COVER STORY year, Medecins Sans Frontieres (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 A. MAUREEN ROUHI, C&EN WASHINGTON detection of tuberculosis infection is based on a skin test. However, the skin test does ^ n ESTLED IN MARYLAND'S BIOTECH similar to that of a virtual drug company: not differentiate between patients with acB ^ 1 corridor is Sequella Inc., a fiveIt will use outside resources and services to tive infection, who are infectious, and pa1 ^ ^ I year-old company that's poised move lead compounds through developtients with latent infection, who are not H ^ B to bring new tools to combat ment. But as a nonprofit, it attracts philinfectious. Furthermore, individuals who m ^ 1 tuberculosis into the marketanthropic contributions instead of raising have been inoculated with BCG vaccine, place within three years. Sequella is the oncapital from investors. which is still being used in many developly company in the world with a singular ing countries to control tuberculosis, also TWO NONPROFIT drug development focus on tuberculosis, and it aims to comtest positive. On the other hand, definigroups also have sprung up to combat othmercialize any product—drugs, vaccines, tive diagnosis of an active infection is rediagnostics—that can help the more than er neglected diseases. The Institute for source-intensive and time-consuming 2 billion p e o p l e worldwide w h o are One World Health, established in July (C&EN, May 17,1999, page 60). infected with tuberculosis, 2 million of 2000, is committed to finding new drugs Sequella's patch, when available, will whom die each year. to treat parasitic diseases. And early this solve this problem. The patch Tuberculosis is one of the soresponds to a protein secreted called neglected diseases — those only by mycobacteria that cause for which drug development has tuberculosis in humans. It won't been grossly inadequate, despite pick up BCG vaccination or their prevalence and the human other mycobacteria, such as suffering and economic loss they those that abound in soils in the cause. The reasons for neglect are southern U.S. And it won't reprimarily economic: These disspond to a previous tuberculoeases are usually widespread in sis infection that has been cured countries where patients are with drugs. Carol A. Nacy, Seamong the poorest in the world. quella's chief executive officer, The view has been that developestimates that the product may ing drugs for such populations is be available outside the U.S. in not profitable, and it is therefore late 2 0 0 3 and in the U.S. in undertaken only with great re2004. luctance by for-profit entities. Patient compliance is anothHowever, new ways to develer urgent need that another Seop drugs for neglected diseases quella product is hoping to have recently come to the fore. meet. In tuberculosis-endemic The existence of a company like countries, compliance is moniSequella, founded in 1997, is tored through DOTS —directbased on the premise that monly observed therapy, short ey can indeed be made from course—which requires public products aimed at diseases like health workers to personally obtuberculosis. That premise is supserve and document patients ported by a study showing that taking medications daily the global market for tuberculoSequella is commercializing sis drugs could be as high as $ 70 0 a wristwatch with a fluorescence million peryear by 2010 (C&EN, detector on the back. The idea March 25, page 42). The study is to formulate tuberculosis was carried out by the Global drugs with indocyanine green, Alliance for TB Drug Devela fluorescent excipient that is opment, often shortened to TB Alliance. approved by the Food & Drug Administration for human use. TB Alliance, established in As the excipient circulates, the October 2000, is a nonprofit orwatch marks the time it crosses ganization committed to deliv- HELPING HAND A nurse with Medecins Sans ering a new tuberculosis drug by Frontieres examines a patient at a tuberculosis hospital in the path of the detector. The device has been tested 2010. It has a business model the self-proclaimed Abkhaz Republic.
PAYING ATTENTION TO UNMET NEEDS
Start-up, nonprofits are developing tools to fight diseases afflicting poor nations
HTTP://PUBS.ACS.ORG/CEN
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COVER STORY 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 detennining 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 alive 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.
PIPELINE Sequella Inc. is currently commercializing five products for tuberculosis PRODUCT
DESCRIPTION
STATUS
WORLD MARKET
Secondgeneration ethambutol
Ethambutol is a first-line drug. Second-generation analogs are up to 100 times more potent and are active against ethambutol-resistant strains. Wristwatch like device records when medication is taken.
