Top private funder of TB R&D moves forward with trials of promising new drug

As part of our reporting in advance of World TB Day on Saturday (March 24), Science Speaks interviewed Patrizia Carlevaro, PhD, the leader of Otsuka SA, to discuss Otsuka’s latest research to address drug-resistant forms of TB, the world’s emerging tuberculosis “hotspots,” and other efforts by the subsidiary organization to tackle TB.

Tell me a little bit about Otsuka. When did it start its global TB program? What was the impetus for starting Otsuka SA (the public health policy/corporate social responsibility arm)?

After 16 years at Eli Lilly, I decided to move to Otsuka. They started looking into tuberculosis research and development at the beginning of the 1970s. A handful of Japanese researchers decided to go into the TB field because it was, and is, a high burden disease in the Asian region.  Around 2002 Otsuka began testing a new anti-TB drug called delamanid [or OPC-67683], which is part of a new class of anti-TB drugs called nitroimidazoles. It’s been a promising endeavor – we just finished Phase II trials of delamanid last year.

So a few years ago, Otsuka decided they were making good progress on the research side, now they wanted to look at what they could do on the public health side, especially in middle-income countries that are lacking adequate health infrastructure. How can we do better in multidrug-resistant tuberculosis (MDR-TB) treatment, management, and prevention? Even when you have new drugs – in order to successfully combat MDR-TB you need to have better methods of administering the drugs, better adherence, and optimized infection control measures to minimize transmission. Otsuka SA was opened last year to address these needs. We also want to look at the advocacy side of TB and see how we can raise awareness in a new way, to improve the political will to address TB even when there is less money to work with in this fiscal climate, and consider how medical providers can get more involved.

Can you tell us a bit about what research Otsuka is undertaking currently in terms of TB drug development? (Where are the trial sites, what are the timelines for these studies, how many people will be included in these studies?)

As I said, Otsuka finished Phase II trials of delamanid last year and we hope to publish results from that trial later this year. The Phase II trials were designed to evaluate the safety, tolerability, efficacy, and pharmacokinetics of delamanid over two months, administered with an optimized background regimen – or OBR – which is a combination of drugs for treating MDR-TB as outlined by the World Health Organization (WHO). This trial represented the largest placebo-controlled trial (in combination with OBR) yet performed for MDR-TB.  Our end point was looking at sputum conversion two months after treatment completion. From what I hear, the data are quite promising but I can’t say more than that at this stage.

We are just now starting to enroll patients for the Phase III delamanid trial.  The purpose of this trial is to determine whether delamanid is effective in the treatment of MDR-TB in combination with other MDR-TB medications during six months of treatment. The investigators are enrolling participants at approximately 15 trial sites qualified to treat MDR-TB starting with Estonia, Latvia and Lithuania, with other countries coming in the near future.

We are planning to enroll approximately 400 patients. The primary endpoint is the sputum conversion over the six months of treatment with delamanid, but all patients will be followed for 30 months after enrollment– so it’s going to be quite a while before we get results, 2015 most likely.

Since this is targeting MDR-TB, we are using a standardized WHO treatment regimen and adding our compound [delamanid] to it, as we did for Phase II. In Phase III we will likely be able to get a better idea of the long-term efficacy for patients treated with this regimen. We don’t have any studies we are conducting on drug-sensitive TB.

Part of the Phase III trials will include MDR-TB patients co-infected with HIV who were not included before. In a region like Africa, as you know, HIV patients are dying of TB at such a high rate it is really important to get this data on the HIV-infected population. In addition, we have just received approval for testing in children from the European Medicines Agency, the regulatory authority in Europe. I don’t know how long the pediatric trial will take, but it may be a few years before an approved pediatric formulation is made available.

What about diagnostics? Are you doing any work to develop a point-of-care TB diagnostic?

Otsuka has a diagnostic business as well. At this stage it is quite early so we don’t have anything that is in testing for TB. It would be nice – as you know, one of the bottlenecks in TB management is that patients are difficult to diagnose, especially those with MDR-TB. There has been huge progress in the past few years in terms of diagnostics, but there is still a lot to be done.

You mentioned testing of delamanid in children, a population commonly excluded in drug R&D. Are there efforts to test the drug in pregnant women?

No. It is common to exclude pregnant women from clinical trials of new compounds until there is sufficient experience with the compound to ensure that it will be safe to use in pregnant women. This is something that will be considered for the future, though we are unable to say exactly when at this time. Already it has been very courageous for Otsuka to be persistent in TB and to come to this level with such a large investment, when many believe there is no business success to be had in this arena. But, that’s why we are here. So now we will see how it goes with delamanid and how we will move forward from there.

