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Asia-Pacific – a Global hub for Hepatology Clinical Trials

Worth Sharing?

29 June 2020
WEBINAR

SCRIPT

Arsalan Arif: Hi everyone, I am Arsalan Arif the publisher of Endpoints news, and I am pleased to be here today as your MC. We have got an important topic today, and a great panel. It is sponsored by Novotech, and we will be talking about Asia-pacific as a global hub for hepatology clinical trials. Now I would like to introduce our panel. 

First up we have Professor Man-Fung Yuen, Chief of the division of Gastroenterology-Hepatology, and the Deputy Head of the Department of Medicine at Queen Mary Hospital Hong Kong. Next, we have Dr. James Hamilton, Vice President and Head of Clinical Development at Arrowhead Pharmaceuticals. Next, we have Professor Ed Gane, Chief Hepatologist and Transplant Physician and Deputy Director of the New Zealand Liver Transplant Unit at Auckland City Hospital and then we have Professor Jacob George Head Department of Gastroenterology and Hepatology at Westmead Hospital. And our moderator is Barry Murphy, the Director of Business development at Novotech. We've got a session here for you today, and if you've got questions you can clear it at the Q&A over there, but now I'm going to start the presentation over here and turn it over to Barry. Barry let us begin.

Barry Murphy: Thanks, Arsalan. So, okay we are very excited to have such a stellar line-up as he mentioned here today, and I also saw the registration list, and delighted that so many familiar names of people who work with both Novotech, […] and there are key opinion leaders with us here today. 

Very quickly for those who do not yet work with us, a quick intro and for a bit of context. So, Novotech is a full-service Asia Pacific biotech focused CRO. And we've local teams on the ground in 11 countries across the region, so that’s Australia New Zealand where we started out, and then the big markets of China, Hong Kong, and Taiwan, and, as well as South Korea, and then Southeast Asia, and Singapore, Malaysia, Thailand, the Philippines, and then lastly India. So, our model has always been to hire and very experienced local, full-time regulatory, and clinical team on the ground in each country which we operate, and to really help our client base navigate the region in terms of local requirements; language, cultural nuances, etc. And we play a huge stock in our KOLs relationships […]. 

So, given the high incidence of liver related diseases in Asia Pacific, it really has become a core area of focus for us at Novotech. Almost all of the Hepatitis work […] all has started with Professor Gane and his team at ACS, before expanding into Asia with Professor Yuen at Queen Mary, which is on the list there as one of the top sites. And across the region including ASAN, and Seoul National in South Korea; both sites […] we have memorandums of understanding in place with. So, it really is an area we work in quite a lot. In NASH, and PBC we have a lot of that as well, and we do a lot work with Professor George at Westmead and look forward to speaking on that side as well. So, […] exciting space now to have this line-up here with us today. On that note, I will first turnover to James from Arrowhead, a long-term client and James and a friend of Novotech. I am very happy, and look forwards to your perspective on the region, and of the work you have done.

 

Dr. James Hamilton: Sure thanks, Barry. I appreciate that. And so, I only have two slides here. But I thought we could put up just the arrowhead pipeline slide. Arrowhead is an SI RNA company. Everything we do involves SI RNA gene silencing. And every one of these programs; the clinical stage program, started in in the Asia Pacific area, and I think every one of these at least the phase one healthy volunteer portion of the study was done at ACS. Or, at least the bulk of the enrolment was at Auckland clinical services in Auckland. And so, we have been working in the region since around 2014; again, most of our pipeline has passed through Asia Pac at some point or another. And I think initially it was the R&D credit that brought us to Australia first, and I think that is is also something that is available in New Zealand, if I recall. 

But that's sort of not the only reason we are there. We have had a great experience overall running a variety of studies ranging from rare disease clinical trials, to dyslipidaemia studies, and really a great experience running hepatitis B studies in the region. We had a phase I/II clinical trial that ended up enrolling about a hundred HBV patients, of the majority of those were enrolled at Professor Yuen site, as well as professor Gane’s site. And then also various sites across Australia. So, the region was very strong in terms of enrolment. Let us go to the next slide since we are talking about enrolment. 

