies. OneWorld Health is developing an oral drug based on a protease inhibitor. Agents: Protozoan parasites Plasmodium falciparum, P. vivax, P. ovale, and P. malariae 1.1 million deaths Transmission: Mosquito bites Chagas disease 18 countries: northern South America and Central America Agent: Protozoan parasite Trypanosoma cruzi 21,000 deaths Transmission: Bites of assassin bugs, transfusion with infected blood, or congenitally from infected mother Leishmaniasis 88 countries: South America, South Asia, sub-Saharan Africa, North Africa, and the Middle East OneWorld Health and DNDI are working to obtain regulatory approval for paramo mycin for visceral leishmaniasis. OneWorld Health will be developing a topical drug for cutaneous leishmaniasis. Agents: Protozoan parasites of the genus Leishmania 11,000 deaths Transmission: Sandfly bites

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