Amidst the battle against a new infectious threat, the fight against tuberculosis, one of humankind’s oldest recorded infectious diseases, is also progressing.

Pretomanid – only the second TB drug to hit the market in over two decades – received conditional marketing approval Monday from the European Commission as part of a new, three-drug treatment regimen for drug-resistant TB. The new six-month, all-oral regimen containing pretomanid, bedaquiline, and linezolid, was authorized for treatment of adults with extensively drug-resistant TB (XDR-TB) or multidrug-resistant TB (MDR-TB) whose disease does not respond to other therapy or who could not tolerate their therapy.

The EC approval follows just on the heels of the regimen’s approval in India, the country with the highest burden of TB in the world, marking two big regulatory advances for the new treatment.

Health Policy Watch sat down with President and Chief Executive Officer of the TB Alliance Dr. Mel Spigelman to discuss the state of TB in the world today, how the BPaL regimen approval impacts TB treatment, and what commitments are ultimately required to control this age-old scourge.

HP Watch: Some studies have predicted there could be 1.4 million more TB related deaths in the next five years due to COVID-19 related disruptions. What is the state of TB in the world right now given the pandemic?

Mel Spigelman: Obviously, it depends country by country. But in general, the state of TB, in terms of health services, was never great. So we were starting off from a pretty low level. Clearly there’s a limited amount of health services, and prioritization is being given to COVID-19, so there’s no question in my mind that health services for TB are suffering.

And it’s not just because of health services being pulled away. It’s so much more difficult for the patient to get to a treatment center even if it is open. It’s difficult to get to treatment. Frankly it’s not completely different than in a country like the United States, where people are also not necessarily taking care of all their health problems because of the fear of limited access that has been made worse than usual because of COVID-19.

So yes, the pandemic definitely is taking its toll on TB resources, facilities and patients’ access. There’s no doubt in my mind that will result in a worse prognosis for TB patients around the world. Whether it’s going to be 1.4 million or 1.7 or 1.2 million more deaths no one knows. But it is having a significant impact and will have a significant impact.

HP-Watch: You mentioned patients’ access to treatment centers has been impacted. Can you explain how treatment for TB is set up in most countries – are countries doing direct-observation therapy or home-based models? What challenges have COVID-19 lockdowns brought to these treatment models?

MS: Frankly not every country does directly observed therapy, so patients don’t necessarily come in every day by any stretch in many countries, and clearly there have been movements towards making it more user friendly. Many countries have home-based models – there are Community Care people who come to check on patients.

But still, patients still need to come into treatment centers periodically to do things like have their sputum checked and pick up the medication. So patients still need to access treatment facilities.

And then you get to issues like drug-resistant TB. In many countries, patients with drug-resistant TB are hospitalized for a part of their treatment. Some of these hospitals have been closed down and converted into COVID hospitals.

It’s not a question of rigidity on the part of the providers. It’s simply a result of scarce resources to begin with. So many have been pulled away, or because of travel and other restrictions, they’re just not accessible now. And even home-based therapy is difficult to carry out when a country is in a lockdown. Community-based workers can’t necessarily get to the homes of the many patients. Lockdowns have a profound effect throughout the whole chain of care providers.

HP-Watch: Earlier in the pandemic, a COVID-19 diagnostic test was developed for the GeneXpert system, which is being used to diagnose TB in many high burden countries. But you have mentioned that there are already scarce resources dedicated towards TB. How have (or have not) countries been synchronizing their COVID and TB responses? Is there more potential to synergize the response to both this old threat and new pandemic?

MS: I think the countries are doing as good a job as they can given the realities, based on what our investigators and physicians are doing in the countries where we have study sites. I just hope in retrospect, one of the lessons learned will be that we need to wake up, both on the country level in non-TB endemic countries, and in the international community, and realize that health issues require much much greater commitment than what has so far been assigned or given to them.

In the past, and that’s especially true for diseases of poverty like TB, they get relatively less attention, less resources than even other diseases, even within the construct of medical care. So the whole system needs to be really notched up quite a few rungs.

HP-Watch: So a new tool, pretomanid, has been developed by the TB Alliance, and could drastically change the face of TB care, especially for patients with drug resistant TB. How does the recent approval of the pretomanid regimen in Europe help advance the fight against the disease?

MS: For the appropriate patients, we can use this pretomanid treatment to go from 18 months or so of treatment down to six months. That makes a big difference in terms of freeing up the healthcare system, making it possible to treat a lot more patients for the same amount of resources. The treatment has a high cure rate – in the range of 90%, and you only have to take three drugs orally instead of what has historically been up to eight or nine.

