Alcohol Liver Disease Stages

hello good morning my name is jean-franã§ois mouney i am the ceo and co-founder of genfit first of all i want to thankyou in the room for interning this meeting and i want also to welcome toaudience via webex and i know that a lot of european investors individual and institutional investors are waiting for this webex so we had during the lastjpmorgan week the idea to organize its r&d event because a lot of investors and analysts raised many questions about the strategy of genfit in the future years and they also asked about what else than nash and phase 3 in nash, do you have other programs ? so we have decided to to present all the pipeline of genfit and sometimes

i know that you will probably discover some things i want to say also that we have a press release which has been published fewminutes ago and where we announced some important things that we will presentduring this meeting so i want also to introduce my colleagues, robert valczak the vice president of research sophie megnien our cmo now in cambridge office and dean hum our cso but i want to thank dr manal abdelmalek she's an hepatologist, livertransplant specialists she is associate professor at the university of the duke university of system

and probably you know she's very known as a lead investigator in manynash trials and she belongs to the nash crn so we would go through thatdisclaimer quickly and then to speak a little bit of ourstrategy our strategies to have an evolution of the company from the biotech r&d company to a biopharma dedicated to two specialty pharma and we want that to be very coherent we want something to be the crossroad between gi metabolic and autoimmune inflammatory diseases so as you can see of coursethe are in nash we have also some programs in cirrhosis, fibrosis cholestatic diseases

we have announced and we will announce and give you more details about the fact that we are launching a trial in pbc we're working on different immune hypotheses and we are exploring also some additional therapeutics areas, gastroparesis is just an example of things that we are interested in in this snapshot i want to comment, this is the pipeline and you you would get off course moredetails during this meeting first of all the nash program as you know it's the must advanced program its a drug development program in phase 3 now we have enrolled the first patient last month and we want toaddress this huge unmet need and probably what will be a blockbustermarkets

in parallel, as you know we have always payed a lot of attention to thefact that you cannot imagine to access the market and of course to treat apatient if you cannot diagnose them and we could not envision to do that at alarge scale with the biopsies to invest it so it's why we are working for yearsnow in a biomarker program its a key for us to unlocks the nash marketand we will tell you more about that and we will also give you the identificationof the different biomarkers of the algorithm the pbc is a new leading program in genfit it is a potentialsecondary indication for elafibranor as you know it's an orphan disease toquestion is always it's still an unmet need

and we think it's it will be anunmet need for many years because even if they are some drugs to treat thepatients probably you need different roads to address the patients withdifferent concerns and additional cardiovascular concern couldbe some example of what we can bring it is an added value on the tracks programs and sophie would give you moredetails about nash programs that will be launched this year and aboutsome program we envisioned in cirrhosis and then we'll give youour approachedabout combo therapy we believe strongly that a combination therapy willreinforce a competitive advantage of elafibranor

we consider that bycombining complementary mechanism of actions we can address the drug to morepeople to more patients we have also some research program targeting end-stageliver disease whit two liver fibrosis cirrhosis programs and one of his program will be launching in phase 2 also this year we will have more information about that ror gamma agonists is very important target whe areworking for years now it's a subject dedicated to autoimmune inflammatorydisease we are thinking about an indication which is autoimmune hepatitis for thisthis drug and and finally just to say that we are working very hard with ourteam about exploring in-licensing opportunities

to continue to developthis strategy, i mean a strategy of current pipeline very diversified but coherent in the field of gastroenterology and metabolic disorders so now we are going to go through thedifferent programs and i would like madam abdelmalek to present the next slide please we will provide more details on the website ofthe company during the day you have some paper in front of you if you have some questions duringthe presentation will address some of these position during the q&a session okthank you for that thank you jean francois i thanks genfit for the opportunity be here with you guystoday in new york

just a little bit of background about myself as it pertainsto my interests in nash as a space i've been in this area of academic interestsince 1995 when we reported the first case of nash progressing to cirrhosis and my career since then for the past two decades has been academically invested in the space from a clinical research prospective patientoriented research and cross collaborations with many people to tryand define mechanisms for the disease acquisition and progression so it's wonderful for me to get to an opportunity in my career where i'm seeing therapeutics so clearly nash's the underlying major underlying cause ofprogressive fibrosis currently in the western world

