Two strong contenders begin journey toward shorter TB therapy
Two strong contenders begin journey toward shorter TB therapy
Global Alliance licenses agent; TBTC eyes moxifloxacin
The Global Alliance for TB Drug Development sealed its first deal in January to start developing a new TB drug, a novel compound known as PA-824. Though its name hardly rolls off the tongue, many TB researchers say PA-824 may have what it takes to radically shorten TB therapy — namely, the ability to sterilize by mopping up persisting, slow-growing mycobacteria. The process of sterilization is what makes TB treatment last so long. If PA-824 proves as talented a sterilizing agent in people as it has in mice and in test tubes, it would fling open the doors to much shorter therapy.
New drug may target TB enzymes
"We’ve already got good drugs, especially isoniazid, that exert a strong bactericidal effect by knocking down big populations of rapidly dividing TB bugs early in the game," says Rick O’Brien, MD, chairman of the Alliance’s Scientific Advisory Board and chief of the research and evaluation branch at the Division for TB Elimination at the Centers for Disease Control and Prevention in Atlanta. "For sterilizing, we have rifampin; the trouble is that it takes six months or more to get there. We think PA-824 may exert its effect by targeting mycobacterial enzyme systems more effectively than rifampin. That’s all still hypothetical, of course, but it’s certainly what the data suggest."
Because of its ability to wipe out persisters in the lab, PA-824 also holds promise as a new treatment for latent TB. And as a novel agent to which TB has never been exposed, it’s logical to assume it could eventually serve as a new weapon against resistant strains of disease.
The deal was concluded following a year of negotiations between the Global Alliance and PA-824’s owner, the Emeryville, CA-based drug-maker Chiron Corp., which focuses on therapeutics for infectious diseases and cancer. The nonprofit alliance was formally launched a year ago with money from the Bill and Melinda Gates Foundation, along with start-up funds from the Rockefeller Foundation. The group has two goals: first, to come up with a new TB drug that works in just two months by the year 2010; second, to sell the drug at an affordable price to poor countries where TB is endemic.
Accordingly, the terms of the deal struck last month prevent Chiron from collecting royalties on sales to developing countries. At the same time, if all goes well, the drug company can exercise a "grant-back" option to sell the drug at a higher price in wealthy countries.
A small privately held company and another nonprofit group were also reportedly contenders for licensing rights to PA-824. The compound was first synthesized by Pathogenesis, a small biotech shop in Washington state. After Pathogenesis was put on the market for acquisition, its owners decided to shelve the compound, along with another promising new agent, rifalazil. Once Pathogenesis was acquired by Chiron, interest in PA-824 began to heat up again.
Johns Hopkins may do PA-824 work
Because seminal research on the compound involved an extremely complicated formulation, the first order of business will probably be to find something more user-friendly and to figure out appropriate dose levels, says Barbara Laughon, PhD, co-chairwoman of the Alliance’s Scientific Advisory Board and a program officer in the Opportunistic Infections Research Branch of the Therapeutics Research Program at the National Institute of Allergy and Infectious Diseases in Bethesda, MD. Several laboratories will probably be awarded contracts for all the preclinical work that will be needed before the compound can be considered for human trials, Laughon adds.
Although Laughon declined to talk specifics, one contender for the lab work is said to be the Center for TB Research at Johns Hopkins University in Baltimore. The TB community took note in January when Johns Hopkins landed Jacques Grosset, MD, a top-notch French researcher who has devoted his career to constructing a meticulous murine model for TB.
"We’re absolutely delighted to have Grosset here," says William Bishai, PhD, associate professor in Johns Hopkins School of Medicine’s Division of Infectious Diseases and Grosset’s new American colleague. "He’s a walking textbook, and his coming here will let him train new generations in the kind of work he does. I’m also really excited about PA-824. It seems as if now is the right time to begin testing it." If the Hopkins center winds up doing some of the work, Bishai adds, "we’d probably start by adding PA-824 to standard therapy to see if we could shorten it. Later, we might try substituting it for another drug."
A promising quinolone enters Phase 2 trial
At about the same time news about PA-824 hit, preparations continued for work on moxifloxacin, an antibiotic many researchers believe will find a new use as a first-line TB drug. A member of the fluoroquinolone family of antibiotics owned by Bayer Pharmaceuticals, the drug is now poised to start a Phase 2 trial carried out by the CDC’s TB Trials Consortium (TBTC). Study 27, as the trial is designated, will enroll up to 450 newly diagnosed TB patients and should start enrollment by the end of this year. Last month’s milestone was the formation of the protocol committee for the study, according to O’Brien.
Even though moxifloxacin is already used off-label for treating multidrug-resistant TB, Study 27 will seek to determine whether the drug is truly safe and tolerable for long-term use. Another even more important endpoint will be how much the drug can increase the rate of two-month sputum-culture conversion, says O’Brien. Because sputum-culture conversion is widely accepted as a measure of a drug’s sterilizing capability, an increase in conversion rates would support the belief that the drug works well as a sterilizing agent and thus could be used to shorten therapy.
As with PA-824, the TBTC isn’t the only group that wants to work with moxifloxacin. The Global Alliance is rumored to be conducting in-licensing negotiations with Bayer.
Researchers at Johns Hopkins are already doing work aimed at establishing whether the drug offers a way to cut frequency of treatment. To do that, the researchers will give TB-infected mice a regimen that pairs moxifloxacin with long-acting rifapentine. In work published before he retired from his post at Hopital Pitie Salpetriere in Paris, Grosset showed that treating mice once weekly with the two drugs (with two more agents added for the initial phase of treatment) worked nearly as well as twice- or thrice-weekly therapy with the standard four drugs.1
"This means moxifloxacin could, in effect, save rifapentine," O’Brien adds. In other words, despite its seductively long half-life, rifapentine is restricted for now to use in just a select few TB patients — namely, those who are HIV-negative and otherwise low-risk, with non-cavitary TB and sputum cultures that convert at two months.
Higher doses of rifapentine should solve part of the problem, many researchers say, so it’s good news that a recent TBTC trial found that higher doses of the drug are safe and well-tolerated. Finding the other piece of the rifapentine puzzle may involve throwing out isoniazid, the drug with which rifapentine is currently paired when used for one-weekly therapy, and replacing it with moxifloxacin. If that strategy pans out, the breakthrough will broaden TB treatment options to include once-weekly rifapentine-based treatment for practically everyone, O’Brien says.
"Those are really the two big issues right now in TB drug development — to find a way to shorten TB therapy, or to make it more intermittent," says Bishai. "Both strategies will be of enormous help to people in developing and developed countries alike."
Reference
1. Lounis N, Bentoucha A, Truffot-Pernot C, et al. Effectiveness of once-weekly rifapentine and moxifloxacin regimens against Mycobacterium tuberculosis in mice. Antimicrob Agents Chemother 2001; 45:3482-3486.
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.