This afternoon, Dr. Mel Spigelman, president and CEO of the Global Alliance for TB Drug Development, and other leading TB advocates will join with FDA Commissioner Margaret Hamburg to launch a new initiative designed to accelerate the development and approval of life-saving new treatments for tuberculosis. There are now at least 9 promising new TB drugs in the pipeline. This project aims to shave decades off the time it takes to bring dramatically improved TB treatments to the millions of patients who die unnecessarily from TB. These drugs are desperately needed tools in the battle against TB, an epidemic that claims 1.8 million lives each year. We spoke with Dr. Spigelman about the implications of this new initiative, called the Critical Path to TB Drug Regimens (CPTR).
Q: I know there are 9 new TB drugs in the pipeline and this initiative will allow them to be tested together and earlier in development. Can you tell me exactly how this process will work—what steps will be skipped and where and how will these drugs be tested?
Dr. Spigelman: What’s important to realize is that the CPTR is not about skipping steps, but rather streamlining processes and creating more efficient pathways to accomplish one goal—to dramatically speed the time it takes to bring new TB drug regimens to patients.
That’s important because developing new drug regimens is an extremely long process. Traditionally, new regimens are developed by successively substituting one new drug at a time into the existing regimen. Each substitution usually takes a minimum of 6 to 8 years. Therefore, for a completely new regimen, substituting one drug at a time, it could take at least a quarter of a century. That’s too long to wait, when nearly 2 million patients die each year from TB.
CPTR allows combination testing of new–as well as existing–drugs at once, reducing the time it takes to develop novel regimens to as little as 6 to 8 years. The CPTR has put together a regulatory science consortium, led by the Critical Path Institute, which will play a key role in validating the regulatory science that will back this process.
Preclinically, compounds will undergo the same battery of tests an individual drug is subjected to, as well as additional combination tests that will generate information that to be used to identify which drug combinations display the most promise. The fastest-acting and most effective combinations will move toward the clinic.
Q: Ever since the first human trials of the first-ever drug used to treat TB, streptomycin, in 1947, Mycobacterium tuberculosis has proven its ability to dodge our medical weaponry by developing resistance to these drugs. There’s a concern that if we continue to introduce new TB drugs one at a time, we will end up repeating history. What, if anything, does this project do to address those concerns?
Dr. Spigelman: You’re right–developing drugs one by one does increase the risk that resistance to therapies will develop. Under the conventional paradigm, by the time a second new drug is introduced into a regimen, resistance could have begun to mount against the first drug.
CPTR will fight the development of resistance in two important ways. First, CPTR regimens will have the potential to markedly shorten the duration of treatment needed to cure TB. This, in and of itself, is absolutely key to turning off the faucet of new drug-resistant cases. Shorter and simpler treatment means better adherence, which cuts down on the development of resistance.
Second, introducing multiple novel compounds at one time means that fewer elements of the regimen are accompanied by pre-existing, widespread resistance.
Q: Why did it take so long to streamline the regulatory process for TB drug approval? Hasn’t the FDA been doing with this with HIV drug candidates for years?
Dr. Spigelman: To make dramatic progress in fighting the TB epidemic, a novel TB regimen is needed. However, as recently as 10 years ago — prior to the inception of the TB Alliance — there were no TB drug candidates under development. In fact, even as recent as four or five years ago, the global TB drug portfolio just wasn’t mature enough to realistically conceive of implementing a CPTR approach to TB drug development. There just weren’t enough drugs.
Now, however, we have multiple new drugs in clinical development, which makes pursuing the CPTR initiative practical and feasible. There is also much greater industry commitment to new TB drugs than there has been in decades. There’s widespread recognition that to make an impact, companies, among a wide variety of constituencies, must work together if they want to impact the TB epidemic. The nexus of these commitments has enabled CPTR.
The FDA has helped streamline the process of developing and registering HIV drugs in the past, but not in the way the CPTR initiative will function. This is in many ways a groundbreaking endeavor.
Q: There have been essentially no new TB drugs in four decades. How could these drug candidates change TB treatment and when might we see the first results from this faster regulatory process? And are any of these new drug candidates being studied for efficacy against the virulent new drug-resistant strains of TB that have emerged in recent years?
Dr. Spigelman: The current TB drug candidates, especially by working together, could profoundly improve the standard of treatment for TB by shortening treatment. The degree of potential treatment shortening is especially profound in drug-resistant TB, which is the hardest to treat. This would be a tremendous improvement over the current standard of six-to-nine months for drug-sensitive TB and 18 to 30 months for drug-resistant TB. The more immediate goal is to shorten treatment duration of both drug-sensitive and drug-resistant TB to the order of 2 to 3 months.
The ultimate goal is to reduce the treatment time needed to cure TB to the order of two weeks, such that it is no different than other common bacterial infections. And, as the pool of drug candidates continues to grow and mature over time, CPTR will close in on that goal as well. We are optimistic that the first CPTR trial will reach human testing within the next 12 months.
Also, with the development of novel treatment regimens, we have the hope of creating 1 course of treatment for both drug-resistant and drug-sensitive disease. Doing so would greatly simplify treatment the world over and lead to more lives saved and much less cost in the management of the disease, which is a major problem in so many of the TB endemic and even non-endemic countries.
Q: What is the potential for these drugs in patients co-infected with HIV?
Dr. Spigelman: The TB and HIV/AIDS epidemics are inextricably linked. Avoiding drug-drug interactions between components of a CPTR regimen and antiretroviral HIV/AIDS treatments is a key priority when selecting combinations. The goal of CPTR is to have markedly improved TB drug regimens that do not interact with anti-retroviral therapies. Thus, our goal is that just as patients with either drug-sensitive or drug-resistant TB could be treated with the same regimens, also patients with HIV/AIDS and with TB could simultaneously be treated for their TB and HIV/AIDS.
Q: Could this initiative be used as a model to advance regulatory science and win approval of new therapies for other diseases besides TB?
Dr. Spigelman: CPTR is a trailblazing initiative for many other disease areas that would benefit from treating patients with combination therapies, such as cancer and hepatitis. In this way, the partnership could serve as a blueprint or model in how to rapidly test combination drug therapies.
Check this link later today to see a video explaining how the CPTR process will work.