Gene therapy - how can poorer countries benefit from the most expensive drugs in the world?

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Kevin Doxzen: Huntington's disease, cystic fibrosis, muscular dystrophy, sickle cell disease, beta thalassaemia, different cancers.

Robin Pomeroy: A list of cruel, often incurable diseases. But what if we could find a cure? Have you heard of gene therapy?

Kevin Doxzen: Gene therapies have really hit the news recently because we are at this inflexion point where the right tools are rising.

Robin Pomeroy: Welcome to Radio Davos, the podcast from the World Economic Forum that looks at the biggest challenges and how we might solve them. This week: gene therapies - a rapidly growing branch of medical science that promises breakthroughs for diseases previously considered incurable. We hear from Uganda on hopes that HIV could finally be conquered.

Cissy Kityo: Gene therapy does not just treat the symptoms, it actually deals with the underlying biology.

Robin Pomeroy: The potential is enormous. But there's one big problem.

Kevin Doxzen: Cost, the huge elephant in the room. Gene therapy priced at $2.8 million for a dose. These are the most expensive drugs in the world.

Robin Pomeroy: So how will the world's poorest ever get access to therapies that could cure diseases from which they suffer the most?

Cissy Kityo: 67% of the world's HIV population is in sub-Saharan Africa. About 40 trials of gene therapy have happened in the world, and zero has happened in a region which has the highest prevalence.

Robin Pomeroy: And it's not just about money. The fact that most of the research and development is being done in richer countries is problematic on a biological level.

Cissy Kityo: So we are talking about genetic alterations in a small population of HIV patients in the Western world, and then we later transfer these products to sub-Saharan Africa. They may not work. We don't know.

Robin Pomeroy: Subscribe to the Davos wherever you get your podcasts. Leave us a rating and review and join us on the World Economic Forum Podcast Club on Facebook. I'm Robin Pomeroy at the World Economic Forum, and with this look at gene therapies...

Cissy Kityo: We are very optimistic. And I think if you don't do anything, nothing happens.

Robin Pomeroy: This is Radio Davos.

Gene therapy, treating disease by manipulating our DNA, is not a new idea. Already in the early 1970s, scientists were discussing it. But now the idea is no longer a theory. With the massive advances in knowledge about the human genome, the genetic material that makes us who we are, scientists are developing ways to treat previously incurable diseases.

It's a complex and costly area, as you will hear from my co-host on this episode. Kevin Doxzen is a Hoffmann fellow at the World Economic Forum and a scientist specialising in genomics. He is particularly interested in the barriers for poorer countries to access gene therapies. Later in the episode, he and I talk to Cissy Kityo who is head of Uganda's Joint Clinical Research Centre and who has spent decades dealing with HIV in that country. And we hear what needs to happen for sub-Saharan Africa to benefit from these potentially game changing technologies.

First, though, I asked Kevin to tell us more about the basics. What are gene therapies?

Kevin Doxzen: Gene therapies. They're not something that has arisen in the last few years. They've been around for decades. And it has a long, really interesting history. But we're at an inflexion point. And so what do I mean by gene therapy? I'll use the FDA's definition.

Robin Pomeroy: The US Food and Drug Administration.

Kevin Doxzen: Exactly. So they define gene therapies as something that seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use.

So it would be great to go into your cells and alter your DNA and really create a permanent fix for certain genetic diseases or infectious diseases or cancer. And for a while, we just didn't have the best tools to do that.

And why gene therapies have really hit the news recently is because we are at this inflection point where the right tools are rising. People are developing these molecular machines with just incredible precision that can go down in your 3 billion base pairs in each one of your cells. There's tools now where you can go and find a single letter and then make a change. And so that's why we're seeing right now over 2,000 gene therapies in development globally.

Robin Pomeroy: Okay. And what kind of diseases seem to be most promising for gene therapies?