and it results in aprocess of necro inflammation ultimately leading to hepatic fibrosis progression and in a minority of patients advanced liver disease cirrhosis andcomplications there are meeting the liver transplantation or the risk ofdeveloping hepatocellular carcinoma the estimated prevalence of nash indeveloping countries right now is approximately 30% and for nafld benign steatosis as high as 50% higher so a huge problem, there are currently nofda therapies an incredibly high priority for our regulatory authoritiesin the fda and ema right now nash is the leading cause of liver disease andobesity and obesity estimate anywhere from 66% to as high and some cohort studies as high as 90 percent of obese patients

and in patients predominatelywith multiple complications in metabolic syndrome and diabetes those that are over the age of 50 in theus- have a higher propensity for having advanced fibrosis or cirrhosis and thisdepiction here suggest that patients who develop fat in the liver a proximally again, 25to 30 percent of patients higher prevalence in diabetics and obesepatients can go on to develop nash and nash currently in in the us, - based on aninvasive studies surveillance studies and hands data is estimated to occur in about 12 to 20 percent of the cohort those that go on to develop nash will develop inflammation in the liver and over many years

progress through fibrosis stagesultimately to cirrhosis or f4 stage fibrosis and then have an increased riskof liver related morbidity and mortality however stepping outside the liverdomain patients with nash are at increased all-cause mortality andpredominantly cardiovascular related morbidity mortality not to mentionpatients with benign simple steatosis are at increased risk for the incidenceheightened risk for incidence of new-onset diabetes mellitus so nash is a risk factor for liverfailure cardiometabolic profile and ultimatelyincrease risk for death

the concern here is this is completely a silentprogressive disease and silent until very late stage signs and symptoms ofadvanced liver disease occur the concern is of patients with nash the leadingcause of morbidity mortality and cardiovascular disease followed by non liver related cancersall cause cancers and ultimately progression to cirrhosis andcomplications this is data that came this is data that came from a former colleague of mine paul angelowhen he was at the mayo clinic and evaluated the homestead county database and ultimately what we're seeing over the past little, over a decade the causesfor need for liver transplant for nash

is incrementally rising compared to otherall other forms of chronic liver disease and what i can anticipate we would seeis the need for transplantation for hepatitis c in the upcoming years willactually declined in the era of new therapies so genfit scientificallyaddresses the disease through its a global approach providing features ofboth histologic improvement in the liver and cardiometabolic protection so addressing two lead causes of potential morbidity and mortality inthis cohort as many of you know the phase 2 study included nine countries56 centers we at duke university were also part of this pivotal study threetreatment arms placebo and two doses of elafibranor

two hundred and seventy-fourpatients randomized and at the end of the treatment period the gold standard which is liver biopsy was utilized to assess treatment response and with thedefinition of nash resolution without worsening fibrosis the protocol definitions for nashresolution without worsening of fibrosis was a score of 0 on at least one of thethree components of nash and the three components of nash on histology orsteatosis necro-inflammation and ballooning of hepatocytes and the progression ofbridging fibrosis from stage 0-1 to 2 and 2 to cirrhosis or advanced hepaticfibrosis after the study was completed and after the data was analyzed in the fieldwas moving forward

we began to recognize that really nash and the definition ofnash should be redefined it should be redefined because steatosis can flocks in the liver and is not the key histologicfeatured account for disease progression so the definition of nash was redefinedmore stringently to include the two features of necro inflammation thatincreased risk for fibrosis ballooning of hepatocytes and necro inflammation so withthis new definition the score of 0 for ballooning had to be achieved and ascore of zero or one out of a three-point scale for inflammation had tobe achieved with no objective score for steatosis so in fact the workingdefinition for resolution of nash became more stringent

