Sounds of Science is a monthly podcast about beginnings: how a molecule becomes a drug, how a rodent elucidates a disease pathway, how a horseshoe crab morphs into an infection fighter. The podcast is produced by Eureka, the scientific blog of Charles River, a contract research organization for drug discovery and development. Tune in and begin the journey.
Mary:
I am Mary Parker, and welcome to this episode of Eureka's Sounds of Science. December 1st is World AIDS Day, and we have come a long way since the day was launched in 1988. Better drugs and treatment plans have made this once deadly disease very manageable. However, prevention is still the best form of medicine, and we have come even farther with the current generation of pre-exposure prophylaxis or PrEP drugs. Joining us today to give us an overview of where we are now is Dr. Jared Baeten, Senior Vice President of Clinical Development and Virology Therapeutic Area Head at Gilead Sciences. Welcome, Jared.
Jared Baeten:
Thank you. And what a fantastic introduction.
Mary:
I'm really excited to have you here. I know that there's been a lot of advancement in this area recently, so I'm excited to hear what you have to say. But first, can we start with you? How did you become interested in virology?
Jared Baeten:
Thank you. And I'll say I can't wait to talk about the science, and like many people who work in this field, the last thing I want to talk about is me, but-
Mary:
Too bad.
Jared Baeten:
Too bad. But I'm with you, and you have asked. I've spent my whole career working on HIV, and I think a lot of it is... I think much of it links to what you... the little bit you mentioned in the introduction. I very much remember the 1980s and then in the 1990s, when HIV was incredibly terrifying in this country... I'm standing in the U.S. right now in my office in California... and all around the world, and when there was neither good treatments nor effective prevention, like we're going to be talking about later, and how terrifying the world was. And I think that drove what I wanted to do in science.
So I went to medical school. I did a PhD in epidemiology so I could understand disease and populations and be able to really aim for population-level impact for lots of people. And from the beginning, I worked on HIV, very much on HIV prevention and HIV prevention with a global lens. So I've worked in the U.S., but also a ton of work in East and Southern Africa and other places around the world because HIV has been and is a global disease. And the only way that we can have the impact that we all around the world want is to be able to attack HIV everywhere where it is.
Mary:
Yeah, my mom told me a lot about it growing up. She had a lot of friends in the community. So even though I wasn't old enough at the time to understand what was going on, later on she explained it to me, and she would bring it up a lot and tell me about how important prevention and things like that are. And I guess it's also important to note that although we have it kind of under control in America and in a lot of other developed countries, that doesn't mean it's under control globally.
Jared Baeten:
Yeah, absolutely right. I think it's really important at this moment in time, especially coming up on World AIDS Day, as you mentioned, to reflect back on the last 40-plus years of HIV. So much advancement, right? HIV has been... So the identification of HIV to understand it. Tremendous science that brings together community and scientists and drug developers and drug regulators and normative agencies that make guidelines and such. Everybody comes together and has leaned in on HIV, and it's a true success story, what modern science should be. Medicines developed that now have transformed, for many people, HIV into a chronic, treatable infection, where people can take a medicine, in many cases a single pill once a day living with HIV, and can have a lifespan that is equal to someone without HIV. And it makes them uninfectious, untransmittable to their partners. Revolutionary.
Mary:
Yes.
Jared Baeten:
And medicines that, for prevention, allow people to take a medicine and to substantially reduce their chances of acquiring HIV. All revolutionary. And yet, it's really important to remember that there are still more than a million infections every year around the world. There are tens of thousands of new infections in the United States. A quarter of people in the United States who are living with HIV aren't effectively treated, and it's not because the medicines don't work against their virus. It's because all the other things that we need to do in testing and in linking people to care and keeping people engaged in taking medicine in the long term don't totally work for them. So we have these amazing tools. And we actually have amazing tools, which I believe and, I think, many others believe, if we just lean in a little bit more, we could end this epidemic both in this country and all around the world over the next decade or so. And we haven't leaned in enough yet to make that truth.
Mary:
This is getting off on a bit of a tangent, but what are some things that we could do better from where we are sitting to help the areas that are more affected?
