The Genetics Podcast episode 43: Diversity in clinical research and COVID-19's impact on people with immune conditions with Dr Sonya Abraham ----------------------------------------------------------------------------------------------------------- --------- Patrick Short: Welcome to the genetics podcast. I'm really excited to be here today with Dr. Sonya Abraham, who's a clinical senior lecturer in rheumatology and general internal medicine at Imperial college in London. We're going to speak both about her research in rheumatology, which covers psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, and a number of other immune mediated conditions where she works on biomarkers, including the microbiome and how they affect these conditions. We're also going to speak about BAME and representation in medical research - this is black, asian, minority ethnic groups. We're going to cover both COVID-19 as well as clinical trials, more generally, and some of the challenges around representativeness in clinical trials. So with that intro, thanks so much Sonya for taking time to be part of the podcast. --------- Dr. Sonya Abraham: Oh my pleasure, thank you. --------- Patrick Short: I was wondering if we could just start with an explanation of what clinical research is, for those who are not familiar, you spend a lot of time running and coordinating clinical trials and clinical research and the science that goes into them. So I wonder if we could just start there. --------- Dr. Sonya Abraham: Yes, absolutely. So I mean, clinical research is really the mechanisms by which we understand human physiology and where the physiology goes wrong and where diseases occur. And so clinical research can involve taking samples - and it's research that's done in humans and it's understanding how diseases might occur, how they evolve, how they change over time, and that can be as simple as taking blood tests or biopsies or doing sort of tests such as walk tests, or hand dexterity tests, depending on the disease of interest. And part of this also relates to the development of new therapeutics, and I think never more than now has clinical research been so important because I mean, sadly with the advent of COVID-19, you know, what we want are things that prevent the disease, which could be treated with the disease, and now our clinical research has just sort of accelerated. --------- Patrick Short: So from your point of view, what, what do the statistics say about BAME representation in clinical research, and and what's the problem here? What's the scale of the problem and what's the result of the lack of representation? --------- Dr. Sonya Abraham: Okay. So, I mean, I would say it's not just about COVID-19, I mean, there is a disproportionate (from the mortality data that was collated by Public Health England, and the government's) there is a disproportionate number of people from black and asian and other ethnic minorities that seem to be affected either more severely or sadly sort of the mortality rate is higher in that group. Now we don't know exactly why, and there are probably both genetic reasons alterations in, you know, the background ethnicity, and possibly also environmental factors and being able to understand that is a work in progress. I think what's important is in clinical research traditionally it has not been a requirement to delineate the ethnicity makeup of people involved in clinical trials. And so I think now this has changed the paradigm for the collection of data in trials, and it will be important going forward that this data is collated. And this has sort of lots of social implications because, you know, what is the difference between your heritage, your ethnicity and how you identify yourself? One's cultural, one's genetic. And I think also with some of the sort of UK consensus data, some of the granularity about the slight differences and variations of ethnicities isn't necessarily captured. So now more than ever, is it important that that data is captured, but additionally, and I think going forward when clinical research questions and hypotheses are formulated and protocols written, there needs to be consideration given to how it applies to the wider population, and, yeah, ethnicity is part of that. --------- Patrick Short: Is there any likelihood that this will be mandated either by the FDA, the EMA, the government - a UK government - or otherwise. --------- Dr. Sonya Abraham: Yep. So, fantastic question, yep, going forward - and it's sad that COVID-19 has precipitated this yet again - yes I think going forward, the regulatory agencies will probably mandate this. Historically, if a disease primarily affected a certain ethnicity and population, you know it may well be that they were the ones that are targeted or you have some populations, but it was never mandated how many of each group or how well it was captured. Going forward, I think, well, it will be. And within the UK and the National Institute of Health Research, there are work