But you know that has not only been the case for HBV; I think in general we have experienced very strong enrolment across other disease areas as well. Specifically, I am thinking of our dyslipidaemia programs. We have ongoing now a program targeting NPTO3 that is in a phase I/IIa clinical study, and another targeting APOC3 both enrolling similar populations. So, there is some […] cannibalization of patients, I guess, between the two programs. But it really has not been a problem because enrolments been so strong in both of those separate clinical studies in the region; specifically, for those studies in Australia, and New Zealand. We have also recently launched a NASH study that is up, and running in New Zealand, and Australia; first enrolling healthy volunteers in New Zealand. And that study will also be open for enrolment at Professor Yuen’s site in Hong Kong, and at our South Korean sites. as well and so the start-up has been great there even despite COVID-19 related challenges across the region in general. The slowdowns, if any, have been much less than other regions that were working in. So, that has been excellent from the standpoint of clinical development. 

You know, one of the other things that I would mention as very helpful to sponsors is the CTA process, and how the regulatory framework works out in both Australia, and New Zealand, and Hong Kong as well. The CTA process is very straight forward from our standpoint. We feel like it is very predictable, and that there is a low risk for regulatory drama. And you kind of know what you are going to get to know what the process entails. 

And something important for Arrowhead; we tend to go where the science takes us. And I think and Professor Yuen can attest to this; if we see something that looks interesting or a signal that looks interesting, we are going to amend our protocol, and study that in more depth. And so, we may end up amending protocols several times to expand studies, and that is happened in various studies. And that amendment process is extremely rapid in all these regions. Particularly in Australia, and New Zealand. That has been our experience. I think an amendment takes you know a couple weeks. General; I think the record was through one of the ethics committees in Australia at Bellberry; we had an amendment approved overnight. So, that was a record time from my standpoint. 

But overall, it has been a great experience, and we look forward to continuing to work across the region with our various programs that are moving from the bench into the clinic over the next couple years. So that is all I have Barry. 

Barry Murphy:  Thanks for that. We have a few questions from the floor, and I can certainly recall about those class submissions. All right, sure it is a good Segway into you talked a lot about working with Professor Gane at the ACS, so I am coming over to you. 

Professor Gane: Thanks Barry! I am delighted to join you all on this symposium this morning. So, ACS “Auckland Clinical Studies” is a dedicated early phase clinical trials unit. It really went into being in 2007 to really meet the demands of the growth, and early phase for hepatitis C. In fact, we were evolved in the first hepatitis C new polymerase inhibitor back in 2005, which we had to use a disused ward, because of the lack of such dedicated facilities. But ACS was born on 2007 and has grown since then. It is now a total of 45 beds, of which 35 adjudicated in patients, and the other 10 can be used for that of outpatients. We have conducted over 230 studies over the last 12 or so years. Most of them being phase Ia or SAD/MAD studies. My interest has been in the hepatitis side which makes up about 50% of the studies performed in that Centre. And really the previous growth was for the first few years for hepatitis C and related therapies. We developed the phase I development for all the programs. But of course, hepatitis C is now of interest, and no longer surrounding early research. We have switched really to the biggest problem on our region which of course is hepatitis B. And New Zealand does have endemic hepatitis B, which is infecting about 3% of the population. And the last five years has been really focusing on early phase development of novel antivirals, and novel immune modulator therapies to treat hepatitis B. And those five years have seen also a shift to umbrella protocols. And umbrella protocols, I think, about becoming increasingly popular, because they provide a means to accelerate the early phase developments. And by that, I mean; we combine the Phase I healthy volunteer path, which is usually a combination of similar ascending dose. and multi-ascending doses, with the phase one being proof of concept, and the patient's population with the target disease. In this case patients with chronic hepatitis B. 

And ACS has been a good site to provide the early phase; phase 1a. They have around 20,000 healthy volunteers on their database, and recruitment of healthy volunteers for the SAD/MAD is extremely quick. But the combination of 1a and 1b umbrella protocol does give you the chance to, as I said, accelerate from early safety, and PK, and sometimes PD, if you have a host targeting drug, or some of the new hepatitis B. You can get a PD signal anywhere, including healthy volunteer. So, that enables us to quickly give the safety, and the PK data to inform the exposure data, and what doses you will go into patients with. 

