How medicines can be tailored to African populations | 91TV
Transcript
- Welcome to the Royal Society, both the people in the room and those joining us online for
- this evening's lecture. I'm Linda Partridge, I'm the biological secretary and vice president
- here at the Royal Society. There are a few housekeeping points to start with. Please
- make sure if you have a mobile with you that the sound is turned off. There are no planned fire
- alarms. So in the event of an alarm sounding, please vacate via the nearest emergency exit,
- which is here, and we assemble to the right of the front door of the Royal Society at the top
- of the Saint James' steps, but let's hope that doesn't happen. There will be an opportunity to
- ask questions at the end of the lecture. So we'll have two roving microphones in the room and also
- Slido for the people online. It's a great honour and pleasure to introduce this evening's Africa
- Prize lecturer. So the Royal Society Africa Prize recognises research scientists based in
- Africa who are making an innovative contribution to the sciences, and the 2023 award has been made
- to Professor Kelly Chibale. So he's professor of organic chemistry at the University of Cape Town,
- where he holds the Neville Isdell Chair in African Centric Drug Discovery and Development.
- He's also a full member of the University of Cape Town Institute of Infectious Disease and
- Molecular Medicine, and a founding director of the South African Medical Research Council Drug
- Discovery and Development Research Unit there. His research interests are in infectious disease, drug
- discovery, and the development of pre-clinical discovery tools and models to contribute to
- improving treatment outcomes in people of African heritage. I now invite him to the
- podium to give his lecture, which is entitled How Medicines can be Tailored to African Populations.
- Sorry, that was a huge pause because I had to get some water, to try and survive the British
- weather that I've found here. Linda, thank you very much for the very kind introduction, and
- thank you so much for all of you here attending in person and those attending online. It's wonderful
- to see many friendly faces coming here, and I feel enormously and tremendously honoured to be giving
- this lecture today, and of course your presence is really appreciated and those online as well,
- thank you so much for making the time to be here. It is such a tremendous honour and privilege to be
- given this award, which I don't take for granted at all, and I have so much to be grateful for and
- so much to thank everyone for, and of course, many thanks that I can spend another lecture
- just thanking people, but I will keep it short and really give some very important thanks that mean
- significantly a lot to me. First of all, I really, really would like to give honour and glory to God,
- my Heavenly Father, not just for creating me, but also for giving me the talent and the gifts that
- I have. I also want to take this opportunity to honour my mother, Elizabeth Malika Chanda,
- for the incredible, enormous sacrifices that she made. Growing up in Zambia, my country of origin,
- I lost my dad when I was only two months old. My mother was a widow and really under very difficult
- conditions and circumstances, really modelled hard work and sacrificial living. So I really want to
- honour my mother, Elizabeth Chanda, for doing that. Thirdly, many thanks to my wife, Bertha,
- in the audience. My wife of more than 34 years. One wife, 34 years. Grateful for the support and
- of course providing a very conducive environment at home. Home is where you go back and lick your
- wounds when things are not going well. So thank you for the support, the encouragement over the
- years and of course, our children, Kalaba, Suwilanji, who is in the audience sitting
- next to very close to his mum. When you see him, you'd think he's the one who got the Africa Prize
- because he looks like me, but yes, there's a difference. He's well built. I'm not. That's
- really important, but also Sechelanji, the last born. As a scientist, of course, or as a worker,
- you spend so much time away from your family. So thank you for your understanding and the
- sacrifices and the support. I would also like to thank many, many collaborators that I can think of
- and research partners. I can't even begin to start mentioning them, but this next line of gratitude
- really is very specially reserved for a number of people or groups of people and individuals. So
- firstly, it's really my mentors. The late Stuart Warren. I'll start with Stuart very briefly. So
- when I came from Zambia to Cambridge, everything was strange. The weather was strange, the food was
- strange, the people were strange, and the science was strange as well, but Stuart took me. If you
- listen to music, there was a song by Rod Stewart many years ago, that the first cut is the deepest.
- So Stuart Warren, the late Stuart Warren really laid the foundation to who I am today. So many
- thanks to Stuart. But additional thanks to Nick Graves, my mentor when I did my first postdoc at
- Liverpool, but also KC Nicolaou at Scripps, when I went to Scripps to do my second postdoc. What they
- have taught me and also given me the opportunity to work in the groups. I would like to thank my
- team members, people in my academic group and also our Drug Discovery Centre. It takes a village to
- raise a child, of course, it's always about the team. It's not about the individual. So
- I am representing those people. In South Africa, we have this instrument. If you were following the
- World Cup in 2010, it's called a vuvuzela. People didn't know what this vuvuzela was. They tried to
- switch off the TV thinking it's noise, but no, it didn't go away. So I'm a vuvuzela representing my
- team members, so all their contributions are really, really appreciated. Many thanks to the
- University of Cape Town. I have spent 28 years at the University of Cape Town, longer than I've
- spent anywhere else in the world because this is my home. So many thanks for the opportunities,
- the infrastructure, and the environment that's been given to me the last 28 years. Finally, but
- not least, it would be very, very remiss of me if I did not express my deep thanks and appreciation
- to Professor Sir Michael Ferguson, sitting in the audience here, for initiating the nomination.
