As most of our readers may know, we support a community of phage researchers and biotech professionals from all over, and aim to cover topics from phage research to development to patient treatments. But we’ve never talked about CARB-X (Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator), one of the current funders of early development phage technologies. So this week, we’re diving in!

Jessica Sacher: Can you start by telling us a little about CARB-X — who is behind it, and what are its main goals?

Richard Alm: CARB-X is a unique funder in many ways. We have five major funders: three governments — the US government (through BARDA and NIAID), the UK government and the German government — and two leading philanthropic organizations, the Wellcome Trust and the Bill & Melinda Gates Foundation. CARB-X is led by Boston University, and we operate as a non-profit partnership.

We fund the development of high risk, high reward antibiotics, vaccines and other preventatives, rapid diagnostics and other innovative products — we look for innovation. We’re global, we fund companies anywhere in the world, and we fund academic groups as well, if they have the capacity to transform their research into a product. Our funders are focused on supporting the early development of new products that address antibiotic-resistant bacteria and that may change how infectious diseases are treated. New products are needed urgently, and CARB-X’s mission is to fund and provide support for the development of products. From both the scientific side, but also from the patient side, having a diversity of approaches is important to tackle the threat of resistance.

J: How did CARB-X start?

R: It started with the Obama administration issuing an executive order in 2014 and creating a National Action Plan in 2015 to address the rising threat of antibiotic resistance that had been identified by the Centers for Disease Control and Prevention (CDC) and other health organizations that were concerned about the lack of investment in antibacterial innovation. The administration published a call for proposals to address the crisis, and Kevin Outterson, a Boston University law professor and expert on the economics of the antibiotic market, partnered with the Wellcome Trust, a leading medical charity based in the UK, to apply. They were awarded a five-year contract, and with $350 million in funding from Wellcome and the US Biomedical Advanced Research and Development Authority (BARDA) and the National Institute of Allergy and Infectious Diseases (NIAID), CARB-X was launched in July 2016. Outterson and his small group moved quickly, launching a call for proposals, and the next spring, CARB-X announced awards worth $24 million plus another $24 million if project milestones were met, to 11 product developers. The Bill & Melinda Gates Foundation, and the UK and German governments joined CARB-X as funders not long after as it became evident that CARB-X was an effective mechanism to steer investment into the development of urgently needed products. CARB-X has up to $480 million to invest in antibacterial innovation. Under Kevin Outterson’s leadership, the CARB-X partnership has built the world’s largest and most scientifically diverse pipeline of innovative products addressing drug-resistant bacteria. It is an amazing story, an amazing achievement in a very short time. Today, CARB-X has about 20 people, and we’ve built out a lot of expertise.

J: What stage of work does CARB-X typically fund?

R: We fund early development — hit-to-lead through to the end of first-in-human trials — so it’s a fairly narrow but crucially important range in the whole discovery and development pipeline. If you are a product developer, you start doing toxicity studies and scaling up production and manufacturing, but you don’t know how good your candidate is yet. And so earlier development is a riskier phase, where it’s expensive to do the work, but you’re not guaranteed of a reward at the end. That’s where CARB-X funders stepped up and said, well, that’s what we need to support. CARB-X is not just about awarding money; we also provide expert business and regulatory support to each of our companies that we fund.

J: What kind of funding does CARB-X provide?

R: It’s not just a grant. CARB-X also provides expert support. I joined CARB-X after having been the PI on a grant for a small company where we had a CARB-X grant, so I know it from both sides. For preclinical work, it’s a 90/10 split, where CARB-X will pay 90% and the company puts in 10%. For phase one or clinical, it’s 80/20. The funding is non-dilutive. So it’s a good deal for the companies.

J: How does CARB-X support groups beyond just funding?