How much do you anticipate this drug will cost?

We haven’t worked on pricing yet at this stage – for the time being we are only producing the drug for the clinical trials. In the next year we will look at this aspect as well. Of course we are conscious that not all patients infected with TB will have the same financial situation so we will need to work to make sure everyone that needs the drug has access to it.

What is going on in Europe right now – is TB resurging there? Why? Where are the TB “hot spots?”

Europe is quite diversified – western and eastern are quite different. There are 80,000 MDR-TB cases in both – including Russia and other former Soviet Union countries. There have been outbreaks in schools in children in Europe, in Italy there was an outbreak in a hospital among newborns because one of the health care workers was infected and passed it on to newborns. The most dramatic TB incidence is in Eastern Europe – you have a very high peak in the Baltics and the Former Soviet Union. The number of MDR-TB patients that are receiving treatment is still very low –despite the fact that they live in Europe. I think it is considered a disease of the past – it doesn’t receive much attention, it doesn’t receive much advocacy.

There’s not much discussion at the community level and TB patients are not empowered like people living with HIV. TB advocates are confined to a small number of experts. Also, since TB is a curable disease, after treatment most patients don’t want to talk about it anymore – they want to move on. But for HIV patients it’s a chronic disease and they stay active advocates.

TB is stigmatized by many, many people who think it is only in migrant populations – so there is not a lot of political interest in addressing it. There was a recent WHO report that said if there were a better treatment for MDR-TB, they could save several billion Euros per year. So, investing in TB is quite cost effective, but that message doesn’t go through, unfortunately.

Speaking of drug-resistant TB – that seems to be surging globally as well?

Yes, China, India, Russia and South Africa remain the four countries with the highest burden of MDR-TB.  The Baltics were a big concern in the past few years, but they have done a great job in addressing drug-resistant TB. In the former Soviet Union, among the prison population, and among injection drug users (IDU), there is a big problem. IDUs have difficulty adhering to therapy. The normal health care system does not try to reach them at all. So that’s a challenge.

In many parts of Eastern Europe there is an old fashioned approach to IDU treatment with hospitalization, and it lasts for many months. The problem is that some of these patients are not diagnosed with TB immediately, so they might infect others in the hospital. That’s where the risk is. Particularly when you have the cold weather and people stay inside with the windows closed – it is more risky. That’s another aspect we need to address if we want to move toward elimination of TB in the next 50 years.  That’s why we need to look at community care models.

Is Otsuka making any efforts to educate the public or influence public health policy in areas with emerging or resurging TB epidemics?

We are starting to work with international organizations like the WHO and the Stop TB Partnership, as well as TB authorities, particularly in countries where we are conducting clinical trials. The political will is important – not only among TB specialists in-country, but also at the political level. Funding allocated for health issues, including TB, are usually decided outside the ministries of health in most of these countries. We want to be more involved in fostering political will to fund TB programs. We started just a few months ago, so we are moving in that direction. We also want to look at and improve the model of care at the community level – an important aspect of reducing TB care costs. People often focus on the cost of drugs, but if you look at the cost of the MDR-TB full treatment care package, certainly drugs are not the most important cost factor. Hospitalization, transportation, diagnostics, nutrition, adherence, etc., they all contribute.

We at Otsuka want to find out if there are any models of care that can improve the results we are seeing. We also want to find out how to engage more patients in the process – we need patients encouraging other patients to complete their treatment regimens even when they are feeling better, to ensure adherence and end resurgence of resistance. When we have new drugs on the market to treat TB there is no point unless everyone is going to use them responsibly, so we can preserve the drugs and their efficacy for as long as we can. That’s a little bit in a nutshell what we are starting to do. In a year’s time we will have a bit more to say.

Are there any other research and development activities Otsuka is undertaking in the TB arena that we should know about?

At this time, our main focus is on the development of delamanid, however Otsuka plans to explore other, additional solutions to help address the global TB epidemic including diagnostics, pediatrics, and HIV co-infection, among others. We are also engaged with partners and stakeholders in the development of public health programs and models of MDR-TB care and control in a variety of high-burden settings. At Otsuka, we believe that the best hope of eliminating TB from the world lies in a combined effort that employs elements of competitive markets and new product development through the promotion of innovation. The problems facing TB include inconsistent or partial treatment, which often lead to the emergence and transmission of drug-resistant strains (MDR-TB). Therefore, it is essential that TB R&D continue both in new treatment, diagnostics, and new tools for patient care.