streams going on to really look at how well that that's captured, but even more it's not just about capturing, it's also the accessibility and availability of these trials to these other groups. One of the difficulties is that there have been (in terms of inclusion) the information sheets, the adverts were all in the primary language of English. So if people do not have English as their primary language, then they wouldn't necessarily have access to the information to partake in clinical trials. And then I think additionally, there are probably sort of cultural variations about people's comfort in undertaking clinical trials, thinking it might be just sort of human experiments, but you know, these are highly regulated processes. So I think there's, there's a case that needs to be made socially, about the education of what clinical trials are and ensuring that that education is available to all groups, despite what primary language they are. But also in terms of the procedures within the trial protocol, the principal investigators, the chief investigators, the sponsors need to look at the sensitivities that may impact in other ethnicities taking part as well. --------- Patrick Short: Yeah, absolutely. From your point of view is the main, the main risk of not doing this right - is that ultimately the medicines that make it through a clinical trial may not actually work for everyone or may not be safe for everyone. That seems to me like a big issue. Are there, are there other issues besides that and is it that diagnosis also suffers because people might have, you know, might present in different ways or what are the, what are the impacts of this research not being not being done in a representative way? --------- Dr. Sonya Abraham: Yeah. So all the things that you, you mentioned, and the fact is that there should be equality of access to, to healthcare and medicines. And this is a big thing, you know, throughout the world, but actually there should be AS equal access to clinical research. And again, it goes to your thing, if there are novel therapeutics, that are being trialed, the applicability to the wider population within that country needs to be determined. One of the very early examples for this was the development for blood pressure antihypertensives - ACE inhibitors - which now are prescribed as standard therapy. But what we know is that the black ethnic groups, they have a polymorphism in the ACE receptor, so interpreters wouldn't work in them. So there are probably more and more subtleties of other drugs that we use or don't use. There may be some drugs that work better in some groups than others. --------- Patrick Short: Do you have any, any impression of how much there is like that, that we don't know out there when, when people look retrospectively at data from clinical trials, is it clear that there's a huge amount of variation that's simply not being captured or what's the, are we going to have to essentially rewrite the book on a number of really common therapies as, as more representative studies are run or, or what do you think? --------- Dr. Sonya Abraham: Yeah, so I suppose there's two parts to this. So there are drugs that have been licensed and some who've been licensed for a few years, some for decades. And so they're probably worth sort of signals from prescribers there, but actually to do it in a robust way, there probably is a need to potentially look at real world evidence of those prescribed and the actual effects. As far as I know that hasn't really been done in depth apart from a few academics with an interest in that. I mean, within my own specialty, within rheumatology, you know, I don't know of any literature, that's actually looked at differences in outcomes dependent on ethnicity. And one of the problems is we don't know, we don't capture the data of that ethnicity when it's prescribed. Hence you can't do the long-term followup. And new drugs in development - yeah, I think it's going to have to be at least thought about and mandated or a reason why it shouldn't apply to look at differentials. --------- Patrick Short: Why aren't people collecting data about ethnicity? Do you, is there any good explanation as to why it is, or is it people just haven't, you know, haven't given it the thought until relatively recently? --------- Dr. Sonya Abraham: I think the issue has always, probably been there, but the urgency and the media has a lot of play with that. So I think that's where it's really come, to a head really. I suppose we could also think about sort of the whole sort of sociological factors in that, 50, 60, 70, 80, 90 years ago, yeah, again, there were therapeutics, probably not placebo randomized controlled trials, but the pockets and the groups of ethnicities was relatively more homogenous within a treatment group. And now with global travel, global migration, people go here and there it's, it's probably different now, but it still doesn't take away from the fact that - and I think this has been known