Jared Baeten:
Yeah. So both in this country and in countries all around the world, whether they be high-income countries or low-income countries or anything between, the tools that we have in our hands, like I talked about a minute ago, all the treatments that contemporary 21st century science brought us, and if we can do testing and make sure that people have access to medications and then be able to talk, even talk like we're doing right now, openly about HIV treatment and prevention in ways that can continue to combat the stigma that many people have for taking HIV medicines, whether they be for treatment or for prevention, the more that we can normalize conversations about HIV and talk about that North Star of getting to ending the epidemic, that gets us there.
And then for prevention and for treatment, actually, it's also, like what we're going to talk about I think in a few minutes, the development of new medications that for many people who are struggling right now might be that switch that allows them to get to success in treatment or for prevention. And those are really long-acting medicines that, I think, meet people often where they are. And I'm really excited to talk about innovations in prevention because the history of prevention has been so powerful, and there's so much more potential that we could all do together.
Mary:
Absolutely. But before we get into the innovations, can you give us a brief history of the development of PrEP and how it works?
Jared Baeten:
Yeah, so the idea of PrEP, or pre-exposure prophylaxis, is that you can take an HIV medicine... You take a medicine that would be able to fight off HIV, and by having that medicine in your bloodstream ahead of time, you'd be able to block the infection from taking hold. The first proof of PrEP about 12 years ago, the first medication that was approved as PrEP was a medication called Tenofovir disoproxil fumarate in combination with emtricitabine. A big, long name, but the brand name was Truvada. And it was a pill taken once a day. Demonstrated in two large global trials, called iPrEx and Partners PrEP, that operated in four continents, thousands of people, and demonstrated for the first time that individuals who had a chance of getting HIV, if they took this medicine every day, it markedly reduced their chances. And in both of those trials and a whole bunch of subsequent analyses that have been done and validated by CDC, by WHO, those sorts of things, the degree of protection, if you're taking that medicine every day, is in excess of 90, 95%.
Mary:
Wow.
Jared Baeten:
So really powerful, right? And I think the... Yeah, the wow. Wow, exactly. So for someone like me who remembers the late '80s, remembers the early '90s, to think of a medication that you could take, not get HIV, the weight on your shoulders just lifts. Now, that medicine approved a dozen years ago in the United States and now used in countries all around the world. There are hundreds of thousands of people every day who take PrEP in this country and around the world. As a result, many people have stayed HIV free, and you can really see it in some places in the world where a good fraction of people have taken up PrEP. So, I'm here in my office, which is south of San Francisco, and San Francisco is one of them. Sydney in Australia is another, London. Places like that where the number of new infections has decreased substantially, not completely, not down to zero, but substantially in the last few years, 50% or more, really as a result of rolling out PrEP.
But taking a pill a day and having that pill in your briefcase, in your purse, in your backpack, in your medicine cabinet, on your bedside table, where your partner, your aunt, your cousin, whatever could discover it isn't workable for all people, as you can imagine. As you can imagine taking a pill every day to prevent a disease you don't have may not register in everybody's major life priorities at that moment-
Mary:
True.
Jared Baeten:
... when people's got jobs to do or kids to manage or the hustle that is life, especially if you're at a time in your life when things are really busy. So that's the whole reason to think about continued innovation, to make new PrEP options that will really be able to appeal to what people need.
Mary:
This is a later question, but we can go... I'd love to hear more about it now. Can you tell us about the newer, longer-lasting versions of PrEP and how those might help underserved populations or even just people who are forgetful about taking a pill every day?
Jared Baeten:
Exactly, exactly. So here at Gilead... Gilead was the innovator of the first medication for PrEP, and we've worked on a subsequent once-a-day pill that's been used in lots of places and now on a new medicine called lenacapivir, which is still investigational and hasn't been approved yet for PrEP, but has had some data readouts this year that really show quite encouraging new results. I'll tell you about those in a second.
But let me tell you where the starting point was. The starting point is people saying to us... People in communities, scientists, doctors around the world saying to us, "There are still too many new HIV infections. We need new versions of PrEP, and we need versions of PrEP that people don't have to think about every day." Because people don't want to think about it every day because maybe they're forgetful; maybe they don't want people to know. They would love something they could keep discreet, private. Maybe they want something that they don't have to just deal with every day. They don't want the dealing with thinking about HIV prevention every day because they've got two jobs to work or three kids to raise or whatever else.
