Potential Shorter, Simpler TB Treatment Heads to Phase II Trials

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The TB Alliance announced this week enrollment of a Phase II trial, NC001 (or New Combination 1), testing the new TB drug candidates PA-824 and moxifloxacin in combination with pyrazinamide, an existing antibiotic commonly used in TB treatment today. The 14-day, inpatient study will be conducted with 68 patients in two clinical sites in South Africa. The drugs were separately tested for safety and efficacy in patients alone before entering the combination trial.

Science Speaks asked Carl Mendel, MD, Senior Vice President of Research and Development at the Global Alliance for TB Drug Development (TB Alliance), some questions about the trial:

In the press release it says “If successful, the combination regimen would take treatment time from currently two years to just six months.” But in the trial, they are giving patients therapy for only two weeks and then watching them for three months. Is this trial more for safety than efficacy? Explain.

This trial is for both safety and efficacy.  The two-week safety and efficacy is an important building block in the development path.  The next step is two-month safety and efficacy, then Phase III.

So the final therapy is anticipated to be six months in length, correct?  What would be the impact of that change? What is the typical treatment timeline for someone with TB now? Multiple Drug Resistant TB (MDR-TB)?

Our current best guess right now of the final treatment length in both drug sensitive and drug resistant disease is four months or less.  The biggest impact of this regimen will be on MDR-TB, which currently is treated with 18 to 24 months (or longer) of therapy, including injectibles.

Beyond the significant treatment shortening benefit, this regimen could drastically simplify treatment and is likely to be much less expensive than current treatment.

The cost of just the drugs needed to treat MDR-TB is approximately $2,000 – $3,000 (this does not include the cost of administering the treatment). The cost of procuring and administering MDR-TB treatment has thus far prevented the scale-up of MDR-TB treatment around the world. Currently, roughly a mere one percent of MDR-TB patients receive World Health Organization-sponsored, appropriate treatment. If successful, the benefits of this regimen could make huge strides in enabling the worldwide scale-up of MDR-TB treatment.

In addition to projecting to be much cheaper to produce, a faster, simpler regimen would result in sizeable savings in terms of administrative costs and human resources associated with providing treatment.

Talk to me about this clinical trial in the context of drug resistance – MDR-TB and extensively drug resistant TB (XDR-TB). Are these the first novel drugs specifically treating both drug-sensitive and drug-resistant strains?

Drug-resistant TB is an emerging global health threat that is extremely lethal, and woefully expensive and complicated to treat. Curbing the emergence and reversing the course of drug-resistant TB is just not possible without the introduction of new, more effective, quicker acting, simpler, and more affordable treatments.

This particular trial is being conducted in patients with drug sensitive disease, but the regimen, which contains a new chemical entity with a new mechanism of action, is expected ultimately to be effective in both drug-sensitive and multi-drug resistant disease and we intend to develop it for both.  However, since Moxifloxacin is a fluoroquinolone, we do not expect that NC001 will be effective in treating XDR-TB, since XDR-TB is resistant to the fluoroquinolones.

This is not the first time a new TB drug candidate is being tested for potential efficacy against drug-resistant TB. For example, TMC207, a Phase II compound being co-developed by Tibotec and the TB Alliance, is currently undergoing testing in MDR-TB patients as well as in drug-sensitive TB patients.

What is truly unique in NC001, however, is the manner in which the testing is occurring.

We keep hearing about hurdles in funding. How hard was it to get this trial funded? What comes after Phase II? Will more funding be needed for the ensuing trial phases or is the process funded with this drug regimen?

This trial was funded by our existing donors.  As we succeed at each stage of clinical development, the next stage becomes more expensive (the reward for success).  We remain dependent on our current and future donors for future funding to support our successful clinical development programs. Additional clinical testing will be needed to register new TB drug regimens, as well as to continue to develop the next generations of even more greatly improved treatments.

[Both new compounds in this Phase II trial are being developed by the nonprofit organization TB Alliance, one (moxifloxacin) in partnership with Bayer HealthCare AG.]

Assuming safety, efficacy and tolerability – realistically, how long are we thinking before these drug combinations can get into the hands of those who need them?

If this novel regimen is successful, we calculate that the earliest it could come to market would be in 2016.

The simultaneous substitution enabled by NC001’s development model, championed through the Critical Path to New TB Drug Regimens initiative will shave many years off of the timeline of any regimen that consists of multiple, previously unregistered TB drugs.

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