about for decades - is the lack of access and inclusion of, of ethnicities in clinical trials and the barriers to that. So I think - and again, I think there's going to be a new branch of research - is that if you look at all the trials, you know, how many of them actually have information sheets that have been translated to the local population where you're undertaking the trial? And I think what's also interesting is there are sort of first attempts, particularly in the UK recently where they've, you know, [inaudible] the NIHR, which is fantastic, looking at translating a number of trials to the most common ethnic languages. But the limitation is there are some pockets where some of those languages don't apply. So if I look at our regions, so I'm a lead within Northwest London and in that area, there's quite a large proportion of people from the Philippines, large sort of Persian population. So a lot of the trials haven't been - as yet - translated into those languages. And we see, you know, local data that those groups have been impacted. Well, there was a government [inaudible] that's not seen because [inaudible] collated data [inaudible] UK - you know, there are local pockets of sub populations that have been affected. --------- Patrick Short: You mentioned the challenges around making people aware of clinical research and education and outreach. How do you, how is that done today and how do you think that needs to change? I mean, the problem you just described makes it seem like we need more, more bottom up and, and kind of grassroots way of getting the word out about the research rather than today, what's a relatively top-down procedure where the materials are written, somebody signs them off and then they're kind of just put out there. Could you just explain how it's done today and maybe how you see that it needs to improve in the future? --------- Dr. Sonya Abraham: No, that's fantastic, and I think you're spot on, it has been very much a top-down approach. I mean, I'd be interested in, you know, how many PIs from - the makeup of the actual ethnicities of principal investigators - because, you know, yeah, perhaps that's different and then those, those subtleties may not sort of come out during the protocols. So again, I'm in agreement that we need to look more at a local population level as well, and bottom up. And it's not just about the healthcare organizations. They need to probably link in with local groups and the social sector with local governments and, you know, in our sector we're also sort of looking, now, with Healthwatch, which are really the sort of patient voices and those lay voices to really try and deeply understand, you know, how much of an opportunity have they had to link in with trials? Have they heard about trials? What are their barriers of not hearing about it? Or why do they not want to take part if they do hear about it? --------- Patrick Short: What is Healthwatch? I haven't, I haven't come across Healthwatch. --------- Dr. Sonya Abraham: Okay, so there are a number of organizations that are sort of set up within the UK that work with local governments to really be the voice of the public with relation to health in the area. So yeah, it is part of the sort of social care actually, yep, with relation to health. --------- Patrick Short: That's excellent. I didn't realize that existed. It's great that it does because it's hard to do some of these things from a top down, you really need that local representation make these things work, don't you? --------- Dr. Sonya Abraham: Yeah, I think that's very important, but I think the other thing that actually could be harnessed more is that, is that of the power of social media. Now again, you know, there've been lots of sort of regulatory challenges with information technology and social media, which in some ways has now transcended again because of COVID-19. And so some of those things have been relaxed, but actually it gets messages out there more. And we know that actually one thing that is universal is the use of social media, no matter what your ethnicity. So perhaps sort of being able to listen within [inaudible] of social media, but again, you need resources to be able to do that and, and also done in a, in an appropriate manner and also, you know, receiving feedback via social media. And we do know now that a lot of recruitment for clinical trials is being used by social media subject to ethical approval. So could this be another way of reaching a bigger group? --------- Patrick Short: Yeah, absolutely. It seems like you need to, you need to meet people where they are, right? And not, not force people to fit into a system that was built a very long time ago that that wasn't necessarily built for the world we live in today. --------- Dr. Sonya Abraham: Exactly. And I think, I mean, I think there probably will be - well, there is in process, you know, toolkits for when clinical trials are designed (this is, you know, particularly by the NIHR in the UK) of