And this has required a lot of work with our regulatory authorities, and our ethics committees. And certainly, the last five years, we have done 28 umbrella protocols. Most of them in early chronic hepatitis B development. So, we would get approval to set up this study, we would accumulate the safety, and the PK data, and health volunteers. And that would be done at one-sided ACS. And meantime collaborating units. And for hepatitis B we have of course in lead set at being the largest patient population in clinical trials. So, MF Yuen in Hong Kong, our colleagues in Seoul, Taipei, Singapore, Bangkok, and across Australia are getting set up. So, by the time we finished phase one, a we are ready to go into the phase Ib. This involves sharing the safety, and the PK data with our regulatory authorities, and with the regulatory authorities across the region. And they will want usually to see that data. And provided there is no change in the design from the original protocol, it does not need to be a formal amendment. But it does need to be approval of the data on phase 1a before you start using phase one be in the patient population. 

This has, as I said, the advantage of having a single unit see how you change it to the healthy volunteer part. We also often end up doing the bulk of the first cohort, and patients given that we have many patients. But of course, we require the big boys across the region like […] to come on and recruit, as they do so well for the patient part of the phase 1 study. I think this collaboration, and especially when we are doing this with the help of a strong Asia Pacific CRO such as Novotech, enables us, I think, to have accelerated drug development. Not only […], but as James said, did now for several different disease entities. That is really all I have to say and I am happy to answer questions later as well. 

Barry Murphy:  Thanks professor Gane. Thanks a lot for those kind words as well. We structured this because of what you described. So, we often start with Professor Gane, then like you said expand to Hong Kong with you Professor Yuen. So, I think it is an appropriate time for you to introduce Queen Mary Hospital and yourself as well. 

Professor Yuen: Thank you Barry. It is very nice to talk to all of you. And in fact, as mentioned by James, and Ed we are doing trials in Hong Kong. The main site I am working as its Queen Hospital Hong Kong. And a bit of background for you; we have 1,700 beds. It is a very acute hospital, and a tertiary centre. And in fact, we had 1,300 ongoing completed trials. And if you are talking about hepatology, we have about 100 ongoing or completed studies already. 

One very particular thing at our centre, when you perform the study it is accredited by the China National Medical Products Administration. so, if you are thinking about doing trials in Hong Kong then your result that we obtained in that trial can be translated to the information or requirement by China NMPA. So, this is a very convenient way that you may consider starting up study in Hong Kong. And concerning our team we have a dedicated clinical, and laboratory teams, headed by me, MF Yuen. And we have clinical researchers, including associate professor, assistant professors, and some clinical doctors. They are helping we worked as a team and helped me a lot in running the trials for our patients. 

Because of a very large load of studies, we are we could have many study coordinators. We have two senior technical offices, and we also have five clinical trial assistants. And you may also know that most of the study that we run has CRO, and central laboratory support. But the thing is sometimes when we encounter patient with urgent problems, we understand that the essential that may be requested some days before we can get the urgent results. Sometimes we need to talk to the sponsor and we made need to arrange and schedule visit and also we need to do the tests as soon as possible, and get the result as soon as possible for our determination, for our studies, or for the patients. So, we have a way strong laboratory supports we have two technical offices, and for lab assistants. So, this forms the team that we run for all the clinical trials. 

And we have a lot of experience if various biotech company mainly working on the trial on hepatitis B. The reason is Hong Kong has a very high prevalence of hepatitis B infection. The bar chart on the left shows the general preference of Hong Kong, as updated in 2019, we have around 8% population in Hong Kong having hepatitis B infection. And the bars actually show to this distribution in even-aged group, but I mean when you are talking about including patients for trial from young age, to before 60, we actually are talking about 7 to 10% of these populations […] having hepatitis B infection. So, we have very strong supports in terms of the patient's source. 

Concerning our centre, the graph, or the bar charts, on the right shows you the difference in terms of the case attendants, new case attendants, and follow-up from up to 10 years period. Since 2016 you can see, we have around nine hundred new cases every year, and we have nearly 20,000 cases attended every year. If you will look at that counts every year, follow-up then you may expect to have 11,000. So this shows you well convincingly that our Centre, we are having a lot of hepatitis B patients being followed up […]

Barry Murphy: Thank You Professor Yuen. So, we have talked quite a bit already about hepatitis B, but we do want to broaden the topics as well. And Professor George from Westmead, we look forwards to you giving us an introduction. And your experience and focus more in the NASH and NAFLD space. And so over to you to introduce us to Westmead, and yourself, for the work you guys are doing. 

