Last week the World Health Organization (WHO) and the TB Alliance joined with pharmaceutical companies AstraZeneca, Bayer, Sanofi and Tibotec in an innovative agreement to share information about tuberculosis (TB) compounds in their drug pipelines and speed the development of new regimens, including the most promising multi-drug treatments, regardless of sponsor. The partnership was formed under the Critical Path to TB Drug Regimens (CPTR) initiative, which was co-founded by The Bill & Melinda Gates Foundation, the Critical Path Institute and the TB Alliance.
Science Speaks sat down with Mel Spigelman, MD, president and chief executive officer of the TB Alliance, to discuss the new collaboration, which promising drug combinations are coming down the pipeline, and how their work is expediting the process.
Tell me about the Critical Path to TB Drug Regimens (CPTR) initiative and why it was developed.
To give you the background, the first drug effectively used to treat TB was streptomycin, and even though so many people got better with this treatment, virtually all relapsed and the TB organisms that came back were all resistant to that drug. So for decades now we’ve known that you have to treat active TB with more than one drug. So now drug-sensitive TB (or TB that has not developed sufficient resistance against the standard treatment) is routinely treated with four drugs, and drug-resistant TB is treated with combinations of even more drugs, sometimes as many as available, including injectibles.
We also know the shortcomings of the available drugs, so when one looks to making rapid, significant progress in treating TB, we know it wouldn’t take just one new drug but it would probably take multiple drugs, perhaps working together with old drugs or maybe just new drugs. Keep in mind that one drug can take six to ten years to develop.
To make progress we really needed to work with all the potential drugs that were available and figure out, in a new way, how to put these drugs together in the best way. So if we have a basket of ten drugs or 12 drugs, what combinations within those really have the best efficacy and work on those combinations, independent of whether some of them are already FDA approved or not. That was at the heart at the CPTR initiative – how to make a quantum leap improvement over what has been done before.
The CPTR program launched officially in March of 2010, and in fact the commissioner of the U.S. Food and Drug Administration (FDA) gave the keynote at the launch. The FDA has been fully supportive of our efforts. But we started thinking about this collaboration about five years ago. We already started to put into place the research tools to do all of the lab legwork – it really requires an extensive amount of test tube and animal research.
Why the push for new drugs to treat TB?
It’s been nearly 50 years since there has been a new TB drug. This tells you that TB is really a neglected disease – it typically affects the poorest of the poor, and that’s not where you make money selling drugs. It clearly tells you that we need a new model for a way to come up with drugs in this area. The second thing is that we all know that bacterial infections are prone to developing resistance against antibiotics– the TB organism is really smart.. There are TB organisms now that are resistant to every single drug that has been available for TB and antibiotics for other diseases, and that’s just getting worse. Clearly this is not unique to TB, that would be the case for any infectious disease, but you have to continually keep up with outwitting the organism. You can’t put everything in limbo for fifty years and expect to effectively combat the disease.
So now we have the challenge of coming up with something better. Even the most straight forward cases of TB still take at least six months to treat. Typical treatment for drug-resistant TB is two years or longer, with drugs that have harsh side effects, including routine injections. And we have strains that are not curable at all. So that’s the predicament that the world is in and that’s why we needed something that really was going to have a dramatic effect but also in a reasonable period of time.
Why is this latest development – the agreement with WHO, TB Alliance and these four pharmaceutical companies – significant?
Basically what we’ve done is we’ve really looked at which companies have drugs that are in the clinic. There are other companies that are doing bench research, but we are looking at where we can have impact sooner rather than later. These companies [AstraZeneca, Bayer, Sanofi and Tibotec] already have drugs that have already progressed to human trials. It doesn’t include the many companies that have research projects just because it takes so long and there is so much uncertainty around which drug candidates will make it to testing in humans.
Were there any companies you had hoped would join the alliance and didn’t?
There are a couple of companies we had hoped would have joined and have opted not to share the information about their drugs. One of the things we do offer for the companies that really are willing to share and participate is the public accolades for doing that.
Do the pharmaceutical companies see any benefit from this arrangement? Or is it purely for altruistic reasons?