and more clinicallypertinent with any progression of fibrosis greater than one point being a worsening the phase study for genfit scientificallyaddresses the unmet need and the paper was published in gastroenterology i was fortunate enough to be a co-author on this paper and it ultimately concluded that the resolution of nash without fibrosis or worsening was most effective in the 120 milligrams treatment arm andthe results were confirmed with an intention-to-treat population as well as subgroupanalyses for moderate to severe nash and the fda's recommendation to redefinethe nash resolution endpoint for future studies

and in addition the publicationconfirmed that or significantly improves the cardiometabolic profile and is safeand well tolerated in patients with nash so of the patients that were in thisstudy 274 12% percent on placebo and pointversus 19% elafibranor this is significant p<.05 to those patients who were reanalyzedwithin a nas score greater than four again you could see a improvement, markedimprovement, in the elafibranor arm and when we take a look at the nas score with anystage of fibrosis selecting out a more advanced treatment group, the improvementof elafibranor was even more pronounced when compared to placebo andthis is really ultimately what matters

what really matters from a liver relatedmorbidity mortality standpoint is what happens with fibrosis and as we can seehere elafibranor compared to baseline improved fibrosis in those that responded totreatment compared to those that didnt and when we take a look at other surrogatemeasures granted we do not have an ideal biomarker but if we look at a validatedsurrogate measures to define what's happening in fibrosis we can take alook at the fibrotests steatotests or the nafld fibrosis score you couldsee again a decrease in the surrogate markers for liver injury and likewise liver injury as defined by alt liver biochemistry it did not affect ast significantly but alt is the predominant

cytologic outcome from hepatocytes. an improvementin ggt and alkaline phosphatase and likewise other markers of inflammationfibrinogen haptoglobin and even c-reactive protein so both fda and aasdl have recommended that it isimperative that any drug development for nash be at least neutral for cardiomã©tabolic risk as i mentionned i am a treating physician i treat many thousands of patients with nash most ofmy patients don't die of their liver disease they die of cardiovascular disease and heaven forbid i put apatient on a medication that will potentially increase theircardiovascular risk i don't need to be treating their liver disease only tohave them subsequently died of a heart attack so it's imperative that anytherapy for nash really improve and advance

their total clinical outcomesboth from a liver related standpoint and cardiovascular related standpoint and as we could see theelafibranor arm markedly improved triglyceride, total cholesterol hdlcholesterol ldl cholesterol and actually even caused an improvement inhdl-cholesterol suggesting that it may have very favorable metabolic profile so genfit differentiation currently wiseof its first line potential global approach with efficacy both in liverhistology and cardio metabolic profiles well tolerated with no safety signal keep in mind that the unmet need currently is that nash's of chronicsilent and potentially progressive life-threatening disease

and that adherence to treatment is not gonna be a short-term therapy it's gonna be probably a very long-term central lifelong care before the metabolicmilieu and that the drug profile for genfit face two takeaways elafibranore have histologic efficacy, good tolerability, good safety and i don't leave river relatedimprovements but cardioprotective properties and that elafibranor has a high potential for first-line treatmentin the nash thank you good morning everyone going from the phase 2 to the phasethree designs for the trial we have a first period of the trial double-blindcure that will be over 72 week treatment

period double-blind we have a hundredand twenty milligram versus placebo and this first part of the study will use onthe endpoint of nash resolution without the worsening of fibrosis so importantlythe definition used will be the one to explain that came from the academicexperts and fda , ema on the definition of resolution meaning we do have to havethe stringent definition of resolution through ballooning has to disappear comedown to zero and information to 0-1 so this is the end point that isaccepted in relevance as a surrogate endpoint to the prevention ofprogression to cirrhosis which will be the long-term points so for this studywe have around we have one thousand

patients for this primary endpoints forthe surrogates approval this was her for the nda approval under subpart h andalso conditional approval in europe so this is ben of course validated and inalignment between the ema and the fda on the use of this surrogatefor approvalof the drug on the market but the study will continue with a long-term extensionperiod so this is still a double-blind treatment throughout the whole long-termexpansion phase of the study between 120 milligrams and placebo and the aim is togo to long-term outcomes and events and these are defined as a compositeendpoint of progression to cirrhosis but also liver related outcomes so thatmeans of the decompensation events that