- I would not be standing here if Mike had not initiated the nomination. So Mike, thank you
- so much for nominating me. All right. I will now turn my attention to today's lecture, and this is
- what I will take you through in the next 35 or 40 minutes. So first of all, I'll start with talking
- about why we need to optimise medicines for the African patient population, and then I'll deal
- with the issue of drug metabolism, variability in the way African patient populations metabolise
- drugs, and I'll go through reasons for that and the implications of having this variability and
- then it's one thing to talk about a problem, a challenge, but what are we doing about it to
- address this particular issue, and I'll finish off with a summary. Okay, I will start with this and
- I'll come back to this again. Humans are African. So you're all Africans here. If you didn't know,
- now you know you're all Africans, yes? The only difference is some Africans chose to live in cold,
- miserable places, but we are all Africans and that's why it's important to optimise medicines
- for Africans, meaning for the human race, and especially for those Africans who were smart
- enough to remain behind on the continent where it's warmer, but why is this really important? So
- one of the reasons for the variability in the way, whether it's individuals or populations, respond
- to medicine is really on the basis of genetic differences in the expression and activity of the
- so-called drug metabolising enzymes, which I'll come back to this a little bit later. Not just
- drug metabolising enzymes, but also transporters, which of course can be important in transporting
- drugs. This variability, for reasons that I'll go through shortly, are poorly understood in the
- African population for at least three reasons. Firstly, we have such a low volume of clinical
- trials that have been on the African continent. I think on average, about three per cent of the
- global clinical trials that happen around the world, three per cent of those happen
- in Africa. This has been the trend. Of course, there's been improvement in more recent years. So
- the consequence of such a low volume of clinical trials is that the African perspective in terms of
- our intrinsic factors, like the physiology of an African and importantly the genetics of an African
- is not considered. Secondly, extrinsic factors like the way a typical African practices medicine,
- for example, at what point of the disease does the patient present themselves for treatment?
- It's usually much later, but also concomitant medication. Eighty per cent of people in Africa
- who don't have access to healthcare rely on traditional medicines and that has implications,
- of course, ultimately for how clinical trials are conducted and products are optimised for people
- that participate in those trials. So typically, it would take five to ten years later from the
- time an innovative medicine is discovered and developed and approved before it's brought
- into Africa. So our clinicians and patients have only experience of this innovative medicine much
- later compared to other regions. So firstly, low volume of clinical trials. Unfortunately,
- especially given that Africa currently is about 15 per cent of the total population
- and accounts for about 20 per cent of the disease burden. So we've got to change that. The second
- reason is that we don't have preclinical tools that will allow us to prioritise molecules,
- for example, based upon their predicted profile in African patients. So those of us who work in
- drug discovery understand that much early on, we frontload an understanding of what the human body
- is likely to do to the drug. So we frontload drug metabolism studies on the assumption that
- the liver is a major organ for metabolism, but there are no African livers available to study
- in terms of the rate of metabolism. So the absence of these preclinical tools is a major
- gap that we have to address as well. Finally, but not least, for historical reasons as well,
- there's limited African data that is incorporated into drug discovery and development, and that's
- something we wrote about last year. So that's the background and the context and the justification.
- Now, what about drug metabolism? I think the best way to start with this is, first of all,
- to understand whether it's a food we eat or the medicines that we take, what goes in must get
- out. What goes in must get out. There are very few molecules that come through the body and excreted
- unchanged, so these would tend to be very polar carboxylic acids, for example. Many drugs, many
- small molecules, rely on metabolism as a means of excretion from the body. So I'll walk you through
- this slide. For the generalist, pharmacokinetics is just what the body does to the drug. What the
- drug does to the body is pharmacodynamics. So this is an acronym we like to use in drug discovery,
- the principles of absorption, distribution, metabolism, excretion. So when you take a
- medicine, whether orally or by injection, but let's assume that the drug is an oral drug, the
- question we would like to ask, first of all, how is the drug going to get in? It must be absorbed
- if it's an oral drug. Secondly, where will it go? How is it going to get there? So it needs to be
- distributed across the body. The next question is how is it broken down? That's metabolism. How
- is it metabolised? Of course, you've seen the diagram of the liver here. The liver is a major
- organ for metabolism. Of course, there are other extrahepatic tissues where metabolism happens, but
- the major assumption is that the liver is where metabolism happens, and I made the point earlier,
- there are no African livers incorporated in these preclinical trials to allow us to understand
- much early on how the African body is likely to metabolise that drug. Of course, the final point,
- once the molecule is broken down, how does it leave? That's the excretion part of it. So that,
- I would like you to keep this in mind as I walk you through the rest of the presentation. The
- question is, can the drug get to the site of action at high enough concentration to elicit
- the desired pharmacological effect? That's a question that needs to be answered. So with that,
- I'm going to switch now to the issue at hand, which is why is this metabolism so
- variable amongst the African patient population? I made this point earlier. One of the reasons for
- the variability in the way people respond to medicines is a consequence of genetic
- differences in the expression and activity of drug metabolising enzymes and transporters. So clearly,
- when you have mutations in the genes encoding for drug metabolising enzymes,
- the issue really is one of variable expression levels, concentrations of the drug in the body,
- which of course has implications on either clinical outcomes in terms of efficacy but
- also side effect profile. Of course, when those genes are related to drug dispositions, this has
- implications on exposure of the drug response in terms of efficacy, in terms of the desired effects
- or adverse reactions, but also the emergence of drug resistance if we don't achieve sufficient
- concentrations of the drug to elicit the desired pharmacological effect. So that's basically what
- is these diagrams are explaining here. So this is a normal metabolizer, however you define normal,
- in terms of the plasma concentrations of the drug. So you can relate that diagram there to this
- curve. So if you plot the concentration versus time, that's your normal concentration there.