While in most of the countries of the European Union, TB is frequently looked at as a disease of the past, there are countries and areas within Europe wherein the percentage of TB infections that are resistant to available treatments is in fact higher than in most other regions in the world.  Approval in the EU provides a new option for patients with highly drug-resistant forms of TB, that has the potential to reshape this treatment landscape.

The availability of pretomanid and the BPaL regimen is also something of a return on investment for our European donors, who are committed to tackling public health threats both at home and abroad. We are profoundly grateful to the governments of Germany, Ireland, the Netherlands and the United Kingdom for their significant long-term support of our research and product development.

HP-Watch: India has become one of the worst affected countries in the world in the COVID-19 pandemic, and has the highest burden of TB in the world. But they also just recently approved this new pretomanid combination treatment that the TB Alliance developed. Can you give me a snapshot of what India looks like right now?

MS: They are unfortunately getting hammered. Yes, they have the highest TB burden in the world and it appears that COVID-19 is becoming a greater and greater problem in the country. It is difficult for a country like India with such a large population and large amount of poverty to cope with these challenges. But, that’s where we’re hopeful that the BPaL regimen, with the new drug pretomanid, can help ameliorate some of these issues by making treatment of the highly resistant forms of TB easier and less expensive.

These are the solutions that have to be found in order for countries like India to have a shot at really getting control of both TB and COVID-19. Obviously, everybody is painfully aware of the limitations today of COVID therapy or COVID vaccinations, but at least there is a huge amount of resources dedicated to finding those tools for COVID-19, which is appropriate. Hopefully, that sends the message that this is what it takes to really get on top of a pandemic and keep it under control. Finding the tools it takes to control a pandemic is just a higher probability when you put $10 billion behind it, instead of a couple of hundred million.

HP-Watch: Speaking of funding for new tools, can you talk a little more about what the TB research landscape looks like right now?

MS: We have the largest pipeline of potential treatments ever in TB history. But it just pales in comparison to what it should be if we wanted to really make rapid progress. Frankly, I don’t foresee another drug coming to market soon. The FDA has now approved two new drugs in the past 20 years for TB, which is the largest single infectious disease killer in the world. And that’s not an indictment of the FDA. That’s an indictment of the resources that are directed into these spaces to allow organizations to really do the work necessary to discover and develop new therapeutics. The funding situation is certainly just as dire with TB vaccines and diagnostics.

You look back in any disease area where there is a significant infusion of resources, such as COVID or cancer, and we almost invariably do much better. Over the course of just the past six months we already have two drugs, remdesivir and steroids, that have shown potential to treat COVID-19. That could not have happened without a huge amount of effort, a huge amount of resources. Now, remdesivir and steroids are repurposed drugs but nevertheless, we’ve only had two new drugs like that for TB in the past 20 years.

I can guarantee you if we had the resources, we’d have multiple new drugs on a very rapid basis. The money that has gone into TB has been used very wisely. And we’ve been fortunate actually in having the progress that’s been made, but it’s certainly not sufficient to meet the needs of the field.

HP-Watch: Jumping back to the pretomanid approval in India, what’s the next step to rolling it out?

MS: The Indian government will be rolling it out selectively within the national TB program. And this is always the case with any new product; you need to educate people on how to use it, you need to prove that it works within your unique setting and healthcare system, etc.

They will start at selected sites and collect their own data because unfortunately we didn’t do any of the clinical trials in India so we have minimal experience for the BPaL regimen in Indian patients. We expect the results in India to be the same as in other countries, but we always want to be sure. And then there will also hopefully be more clinical trials going on simultaneously, looking at how to make the treatment more effective, using it in different combinations, etc.

But again, everything that one tries to do in the midst of this pandemic is 10 times more difficult in some ways. We’re certainly seeing that also in terms of rollout of pretomanid in many countries. Frankly, I give the Indian government and Mylan, our partner that really drove the approval process in India, all the credit in the world that they have approved this regimen so quickly. It’s been unbelievably efficient given the timing that we usually see for TB.

HP-Watch: So to end, we’re not on target to meet the 2035 goals to reduce new TB cases by 90% and to reduce TB deaths by 95%. What do you think needs to happen to ultimately meet those goals?

MS: A huge amount. First, we need better tools; we need a vaccine, a point of care diagnostic, and even more rapidly effective and safe drugs.

And we also need to strengthen healthcare systems. Even if you have new tools that are great, you still have to have very functional healthcare systems that have the resources to deliver the tools and oversee patients.

And it just means a much greater appreciation for and commitment to what it takes to turn diseases into relics of the past. It all just really comes back to, are donors and investors willing to put more skin in the game? Because if no one is willing to do that, I’m hard pressed to think of anything you can accomplish if you don’t have resources to get there.

Image Credits: Dato Koridze/STUDIO for TB Alliance, TB Alliance, Dato Koridze /STUDIO for TB Alliance, International Labor Organisation Asia.