ensuring that certain tick box things have occurred. And I think in the future it will involve, you know, consultations with the local population and, things - what's the word - and being open to thoughts from the various ethnicities. --------- Patrick Short: Yeah. That's excellent. Have you been working directly on any COVID-19 related trials? Have you been sort of pulled into some of the, some of the urgent studies? --------- Dr. Sonya Abraham: I haven't directly, I haven't taken on any PI roles. But I know locally that, you know, we have contributed to a number of both interventional trials and also those in primary care, I've helped to sort of try and facilitate that. So some of the primary care ones were early, early treatment. And, you know, what was obvious from that is that they weren't really translations in that. So that's being rectified now. So having a sort of different eye and a bird's eye view and a wide angle view of what's going on with the trials. And I think to date it's not absolutely clear how many patients from the various ethnicities were included in those trials. So that's going to be a piece of work that we're undertaking locally. --------- Patrick Short: We had - I had Chris Wigley and Richard Scott from Genomics England on the podcast a couple of weeks ago. And I was really glad to hear that from the very beginning - they have a large genome sequencing project that's underway - and they're planning to be representative across the UK in terms of ethnicity and, and gender and you know, postcode and all of the important demographic variables in that study from the get-go, which I thought was really good leadership because you know, it's, you hate to spend all this time and do all this analysis, not collect the data and then look back and realize the study really doesn't represent the country at all, but just a small, smaller group of people that were you know, that were easiest to get to because of language or some of the other reasons you've mentioned. --------- Dr. Sonya Abraham: Yes. I mean, some of this sort of came to the front where, you know, actually on death certifications, ethnicity is not recorded and, you know, there was a historical reason probably for this, that it really was not that variable. I mean, I don't know how long that, you know, it's a formal regulated document, the death certificate. So a lot of data wasn't captured early on. So again, COVID has triggered, you know, re-looking at the birth data, the death data, [inaudible], registry data and census data and how that's captured. --------- Patrick Short: The, the rate of death in BAME groups in one of the studies that I read was, was almost two and a half times the population. So it was like 30% of the deaths despite being 10 to 12% of the population, which is, is really, it's a terrible statistic. And, you know, to not know why, and to kind of have only more questions of, is it, is it genetics? Is it you know, some something to do with you know, is it being not caught early enough? There's, there's just so many questions to not have the ability to answer is, is, is really a problem. --------- Dr. Sonya Abraham: Yes, no, absolutely. And actually that brings up another point really is that, you know, people who were sitting at home with symptoms - the differential sort of fear factor for going into hospital and seeking help. So absolutely I think that's had some implications as well. --------- Patrick Short: Yeah, well, it's, it is well-documented that not everyone gets the same, the same treatment in the, in the hospital or the GP or whatever. So there's kind of deep societal challenges that, that contributes to this as well aren't there? --------- Dr. Sonya Abraham: I mean, I wouldn't say so much treatments and I think what is amazing and wonderful about the UK is that, with the NHS that we have, people have access to treatment free at the point of care. And, and they will get the same treatment, no matter if you're a prince or if you're a pauper. Now I know that sort of healthcare system isn't there throughout the world. It's something to be fantasticly proud of. So it, you know, it wouldn't matter if you had insurance or not, you would come in and you would go down a protocol for treatment to help support you. --------- Patrick Short: Yeah, it is. When I speak to people back in the US where I'm from, it's surprisingly difficult to, to kind of articulate how well the system does work over here - people can criticize parts of it. But if you look at the numbers, I think we - in the US about twice as much is spent per person for outcomes that are not as good as here in the UK. So it's kind of patently obvious that the system is broken, but there doesn't seem to be the will to fix it for some reason. --------- Dr. Sonya Abraham: I mean, one of the other things, I suppose, is the really sort of global sharing of data with the ethnicities. (I mean, some of it wouldn't have been captured, but what there is.) So, you know, the potential to