- So if you have a poor metabolizer, somebody with a poor metabolizer phenotype here, so you expect
- the concentration to be much higher, obviously, because they're slowly metabolising the product.
- The other extreme is you have a fast metabolizer, which of course means that the concentration is
- going to be below the normal metabolizer. So this is the implication of either underdosing a patient
- or overdosing a patient and this has serious implications. The story of efavirenz. This is
- an HIV drug that was launched in Africa, I think in Zimbabwe probably about 2015 or so, where the
- enzyme that is known to metabolise this drug in Caucasian patients, in people of African heritage,
- there is a genetic polymorphism that renders people of African descent slow metabolizers,
- which means for the same dose, people are being overdosed, and of course, when people are
- overdosed, there are side reactions and then they cannot adhere to the treatment regimen. Therefore,
- of course, that increases drug resistance and of course, lack of compliance to the therapy. All
- right. Why is this a big deal? I can go into many other variables and factors but just focusing on
- metabolism. So these cytochrome p450s, or SIPs as we call them, these are the most common drug
- metabolising enzymes. They carry out what we call phase one metabolism, basically to carry
- out chemical reactions in the molecule that makes it easy for the body to excrete the drugs. Many
- of these enzyme alleles have only been identified in the African population, or at least they exist
- at much higher frequencies in African patient populations, which of course has implications
- not just for the efficacy of the drugs, but also adverse reactions, and of course, then it becomes
- challenging to translate clinical trial data from other populations to the African population
- because this is not really considered fully. So with that background, the question is, so we have
- problems, we have challenges. What can be done? What should be done? So I'll walk you through what
- should be done, but importantly what we are doing to change the status quo. Before I get there,
- I want to just take advantage of the recent pandemic and just remind us of the many lessons
- that we learned from the COVID-19 pandemic. There are many things I can list here, but these are
- very important and very, very relevant to today's talk. So what COVID-19 did was emphasising the
- importance of every nation, every region, every continent, particularly Africa, to bolster
- the public health infrastructure capacity, but also importantly, the R&D, the research
- and development. We saw how with supply chain challenges, unless we have local manufacturing
- or local innovation to leapfrog progress and charter homegrown solutions is a lesson that we
- learned from the COVID-19 pandemic. We learned about why we need skills. How can we retain
- people? How can we retain talent in Africa? I had the privilege of getting my education from the UK
- and the US and had an opportunity to go back to Africa. Not many people can do that. Not many
- people have been afforded that opportunity to do that. So if we keep training people and not create
- mechanisms to create that absorptive capacity to attract the talent, nurture the talent, develop it
- and retain it, we're going to keep throwing money down the drain. But also what we saw during COVID
- was it's not just research partnerships, it's also funding partnerships. So what can be done? I will
- share with you just three things that can be done, should be done, and are being done in some cases.
- I'm going to address this on three levels. First of all, addressing the issue of clinical trials,
- number one. Number two is addressing the issue of developing capabilities and capacity in close
- proximity to where the patients are. There's a very strong correlation between the genetics
- of the population, the social and physical environment in which those patients live,
- and treatment of disease. Therefore, it's a no-brainer that building drug discovery
- and development capabilities in close proximity to the African patient population in their social and
- physical environment is the best way to address the unmet medical needs, but importantly as well
- for the innovative pharmaceutical companies, this data that we generate in these regions, if we
- participate in this R&D, becomes important to the global pharmaceutical industry whose mission it is
- to serve patients across the globe. So clinical trials, easy. We have three per cent of clinical
- trials that happen. What we have to do is two things. It's to increase the number of clinical
- trials that happen on the continent for obvious reasons, but secondly, and importantly, increase
- the number of Africans participating in those trials. It's very important because Africa is not
- a country. It's not a country. It's a continent, and it's a very heterogeneous continent.
- It's very diverse genetically. West Africa, East Africa, North Africa, Southern Africa. The level
- of genetics is so, so diverse. So we have to increase not just the number but also the number
- of people that participate in those trials. This is a quick image here. This is a busy slide but
- the message on this slide is very simple. A very low number of clinical trials that happen on the
- African continent in comparison to the rest of the world, and these trials mostly happen in two
- countries. It's in South Africa and it's in Egypt. So this has to change. We have to do more of these
- clinical trials across different regions of the continent. So that's the number one thing to do,
- to address clinical trials. The second thing that we have to do is to build the discovery capacity
- and the development capacity, including local innovation as expressed in local manufacturing,
- in close proximity to where the patients are, and this is what we have done. So building local
- innovation, building capacity is exactly why we established our Drug Discovery Centre in 2010. If
- you didn't know about 2010, 2010 is the year that we hosted the Soccer World Cup. It is the most
- significant year in the history of humanity, and anything that you start in the year of the World
- Cup is a big deal. We didn't talk to FIFA. They didn't talk to us. But as it happened, we launched
- the centre in 2010. So the last 13, 14 years we have been on a mission to conduct infectious
- disease drug discovery. We have been on a mission to build drug discovery infrastructure. We have
- been on a mission to develop tools and models that will allow us to prioritise small molecules during
- their optimisation, but also allow us to stratify patients for clinical trials, and I'll share some
- of that with you today. Importantly as well, we've been involved in training the next generation of
- African scientists who understand team-based scientific research. That's what we've done.