R: A lot of the companies we fund have less than 10 people, and they don’t necessarily have everything they’re going to need in terms of expertise at the company at the same time. CARB-X provides expertise that is needed as the projects progress. CARB-X has a network of over 200 expert consultants, and we build a support team for each project. If a company needs regulatory support or toxicity support, we have a team that follows the project, offers advice, all the way from scientific expertise through to fundraising and business development. So it’s really that wraparound support that I think a lot of companies benefit from, making it quite a unique funding mechanism. These services are free-of-charge to the companies that CARB-X funds.

J: What kinds of antimicrobial strategies does CARB-X like to fund?

R: We have expertise in various aspects from a scientific side, because we don’t just do therapeutics, we do preventative vaccines and diagnostics as well. There are three main pillars. In the early days of CARB-X, the focus was primarily on small molecules, because that’s what the CARB-X team knew best. Then in 2019, which was our most recent full funding round — we had four separate rounds involving small molecules, diagnostics, vaccines, but we also had — and this ended up being the largest set of applications — what we just called ‘non-traditionals’. That’s when we got quite a few phage applications.

J: That’s great to hear! How does CARB-X think about phage?

R: We had always wanted to bring more phage into the portfolio. I think the phage landscape is certainly building a lot of momentum. Twenty years ago, it wasn’t really part of Western medicine, so there were skeptics, but I think in the last five to ten years, there’ve been a lot of individual cases where it’s been shown to be clinically successful. Now companies are obviously pushing forward with randomized clinical trials, in the case of say Locus Biosciences, for example, where they’re now saying it could be a first line therapy if used appropriately. So it’s not just for emergency INDs anymore, and I think that’s really exciting. But there’s a lot of understanding that needs to come with that, because phage is playing catch-up if you compare it to small molecules. So I think CARB-X really wanted to get into that space and understand that.

J: How long has CARB-X been around, and how many companies have you funded to date?

R: We started in 2016, and we’ve had about 1160 applications to date. We’ve funded about 78 projects, and we’ve currently got more than 50 active projects in our portfolio, and that number will grow in the coming weeks.

J: Do you find that the companies you fund that are working on different things have similar needs?

R: It’s interesting — within the last year, as we’ve brought more companies in, we’ve started to understand that a lot of companies come to the same point of development and have similar issues, maybe it’s that they’re working on the same indication, and there’s not a good animal model, for example. So we have internally debated: ‘is there a way that we can provide support for cross project opportunities, and provide value even beyond our funded companies?’ Being nonprofit, our goal is to help the ecosystem.

For example, some of our therapeutic companies are exploring opportunities to work with some of our diagnostic companies to match their particular technologies. We’re interested in doing more of that. ‘Aligned by design’ is a little catchphrase we use, where we try to match companies we fund with each other so they both benefit.

If you look at phage, obviously one area that will need to be understood is, how much do you need a diagnostic to identify your patients? I think the closer you get to that empiric treatment, given the natural specificity of phage, the more important it’s going to be to understand your patient population, what they’re infected with, and the need for a rapid diagnostic. I have spoken to a couple of our phage companies about how they’re thinking about their patient stratification, not just for clinical development, but obviously also post approval — how’s it going to get used clinically? And I think that that’s an important thing to start thinking about as early as possible.

J: What kind of advice would you give phage biotechs and academic groups looking toward clinical trials involving phage therapeutics?

R: My advice would be to think about what patient population you’re going after. Start your program with that end goal in mind, be it the unmet medical need or the patient population, and think about how your product would get used clinically, and build some of the expectations that you need to demonstrate clinically into your preclinical program straightaway. And if you’re talking about empiric use, then think about how you’re going to select your patients. There was just a paper I saw recently, against Achromobacter — I think it was Adaptive Phage Therapeutics — they’ve done it in combination with antibiotics, and I think that was a really interesting story. If you’re going to have a combination product, think about how you need to demonstrate benefit preclinically, to make that translational step to your clinical proof of principle easier. It may mean asking, at which point during the clinical treatment schedule does a phage and an antibiotic best synergize to give the best clinical outcome? Do you give them at the same time? Do you offset them? What is the cadence? And that may be different depending on what antibiotic you’re giving it with, or even what phage family you’re using. I don’t think there’s enough understanding around that yet. We’re going to need clinical evidence for that, until we can look at things preclinically and say, okay, we know that’s going to translate clinically. But I don’t think that’s known yet. I think that’s some of the clinical science that the phage field is going to be addressing hopefully soon. It will take time, obviously, but I think there are so many important questions. So that would be my advice. Start with the end in mind.

