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Dr. Aaron Korkegian Talks Tuberculosis and Drug Discovery

By February 27, 2019No Comments

Dr. Aaron Korkegian is a Scientist at the Infectious Disease Research Institute (IDRI) in Seattle working in tuberculosis (TB) drug discovery. Dr. Korkegian sat down with us to discuss the TB pandemic, and what IDRI is doing in collaboration with industry to improve current treatments.

My understanding is that a cure for TB already exists. Why is it that IDRI is interested in further drug discovery?

Good question. In a lot of developed countries like the United States, people view tuberculosis as a disease of the past, but this is not the case on a global level. In fact, it shocks most people to hear that TB is actually the leading cause of death by any infectious disease. In 2017, the WHO reported that TB infected 10 million people, and killed 1.6 million people. The total infected population is estimated to be 1.7 billion. So it’s actually a huge problem.

The issue with finding a cure for TB isn’t that there aren’t any drugs that treat it, or that a vaccine doesn’t exist. The issue is their effectiveness. The vaccine is only slightly protective in children, and it doesn’t protect well into adult years. As for drugs, the current regimen consists of four drugs taken over the course of two months, followed by two of those drugs taken for an additional four to seven months. So you’re looking at six to nine months of an antibiotic course, which is especially tough considering that the drugs make you feel ill. The recommended course of therapy is actually called direct observed therapy, because it involves someone literally coming to your door and watching you take the pills. In developed countries this has kept TB levels down, but the high cost of this treatment in combination with the fact that TB symptoms can abate after a few weeks of treatment make compliance very difficult in other countries. The other major issue is that the current regimen is over 50 years old. This has led to a rise in resistance, causing the number of cases of multidrug and extremely drug-resistant TB to become quite high.

To combat these issues, new antibiotics are needed that avoid current resistance mechanisms and drive down the course of therapy to two months or less. They also need to be stable, easily deliverable to different parts of the world, and capable of being given at clinical points of care. In other words, not injectables or anything with a fancy delivery system. Oral drugs are ideal.

What is it about TB that makes it such a difficult disease to treat?

The problem is that TB can typically be contained, but not eliminated, by the immune system. Once infected, the bacteria can go into a latent state where the host doesn’t even realize that they have it (which is why the infected population is so much higher than many realize!). But if that host becomes immunocompromised then it can reactivate. It’s targeting this latent population of the bacteria that makes TB such a difficult disease to treat.

What is IDRI, and how is it involved in the mission to eradicate tuberculosis?

IDRI is a non-profit pseudo-biotech that straddles between academic and industry models, and is interested in targeting diseases that have an impact on global health. This includes things like TB, leprosy, and chagas disease, among others. Efforts to eliminate these diseases require both preventative measures like vaccines, as well as treatment measures like drugs.

How does IDRI work with industry partners?

Good question! One of our most successful partnerships is with Eli Lilly, and is called the Lilly TB Drug Discovery Initiative. Eli Lilly is obviously a for-profit company, which is a bad word for a lot of people in the public sphere. But the people at Eli Lilly are concerned about global health, including TB. The obvious problem is that there is very little return-on-investment with TB, so if you’re a for-profit company, it doesn’t make financial sense to study. But you can still support TB research, which is what Eli Lilly does. One of the most valuable assets that a pharmaceutical company has at its disposal is their large small-molecule libraries for drug development. Eli Lilly has given us access to these libraries for screening, in the hopes that we can identify compounds that are active against TB. They’ve also donated robotics equipment to us that they’ve gained upon acquiring companies, but no longer need. Furthermore, they’ve been active collaborators throughout the partnership, with staff who are dedicated to supporting the program. They provide project guidance and expertise in medicinal chemistry. It’s been hugely beneficial.

What type of drug screening are you doing with these libraries?

As I mentioned, TB is often contained, but not killed by the immune system, and exists in a latent phase within granulomas. The bacteria inside these masses are in a low oxygen environment, and not replicating. They’re essentially sedated. The problem is that to treat TB, we need a drug that can penetrate granulomas, and any other compartment where the latent bacteria might be hiding, including macrophages and the lung itself. The other problem is that we need a drug that can target the different metabolic states of bacteria that are a consequence of these differing environments (ie. low nutrition, low oxygen, etc).

To find a drug that can do this, we screen libraries using high throughput in vitro assays, which model, as best as we can, the conditions of the bacteria. This means that we perform drug screens in low pH, low nutrition, low oxygen, etc. conditions, and look for compounds that kill the bacteria. We’re modeling the outcome that we want in an in vitro assay, so that we can then rapidly process the compounds. IDRI is a leader in this type of novel assay development and for TB drug discovery.

Has IDRI advanced any compounds?

We’ve definitely advanced compounds! The drug discovery pipeline goes from screening to hit identification to lead optimization to pre-clinical and finally into clinic. We have a lot of compounds in what’s known as hit-to-lead, which is moving the hits into lead compounds, and we have some that are in lead optimization. There’s also a compound that is in pre-clinical. Unfortunately, the attrition rate is quite high, which is true of any drug discovery program. It’s often stated that it takes about a billion dollars to develop a drug. And TB is especially difficult.

Considering that so many people view TB as a disease of the past, do you think that education of the general public is important?

Yes. Ultimately, how quickly we get to a solution is driven by funding, which is largely gated by government, and the government’s actions in turn are gated by the general public’s awareness. We’re very thankful to charitable organizations that have put a lot of money into global health, such as the Bill and Melinda Gates Foundation, but ultimately helping to inform the general public is key.

Thank you for taking the time to discuss your research with us, Dr. Korkegian!