- This is the infrastructure that we've developed with our partners. Of course, we have chemistry,
- synthetic chemistry, medicinal chemistry, we have computational chemistry. We introduced artificial
- intelligence to build models using the data we've been generating over the last decade or so to
- bring efficiency to our drug discovery programmes. We've also developed across the medical school,
- a pharmacology platform. We have a suite of metabolism assays, physical chemical metabolism
- assays all across to doing our own rodent pharmacokinetics to understand how the animal,
- the mice before we do the efficacy experiment is going to handle the drug, which might kind of
- reflect how the human body might be able to handle the drug as well. An important platform as well
- is this pharmacometrics platform and this allows us to do modelling to predict human dose using a
- whole variety of parameters from the discovery phase and other properties of the molecules.
- We also have biology platforms, again reflecting the disease focus of interest within our centre,
- including an enzymology platform where we do protein expression, purification,
- setting up biochemical assays, miniaturising them, then doing high throughput screening,
- and of course, when you are running such a complex organisation, it becomes important how you store
- your data and sample management. So this is not a picture that existed when I moved to Cape Town
- 28 years ago. This had to be built from scratch and if you consider that and put into perspective
- what we've done, it's been a remarkable journey with the team over the last few years. So just
- a few points on this busy slide. So when I'm at University of Cape Town, I have two appointments.
- One is an academic appointment, I have an academic group, and the other one is a centre. So I'm not
- talking about academic group, I'm just focused on the centre here. I used to have five postdocs
- in chemistry when the programme started in April of 2011. We've grown the team to about 75 people,
- and about 90 per cent of those have postgraduate degrees. Importantly, we've conducted programmes
- in three disease areas, malaria, TB, and antibiotic resistant microbial diseases. At
- the end of the day, when everything is said and done, what have you achieved in drug discovery?
- So we're very proud that we've delivered two pre-clinical candidates in this space,
- but also our most significant success was getting a compound, working with partners, international
- partners, but us leading the effort that reached phase two human trials, and of course, developing
- a huge network of research and funding partners. This gives you an idea of, of course, everything
- we've done from scratch all the way through to the advanced stages. In this business, there's a very
- high attrition rate. As we say, in the discovery of medicines, you have to kiss many frogs before
- you meet the prince and that's what is reflected here. What else is being done? Okay, I spoke about
- building drug discovery development capabilities in close proximity to the patient, and I told
- you earlier about one of the lessons from the COVID-19 pandemic was the importance of local
- manufacturing. So what are we doing to address this issue? I want to start with this slide
- here. It's a busy slide, but I'll try and keep it simple. So what you see at the top is the R&D
- value chain. So you do the discovery. You do the pre-clinical development. If that is successful,
- you do human clinical trials, phase one, phase two, phase three, and then everything goes well,
- the drug is approved. But there's another value chain that we often don't think about and that's
- the manufacturing value chain. Many people focus on this type of manufacturing here. Manufacturing
- a product that's been approved by a regulator. That's not the only type of manufacturing. The
- second type of manufacturing is manufacturing for clinical trials. When we discovered that malaria
- candidate, we could not manufacture five kilograms of material we needed to do the phase one trial.
- So we had to outsource this to India, but this is an opportunity to set up companies focused
- on manufacturing to support clinical trials. Especially, now we are saying we need to push
- the number of clinical trials happening in Africa. We cannot do that without thinking about where are
- the products for manufacturer are going to come from? The final part of the manufacturing value
- chain is manufacturing for pre-clinical studies. It's almost embarrassing, we have to go to China
- and to India to scale up, to get half a kilogram of material to do extensive safety testing.
- This is going to change and we are changing that, and this is a programme that is currently being
- supported by USAID. USAID is from the American people, that's what USAID means. So this is a
- project we've been doing under a programme called Metrics, which is an independent special project
- we've been supporting for the last more than a year. December is the final month, and we're
- looking to renew this grant from here, but this is a pilot project to really focus on optimising
- processes for manufacturing as a pilot project, three antiretroviral drugs. It's one thing to
- talk about local manufacturing. It's another to think about bringing competitive technology that
- make it possible, at a cost level, to produce those ingredients at a competitive price. Many
- government policies require you to go for the cheapest supplier. Nothing wrong with that. So we
- can't just talk about local manufacturing without thinking about economies. So this is what we're
- doing here is to really optimise the synthesis of three drugs that we are focused on as a pilot
- project. Secondly, this is allowing us to bring this technology, flow reactor systems from the
- US to South Africa, that will allow us to do this process improvement, optimisations, and deliver a
- product or a process or innovation that will be at least as competitive price wise, but in fact, the
- target is to make it even more competitive price wise. Importantly, of course, it's developing
- the skills, not just around this technology, but it's developing the skills for process chemistry
- development. So this is moving away from drug discovery. It's addressing some of those gaps
- that I shared with you, where we needed to produce enough material to do a phase one trial. We needed
- to produce enough material to do extensive safety studies, but without this capability, we couldn't,
- we had to outsource, but we are doing something about it. This is the potential impact, of course,
- of this project. I don't want to labour the point. A lot of the work that happens in South Africa,
- probably most of Africa, is a huge formulation industry. The active pharmaceutical ingredients,
- the medicines themselves, those pretty much have to be imported outside of the continent,