J: I want to link back to something you said earlier, that even academic groups might be fundable by CARB-X, if they can transform what they’re doing into a product. Can you talk more about what that might look like, or how you might assess that?

R: A few of our funded programs are in Universities. For example, we fund a program with the University of Queensland in Australia, and within the university system, they have a fairly sophisticated business development capability where they spin out technology into small companies. It is essential that these teams have that type of support. So we’re not averse to funding universities that have that business development capability. We don’t fund pure science or basic research at a university. We still need to see that application — how would you take your research towards a product — because ultimately, we’re about funding products through to the end of Phase I. For a university to qualify, they need to have a good tech transfer office, they need to have that business acumen within the university structure that the principal investigators can draw on, as well as their share of the cost of the project. Quite often, with universities, there’s some drug discovery experience, but not as well developed within a university as it is within a company. So that’s an area where maybe CARB-X could provide some additional support, to bring that pharmaceutical experience to a university. We have several research institutes in the portfolio, in Germany, the University of Queensland in Australia, and an academic consortium in the UK that has spun out a company already. We have a few examples, but they do need to fit the criteria, that their goal is to develop a product and not focus on primary research.

J: Awesome. I want to just go in a little bit deeper on the phage-based companies that CARB-X has funded — what made them seem more attractive, or more likely to succeed than other phage applications you’ve received?

R: We are currently funding Eligo Bioscience and Locus Biosciences, and there are one or two more that we are looking at closely. Hopefully, we’ll be able to announce these soon. Eligo came in through a preventative round actually, because they’re looking at preventing an infection in a specific patient population by using CRISPR-engineered phage to remove certain pathogens from the gut of patients prior to surgery. Locus is more of a therapeutic, in that they’re looking at Klebsiella phage for urinary tract infections. At CARB-X, our approach was to try to understand the whole field, and to recommend to our funders different companies that look at different aspects of phages. We don’t really know where phage are going to be the most successful clinically yet. In order to maximize that understanding, it was important for us to fund companies that look at different aspects. But again, it comes down to the innovation of the product, how they had thought about their patient population, how they figured they would use it clinically. The application is a multi-step application phase, culminating in a presentation to our external advisory board. There’s a lot that goes into it. The two that we currently fund are both using engineered phage, and they’re both CRISPR-based phage. The ones we’re looking at now are a little bit different in certain aspects. One is a therapeutic, one is preventative. We really want to understand where phage can make the biggest impact and bring those products forward as fast as possible.

J: So it sounds like you’re not just thinking of engineered phages as being ideal because they’re potentially more defensible from an IP perspective, but rather that you’re seeing phage engineering as one element of a larger strategy that would ideally cover many diverse approaches — is that right?

R: CARB-X obviously looks at IP as part of our due diligence. We want to make sure that the groups we fund have the ability to either have a fully active license or freedom to operate in their space. But I think for phage, there’s not a lot known from a clinical aspect. And so for me especially, it was more about where that phage is going to fit in. Where is their niche going to be? Is it a standalone second therapy, is it patients that are at the highest risk of mortality, so it’s your last resort? Is it in combination? Those are different areas that I think we need to understand better.

J: How do phage technologies compare to small molecule antimicrobials that you’re used to evaluating and funding?