say, well, if you're an Indian living in the UK and the rates there compared to the Indian groups, living in India, or the Chinese populations in the UK, or the States, or whatever, compared to the country of origin, now that would also help sort of understand the genetics differentials potentially, potentially. But I think one of the things that's really drawn up is, you know, the careful acquisition of data and sadly it is not standardized and it should be in a world where we've got all this technology. We can talk here and it's, yeah, it's beyond belief that we can't standardize the way we capture data. And it's great - we have the WHO, which are fantastic, but it's a shame that they can't actually edict in times like these with pandemics, how things have to occur and people have to abide by them unless there are exceptional circumstances. --------- Patrick Short: Yeah. I completely agree. It's been, there's just been a incredible array of different, (even if we take COVID as an example), ways of collecting data that it's, it's going to be a real challenge to analyze everything cause everyone's collecting it and they've picked their own special way to do it. And there's a thousand projects that have, that have kicked off each analyzing it in a slightly different way. --------- Dr. Sonya Abraham: Absolutely. And that is really worrying and scary. And I think, again, it goes back to the carefulness of clinical trials and slowly and carefully because traditionally they were a little slow, but actually it was all about being careful so that you could answer the scientific question in a very safe environment, and it would take time. And as you said, now there's been an acceleration of all the trials. And if you have the word COVID-19 it accelerates and it goes in, and again, you said it, it's the differential ways in data collected - the slight differentials in the protocols of inclusion, exclusion criteria. And what's happened is there's been accelerated publication and then one day drug, (and there's a certain drug I think everybody knows about) is in and good, the other day, that drug is not good. And then the other day, maybe it actually might be good. And yeah, it's, I think it's not just the regulatory agencies. And I think some of them have been absolutely fantastic. I mean, in really helping to support the acceleration, but it's looking - scrutinizing on the investigators, how they write their protocols and how they report. And I think a responsibility also lies with the editors of high impact journals as well of what and how they report. You know, we've seen retractions in some very prestigious journals and yeah, so, so scrutiny really needs to be there. --------- Patrick Short: I'm thinking of the Surgisphere debacle, and I think it was the Lancet where some company - that they claim to have all of this hospital data, but they wouldn't actually show anyone that it existed, and none of the hospitals ever remembered signing any agreements or working with them. And so it was quite possibly all, all kind of constructed just to create this high-impact journal publication, which is, is unbelievable if you think about it, but the journal to their credit did retract it fairly quickly, but sometimes the damage is done because the information gets out there in the media. There's no taking it back. --------- Dr. Sonya Abraham: Yes. And then it impacted other clinical trials that were really trying to get the proper [inaudible], and, you know, it's also a sort of testament and it upsets me that, you know, people point the finger, people blame and saying, oh, well that wasn't credible, or this wasn't credible, or this - it's doing this job, bad job, and they've been doing, and, you know, in times like these there is no point in pointing fingers and putting blame, you know, we try to make the best of it. --------- Patrick Short: Absolutely. One thing that I want to ask you is we, as a world right now, we're spending a lot of time talking about COVID-19, but a lot of your work is on immune mediated, especially inflammatory disorders and it's disorders like these, these people are at higher risk of mortality from COVID-19, and it's more challenging to, to conduct research because it's less safe for people to leave their homes. It's an immune system compromising condition in many of these cases. Has that affected your work at all? Have you had to shift the way you do things in order to continue doing your, you know, your important work in psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis and others? --------- Dr. Sonya Abraham: Yeah. So it's been an interesting journey really because at the beginning, and yes, as you said, the group that we treat, it's not just inflammatory arthritis, but patients with connective tissue disease and lupus and people, it's their sort of immune modulators, and there was a big worry; are these people going to be so immunocompromised, they're more likely to get the infection and if they get the infection, are they