- which of course is a major cost issue here, and of course, the goal of this is to demonstrate
- the potential for us to support cost competitive API manufacture, using some smart technologies
- that make it possible to do this. Of course, we have to then think about implications on supply
- chain issues when there's another pandemic or epidemic, that we can do this locally and not
- just cry about problems. What else are we doing? I can give you many lessons that we've learned,
- from how we built the centre from scratch to what it is today. So this was not capacity building for
- the sake of it. It was capacity building with a model focused on getting the job done and
- building capacity, while getting the job done, and we worked with partners that you will see
- you on the next slide, to see how we can begin to expand the ecosystem and community in Africa,
- share the lessons and learnings that were generated from the University of Cape Town, to
- see how we can benefit across the continent from economies of scale, to make business sense for
- what we do. This is the programme that we started. I'm very proud to see our colleagues and friends
- from LifeArc and from the Gates Foundation who are supporting this pan-African initiative called
- The Grand Challenges African Drug Discovery Accelerator. We got significant funding from
- LifeArc and the Gates Foundation to really support a network of scientists across Africa focused on
- getting the job done, working on projects, synergizing, building on the expertise available,
- sharing infrastructure, sharing capabilities and move projects forward. So it really is
- about scaling up on this based on performance, based on excellence, and this I think is a very
- significant development since we began doing drug discovery. We cannot do it alone in South
- Africa. We have to make sure that at least at the regional level, that we empower other groups
- to replicate what we've been able to do in Cape Town. So watch this space. So really tremendous,
- thanks to LifeArc and the Gates Foundation for supporting this programme. The final part of
- what can be done and what are we doing. I've told you about what needs to be done at the level of
- addressing the low volume of clinical trials and I've told you the importance of building capacity
- and capabilities in close proximity to where the patients are, including local manufacturing
- capability. What about preclinical tools, which is the final part of what we're doing, and I will
- share with you just one project. It's another project but this I think will make the point. I
- mentioned earlier the absence of preclinical tools that will allow us to prioritise drug molecules
- during the optimisation based upon their predicted profile in African patients, and I told you that
- this variability that we see in the way people respond to medicines as a consequence of genetic
- differences in the expression and activity of drug metabolising enzymes and transporters,
- is not well understood in Africa. So what are we doing about this? Ideally, we want to be able to
- do clinical trials and as we do clinical trials, we can also add a genotyping component to the
- trials so we can monitor people who can either be characterised as normal metabolizers or fast
- metabolizers or slow metabolizers and then link that phenotype to the genotype, but we're not
- there yet for a variety of reasons. This project is a programme started by GSK and Novartis.
- The two companies got together in about 2019 to initiate this project called Project Africa
- GRADIENT. GRADIENT is an acronym for Genomic Research Approach for Diversity and Optimising
- Therapeutics. It's to understand, at the end of the day, of people being underdosed or overdosed.
- There has not been any pharmacogenomic studies to understand the impact of genetics on response to
- therapy. That's why this programme was started. So our project is also in collaboration with our
- colleagues, Ersilia. This is an open source AI not for profit company based in Barcelona, but also
- working with the South African Medical Research Council here. So this project is really about
- integrating artificial intelligence with existing mathematical models that are used to predict the
- human dose. The artificial intelligence part is to identify genetic variants that are prevalent
- in different parts of Africa that are likely to affect the metabolism of malaria and TB drugs,
- and then incorporate the effects of these genetic variants into existing mathematical models to then
- propose tailored dosages that could be validated in a phase one ethno-bridging study to confirm
- whether that in fact can be recapitulated in people. Why did we resort to AI? First of all,
- the things that underpin AI, if we don't want to miss the AI boat in Africa, we've got to make
- sure that three things are in place. The three fundamentals of AI. We need access to affordable
- and reliable electricity. It's a no brainer. Secondly, we need access to affordable and
- reliable digital infrastructure, the internet. Finally, we need granular data. We can't talk
- about AI without making sure that those simple basics are in place, but we are using AI here.
- We have used AI here to leapfrog the barrier of small data sets and use a technique we call
- transfer learning, where AI models built from the cancer field. Cancer drugs are some of the
- most widely studied drugs, with different assays and models used to derive models from cancer, and
- then we use transfer learning to retrain, refine those models for a new but related task. So this
- is what we've done. This has all been completed and we're writing a manuscript now. So we use
- transfer learning, don't worry about the language here. So we use knowledge embeddings, we build
- a knowledge graph and then we rank these genes. The genes that encode drug metabolising enzymes.
- We call them ADME genes. So these are genes that are involved, that encode for enzymes that are
- involved in metabolism of drugs, and we use large language models to prioritise those pharmacogenes,
- and as I said earlier, we then incorporate those pharmacogenes into existing pharmacokinetic
- models. Physiologically based pharmacokinetic modelling or nonlinear mixed effects modelling to
- then propose a tailored dosage. So this work has been completed actually end of August and we have
- almost finished the manuscript. We need to get it approved by GSK and Novartis, but they want us to
- publish the results and they are very exciting. All right. The ultimate goal of this effort with
- AI is, of course, to build an Africa-specific knowledge base using AI, including those frequent
- gene variants that you find in Africa. So this could be Africa specific genes or genes that are
- abundant in Africa. Of all the drugs that are used in Africa, so this is a very powerful platform.