Kevin Doxzen: The first diseases that come to mind are genetic diseases. So diseases that originate from we'll call them mutations in your DNA, leading to a negative condition. And there's thousands of them. They range from fairly mild ones to some that are completely debilitating. And this class of diseases includes things like Huntington's disease, cystic fibrosis, muscular dystrophy, sickle cell disease, beta thalassaemia. Another class of diseases would be malignancies. So different cancers. And there's a class of gene therapies called CAR-T therapy that addresses those. And then another one is infections. We'll hear later from Cissy Kityo in Uganda, who's interested in using gene therapy for HIV.

Robin Pomeroy: So a lot of these diseases are considered incurable. Many of these, certainly if you think of HIV, cancers can get to a point where they are incurable, a lot of those genetic diseases you're talking about. And gene therapy offers this kind of breakthrough way of treating them and of curing them. Are these already in use? Are patients already taking these? And how do they take them? Is it a pill? Is it an injection? Is it a surgical procedure?

Kevin Doxzen: Fantastic question. And that's really where a lot of the conversations are right now is: how do these therapies work and how can we make them more efficient? And by doing that, how can we make them more affordable?

And so gene therapies work in a few different ways. We can divide them into something called ex vivo and in vivo. So ex vivo is we remove the patient's cells from their bodies. We make the genetic change we want to make and we put them back into the patient's body. So you can kind of think of it like a stem cell transplant. And that works really well for diseases like, say, sickle cell where we can go in and remove the stem cells that create your blood cells, make the genetic change and put it back in. Specifically in the bone marrow.

But that doesn't really work for, say, something like Huntington's disease. We can't take out the brain. So that's when we need approaches that fall under the in-vivo category where we just make an injection of the gene therapy molecules into the body. And that's kind of where the future's going, because it's just simpler.

But that is a huge bottleneck, because how do you get these gene therapy molecules to the cells you want to edit? You don't want to start editing the wrong cells. You want to be efficient with how you're delivering these gene therapy molecules. And so a lot of work right now is in targeting the right cells.

Robin Pomeroy: Okay. Now, let's talk about kind of the central problem here, because this all sounds very promising. But I guess the central problem we're looking at in this episode of Radio Davos is the cost side. Give us some idea of what the cost is of some of these therapies.

Kevin Doxzen: Yes, I think we don't need to look too far in the past to get a snapshot of the costs and kind of the huge elephant in the room. And so Bluebird Bio, they had a gene therapy approved that was priced at 2.8 million [US dollars] for a dose, and that was for beta thalassaemia, a rare blood disease. One month and one day later they had a gene therapy approved for rare neurological disease, and that was priced at 3 million. So they beat their own record.

And so these are the most expensive drugs in the world. And we're at a really interesting time where the whole health system, the pharmaceutical companies are just trying to figure out how to make these drugs accessible.

And on one end, with the pharmaceutical companies, these are supposed to be curative medicines. So if I treat a patient, ideally for the rest of their lives, they're cured, right? Where unlike other medicines, they have to take a pill every day or every week. So you just have a different economic model.

Another side, manufacturing, these are not cheap to make and they can account, just the manufacturing costs can be six figures. And in the U.S., we're also now dealing just with market forces. How high of a cost can the market bear or how high of a price can the market bear?

And then there's this question of value, where curing someone from a disease and that person may be, you know, normally for the rest of their life they get a blood transfusion or, you know, some procedure that that costs the health system money over the decades of their life. Then if we have a curative therapy, in theory you're saving the health system, decades of blood transfusions or these other procedures. And so there's a huge value of gene therapies to the health system. But you're paying for that value all at once, upfront, with this one-time injection.

So just really complicated and interesting economic forces going on right now. But I think with technological innovation, these prices and these costs are going to drop over time. But that doesn't translate very well to low- and middle-income countries.

Robin Pomeroy: Okay. So we're going to look at that particular issue now. So give us an idea of what this problem is for poorer countries.

