Funding shortage imperils promising quinolone trials

$20M to $30M needed

Trials for the most promising new candidate on the horizon for shortening TB treatment may never get off the ground unless a funding source can be found, says William J. Burman, MD, infectious disease specialist at the Denver Medical Health Center and chairman of the Core Science Group at the TB Trials Consortium (TBTC).

Exciting trial data from India suggest that adding a fluoroquinolone to both the induction and continuation phase would pack so much punch that both the frequency and the duration of treatment could be scaled back substantially. The problem is that the cost of the trials is expected to run between $20 million and $30 million, says Burman.

Despite that obstacle, researchers are plowing ahead on several fronts. That includes work on possible designs for a trial involving one of the drugs; negotiations with Bayer Pharmaceuticals, which holds the license to make the drugs; and tests of early bacteriocidal activity (EBA) to help researchers decide which quinolone to use.

Looking to AIDS for a model

As for funding, Burman says it’s wrong for TB control programs to have to fight over the same meager pie as TB researchers. The best solution would be to give the Tuberculosis Trials Consortium its own line item in the budget, a perk the AIDS research community has long enjoyed. "You don’t see Ryan White [treatment] money having to compete with AIDS research money," he points out. "That’s the way it ought to be for TB, too."

Debate on appropriations for domestic TB spending for 2002, set to start last month, was postponed by terrorist attacks.

Finances notwithstanding, other prospects for the trials look good. Giorgio Roscigno, former chief of the New York-based Global Alliance for TB Drug Development, is negotiating with Bayer Pharmaceuticals.

Bayer also dispatched envoys to a recent National Institutes of Health meeting on new TB drug development. "They mostly sat back and listened, but they weren’t actively discouraging, which we took as a good sign," Burman reports.

Last month, TBTC researchers met with other TB experts at the Centers for Disease Control and Prevention to explain various possible trial designs. One permutation on the table would substitute a quinolone for ethambutol, or perhaps isoniazid, in the initial phase of treatment, says Burman. "Ethambutol does nothing, for all we can tell, so from an efficacy standpoint there would be essentially zero risks," Burman says. "Isoniazid also does relatively little in the context of four-drug therapy."

Next, the idea would be to take a look at efficacy by measuring culture-conversion rates at two months, says Burman. Data from recent trials of quinolones conducted in Chennai, India, grabbed researchers’ attention, indicating that adding one of the drugs may increase conversion rates by 10% or more. To everyone’s considerable frustration, the Chennai trials failed to include a control arm. Still, if the TBTC can replicate anything near the Indian researchers’ results, the impact could be profound.

Once-weekly dosing a possibility

TBTC researchers also like the idea of adding a quinolone to the continuation phase, where they might team it with long-acting rifapentine (RPT), says Burman. Doing that might reduce frequency of dosing to once weekly — as in Study 22 — but more effectively, because many experts have decided that a quinolone is probably going to prove a stronger partner for RPT than isoniazid, the agent teamed with it in Study 22.

Work also is under way to help researchers decide which quinolone to use. Toxicity concerns are mild, Burman adds, because the drugs already have been used extensively as second-line agents in treatment of multidrug-resistant TB, as well as in some AIDS trials. To weigh the efficacy of the various quinolones, the consortium is about to start tests of EBA by assaying subsequent sputum samples to assess kill power early in treatment.

Candidates to be vetted in the EBA studies may include levofloxacin (which is backed by the most clinical experience and toxicity data), moxifloxacin (which performed strongest in recent work in animals), and gatifloxacin (fewer data exist for this drug, Burman says).

To help cut costs and expedite enrollment, the TBTC will probably collaborate on the trials with the National Institute of Health’s TB Research Unit, says Burman. The collaboration would be a first, but it’s not a done deal. One potential problem is that the TB Research Unit’s mandate, on paper at least, directs it to look for surrogate markers, not to conduct trials.

That brings Burman back to why the TBTC deserves its own funding source. It’s the only agency in the country equipped to conduct TB trials, he points out. The reason is simple: Trial sites all have close ties to public health TB clinics — so close that in some instances, the trial site is the TB clinic. That means ready access to TB patients. "That’s been a good move," Burman adds. "It’s what has let us be a successful TB research organization."