Professor Jacob George: Some of you may know that I work in Westmead hospital, which is in the west of Sydney. And for those of you who do not know; Sydney is Australia's largest city, and the Sydney population is about five million people. In the most of Sydney one of the unique advantages is we have got a very multi-ethnic, multicultural population, so we got large populations with hepatitis B. It is also an area of Sydney that is socioeconomically disadvantaged, and because of that, we have a high prevalence of fatty liver disease. 

The hospital itself was set up in 1980, so it is relatively speaking in historical terms, a small hospital. But it is had a very rapid growth. So, talking it in 2020, we are now the largest hospital in the southern hemisphere. We service 10% of Australia's population, and we have got a thousand beds. And in Australia like many of the other affluent countries patient care is very much outpatient based. And so, we currently see about two million our patients at Westmead every year. And the hospital has got about 440 ongoing and completed clinical trials. And some of the headline trials that were done at Westmead include oncology trials, we got the checkpoint inhibitors approved for use in melanoma, and for lung cancer. And a lot of those melanoma trials were led from Westmead Hospital. 

In terms of hepatology clinical trials, we have been involved in clinical trials since 1990.  and in fact, the original hepatitis C trial, where hepatitis C was approved.  For when interferon was approved for hepatitis C back in 1990, the original FDA audited trial, was, we were the chief centre for doing that. So, we have had a very long history, and just looking at the number of trials we have done since 1990, it is more than about three or four hundred trials we have done. But currently we have got about 52 ongoing clinical trials. 

One of our advantages we, unlike Ed Gane of the ACS, currently at Westmead we do not we do not have a dedicated phase one unit. But New South Wales which has about 40% of Australia's population, state government has realised that it is important to be involved in phase one trials. And there are significant moves underway through the state government to set up one, or two phase one units in our state. So that has been a big part for going to the future. But our unit has been Hospital in the stall in the centre is very well known for its work. In translation, in clinical research, and thought leadership in the diseases. 

So just going back to some of our highlights; most of you would know which is like IL-28, and IL-28 is largely irrelevant now, but it was one of the biggest discoveries in terms of personalized medicine at the clinical interface. And we were one of the three units in the world that simultaneously published the Association of IL-28B or what we call if you are on lambda three with it is C response rates. One of our key roles is working on fatty liver disease, and many of you in the biotech industry have seen these papers that have come back.  We are talking now about a new name. So, we are not talking about NAFLD anymore, and we have proposed a new name published in gastroenterology earlier this year to call it metabolic associated fatty liver disease. And very recently, I think it is a month ago, it was highlighted in the journal of hepatology 4 days ago, we have suggested a new way of defining metabolic associated fatty liver disease. 

So, if you think about non-alcoholic fatty liver disease which is previously used, it is a diagnosis of exclusion, meaning every patient who does not meet any other liver diseases. But with this new definition for fatty liver disease we've got a very clear, simple definition, that can be used interface, what that means from a clinical trial is that you can actually have the very homogeneous group of patients diagnosed by very positive criteria. And particularly when you have a disease like NAFLD, or metabolic associated fatty liver disease, where the you know the clinical trial benefits have not been enormous. So the you know the response rate is ten, to fifteen, maybe twenty percent better than placebo, when you're looking at drugs that have small effect sizes, because of the complexity of disease a homogeneous clinical trial like you would exactly, is actually very important. And very recently both getting started and of data is coming that this new definition works better to characterize patients with fatty liver diseases. 

We have also done work on lead fatty liver disease in Asia. So, we do a lot of translational research, a lot of phase two, and phase three clinical trials, and we do provide a lot of thought leadership in the whole area of hepatology. So that is the only slide I have got. Back over to you Barry. 

Barry Murphy: Thank you for that great introduction. And what we want to do now, is get away from the slides. We have some questions that have come from some people, when they had registered, and others that will come in live as well. So, we will do our best to get there everything in, and if we do not, we will follow up with. And I will try to direct them as best I can, but feel free to chip in, and make it as free, being a discussion as possible. We do not have to be too rigid. If you answer them if anyone and want to add anything as well. 