It’s our view and I think that of the vast majority of people, that again TB is a neglected disease. It affects the poorest of the poor. These mostly aren’t people who can afford to pay for drugs, and therefore in many cases donor agencies pay for the drugs. The pharmaceutical companies have not typically been involved in TB drug discovery and development. They are basically doing it out of corporate social responsibility and altruistic purposes. Recognizing these companies is a good thing to do and I think it brings the appropriate recognition to these companies that they are willing to work for the common good.
Is there a particular combination regimen that you all hope to put out that was the impetus for this alliance? Or is it just to facilitate research into the potential of combination regimens in general?
We’ve approached this from a very agnostic, empirical point of view. We took all of the drugs from these companies and a few years ago we started a pre-clinical evaluation. Looking at these 12 or so drugs, both old and new, what are the best regimens? Which work best? Which cure the fastest? We just let the data speak for itself. We didn’t go into it with any pre-conceived notions – we just set up the trials with the partners, ran those experiments, and those that came out the best came out the best, and those are the ones that we moved into human testing.
We hear that the first novel regimen is in the works and is progressing well – can you talk at all about that and the impact this might have on the pandemic?
The first regimen – and it speaks to the fact that we’re doing this in an unbiased way – is a three-drug regimen. One drug is totally new, one is an antibiotic that has been around for a while but has never been approved for treatment of TB, and the other is a drug used for TB treatment for decades but still contributes a lot. We call it PaMZ – PA 824 (the totally new drug), moxifloxacin (the existing antibiotic not approved for TB), and the third is pyrazinamide (the existing TB drug).
This novel three-drug combo happens to treat both drug-sensitive TB and many forms of multidrug-resistant TB (MDR-TB). It also can be given with antiretroviral therapy (ART) so patients with TB/HIV co-infection can be treated simultaneously, and it projects to diminish treatment time significantly. The regimen can be given orally once a day, which is a great improvement overtreatment seen with drug-resistant TB, which almost universally includes injectibles that are very difficult to deliver in resource-poor settings.
Another substantial benefit of this regimen in comparison to existing MDR-TB treatment is that PaMZ projects to be much less expensive. The cost and complexity of current MDR-TB treatment limit its availability to those who need it.
PaMZ is now moving into late-stage Phase II work where patients will be treated for eight weeks and if that looks good we’ll move it into the last stage of testing.
How quickly could you see this regimen being made available to the masses?
It is dependent on our ability to gather resources to do testing – it really gets much more expensive as the trials progress, especially the phase III trial, which can easily cost upward of $50 million. If we had all the resources available something like five years would not be out of the realm of possibility.
But this is an ongoing process. We now have regimens in the lab in mice that look even better than PaMZ, but we’re not going to wait around until we find the perfect treatment. However, once we have significant improvement then we’ll move the next generation forward.
What is the FDA’s role in this – how are they helping to expedite the development timeline?
The FDA has been fantastic in terms of being so open-minded about understanding the need that’s out there for these drugs – protecting the safety of the population but also supporting innovation in that context.
We just had a CPTR meeting of more than 100 members and Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, gave the keynote address. The FDA really has taken this on with the due deliberativeness and seriousness that the development of new TB drugs deserves.
The FDA works to shorten the drug review time as much as humanly possible. They work for expedited drug approval, and have said if you have something that is really an advance for a life-threatening disorder, you can get expedited approval even before phase III trials. They also are collaborative in the design of studies, which also helps expedite the registration process. I would also add that, as Dr. Woodcock outlines in an article in The New England Journal of Medicine, that this innovative drug development and approval process has become not just an issue in TB but in cancer and a variety of other diseases where you need combinations of drugs to effectively treat — some of which involve new drugs. This is a whole area now that does not only concern TB but other diseases that play a role in the health of the U.S. population.
The way that a lot of this research is being done isn’t necessarily through traditional means – the FDA has been very welcoming to these outside-of-the-box approaches and working with the partners to figure out innovative and faster ways to do things. It’s interesting that a field like TB that has been neglected for decades now can be so innovative in expediting new drug development and blazing trails in the development of drug combinations.