more likely to have a worse outcome? And really nobody knew the answers. And so things were sort of done, and again, sort of slightly differently in slightly different countries, but this was very much a sort of pragmatic clinical approach. And it was made sure that if people are on immunosuppressants, that they were shielded and minimized their risk - if they're on steroids to minimize their risks, but it's also impacted - because there was lack of evidence - you know, the, the morbidity - some of these patients have flares in their disease just, but the jury was out - can you give him steroids? Can you not? Can you inject their joint with steroids? Can you not? And so there was a period where people were suffering - okay not from mortality or from COVID, but from their inflammatory arthritis. [Inaudible] in terms of, I mean, I think it was a great time to be a rheumatologist in terms of - the therapies that were being trialed in COVID - a lot of them came from rheumatology. But I think what's interesting is that rheumatologists didn't seem to be that consulted with some of these drugs that were licensed. So we see all the advent of using interleukin six receptor hydroxychloroquine, which is a drug that's been around for an extremely long period of time and used very successfully in some autoimmune conditions, such as lupus and Sjogren's. And so I think there's one, that's one part, and then the sort of linking in with pharmacologists and also the pharmaceutical drug companies. And then what I've also seen is lots of biotechs, lots of new novel therapies that were going to be trialed in auto immune disease. They took those drugs and said, oh, there is some circumstantial evidence that it has been useful in that hyper inflammatory response in COVID-19, so let's trial it in there. And we've seen a lot of drugs fall by the wayside. And what's really interesting is you know, probably for me the best, most effective drug in inflammatory conditions for which Philip Hench got the Nobel prize along with Reichstein and Kendall in 1959, which was corticosteroids. So they showed that dexamethazone is particularly useful in that sort of inflammatory syndrome group. I mean, of course, they have really bad side effects, but it's interesting that some of the oldest drugs seem to be effective and some of the newer ones don't, to date. --------- Patrick Short: Why is it that the drugs that were originally used in rheumatology are likely to be effective? Is it, is it against this later onset cytokine storm where the, the body you know, goes into immune overload? Is that, is that what it is, right? --------- Dr. Sonya Abraham: Yes. Yes. And, and so, yep, that hyper inflammatory response, although there are some thoughts that the way hydroxychloroquine may work is that it also may stop the, the virus actually infecting the cells as well - if given early enough. And I think that's the problem, it's, you know, at what stage are certain drugs, the best to be used. And what's happened is all of the drugs are used in hospital when the patients are probably coming quite late, and sort of looking at using it earlier. So, I mean, and it also sort of, I mean, a lot of sort of questions or philosophical questions also come out of this, is it used - is it better to use drugs that have been around for a long time when we know their safety profiles and trialing those, or trialing brand new drugs where we know their mechanisms of action, but we don't know their safety profiles in COVID-19? I'm not saying which one is right, or one is wrong, but yeah, it's a good reflection. --------- Patrick Short: Yeah. And, and I think the other thing to consider with both of those is how they end up being priced. I, I assume with something like dexamethazone, it's off-patent and everyone in the entire world can make it. And so anyone who needs it will be able to get a dose. Whereas the remdesivir is a new drug, and they're, you know, I think they had originally planned to price it around £3000 a dose. I have no idea whether that's reasonable or not, but there's more, there's always more debate in how you price it, if something is new and under patent than if it's a tried and true, right? --------- Dr. Sonya Abraham: Well, yes, but I mean, you know, and I appreciate, you know, that costs have to be reaped, but actually there's this ethical dilemma that really it should, you know, drugs need to be accessible for things like this. I mean, you know, [inaudible] remdesivir and they may price it at that, but you know, it really has had accelerated - you know, if it comes out - it'll have accelerated status to be licensed. So the timing would be a lot less than if it had to come for other diseases. But I think what was interesting and I read this really early on and it was very naughty, but good on the FDA to have reviewed that, was, I think one company that was producing hydroxychloroquine actually increased the price of it during COVID-19, which was, I mean, how could people do