So, there was a lot of interest in from the registrants, and even coming in on the umbrella designs of the different types of studies that people have been able to run in the region. So I am going to start with James, James with you from the sponsor perspective; and you kind of touched on it and being able to do multiple amendments, and see different things, depending on what data was emerging. So, can you provide a bit of an overview of the type of study designs that you would be able to conduct in Asia Pacific, and how successful were they as a region? Being in terms of flexibility, where they claim a new umbrella type designs that Professor Gane, and Professor Yuen and spoke about as well? 

Dr. James Hamilton: Sure, so, thinking back I think we have not run a study that was not an umbrella design, or at least some variant of that. And maybe early on some of our studies were sort of plain vanilla and single dose escalation. But we tend to design our studies in a way that we do SAD and MAD, SAD in healthy volunteers and MAD inpatients if possible in an intercalated design; where you start with your healthy volunteers, and then vote to agree to dose escalate. And then, in parallel, with your next dose in healthy patients, enrol a dose in patients. So, your healthy’ s are always a dose level ahead of your patient cohorts. And that works well particularly when there are many patients because the healthy volunteer component of the study always goes faster than the patient enrolment. It worked very well in HBV for example, when Professor Yuen had access to many patients. And so, we were able to fill those cohorts quickly. 

But we have done those types of designs, SAD, MAD, in healthy volunteers. Also, I am thinking of our alpha 1-antitrypsin program, where we did not enrol any patients with alpha 1-antitrypsin deficiency, but there is a serum biomarker that we could measure in the healthy volunteer. And so, we were able to run SAD and MAD almost in parallel. Again, a kind of a stepwise interpolated design, and with SAD always proceeding that Multi dose aspect of the studies. We have done similar umbrella type designs with dyslipidaemia, where patients with high triglycerides are enrolling, after healthy volunteer cohorts have been enrolled. And I think Ed had touched on this. 

Our experience has been that the regulatory bodies, and the ethics committees are in general fairly accepting of that type of design, if the healthy volunteer data is available. And you know from at a specified dose level before enrolling patients at that dose level and it has never been an issue. So I think over the years the ethics committees particularly it become more comfortable with that type of a design and I think we get much queries from ethics committees, when we submit that design now, than we did say four years ago. 

Barry Murphy: Yeah, it looks great to hear. I mean I can just pull it a little bit further than in terms of regulatory. So, when you then you have done so much of your work in Asia-Pacific, and obviously being very successful, so there was a couple of questions around the acceptability of the data from Asia Pacific. So, when you take that data back to the US, or anywhere else how acceptable is it for the regulatory bodies in the USA, to go into later phase development to the FDA, and even for investors in pharma? 

Dr. James Hamilton: Yeah, and the studies done and in all of these countries, and all of these sites is done under ICH, and so that data has been acceptable, when we go to Europe, or when we go back to the US. We had not had any problems in that regard. 

Professor Gane: I think there has been very good communication between the two of people run ACS Professor Richard Robson, pharmacologists, and Dr. Christian Schwab have had ongoing conversations with our regulatory committee, which is subcommittee of therapeutic medicines at the Ministry of Health. And they have continued conversations, and they are very strict about guidelines, on how are we design several protocols. So, you must be sure that when you move from healthy’ s into patients that you do not go above a certain dose ceiling, or a certain does exposure. And James has already alluded to that. Yet, you always go the doses lower than you are looking to achieve […]and provided you have good sharing of the phase 1a data with the regulatory committee, before you get permission to embark on the phase 1b initially in ACS, and then throughout the region, there should not be an issue. I think yeah there was initial resistance from sponsors, some of the sponsors early on still wants to split their healthy volunteer, and patient studies, and do separate study protocols. But I think more and more, we have seen people move towards this single protocol umbrella approach. I think James brought up the issue about doing SAD single ascending dose in healthy volunteers, and then doing multi ascending doses in patients. And that really lends itself very well to investigational agents, which we know about the delivery and, the general safety protocol, I think. Which we certainly have a feel for the SI-RNA approach. 