Preclinical: Lead compounds are being optimized in advance of formal preclinical toxicity studies Preclinical: Device is being tested on animals
$300 million to $500 million
Heat-shock protein DNA vaccine shortens period of drug therapy and reduces evolution of drug-resistant strains. Band-Aid-like patch detects active tuberculosis only. Device determines drugresistance profile of a patient's infection in two days.
Going into Phase I clinical trials
$700 million to $800 million
Phase III clinical trials
$700 million
Phase I'clinical trials
$300 million
Drug compliance monitor Therapeutic vaccine
Transdermal patch Bronx box
$100 million
SOURCE: Company data
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COVER STORY Existing drugs for tuberculosis have I from the twin epidemics of H I V and tu- I Freire says. "Our strategy includes novel many shortcomings, Freire points out. berculosis, have made new medicines imcompounds as well as analogs and derivaTreatment lasts six to nine months and is perative for public health," she says. tives of existing compounds that can be complicated by the rapid development of Ύο deliver on the promise of new drugs improved to match the required drug prodrug-resistant strains; in addition, many by 2010 on a modest budget of $300 milfile. There are also important opportunidrugs have terrible side effects. These faclion, TB Alliance focuses on late-discovties in evaluating existing drugs that have tors, "compounded by the problem arising I ery and preclinical-stage compounds, not yet been used for tuberculosis."
I I
I : ! HOPE Research by Natalia Kurepina at the Public Health Research Institute's TB Center Laboratory in Newark, N.J., is aimed at eliminating tuberculosis.
>WiCKeD
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 su pervision; it must treat multiple-drug-resistant infections; and it must act against latent infection. I "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 demon strate sterilizing activity to deal with la tent infection. "We are enthusiastic about PA-824 because it has a good chance of I meeting all three objectives," she says.
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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 D N A 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. HTTP://PUBS.ACS.ORG/CEN
"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 fiveyear 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 re-
luctant 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. 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
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COVER STORY both systemic disease in babies and pulmonary disease in adults." The Sequella Foundation persuaded the community not to worry about a gold stan-
ter than what's available. It still will make a big difference." Patients with tuberculosis have much reason to hope for new remedies. Help is
uation 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
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."
Nacy
also on the way for people suffering from other neglected diseases. OneWorldHealth,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 a t t e n t i o n among large pharmaceutical companies, and the sit-
Freire
dard 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 bet-
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 N I H , 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 develop-
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COVER STORY ment 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 offpatent 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, Medecins Sans Frontieres, is still identifying cofounder institutions to help create the new legal entity Nevertheless, D N D I 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
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WAITI NG 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. product available in two years," says Els Torreele, cochair of Medecins Sans Frontieres' Drugs for Neglected Diseases Work-
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COVER STORY an international virtual drug development network work in a systematic way" Two projects involve developing fixeddose drug combinations to treat chloroquine-resistant malaria. "It is widely ac-
cepted that drug combinations are the best way to slow or prevent the development of resistance to drugs,"Tbrreele points out. In these projects, eight partners worldwide are working on one-pill combinations of
RALLY Nonprofit groups target parasitic diseases DISEASE, CAUSATIVE AGENT, AND MODE OF TRANSMISSION
DISTRIBUTION AND ANNUAL DEATHS
Malaria 100 countries: tropical Africa, Agents: Protozoan parasites Asia, and Latin America Plasmodium falciparum, P. vivax,1.1 million deaths P. ovale, and P. malariae Transmission: Mosquito bites Chagas disease 18 countries: northern South Agent: Protozoan parasite America and Central America Trypanosoma cruzi 21,000 deaths Transmission: Bites of assassin bugs, transfusion with infected blood, or congenially from infected mother Leishmaniasis 88 countries: South America, Agents: Protozoan parasites South Asia, sub-Saharan of the genus Leishmania Africa, North Africa, and the Transmission: Sandfly bites Middle East 11,000 deaths
PROJECTS
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.
OneWorld Health and DNDI are working to obtain regulatory approval for paramomycin for visceral leishmaniasis. OneWorld Health will be developing a topical drug for cutaneous leishmaniasis.
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artesunate w i t h mefloquine and w i t h 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. D N D I believes, as does W H O , that combining artesunate with mefloquine or amodiaquine will yield a drug with better efficacy, Tbrreele 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,"Tbrreele 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. 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 D N D I 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, D N D I 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. • HTTP://PUBS.ACS.ORG/CEN