We sat down, and we worked, and we backed-and-forthed with all of that input and with all of that advice, and we developed a medicine. The medicine is called lenacapivir. It's very, very specifically designed to attack the HIV virus. It attacks the structural elements of the virus, the things that hold the virus together, called the HIV capsid, and it disrupts that. And as a result, it's able to prevent the virus, for HIV prevention, from being able to infect someone. The medicine is extraordinarily potent, actually the most potent anti-HIV medicine ever developed, and has a really long half-life. So it's able to last for a long time. As a result, it's formulated as an injection that can be given just twice a year to prevent HIV.
Now, this medicine was tested for years in chemistry development and preclinical studies to understand... to optimize for potency and for half-life, to develop the very best molecules. In fact, we actually tested 4,000 molecules to get to the one that is lenacapivir, and then in early clinical studies to demonstrate its safety in people. This year, the information that's read out is from two incredibly large studies. These are called PURPOSE 1 and PURPOSE 2. These are studies of lenacapivir being evaluated as PrEP in over 8,000 people from four continents, including the United States and elsewhere in North America, and in women and in men as well as in transgender and gender non-binary individuals. So the most diverse population, the most global population that's ever been evaluated for PrEP.
These two studies evaluated whether lenacapivir could be safe and whether it could be effective for HIV prevention. We're really pleased. Large studies like this, as you can imagine, take a goodly amount of time to launch and then to enroll. It takes months and months to enroll thousands of people. And partway through the studies, what happens is that an independent committee of scientists looks at the data and evaluates whether the study has already, even partway through the study, achieved the result that it was aiming for. We're really pleased that that independent group came back and said, "We want you to know that you've achieved your result already." In the PURPOSE 1 study, there were zero infections among more than 2,000 women who received lenacapivir for HIV prevention.
Mary:
Wow!
Jared Baeten:
And then the PURPOSE 2 study... Yeah, wow! Wow is right. You're never prideful enough to aim for 100% in anything you plan for in science. So when you get a result like that, it hits you. It hit me. It makes you speechless because you don't get moments like that ever in science. And then the PURPOSE 2 study, there were only two infections that occurred in the PURPOSE 2 study in 2,000 individuals in that study. And in fact, 2,000 individuals, that means 99.9% of them did not acquire HIV. So two really striking numbers between PURPOSE 1 and PURPOSE 2, and those have now catalyzed a whole series of plans to figure out how to quickly register the products for approval with regulatory agencies and be able to aim for access in this country and all across the world.
Mary:
How did your team and you feel with those kind of insane results?
Jared Baeten:
You can never plan for something this striking. So when I saw the PURPOSE 1 results read first in June of this year and when I saw the zero, I stopped. It takes your breath away to see something that you've hoped for as a scientist, but also as a person living in this world, living in this world where there's been HIV for 40 years and where it has been so devastating and continues to be. So just to stop and recognize how transformative that kind of result could be, that I had to just stop actually for a few minutes and just appreciate that moment. And then similarly, for the PURPOSE 2 result, it was in September, I was a little bit better primed for a comparable result, having lived three months earlier through the first one. So the pause was not quite as long.
But I think when you put them together... My entire career has been focused on HIV prevention. I'm a physician. I've done a lot of HIV treatment. I do a lot of work on developing new medicines here for the treatment of HIV as well as for treatment of viral hepatitis and other diseases. But I've always had a touchpoint with HIV prevention in my research, and all of this together is a reminder of why we go into this kind of work in the first place. We go into this work to strive a little bit more every year for something better, always hoping to be able to get to something that could be really transformative, transformative for individuals and transformative for the world. This is that moment. Scientifically, this is this moment. And I think what I'm looking forward to in the future is being able to see this amazing science be transformed into amazing impact. And that's why we're working so hard around here right now to take this medicine from all the science that we have, reach for regulatory approvals and large-scale manufacturing, and then delivery and access for all around the world.
Mary:
That was actually going to be another question I was curious about. What is the supply chain like on this? Is it a delicate product that needs to be stored at some sort of narrow band of temperatures, or is it something that can be transported more widely?