But there's always going to be some a lot of our IPs where you actually need a MAD data and healthy’ s. I think we've seen that, they've been a few recent examples; even in the field of hepatitis B, when we look at some of the toxicity is associated with some of these small molecules, where the exposure and healthy’ s being very small. And then when you go on to patients you starting to see evidence of toxicity, when you haven't had reasonable you haven't had MAD for example, or you haven't had MAD maybe for more than seven days in healthy’ s. So, you are stuck with trying to interpret a signal, and the patients are not clear whether that is related to the disease. In particular ALT elevation, or whether they're related to potential drug-induced liver injury. So, I think for most Investigation agents you will have some MAD and Healthy’ s before you go into the patient part, but not all. My understanding, and I will ask you MF for comment, so as I think we put a major protocol amendments before we go into part one be, provided the dosing schedules in patients as well within the ceilings outlined in the protocol, when it was submitted and approved. So other than just submitting the safety the PK, and have available the PD data from healthy volunteers, we do not submit a major protocol amendment. MF could because you often start off with the part 1b, you obviously will get to submit the safety and PK data from ACS […].

Barry Murphy: […] Yeah, because that was kind of my next question, I know what we do is you would submit […] as we submitted for ACS. And then we roll into the patients with the data that becomes available. Which are what speeds it up so quickly, as James touched on that as well. And yes, Professor Yuen from your perspective has there ever been any questions on that approach or challenges here from the ethics committees, or the regulatory body in Hong Kong? Is this something that you know you have been involved with, in a similar way to ACS, in kind of educating you to some extent on the best approach and how it streamlines development?

Professor Yuen: In fact, interestingly, what I will from there is, we work together with the ACS. Usually I mean perform excellently in doing the healthy volunteer parts, and then we tried to, I mean, speed up the recruitment, for the subject, or patient's parts concerning the process in the IRB et or the ethics committee in fact they actually love to have this umbrella protocol. Because, I mean, when we present, we study to them. In fact, we presented the whole set of the study design including a set at the Met. Although they said not be done in Hong Kong, usually would be done I mean what was done in Australia, in an ACS, then they were asked something that was what a result on that? What is a plan of the is a set protocol? And if you put all the, I mean, SAD and MAD, together in the umbrella protocol, they actually feel more comfortable, to approve these studies so that is actually a positive, rather than a negative approach, by using the umbrella protocol. 

[…]

Barry Murphy: it has been incredibly effective for a lot the sponsors we work, and obviously James talked about this as well. And I guess what we have seen it the most is obviously in hepatitis B. Is there is any reason for that? Or these types of umbrella studies suitable for many different indications, and just something that has seen they are caught on in hepatitis B. But have you seen it across a range of indications, expanded across the communications as well? I guess for both of you, Professor Gane, and Professor Yuen, and James as well? If you want to chip in on things you have done. It would be great to hear your thoughts on that. 

Professor Ganes: So, we have performed umbrella protocols in the variety of other diseases. Obviously, I am not the PI for those. We have respiratory positions, haematologists involved in some of the compliment, and numbers of studies. Small molecules for respiratory disease. And we have heard about other SRNA disease states. I guess the one spectrum of diseases where we have tended to go straight into patients has been, of course, are oncology. And I think most oncology platforms. The SAD, and MAD has been in patients. Not all. Certainly, the vast majority. For most other disease entities, we do we have looked at, or performed umbrella protocols. 

Professor Yuen: I think, […] the special consideration is for something Hong Kong is that we do have a lot of patients. So, once the umbrella protocol is in place. Once the healthy volunteer phase has been completed, then we can speed up the recruitment very quickly […] 

Dr. James Hamilton: Barry, we ran in terms of other disease areas, I mean we ran our dyslipidaemia, it was a hypertriglyceridemia study in healthy volunteers, and patients with elevated triglycerides. And we basically replicated our HBV umbrella study design, and ran that in, still ongoing, that very successfully in Australia and New Zealand. And another circumstance where that patients are not that hard to come by. It is not a rare disease, so there was no problem in enrolling healthy volunteers, and no issues finding the hypertriglyceridemia patients as well. So, it worked well for that indication. 

Barry Murphy: Thank you. So, just Professor George you have been we have been waiting patiently, so I am going to switch and have a couple of questions here for you as well. And so, you talk about a very focus in translational medicines, and I also know you have done a lot of research in personalized medicine, and the contribution of post genetics, and immunology. Can you tell us a little bit more about that work, and what you see is that the future of personalized medicine in hepatology?

