People often think of tuberculosis as an old-fashioned Victorian-era disease, but that couldn’t be further from the truth. In fact, 1.6 million people died from TB in 2021 alone, making it the second-leading infectious killer after COVID-19, according to the World Health Organization. It’s also the 13th leading cause of death worldwide.
Its ubiquity doesn’t mean that TB is easy to treat, though. Instead, the opposite is true. Patients have to take a cocktail of antibiotics, and even the easiest to treat form of the disease, drug-sensitive TB, takes about six months of treatment and ongoing clinical monitoring. The trickier drug-resistant TB requires up to two years of treatment.
Such complex regimens are especially difficult in low- and middle-income countries where the disease burden is the greatest. Despite this, global investment in TB is lacking, and tuberculosis treatments haven’t changed much in about 40 years.
Because TB must be treated with multiple drugs, collaboration between for-profit pharma companies, nonprofits, governments and other organizations is crucial to success in advancing treatments, explained David Holtzman, clinical development leader at The Bill & Melinda Gates Medical Research Institute (Gates MRI), whose work focuses on TB drug development.
“You have to treat TB in combination, which means you need multiple medications, and if you're looking for new drug treatments, new regimens for TB, it clearly requires collaboration to work with various partners who have the drug assets or compounds to put into a new regimen or has the know-how to develop or conduct those trials,” Holtzman said. “At Gates MRI, we are really all about collaboration, bringing the groups together that have that know-how.”
To that end, Gates MRI recently announced a collaborative licensing agreement with Merck and Co. to evaluate two preclinical antibacterial candidates as potential components of combination regimens for the treatment of TB.
"No one company is going to be able to have all the assets to form a novel regimen (for TB)."
Clinical development leader, The Bill & Melinda Gates Medical Research Institute
Gates MRI is also a member, along with Evotec, GSK, Janssen Pharmaceuticals, the Bill & Melinda Gates Foundation, TB Alliance, and Otsuka Pharmaceutical, of the Project to Accelerate New Treatments for Tuberculosis (PAN-TB collaboration), which aims to bring its “collective efforts and assets together to identify new regimens that we can study in the clinic,” Holtzman said.
PharmaVoice recently caught up with Holtzman and discussed Gates MRI’s new deal with Merck and the TB treatment development landscape as a whole.
The interview has been edited for style and brevity.
PHARMAVOICE: Can you explain this new licensing agreement with Merck and how might it help solve some of the issues with TB treatment?
DAVID HOLTZMAN: It's an exclusive license for two compounds — MK-7762 and MK-3854 — with the disease indication of TB focused on low-and-middle-income countries, and there's a specific list of those countries where the agreement focuses on.
It encompasses the full scope of development for these compounds: The preclinical work necessary to get them into the clinic, the full range of clinical development, and obviously, the CMC work and regulatory interactions as necessary for that. We're very excited about these compounds based upon what's been shown through Merck’s work in the preclinical development and we are excited by their potential promise to be potent drugs against TB that also have the potential to be safer in patients than some of the similar TB compounds that are currently in use. We are hoping to be able … to evaluate MK-7762 in the clinic next year, seeing whether it’s able to be safe and effective for patients, (and) looking towards our endgame of whether it can be included in a novel TB regimen.
How does this deal with Merck fit into Gates MRI’s broader TB strategy and framework?
It fits strongly with the PAN-TB collaboration with those other partners, so this is really part of our overall strategy of working toward finding a…regimen that treats both drug resistant and drug sensitive TB in shorter duration and current standards. Current standards are six months or more, and we're really targeting a much shorter regimen (three months or less) that could treat a drug resistant or drug sensitive TB. So this agreement with Merck is part of our overall plan in working to identify compounds that could be slotted into a novel … regimen that could be evaluated in phase 2 and phase 3 clinical trials. It's difficult for TB programs in low- and middle-income countries to administer regimens that are six months or longer and require frequent clinical monitoring.
How important is collaboration for this kind of work?
With TB drugs I think collaboration is so important and vital if we are going to be successful in finding novel TB regimens. No one company is going to be able to have all the assets to form a novel regimen, given that TB — the organism itself — requires combination treatments with three or four antibiotics for a prolonged period of time. So there is the vital need for collaboration, not only with the companies that have these products, but also we’re so invested in collaboration with our partners in the field who are so experienced with conducting TB trials, treating TB patients and getting feedback (from) TB-affected communities about what is important for people who've lived through TB and hearing feedback on what really would be important in terms of reducing duration of treatment, and ideally, finding a safer regimen that's still effective.
What’s the rough timeline for developing the Merck compounds?
They're in slightly different places right now in preclinical development. We are working towards having everything prepared for an IND submission for MK-7762 hopefully in the near future (and are) hopeful that we can be able to get into the first clinical trial with that compound in 2023. The other compound, MK-3854 requires a bit more preclinical work and CMC manufacturing work. We're very eager to get both of them into the clinic as quickly as possible to evaluate their potential.
Gates MRI is a nonprofit. How is this license agreement special or notable in that sense?
It’s novel in the sense that we’re partnering with a for-profit company like Merck. We're really excited (about) working with companies (which) find these promising compounds but that, within the specific disease area or space, may not have the ability to take us through the full range of clinical developments.