Kevin Doxzen: The main issue is these countries carry the highest disease burdens in the world. So there's this ethical question of if we have a cure for a certain disease and a majority of those people live in certain countries, we need to find a bridge. We need to find a way to get these therapies there.

Also, we're talking about genetic therapies. We look at Africa in particular, this continent is the most genetically diverse continent. And so if we're making a gene therapy in the US, odds are pretty good it's not going to translate in safety and efficacy directly to patients in Africa. Just have different DNA, different variants across their 3 billion-letter genome.

And so that means we need to do clinical trials on the continent, and then we need to develop these gene therapies fit for these health systems. So we can create gene therapies that work well at certain hospitals in the U.S., but we need to design manufacturing tools, we need to design all these different pieces that fit within health systems in these low- and middle-income countries. And that's what we'll talk about.

Robin Pomeroy: Okay. Well, let's hear this interview, then. You and I spoke a few days ago to Cissy Kityo, executive director of the Joint Clinical Research Centre in Uganda. She's a very prestigious figure in Ugandan healthcare and has a distinguished career, particularly looking at HIV in that country. And she talks about the lessons we should learn from the past of HIV treatments in Africa, also the lessons we should have learnt from COVID and COVID vaccinations and how that went or didn't go around the world quickly enough to lower-income countries. Let's hear the interview.

Kevin Doxzen: Thank you for joining us today, Cissy. So in May this year, you received Uganda's Golden Jubilee Medal for Outstanding Service and Loyalty, which is considered the highest civilian award in Uganda. And so you have this breadth of experience and knowledge of the HIV epidemic in Uganda. And I think I'd love to start there, because in order to really understand an advanced therapy, an impact it might have in a few years, we kind of need to understand the history. What value is it serving? What holes does it fill that current therapeutics don't fill? And so I'd love for you to give us a snapshot of the history as you've experienced it. And then that can help frame our conversation about maybe where can and should we go.

Cissy Kityo, Executive Director of the Joint Clinical Research Centre in Uganda: The history of HIV in Uganda started in 1982, when the first case of AIDS, which we called 'slim disease' at the time, was identified in southwestern Uganda. The HIV spread. Initially, it was thought this was witchcraft from Tanzania. In 1984 we were able to have tests in the country and we were able to diagnose people and a lot of education then started, that this was a disease that was happening elsewhere and how could we prevent it? So all this communications and advocacy for prevention started.

But between 1982 and 2004 when we started scaling up ART [antiretroviral therapy] is what I would call in Uganda the pre-ART era. So during this time, many, many people got infected. Uganda became the country with the highest HIV prevalence in the world because there was really nothing to offer. It was at the height of the HIV epidemic that the Joint Clinical Research Centre was set up in 1992. And the objective of this was that we find a scientific intervention and retroviral therapy is also called ART.

Robin Pomeroy: Which is the first type of treatment for HIV. Is that right?

Cissy Kityo: That's right. In 2000, we did import antiretroviral drugs from India, generic ones. And this is when the prices became about a third. And we continued to negotiate with both the the inventors and then the generics [makers] and the prices came down. And because the prices came down, many more people could afford to access the treatment. We opened up clinics around the country because then people would not have to travel all the way to Kampala to collect antiretroviral drugs. Employers were able to provide treatment for the employees instead of letting them die. Families could come together and fund raise money so that they could buy these drugs. But we only had about 10,000 patients accessing treatment.

Robin Pomeroy: That's 10,000 out of how many people who would have had HIV at that time?

Cissy Kityo: At that time, it was estimated we had about 1 million people. Before that, we had about 1,000 who could pay. Then we rose to about 10,000 because we had generics and they were much cheaper. But this also had to be sustained every day. And with the ongoing advocacy, we trained many others to be able to provide the antiviral therapy. We rolled it out in the country. We supported capacity building for other countries that had not started ART. We worked with the WHO We worked with our Ministry of Health. And now I think that became history. People could live longer. They could be there for their families. They became more productive.