Professor Jacob George: So, to answer that question like this from a hepatologist perspective, the morphological appearance of the liver irrespective, […], morphologically there's only about three different phenotypes in the liver; is fat; is inflammation; and this fibrosis. And so that is the pathology pathologist is looking at. And what governs that, really depends on a whole host of factors, and in the case of hepatitis C, it is a single agent, such as a virus. Or have hepatitis B for that matter, but even in those diseases, we know that host genetics, you know two people can have hepatitis C; one has very mild persistent disease that doesn't end up killing them. Another one has aggressive disease. Similarly, in hepatitis B some people with NAFLD have very active disease, and so clearly there is individual modifiers of disease phenotype. And if you think about it in a very broad perspective, there are host genetic variants that might be involved in modifying your phenotype, there is your environment without outside your body, which is you know your diet, your physical activity. and if you think that the agent sitting, we have gone through this nutrition transition very rapidly. So, in the rest of the world with the Industrial Revolution in Europe it took 150 to 200 years to go through. In Asia what we are going through this transition very rapidly over 20 to 30 years, having poor quality energy dense, low fibre diets, much reduced both internal physical activity and regular physical activity. So, there is the environment is a modifier and then the environment within […], and all directly impacts disease phenotype. And one of the things that we couldn't do before, which we can do now; is before high-throughput genomics bioinformatics, and computational biology techniques, to be able to integrate all of that information to try, and work out how an individual person might respond whether it's to a drug, or to a disease. And try to see is looking at genetic variation and how that impacts liver phenotypes and inflammation and fibrosis, and we have showed that there is at least five, or six genes that impact inflammation, and fibrosis in the liver. […] 

But when you look at liver diseases, very broadly speaking, all the known variants still only account for twenty percent of the heritability. 80% of heritability is still due to genes with small effect sizes. And I think what we will see is strategically going over the next 10, to 15 years, is we need to integrate the known gene, and the new genes that we will be able to find, and then develop scale algorithms.  And it what we call in the field, polygenic risk scores, and this becomes particularly relevant in associated disease because as I mentioned before your effect size is very small 10 to 15% above the placebo.

And so if you can have a homogeneous group of patients, categorized on a polygenic risk score for example, then you're more likely to find subgroups of patients, where drug A will work, with a 40% difference from placebo versus drug B. And I think that is where the field is going to move. I think it is very possible in the next five, to ten years that we will have these sorts of polygenic risk score sub phenotype patients. It is already happening in cardiology 

Barry Murphy: hepatitis B I think is the one where people automatically think Asia Pacific. Whereas Australia lots of biotechs here who do a lot of their work in the USA, given the patient populations, and that that would be here anyway. But maybe we could touch on a little bit of the landscape in terms of the epidemiology of NAFLD, and NASH in Asia Pacific or even specifically in Australia. How has that change, or have you seen a change over the last say five years? And do you see it changing further five, to ten years? 

And then how would that impact recruitment, availability of patients, things like that? 

Professor Jacob George: To make a point of, one is Asia Pacific is undergoing this nutrition transition. In 1/5 of the time the European, and American continent went through. So, we are getting these rapidly rising increases in both incidents, and prevalence. India is the home of type 2 diabetes in the world, the amount of obesity. Partly perhaps because of the one-child policy in China. But huge amounts of obesity, and type 2 diabetes in China. And that is a big part of our region. But even in all the other countries, what this nutrition transition means very rapidly increasing incidence of fatty liver disease. The other thing to note is that with this and with this increase in affluence; alcohol is a big problem in Asia. And so, you have a compounding synergistic effect of both alcohol, and metabolic diseases acting together towards in the phenotype. 

And I think we really need to be starting to think do we want to be treating real patients, and if we want to be treating real patients, yes we may not want in a metabolic fatty liver study just to treat people who are drinking, you know 15, 20 standard drinks a day. But there is a role for a lot of patients and drinking much more than we would currently classify as excluding them from metabolic fatty liver disease. And I think we need to be really you know protocols etc. might be quite useful. So, having patients with pure metabolic disease metabolic plus you know minimal to moderate amounts of alcohol.  

They will respond differently to the drug but because 60% of the population consumes significant amounts of alcohol. You need to include them in the clinical trials. 

Barry Murphy: You know, it is such a competitive space here. So, I know that I guess between the increasing incidence in Asia-pacific, and the increasing competition here, I do think we'll see even more and more biotech’s look to the region, and to sites like Westmead to support recruitment.