R: For the small molecule antibiotics, there’s so much known about PK/PD, dosing, how you estimate the dose, what you need to see preclinically in animal models of infection to translate that dose to humans. Because of the uniqueness of phage, a lot of that hasn’t been fully explored. I think that science is going to be fascinating in years to come. If the phage replicates at the site of infection, obviously, you make more drug, per se, which is something you don’t do with small molecules. So that’s a really neat aspect, and that obviously changes your pharmacokinetics, if you want to call it that — they behave differently, because now your body’s not getting rid of it. It’s actually making more.

The one thing coming from a small molecule background that is fascinating to me is the toxicity, or lack of toxicity — it seems, from a development speed perspective, that you seem to be able to get into clinical trials or into patients with far less toxicity work than with a small molecule, because phages are deemed safe. That’s great in terms of accelerating products to market, and it was a real paradigm shift for me, to think that you don’t have to do a full 28-day toxicity study in two animal species before you can go to an IND. The FDA has initially embraced that — there isn’t necessarily a requirement for the full tox package that we’ve come to expect for small molecules. I think everyone’s still learning, the regulators are learning, the scientists are learning, the investors are learning, and the clinicians are learning. And I think it’s an area where the momentum is there now. The question is, where’s it going to end up that’s going to provide the best benefit to patients? CARB-X is happy to play its part in understanding that equation.

J: Are there any recent developments in phage therapeutics that you’re particularly excited about lately?

R: There’s not a lot of information yet around distribution of phage. If you give them IV, if you give them orally, or through inhalation. How do they get to the site of infection? Are different phage families better at crossing certain barriers? There’s a lot of questions around that, because as you understand the distribution, you could suddenly open a lot more clinical indications that could be treated by phage, if you understand how to deliver and how to formulate it, and how to get it to that site of infection. As we begin to understand some of the data around distribution and dosing routes, I think as that gets explored, you’re going to get additional therapeutic options being opened up.

J: That’s really exciting — I haven’t heard that angle before — that looking at where phages go in the body could lead us to uncover new opportunities for therapeutics.

R: Yes, that’s that translatability bit from the primary science to ‘now we’re going to make a product and get it to the site of infection in a human’. IV is how a lot of phage has been delivered in the emergency INDs. But think of inhalation for lung infections, where you could get such high concentrations directly to the lung, or oral if you could work out phage families that could be better protected through the gut. Eligo, who we’re funding, is looking at that, because they want to target the gut bacteria. It’s really going to be exciting to see how many different therapeutic options can be opened up through understanding phage distribution. And understanding the elimination on the other end of that — how does your body get rid of it at the end?

J: Is there anything else you want to add, as we wrap things up?

R: The thing I like about phage, and it’s a double-edged sword, like many things, is the precision at which they can kill certain pathogens. And have we moved beyond the age of a broad-spectrum compound that can knock out everything, that the doctor can just prescribe and walk away, and knows that everything will be covered? I think we are moving away from that. We’re not necessarily down to personalized medicine, but we’re down to focused medicine. If you look at the number of species-specific drugs being developed, and not just phage, but even other small molecules — this is going to come to a head.

How do you fit that into the paradigm of diagnosing patients who are going to benefit from a specific treatment? I think, from a preservation of the microbiome perspective, having precise killing of the pathogen is really important. But with that comes, obviously, the risk of ‘am I treating all the bacteria that are involved in an infection?’. And so if you go into an indication that is known for having polymicrobial infections, you’ve got to know everything that’s there, because you don’t want to kill half of what’s causing the infection and leave the other half there.

The precision of phage is really exciting. But it’s got to be put into the clinical context, as to where it will be used. Diagnostics have a role to play there. And different phage companies are obviously addressing the resistance issue differently. As people understand more about the biology of phage, maybe there are other ways to address the escape mutants that you may get, that give you that resistance. I also think the ability to engineer phage is super cool. If you can start to do tail fiber engineering to broaden your host range, prevent rapid resistance, slow it down… all of that will only add to the clinical benefit that phage could bring.

Thanks to Atif Khan, Sheetal Patpatia, and Stephanie Lynch for their work writing summaries for the What’s New section this week!