that? So, yeah, that's come back down now, but there was a transient time where they did that. So the people profiteering from tragedy is really unacceptable, particularly health tragedies. --------- Patrick Short: Absolutely. Is it, is it hydroxychloroquine that is, that is commonly used in lupus? Because I know there was a concern at one point that the US was stockpiling it and that people may not be able to, to actually get the drugs that they needed to manage their, their lupus on a day-to-day basis. --------- Dr. Sonya Abraham: Absolutely. And I think the governments were aware of that. And I think, I mean, I know certainly in the UK and I'm pretty sure in the US as well, and hopefully other governments, that when this was alerted, that they did ensure that there was a decent supply for, for the diseases that they're licensed in or prescribed in as well as the sort of clinical trials. But there was a period where, and this is sort of the off target social impact, is that suddenly people were getting prescriptions - instead of two or three months - getting six months prescriptions. So suddenly people, you know, potentially stockpiling within their own houses - and I'm not saying what's right or wrong, it's just the observations. So that was panic mode. And I think, I mean, there's, again, you know, the availability of medicines and other things, because I think countries are now realizing how much reliance there are on other places to bring in - important and export - not just on drugs, but other things as well. So yeah, it will be interesting how things evolve in the next 10 years to ensure that there is a readily available stock of essential things. --------- Patrick Short: How does it actually work in, in the inflammatory diseases that you cover? What are, roughly speaking, what proportion of people are taking one of the older, more tried and true kind of treatments versus some of the new injectable biologics, have you seen that change a lot in the last 5 or 10 years? And I'm just interested in where you see the future of these kinds of very, very, very challenging to treat and, you know, they affect quality of life in some people very dramatically as a result of, of the challenge to treat them. --------- Dr. Sonya Abraham: So, I mean, I would say for the last sort of 15, 20 years, you know, the advent of biologics in auto-immune inflammatory diseases has really sort of transformed the whole environment. And so people almost, you know, can live generally normal lives because of the biologics. And what's probably changed in the last sort of four or five years is the advent of biosimilars because biologics were extremely expensive. You know, they were around sort of between, well in the UK between £8,000 to £15,000 a year, I think in the states, it was considerably more, you know, about $20,000, $40,000. So biosimilars are now come, and so they're offering drugs with the same targets for either 50%, less or 60, 70% less and more and more biosimilars are coming. So it probably will be that patients are going to have more and more access to the drugs because there's possibly less impact on the economy. --------- Patrick Short: Right. For people who aren't familiar with the term (and I just want to make sure I get it right as well), the biologics are large complex molecules in contrast to small molecules that are, you know, were the earlier generation of therapies. A biosimilar is essentially something that is, similar right? To the biologic. It's not exactly the same structure, so it's not, you know, there's no risk of kind of infringing on someone's patent, but essentially the biosimilar molecule does, does roughly the same thing and the clinical trials often are just showing non-inferiority right? So they're not worse than, than what exists out there. --------- Dr. Sonya Abraham: Absolutely. --------- Patrick Short: We've covered a lot of ground here, and I think we've been going for almost an hour now. So I was wondering if we could just close off here with your view, you've talked about how biologics and immune inflammatory diseases are, you know, have been transformative. Is, is there a next wave of therapies? What is - what's coming next here? Or do you think the age of the biosimilars is going to be the next big age and there may not be a step change in effective treatments for, for a little while? --------- Dr. Sonya Abraham: Yeah. So I think there are sort of two ways of looking at it, I think there'll be one where you're treated very early. So if you treat very early, maybe you can switch off that perturbation. We still haven't got treatments for that, but, you know, that's, that's one way of looking at it. I think treatments are evolving and it's interesting because again, you know, steroids did transform the landscape back in the day in the fifties and sixties for people affected with arthritis, then sort of the advent of methotrexate, the TNFs. And so all those drugs - the oral drugs so methotrexate, sulfasalazine, hydroxychloroquine, the