Professor Jacob George: Yeah. 

Barry Murphy: So you have questions come in. And now we are getting close to the end. And this one I do like it is similar think professor getting to what John our CEO, you talked about when you did your fireside chat. A broad question I guess for yourself, professor Yuen, but the hepatitis B is such an exciting space we've seen a lot of development there, there was obviously a lot of AI, and we're now seeing immunomodulators […] and things like that come in. And then everyone is trying to find the right combinations. So, I guess, what do you see as the future development, and where do you see the biggest opportunity to reach that functional cure? I guess, what are some of the biggest challenges in getting there? So quite a broad one for both of you before we go. 

Professor Ganes: I get asked about a lot and think about even more. I think for the next five, to ten years I think we're looking at functional cure as being sustained […]. We are looking at a combination of drugs, and then with the backbone will be […] translation inhibitor such as SI RNAs. I am sure the current phase 2 studies, which are now exploring, SI RNA as the platform on which there's other drugs are incredibility exciting […]. 

But the future and then the future which is approaching very quickly; we will be looking more I think it’s gene editing. We have not talked about gene editing today, but I think to me that's probably the most exciting prospect for sure not only of inherited diseases, but also of infectious diseases. But I think that probably more than five years away from, well maybe not, more than five years away from becoming established for infectious diseases. But no, I think we will achieve functional cure within the next few years in the proportion of our patients using a gene style, such as SI RNA combined with other drugs. But I'd like to hear what others say.

Professor Yuen: Ed, I agree with your approach. But the thing is I mean just like to add that we now have a very potent antigen suppressor. For example, SI RNA as you mentioned, definitely very useful, very potent without significant side effects. My comment is, I mean, for the future for a functional cure, and I am very sure, I am very sure, that we will achieve some patients. For example, we are talking about 30%, 40% of using this new drug combination, all right. I think the future development may be further enhanced, by looking at the precision medicine for patients. I am thinking say for example, we have different groups of patients, big patient with different surface antigen level. 

Some patients may just require leukocyte plus SI RNA that can achieve the function of cure, and some patients may even require leukocyte plus SI RNA, and even now immunomodulators. […]

Professor Ganes:  I think we learn a lot from hepatitis C, and hepatitis C was easy in retrospect compared to hepatitis B. But the ability […]  to do platform studies; where you have multiple cohorts in phase 2, where you're combining different early drugs, I think that is going to become more popular certainly in hepatitis B development in the future. So, phase 2 platform studies combining two, or three different probes. And smaller cohorts very much like the earlier phase three drug development. 

Barry Murphy: Excellent, great, yeah okay! I think we have a lot of sponsors we all work with on the phone who are hoping to achieve that functional cure with your support. And I think we are basically going to the end I might just ask you to close James. 1 final question for you and if you did one or two pieces of advice to USA biotech’s or EU biotech’s on the phone listening about conducting trials in the region, what would they be? 

Dr. James Hamilton: Yeah, I think, I think, the key advice would be to work with the experts in the region, that know, that they have a broad reach, and know that through the ins, and outs, of how the CTA process works there. What is typical for regulatory processes in each of the various countries. And what is standard for the various ethics committees because they are all a little bit different. And now we have had experience with a lot of them, and we kind of know how they operate. And what and what things are buzzwords for various ethics committees, and what you are getting a query on. And I think for a company that has not worked in the region before, it's helpful to go into that with, you know, with help, with help from you know be it from the sites, or from the CROs. Advice that can help you navigate those various channels.

Barry Murphy:  Thanks James. As you know we are always ready to help, and the team at ACS, Westmead, Queen Mary are as well. Thank you all very much. We are just out of time Arsalan, I will hand back to you. 

Arsalan Arif: Thank You Barry and thank you to the entire panel. And thank you Novotech really for bringing the discussion to endpoints news. I learned a lot today. We were led by a fascinating panel, we had a bunch of content we covered, and important content covering key hepatology trials in Asia-pacific. I also want to thank our audience for attending and appreciate our entire panel for sharing their expertise. A lot of deep expertise here we had today Professor Jacob George, Professor Man Fung Yuen, Dr. James Hamilton, and Professor Ed Gane. From Endpoints news, I am Arsalan Arif and I wish everyone the great rest of their day. Thank you.

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