Right now, what is happening? We have goals set by UNAIDS to reach the 90-90-90. The first 90 is testing at least 90% of people, knowing their HIV status. Then 90% being linked to treatment. And then 90% having viral suppression. But this has moved from 90 to 95, and now the target is to have epidemic control by 2030. We should be having less new infections compared to the deaths.

So while antiretroviral therapy has revolutionised HIV and made HIV like any other chronic disease, like hypertension, like diabetes, you need to take your drugs every day, though. And the moment you don't take your drugs consistently, the virus will start multiplying. And we have had many patients that get fatigued. Some of the patients we have, we started them on treatment when they were three months. Now they are adults in the clinic. We've had relapses. We have gotten also a development of resistance to these antiretroviral drugs. And so these are some of the challenges, especially with adolescents, to adhere to their treatment. And also, many men don't want to seek care in time or even adhere to their treatment.

Robin Pomeroy: You mentioned before the kind of the tiny fraction of Ugandans with HIV who are being treated. I mean, what is what is that situation today? You mentioned this target of 90 or 95%. Is that the reality now? What what is your estimate of those people with HIV actually getting treatment?

Cissy Kityo: In Uganda we have about 1.3 million people who are on antiretroviral therapy. We are still looking for more - those ones that have been tested but may have the infection. But we are close to the 95. Now, the target of epidemic control by 2030 is what we are looking at. And when we hit that target, what that means is that you continue to need antiretroviral drugs even beyond that, you have to take them for life. And what we are seeing is the funding for antiretroviral therapy from international programmes - except for PEPFAR [the U.S. President’s Emergency Plan for AIDS Relief] - it has sustained the amount it is giving. But the funding agencies, the funding is going down.

So while we are looking at epidemic control, the funding is coming down. Yet we have to sustain the antiretroviral therapy. So that is the precarious situation in which we are - we may not meet the target of 2030 because of all of these problems and also of the funding which has to be sustained. When the funding is coming down we are not seeing our governments stepping up to fill that funding gap. So we need another tool in the mix. How are we going to deal with this HIV epidemic?

Robin Pomeroy: So this is probably where Kevin can come back in now and talk about gene therapy. Kevin?

Kevin Doxzen: Yes. So one of the huge value gains of a gene therapy is that it's a one-time injection for a very durable, long lasting, quote unquote 'cure'. And so kind of a multipart question I have is 1: how is gene therapy approaching HIV? If you are a person living with HIV, what is going to happen to your DNA? The other part of the question is, should we use the word 'cure'? If I'm treated with gene therapy and I'm living with HIV, is it going to be controlled for the rest of my life? Will I be able to transmit it to someone else? So if I'm a patient, how do I think about this?

Cissy Kityo: In simple terms, gene therapy is the alteration of our genetic material in the cells, in our bodies. And this alteration is dealing with the smallest functional unit of the genetic material, which we call a gene. Some of these genes are hereditary. They are inherited from our parents.

So with gene therapy, we can inactivate that damaged gene or that abnormal gene. We can actually replace that gene with a healthy gene so that we live a healthy life or treat that disease. Or we can add a gene to treat the underlying disease. So gene therapy does not just treat the symptoms. It actually deals with the underlying biology.

Gene therapy right now that is happening, there are different strategies, but those are the basic principles. Now I'll talk about HIV, but gene therapy can be used for many other diseases.

The way we look at it and know when one gets infected with HIV, HIV will embed in our genetic material and may start to replicate any time. So this is what we call the reservoirs of HIV in the body. When we talk about gene therapy today and what is happening, some of the strategies are targeting that reservoir so that we can remove it. And this reservoir is what enables the HIV to start multiplying when you stop your antiretroviral drugs.

When we talk about cure for the perspective of our patient, we can talk about it like functional cure, or complete cure, where we remove the reservoir. So in terms of functional cure, we could stop the virus from being able to multiply and then you could be off your antiretroviral therapy - for life.