Jared Baeten:
Fortunately, it is room temperature storage. So it's a syringe. I'm sorry, it's an injection. So it comes with a syringe. It comes in a vial, like you'd expect. But all of that can be stored at room temperature, which is fantastic when you think about how one could distribute HIV prevention in lots of different settings in the world, lots of different clinics. And I'll be honest, that was part of the back-and-forth that we talked about earlier. With all the advice we got in developing what would be really an optimized new type of PrEP, one of the strong statements, and there were many strong statements as you might expect, but one of the strong statements was, "Please don't have a cold chain so that it can be deliverable in as many places as possible." And regardless of what country you live in, as many places... Cold chains really can limit. Yeah.
Mary:
Yeah. I mean, I think we saw that with the first of the COVID vaccines, how they were pretty fragile. I mean, it was impressive they were made so quickly, but they were also a little bit delicate, which doesn't work for everybody everywhere.
Jared Baeten:
It doesn't work for everyone everywhere. And that's why it's really important when one does drug development to, first of all, recognize that there's iteration. There are medicines now that originally were delivered with freezers or refrigerators or something else that get evolved into something else. But also to have the conversations with governments, with clinicians, with communities from the start to try to aim for what's going to be best, what's going to be the best product that could be developed, and how can we get as close to that as possible from the get-go.
Mary:
Who is taking PrEP, and how have those demographics changed since it was first approved?
Jared Baeten:
Yeah, so in the United States, I think there's been a lot of work done by many, many people to characterize who takes PrEP. And I think the great thing has been that people do take PrEP. And we talked about this before, that there are hundreds of thousands of people all around the world who take PrEP every day. And that's many, many different kinds of people, and yet, there's some disproportionality in who's taking PrEP right now. In the U.S., gay white men tend to have very good PrEP uptake, and in contrast, men of color have lower use in general across different demographics of populations. And women in the United States have had sort of the lowest uptake of PrEP. And of course, within each of those groups, there are some people who take PrEP well and some people who don't take PrEP well, but those are sort of the overall averages.
And around the world, the same plays out in many, many different countries. So for example, in Sub-Saharan Africa, where the HIV epidemic is somewhat equally split between men and women, particularly and even more so, there's more HIV in young women than in young men. So it really leans in towards adolescent girls and young women. Their PrEP use has been, in many, many different studies, to be much lower than one would want, and particularly persistent use, continued use for six months, a year, two years, as long as one would really need it. All the more reason to think about a medicine, a potential medicine that could be given twice a year, because the ability to persist for six months kicks in on day one when something is given twice a year. But the ability to persist for six months with a daily pill for some people is really, really challenging.
So there's so much opportunity. In the United States, it's estimated that maybe a quarter to a third of people who would most benefit from taking PrEP are taking it right now. And then even above that... So there's a lot of headspace to imagine to be able to really get to the kind of impact in this country that we'd like to get to. And even above that... Those are the people who most benefit. Above that, there are many people who potentially would want to think about PrEP for reducing their chances of HIV, although they may not be identified as the greatest risk. So there's a lot of opportunity to think about being able to meet people where they are for HIV prevention with something that would be really presented quite differently than a pill once a day.
Mary:
Yeah, absolutely. Is there anything that you are working on to market it in other areas? What kind of marketing can be done outside of the U.S.?
Jared Baeten:
I think the fact that the United States is one country where there's marketing of products on TV and commercials. In addition, one of the things that I've seen, because I've worked on PrEP for a long time... I was one of the leaders of one of those first trials of the first medicine for PrEP, so I've worked on PrEP for a long time now. Conversations about PrEP have percolated into mainstream moments so that on a television show, not as a commercial... Maybe as a commercial, but that it drops into a television show in a casual conversation as part of whatever drama or comedy you're watching, and it just comes in. And I think that signals that really it's an opportune moment in the world right now to be talking about prevention and to be talking about what we could do to really reduce new HIV infections, because it's enough in people's heads in different sorts of ways that I think there's a really good time to be talking about HIV prevention.