- It's not just for malaria or TB, and of course, we have to continually refine the models using all
- sorts of sources, including biobanks and data that has been generated from other sources. We wrote a
- piece in Nature this year to really describe how AI could be used in this way. Finally, this is
- a summary of what I've been telling you about so far. Okay, I've told you of the importance
- and the need to develop tools and models in close proximity to where the patients are to
- understand their real unmet medical needs in their social and physical environment. I've told you the
- implications of this variable metabolism, which contributes to variable response to medicines,
- and of course, variable experiences of patients in terms of adverse effects, and of course, the
- impact of this variability is not well understood in Africa for reasons that I have, some of them
- have described. I've also described to you the importance of not just focusing on the innovation
- side of things, but also to look at manufacturing as a value chain. It's not just manufacturing of
- a commercially approved product, but it's also manufacturing for clinical trials. It's also
- manufacturing for clinical studies. Those present opportunities to create jobs, spin out companies
- that fill that gap, especially if you can benefit from economies of scale when many people are doing
- this on the African continent. Then of course, I just described to you how we've used AI to predict
- Africa abandoned or Africa specific genes. So that's the end of my presentation but really, just
- to thank the funders. I won't go through every one of the funders but you can see it's a combination
- of philanthropic organisations, pharmaceutical companies and of course, a big shout out to the
- Government of the Republic of South Africa for their enormous support over the years as
- well. This is the team. You can see, this is not British weather, this is Cape Town weather. I also
- want to leave you with this African proverb, very important proverb, for reasons that you'll see in
- a second. It says, if you want to go fast, go alone. If you want to go far, go together. In
- other words, it's like Liverpool Football Club, you never walk alone and you never fly alone,
- and that's exactly the point here. This t-shirt I'm wearing, by the way, is a t-shirt for a rugby
- team that I'll talk about, show you a slide here. This is a University of Cape Town slide as well.
- Of course, this is Jurgen Klopp. Watch the guys in the background of this photo. Very jealous,
- look at them, very jealous of me. Of course, why is this guy there? I think he's the greatest
- England midfielder ever, Steven Gerrard, and that's a very objective view by the way. This
- is the tweet of the century. Chris Schofield, colleague from Oxford, of course he's also like
- me, a Liverpool supporter, and I told him about this experience of flying with Jurgen Klopp and,
- you know, breathing the same air as this guy there for 11 hours, going to Cape Town, and
- I sent him the pictures as evidence and he asked me for permission, can he use them? I said, yes,
- sure. Look at this tweet. It's the tweet of the century. You never walk alone. You never
- fly alone. Kelly Chibale and Jurgen Klopp, great science and great football flying together. That
- really, really is a big deal. I'm not just into football. I am from the country who are the world
- rugby champions and there's more coming, world rugby champions. I seem to have this fortune of
- just bumping into these people every time I'm travelling. This was in June, so South Africa
- had just played Wales, and of course, you know the result there, you know what happened. So anyway,
- there's my wife Bertha with Rassie Erasmus. By the way, I didn't ask them for pictures. They
- asked me. So there's me, Rassie Erasmus, and the whole team. There's Ox Nché, Siya Kolisi, and the
- whole team there. It's not just the national team that is important.
- This is a very important slide. The home of perpetual winners of the world, the University
- Rugby Club. If you didn't know this, you should know this today. The inaugural World University
- Rugby Tournament was held at Oxford in 2015. My son was actually in the squad. They won that
- inaugural. Four years later in Japan in 2019, they defended it and last year, and by the way,
- 2019, the Springboks also won the championship last year in France. They also played and they
- also defended it. Perpetual winners. So this is the way it happens. So this is the campus
- of University of Cape Town. My office in this building and I live here. This is my house. I'm
- the warden. So when I say to my American friends, I say I'm a warden of a residence. They say, oh,
- you're in charge of prisoners? I say yes, I'm in charge of undergraduate prisoners. So I live here,
- and this is where they train. This is where the world champions came
- from. They all played here. That's where it happens. Just below my house, and of course,
- that's another view of Cape Town of the campus, a beautiful campus. Finally, but not least,
- it's Cape Town. What can I say? This is the Mother City, and it's not just a Mother City. It's a
- promised land, and that's why I never left when I went there. Thank you so much for your attention.
- Thank you so much for a wonderful, wonderful, inspiring lecture. Absolutely terrific. It's
- now open to questions and we've got microphones. There's one here and then one here. Thank you.
- Hi, brilliant talk. Thanks so much. My comments about data sharing in relation
- to capacity building for drug discovery in Africa. Could you comment on how well Africa
- has access to data sets outside of Africa and how useful access to those data sets might be?
- Actually, the answer is no. It's very limited. Actually, if anything,
- it's the other way around. It's actually people outside of the continent that want to have access
- to the data that's been generated in. So let me give you an example of initiatives where… See,
- unless Africans can generate the data on it and exploit it, which of course is how it should be,
- but for drug discovery, it depends on what kind of data. So the example I showed you earlier,
- we use our own data from our various assays over a period of ten years and we use that data
- to build AI models and integrate them into our drug discovery programme. So I think that you,
- Africans themselves, have to take the lead in generating that data. It's not
- easy to access other data from outside unless of course, they are publicly available. So some of
- the database we were using for the AI component, unfortunately this is a database called farm GKB.
- This is a pharmacogenomics database that contains all sorts of genomic data there,
- but there's less than ten per cent of data from Africans. So there's actually even,
- right now the example I showed you of the GSK Novartis project Africa GRADIENT, last year, there
- was an announcement by four pharma companies. This is in the public domain. Roche, AstraZeneca, Novo
- Nordisk, Regeneron each contributed $20 million to Meharry Medical College, which is a historically
- black college in Nashville, to sequence half a million African American, African genomes because
- this data is just not available. Plus, we don't have a biobank. You have a biobank here in the UK,
- but that contains less than five per cent of data on people of African heritage. So it has
- to be led by Africans themselves because it's not easy to access that data outside of the continent.