Let us look at 50 years from now. Is it our governments that are going to sustain the antiretroviral therapy? Right now we are looking at what we call long-acting antiretroviral therapy. Instead of taking a pill every day, there are now injections that can be given every two months. And these studies have been done in the West. We are right now doing the first trial in sub-Saharan Africa. And in the West, patients were very happy that they do not have to take a pill every day. They could just come into the clinic every two months. There are new developments of these long-acting antiretroviral therapy that you can give every six months. We are looking to see how to also use these. But the ultimate goal is off your therapy for life: functional or absolute HIV cure.

Kevin Doxzen: There's this theme I keep hearing from you as we talk about the arc of HIV treatment. And that theme is research and development will begin in the West, you know, basic research, human testing, market access. And then we begin to think about how can we deliver this, make it accessible in other parts of the world.

There are certain reasons for that. One is just the research infrastructure in the US or Europe and the amount of funding and the efficiencies in which companies can go through a clinical trial.

In order to really think about long term access, we need to disrupt this thinking. This isn't going to work. Drugs made for the US market for US hospitals and care facilities just might not work in health systems of other countries. And we can talk more about why that's the case. But I'd love to hear your thoughts on what is the role of bringing research and development to Uganda. What is the role or purpose of performing clinical trials in Uganda not 10, 20 years after the West, but while the West is doing this.

Cissy Kityo: 67% of the world's HIV population is in sub-Saharan Africa. About 40 trials of gene therapy have happened or are happening in the world, and zero has happened in a region which has the highest prevalence.

Also, studies have just been done, supported by NIH [US National Institutes of Health] actually in H3Africa [the Human Heredity and Health in Africa Initiative], and they have found that Africa has the highest genetic diversity.

So we are talking about genetic alterations in a small population of HIV patients in the Western world. And then we later transfer these products to sub-Saharan Africa. They may not work. We don't know.

So what we are saying, also from lessons learnt from antiretroviral therapy, is that we need to be part of the research and development of gene therapy as it happens, because we are the biggest beneficiaries. And we know that the gene therapies, today there are about 20 gene therapies on the market, but none for HIV yet. But it will be coming. Those therapies are very expensive.

And because we find this is a very big gap, we did catalyse the formation of what we call the Global Gene Therapy Initiative, which has over 60 members who are volunteers with expertise in different fields, to help us move gene therapy to low- and middle-income countries.

But cost is one of the issues that we are looking at. We cannot afford the way pharma is developing gene therapy and we have many people supporting us to see that we have an affordable product, that we develop the necessary infrastructure to manufacture that product in Africa, not in the US. And we also have trained personnel to be part of the research and development, including basic science. Because I think we need to develop products here for Africans developed by fellow Africans.

Robin Pomeroy: You're both making the point here that the research tends to happen in the richest countries in the Western countries. So both on a on an economic level in terms of then how and when these drugs get distributed to the rest of the world, but also even on a biological and therapeutic level, this isn't good enough really, and things have to change. And we've learnt that lesson, Cissy you were saying, from the way antiretrovirals were developed and then rolled out and how long that took. Is there any hope that those lessons will be learnt and things will be done any better this time? Obviously there are these initiatives trying to make those changes. What do you think, Cissy? Are you optimistic?

Cissy Kityo: Very. The other example that has shown us that we have to have our own research if we want access is the COVID-19 vaccine. It was developed in the Western world and when we needed to use vaccines for our populations, the priority was for the Western world, because we didn't have anything, we had to wait.

So we are not going to wait. We have taken bold steps. We are being proactive about what we want, but we are not doing this alone. I think we have a lot of people helping us, including Kevin here and the Global Gene Therapy Initiative, as I say, it has volunteers and each of them is coming from a very strong institution that can help with funding, with training, with ideas, with strategies.

We are very optimistic, and I think if you don't do anything, nothing happens. We have moved several strides to address some of the challenges. It is not easy, there are challenges to be overcome. But these challenges can be overcome if you are serious about what you are doing.