steroids - they affect lots and lots of inflammatory proteins. Then the anti TNFs and the biologics came - so [inaudible] interleukin-6 - effects on T-cells, interleukin-17s, they affect one cytokine directly by antibody. So they, they shut off and bring down that one hyper inflammatory protein, which may have other effects on some of the other proteins. But now what we see is there are new drugs that are coming out, but having that sort of wider implication on lots and lots of cytokines. So it's going back to those sort of steroid days, which I think is interesting. And yeah, I mean, one of the things with inflammatory arthritities is, they're not monogenic - because there is a big advent of gene therapies and we see transformation so in hemophilia, but if we're able to understand more and more about them, are there ways of modulating some of the genes causing inflammation? But I mean, you know, I think we're looking 10, 20, 30 years down. So yeah, hopefully we'll be speaking in 10, 20 years, --------- Patrick Short: Absolutely --------- Dr. Sonya Abraham: and there may be transformations. And then going back to something that obviously is of interest to me, and that is the micro-biome is, you know, we see potentially a future where it will be a combination of treatments, but also your microbiome environment. Now, whether this will be treated with food supplements to alter your microbiome or actual capsules or other things, that, you know, reset the, the proportions of the pro-inflammatory, the good bacteria and the not so good bacteria. I think that's possibly going to be a real reality. And I think that's probably going to be a lot sooner than say gene therapies in [inaudible] inflammatory arthritis. So yeah, I can see, 7 to 10 years, it could be. We already know, in the devastating diarrhoea Clostridium difficile, that, you know, microbiome therapy and fecal transplants, which don't sound very appealing, but, you know, they've been approved. --------- Patrick Short: Right, and incredibly effective. --------- Dr. Sonya Abraham: And very effective. --------- Patrick Short: How, how would the microbiome work in, in something like ankylosing spondylitis or, or RA or psoriatic arthritis, does the microbiome play a role in, (cause my understanding in ankylosing spondylitis is that there's kind of spinal fusion and, and kind of deep inflammation in the spine) is there is the microbiome playing a role there potentially? --------- Dr. Sonya Abraham: Yeah, and it's thought to be potentially originating from intestinal microbiome. So the bacteria in the gut, and we know from inflammatory bowel disease studies, that there are altered microbiome. We know comparisons across looking at patients with psoriatic arthritis and rheumatoid, and ankylosing spondylitis that there are alterations in the proportions compared to say normal, healthy volunteers. And, you know, our research is really focusing on trying to understand what the differences are, but it's more than - and what's been published to date is what you observe at that moment. But actually it's not about just the bacteria. It's about the interaction of the foods we take, but also the bacteria, and how stable this is over a period of time and what the chemicals, those bacteria - say with the food interactions - produce that then affect the immune cells, and then what happens to those immune cells. So what we really, and what we're doing is really looking at that integrated approach. If, what happens when you compare people, their diets, their micro-biome, what chemicals are being produced and how does that affect the sort of genetic expressions in pro-inflammatory cytokines in the immune cells? --------- Patrick Short: Incredible, it, it really is a complex system, isn't it? And you have to look at it with that integrated approach. --------- Dr. Sonya Abraham: Yes, yeah. --------- Patrick Short: Well, I'd just like to say thank you so much for taking the time. I always learn an incredible amount speaking with you. So thank you. I think we covered a tremendous amount of ground today around representativeness in clinical trials and, and some of your work in immune mediated, inflammatory disease and arthritis. So thank you. I really appreciate it. And it's, it's sunny where I am here - hopefully it is where you are and you can get outside and enjoy, enjoy some of the nice weather. --------- Dr. Sonya Abraham: Thank you. Are you based in the UK? --------- Patrick Short: Yes - in Cambridge. --------- Dr. Sonya Abraham: Oh right ok, nice. --------- Patrick Short: Despite the [american] accent. --------- Dr. Sonya Abraham: [Chuckling] That sounds very sunny [inaudible]. Yeah, based in Surrey, [inaudible]. So it's dull cast but it's not raining, so that's not too bad. --------- Patrick Short: Excellent. --------- Dr. Sonya Abraham: But thank you. Yeah, no, it's been a real pleasure. It really is - it's great, yeah, discussing with you. Thank you. --------- Patrick Short: Great. Thank you.