- Good evening, Professor Chibale. Good evening to everyone. Thank you first and foremost for
- your presentation and I would like to start by congratulating you for receiving the Royal
- Society African Prize, and also for receiving funding to continue your research via the AI
- 2050 initiative. So my question is around funding. My name is Cedric. I'm a medical
- doctor. I left my home country in Africa last year because of my deep interest in the drug discovery
- and drug development and as you've clearly highlighted, funding plays a crucial role in
- the drug discovery process. So a report in 2021 by the African Academy of Sciences estimates that
- less than two per cent of biomedical research funding goes into Africa pharmaceutical R&D,
- which pales in comparison to the billions of funding invested in other regions. So my
- question is, what strategies do you believe could be implemented to improve this, and how can an
- increase in funding translate into a sustainable pharmaceutical sector on the continent? Thank you.
- Okay, so first of all, I think that sometimes there's a misconception. I don't think that
- I'm entitled to anything. I don't think that anyone owes me anything. I don't think anyone
- owes anyone anything but I think everything starts with… So for example, in South Africa,
- we have the South African National Research Foundation. So this is a government funded
- organisation that gives funding for research and they have criteria of eligibility, and that's true
- of any funder because that's taxpayers' money. So first of all, I can't demand to be given money
- from UK taxpayers or American taxpayers. I can't. However, what we've done here is that everything
- starts with having mutual interest. When there's mutual interest, there's mutual responsibility,
- and when there's mutual responsibility, there's mutual accountability, there's
- mutual respect. I'm emphasising mutual, mutual, mutual. The funding we've gotten from partners,
- not just the Government in South Africa, but elsewhere, because there was mutual interest
- working on global projects. So you will find it. So there's nothing like African funding or not.
- Where there's mutual interest, things come together naturally. Now what can people do? Well,
- I can't tell governments how they should spend their money. It's all about priorities. So when
- you land, you come to this promised land, you come to the airport, you look around. Oh my goodness.
- Incredible beauty. And then you start driving. You go onto the freeway, the N2, just from the
- airport. You look on either side, you see the conditions people live in, and I say to myself,
- why should the government give me money for blue sky research when politicians, what do they want?
- They want to get elected and re-elected. It's easy to build a house and talk about it than to give me
- blue sky research. So it's all about priorities, and yet the government of South Africa has
- prioritised research. It's all about priorities. There's money. It's how you choose to use it. So
- the responsibility ultimately is on us Africans to decide how we want to prioritise. I'm not a
- victim. We shouldn't be seen as victims. People must, you know, do what depends on you. They are
- always partners, and I always say this. There are good and bad people and idiots from everywhere.
- As long as there's mutual interest, things happen naturally.
- Thank you.
- Thank you. Hi, my name is Nyra. I'm from Uganda. I recently finished my undergrad.
- I basically have two questions. Actually, what was I even going to say? I'm focusing
- on antimicrobial research currently, that's why I'm looking for a master's around there,
- but my question is how are we going to fight the stigmatisation of things like clinical
- trials and the growing mistrust in people like scientists? I did pharmaceutical sciences. You
- keep on telling people do this, do that, don't do that, and they'll be like, how am I supposed to
- trust you people? The internet is really killing us as scientists and the drug discovery thing,
- because I can't bring a new drug, everyone is used to the old drugs. Even with paracetamol,
- we had some yellow drug, we used to have new drugs coming. People don't want to take
- it in Kampala because they don't trust it. That's my first question. Should I wait or?
- Let me answer this one quickly. Well, first of all, thank you for raising that. It's a trust
- deficit that is not just in Africa. We saw it in COVID as well. It's everywhere, but the African
- context is a bit unique. Part of the reason is the effects of colonialism, for example. In South
- Africa, apartheid just ended very recently. So in the US, African Americans, the Tuskegee incident.
- So there are things that have happened that have made people suspicious, but here's what I say to
- people. I grew up in Zambia in townships and villages in there. There's something that I
- took for granted that I only much later in life, I realised two things. First of all, I'll get sick,
- and our then government of the day really invested in education and providing health facilities. I'll
- go down with malaria multiple times and I'll go to the health facility, get malaria medicines and get
- cured, and if there wasn't those medicines, I'd be dead. Now I took it for granted. Only much later
- in life I realised two things. Firstly, someone, somewhere invested in the research and development
- to discover this medicine that I'm benefiting from. Secondly, someone somewhere volunteered
- to participate in a clinical trial for my benefit. When you understand things from that perspective,
- you will not be mistrusting anyone because we take so much for granted that other people have
- done on our behalf. I think what is needed is just education. We need to involve communities. We must
- respect communities, but we must explain things. Of course, who says it matters? I just gave you
- this example. The trust deficit, absolutely a problem, but we need to understand that any
- kind of innovation is pointless if there is no access to that innovation. So we have to
- really clear this trust deficit that we have with communities and involve them as early as possible.
- Thank you. So my second question will be how do you plan on expanding into different African
- populations? I hate to quote you, but you said Africa is not a country, it's a continent. Most
- of your research is based in South Africa, which I quite understand, but how do you plan on expanding
- into different parts of Africa, like East Africa, Central Africa, West Africa? How do you plan on
- involving the youth in those countries, and how do you plan on attracting us back? I did my
- pharmaceutical science degrees here with organic chemistry. So how do you plan on attracting us to
- go back to our home countries to actually apply the knowledge we did acquire in these countries?