You asked about places around the world, and one of the things we say at Gilead all the time, we have a vision that what we would like to see nothing more is to end the HIV epidemic for everyone everywhere. And so we've been working... And we really see that lenacapivir has the potential as it goes through regulatory review in every single country, which it does a regulatory review by every country, which is going to cascade over these next few years. We need to figure out how to make it workable and accessible and available in every one of them. One element of that has been a strong focus from the moment we had results of the PURPOSE trials on low and lower middle income countries because those countries carry well more than their share of HIV. They have since the beginning, and there's really opportunity to be able to think about prevention making a big difference there. We talked about adolescent girls and young women in Africa a moment ago, for example.
So one of the things that we announced... The moment we had the results of the PURPOSE trials, we announced that we had signed voluntary license agreements with generic manufacturers so that they would be able to take all the technology and information on how to make lenacapivir and be able to make it for 120 low and lower middle income countries around the world. And those manufacturers, for example, produce HIV drugs every day for HIV treatment for those countries. And they could produce at large scale to be able to make high-quality, affordable versions of lenacapivir as quickly as possible for those countries. So part of this is, as we're thinking about making the impact all around the world, it's all kinds of different strategies and all kinds of intentional, creative, meaningful partnerships that are going to be able to make this work.
Mary:
That's amazing. My last question was, can you tell what Gilead is working on now to improve PrEP? But it kind of seems like the biggest area of improvement might be that access. And doing those licensing agreements seems like kind of a no-brainer way to do it. That's really cool.
Jared Baeten:
Thank you. No, it's-
Mary:
It makes perfect sense, you know?
Jared Baeten:
It makes perfect sense. And I just want to... And beyond those 120 countries, it's everywhere in between. So we're actively working on what access and planning looks like for every other country in the world because we really view that each place needs its own plan, and it needs us to lean in and be dedicated to what's going to work for them and really be able to attack HIV where they are. And that includes this country, of course, where we've had so much success in HIV and so much success with innovation and science, the very best of what innovation can do, and where we still have gaps for treatment and prevention that we could really make a difference.
So what else are we working on? As a scientist, it's great to take a moment and celebrate great scientific results, but we don't do this work just to get a great result or to write a paper in a high-impact journal or something else. We do this so it actually gets to people. So the next step is actually all kinds of innovation in regulatory filings and in manufacturing. So, that is simultaneous regulatory filings in a whole bunch of countries all around the world so that we can get the medicine to people faster, and manufacturing adds enough volume so there's no shortage when things are approved.
I think another piece that's been really important in the PURPOSE studies, in addition to the diversity in geography and race and ethnicity and gender that was included, we also intentionally studied lenacapivir for safety and efficacy throughout pregnancy and in adolescents who enrolled in the studies, people who often, when you're making a new medicine, often don't get scientific information until years after the first scientific information reads out. So we're very happy in the PURPOSE studies we have that information from the get-go. So another piece of innovation is, in the regulatory reviews as well as in medical guidelines, to be able to provide the data to be able to speak that this medication, if approved, will be able to be used in younger people and in individuals through pregnancy and in a wide variety of people, which is really important to get that information from the get-go so that people don't have hesitation.
Mary:
Yeah.
Jared Baeten:
And then I think we're never done. So I think back in our laboratories and in our manufacturing, we're constantly thinking about how we can innovate more really to meet people where they are and to be able to have the greatest potential impact we could have. So I think we're never going to count ourselves done until HIV is done. And with that in mind, maybe we'll talk again in a few years about something else that just pushes us a little bit further in trying to get to the end of the epidemic.
Mary:
I mean, yeah, anyone can be at risk, so the best course of action would be to make it possible for anyone to be able to take it.
Jared Baeten:
I think one of the things that we've all learned, as clinicians and scientists and people who've worked on PrEP for a long time, is that there are lots of reasons that people may need or want PrEP and be able to meet people where they are for that, for reading what's in their heads and what's coming in their lives to be able to say, "I need this, or I want something for PrEP." We've got to meet them where they are, and I think when we do that, we're going to have a big chance of cutting new infections.
Mary:
That would be amazing. Thank you so much, Jared, for sharing your expertise. These are some really exciting developments, and I'm so glad you could tell us about them.
Jared Baeten:
It was a real pleasure. Thank you. Thank you for talking, and I hope we get to talk again.
Mary:
Absolutely.