Kevin Doxzen: So one stakeholder that I'd like to to discuss are the local politicians in Uganda. You've engaged many, many times with these leaders over the years talking about equity and really describing the cost effectiveness of gene therapy. But the road we're describing is long. This isn't going to be one, two years. We're talking, you know, five, 10, 20 years, from research through clinical trials to market access to scaling and integrating with the clinics. But oftentimes political regimes or policy leaders, their tenures aren't 20, 30 years or their budgets are a year or three years. And so when you're talking with people in the government, how do you frame this? Like, why should they think about a therapy that isn't going to be available until 10 years after their tenure, when they have immediate asks to deliver on agriculture or AI or other facets of the country? What do you say to those political leaders?

Cissy Kityo: So if this process is going to take long, if we don't start today, then we are extending the whole time that it will take.

As I already explained, HIV we need lifelong treatment. We have about 1.4 million people in Uganda [with HIV]. We do not have the resources as a government to treat these people for 60, 70 years. The best thing we can do is to see how can we cut these costs. Even working with development partners like Global Fund or even PEPFA, how can they help to facilitate the process to getting to where we need to be in terms of curing patients who have HIV and not requiring lifelong treatment?

Gene therapy is not just for HIV. Gene therapy is a frontier of science. So while the front-runner is HIV, we know that these are platforms that can be leveraged to treat many other diseases that are highly prevalent in our populations.

So we've already talked and presented to our president. He appreciates the problems and what we need to do today to change tomorrow. He's willing to support us in terms of policy and even funding. Right now, we are working on the biotechnology bill, which includes gene therapy. So I think we have been good advocates and we have the government on our side.

Research and development is a long roadmap, but it can be shortened. And one of the things that you talked about was, do we need to wait until all the trials are done in the West before we do them in Uganda? No, we are saying no. We should be doing these trials. And we've talked to our regulatory authorities that approve the trials here, we should be doing these trials alongside, because we are different population and we should be evaluating these products.

First of all, we should be developing the products. Yeah, but we need that infrastructure and trained people to do that. And we should be evaluating these products that we have access to, products that are not as expensive as what you have in the US. We should be evaluating them alongside Europe, or US, so that we can shorten that roadmap. We do not want to be left behind like we have been before. And we call on anybody that can help to join hands. Because I think without these collaborations, we cannot get where we want to be.

Robin Pomeroy: So Kevin, that was our interview a couple of days ago with Cissy Kityo in Uganda. Now, if people listening to this want to find out more about gene therapies and about what we've been discussing today, where should they go?

Kevin Doxzen: I recently released a White Paper covering this specific topic of gene therapies in low and middle income countries, and that came out 18 October. So you can find that on the World Economic Forum's website.

Where I would direct listeners is to resources made by the Innovative Genomics Institute, which is joint between UC Berkeley and UCSF, and they just released a resource called CRISPRpedia, which is a fantastic resource that has very understandable definitions of genome editing tools and various gene therapies and has videos and games and graphics.

Robin Pomeroy: Kevin Doxzen. Thanks for joining us on Radio Davos.

Kevin Doxzen: Thanks for having me.

Robin Pomeroy: Kevin's written several articles about this for the World Economic Forum's Agenda blog. Find them at weforum.org, where you'll also find the White Paper that he mentioned. It's called Accelerating Global Access to Gene Therapies: Case Studies from Low- and Middle-Income Countries. Thanks to Kevin. And thanks to our guest, Cissy Kityo in Uganda.

Please subscribe to Radio Davos wherever you get your podcasts. Leave us a rating and a review. And join the conversation at the World Economic Forum Podcast Club. Look for that on Facebook. This episode of Radio Davos was presented by me, Robin Pomeroy with editing by Jere Johansson and studio production by Taz Kelleher. We'll be back next week, but for now, thanks to you for listening and goodbye.