- Well, the answer for me is exactly the lesson we've learned here. First of all,
- you have to understand why do people leave their countries? Well, because there's no
- opportunity to do that there. Secondly, I am from Zambia originally, Zambia is my home country,
- but I've lived in South Africa. That's where I got an opportunity. So I don't blame anybody if they
- decide they want to live in the UK or wherever they want to leave, that's a personal decision
- and you must do what is important for you and your family, but we also have to understand that
- the model of how we grew the centre to what it is today was not about having everything.
- It was about working with partners in the UK. The Medicines for Malaria Venture, for example,
- was the first partner we ever had. It gave us an opportunity to work on this project and they
- helped us access other partners, which we didn't have. So we had gaps, but through this network
- we managed to access those partners. The most important thing was that we had this opportunity.
- We focused on doing what we could do with what we had then without wishing we had everything,
- and when we showed success, success brought even more success, even more success. So you have to
- start from somewhere, but it's about a network of partners. Drug discovery infrastructure is not
- for everybody. I mean, procurement of chemicals. How can you do drug discovery if it takes you six
- months to order a chemical reagent? Forget it. So we have to understand that when we form a network
- of partners, people must focus on what we can do regionally and work with other people who can do
- other things that they cannot do. That's what I would say here, but it's small steps. Look, the
- people working in HVD now, they're not all from South Africa. They're from all over the world.
- We brought in people from America, from Europe and from other parts of Africa. So for now it's there,
- but that's a model that's being replicated, as I showed you on that Grand Challenges
- African Drug Discovery Accelerator. So we're beginning to expand the ecosystem.
- One last question at the back.
- Thank you very much. Two quick questions or observations. Before COVID, there was
- an event over at the London School of Tropical Medicine in Russell Square.
- It was actually put on by a white person. The person wasn't African, Black African. I hope
- you're not coming to take my photograph because I don't want my photograph taken, that's why I'm
- stumbling. Thanks very much. Okay, so what they demonstrated was that Africa was the country that
- received the most out of date or short lived medication. I wondered if you thought that
- there's something that can be done about that so that it can be repurposed so that they don't have
- such short life medication. That's the first one. Second one is, I think it's great, drug discovery,
- but I'm wondering, do you think that if you help the mental health of the people that are there
- and that are involved in drug discovery, they may speed it up, or do you think that aspects
- of mental health and psychiatry aren't relevant in the role of the pursuit of drug discovery?
- Thank you very much. So the first part of the question is really about counterfeit
- medications. This is not just medicines that are imported into Africa. It's also
- the nonsense that happens in Africa itself. So you have these unscrupulous people that
- do this. So this is why I think with the - because we haven't historically had a
- harmonised regulatory environment. So the start of this African Medicines Agency, I think is a
- very important step in addressing this issue of fake medicines and counterfeit medicines,
- because we can really coordinate intelligence or whatever across countries because we have these
- common policies that are going to be under the African Medicines Agency when it becomes fully
- operational. So yes, I think the way to deal with that is actually not even think about it, they
- are sent to Africa. I think most of it is really just criminals trying to take advantage of it.
- These were big pharmaceutical companies that this person had
- done a lot of research on. So we're not talking about the kind of person whose
- briefcase is their office. We're talking about the big pharmaceutical companies.
- I can't speak for them. I don't know exactly what that particular case is, but of course,
- when you import a medicine, you must check when is the expiry date, and you shouldn't… What I
- often find with these things - I'm not defending anything, I don't even know what the stories are,
- but there's always two sides to the story and so I really can't comment because it's beyond me. Your
- second question on mental health. First of all, the problems are very complex and there are many,
- and I think it's a question of focusing on what can I do that depends on me to do and
- other people contribute in other ways because it has to be holistic. But also for me, this is
- not just about drug discovery. This is more than drug discovery. This is about entrepreneurship.
- This is about creating jobs. This is about using science for development. This is about developing
- infrastructure and retaining talent on the African continent. You cannot guarantee success in this
- business. There's so much failure, but while it's happening, people have careers, people
- have jobs. That's important as well and that can help their mental health as well. Thank you.
- Thank you so much. We can continue the discussion next door afterwards but now I'd like to present
- the medal and scroll. So I think if we go in the middle, they're going to want to take pictures.
- So the Royal Society Africa Prize 2023 is awarded to Professor Kelly Chibale for his
- exceptional leadership and groundbreaking work in drug discovery for African endemic diseases.
- Hip, hip,
- hooray!
- Thank
- you.
Join us for the Royal Society Africa Prize Lecture given by 2023 winner Professor Kelly Chibale.
Within the context of innovative pharmaceutical research and development (R&D), African populations have historically been neglected from the perspective of inclusion of African data in the discovery and development of new medicines. Coupled with the generally low volume of clinical trials in Africa and absence of African-centric preclinical discovery tools and models, this has contributed to the suboptimal efficacy and safety of some medicines used in African populations. How populations respond to medicines is influenced by, amongst several factors, the genetics of a given population. Within this context, African populations have greater genetic variation relative to other populations worldwide. At this juncture it is noteworthy that there is a link between the genetics of a population, the socioeconomic and physical environment in which patients live, and treatment of disease. This warrants the development of capacity to discover and develop medicines near patient populations while also developing tools and models to facilitate a stratified medicine approach.
This lecture will describe efforts to develop medicines discovery capacity in Africa and R&D approaches towards tailoring medicines for African populations.
About the Royal Society
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