are linked to cirrhosis and importantlywe also have total mortality and our expert also explains in the totalmortality were expecting mortality from cardiovascular events to occur in thesenash patients and so this is gonna be the full design and a total of twothousand patients will be enrolled to have the answer of the whole global studybut again the first 1000 will be the ones used after seventy two weeks oftreatment for your the submission of authorization to market this is to showyou the timelines a prospectus with the studies so as you know we are notinstalled recently the the first asian recruited into the study so we have thathere we count the seventy two weeks of

treatment the last patient for those1000 patients needed for subpart h approval will be recruited in one year'stoday's the one-year equipment period for the first 1,000 patients and thenyou have to wait 72 weeks of treatment for the readout of the results so thenof course this follows with the nda submission and then approval on for thisis important because we have the fast track designation we are using a rollingreview meaning it's a shorter term for for regulatory approval so we expectthis by around 2,000 in nineteen friend you approval due to the fast track andwe will have the other parts of the file industry already submitted and reviewedbefore the final results of the phase 3

of course there are other aspects withinthe face read this is just you know the central face three design but we alsohave everything around the fool you know trial development plan a trip to marketof the drug that inputs pricing reimbursement and market access in thisis going you know starting alongside in parallel with the phase 3 clinical trialand developments and we also in the nineteen represent more and more intodetail the biomarker validation and qualification program around a globalleader in the national field that's already started of course in that willbe pursued and continued to be in parallel with the face three years withthe face 36 we are also having a lot of

actions in the disease awareness ashfield as a whole and of coursepartnership discussions and more about all these things are ongoing and youknow really make that the full program around the face retrial and you haveyour timelines for the estimated market entry and i will go into more detaillittle bit about other nationalities apart for this long face retrial atfirst after what i want to do it in the next few minutes is just a talk a bitabout our biomarker program field of of nash has as many of you may already knowwe spoke about this in the past jen fit when we think about nash like tothink about you know the company who's

really considering the global clinicalmanagement of nash patients and k as we just heard interface to be true but weclearly show with all the fibrin or is that not only look at the liverhistology where the compound lead resolve nash without worsening offibrosis but the other aspect which is very important is the car to metabolicaspect in there we show it to see where the compound is able to improve yourcardiovascular risk so you know this is really a third party standpoint part ofthe global clinical management of nash patients now in the same themes takingabout nash patients and the global managed management operations we have tothink about biomarkers we know today

that the gold standard to diagnosepatients at a confirmed diagnosis of patients as having nash is the biopsyand we all know that that is imperfect gold standard two major stakeholders inthe field know this regulatory agencies experts in if youlike professor abdul malik calls a working farm workers as well so this issomething we had built into her entire face to be program throughout her faceto be program when the patients came in for their clinical follow-up surgery twomonths we had collected blood samples and store them away optimally optimallyreally for biomarker discovery so subsequent at the end of our troubledtaking up the samples and we really

looked into that so we all know you knowwhy would we want non-invasive biomarkers for different reasons forthat and maybe on the fact that but the biopsy is in communion discomfort forthe patients and so on another part aspect is that we all realize for didn'tnash market reaches maximum potential is very important to have thesenon-invasive biomarkers to be able to identify these patients for treatmentbut coming back to patient management i think it's this is also important forthe patience as we heard from dr. abdul malik that nash's a senate disease kethroughout the big part of the process intelligence is pretty late stage andthis is why would you want to do is get

in there identify those patients whoneed to be treated before they progress into later stage this season this is whywe need a non-invasive biomarker and then directs aspect of course we thinkabout the economics of mashed up there we see the numbers here that cost ofperforming a liver transplant that came in and this has really escalated interms of cost or last few years and really the idea is to identify thesepatients early treat them avoid them from moving onto later stage diseaserequired so with that in mind the question we asked with their program wasreally we want a non-invasive biomarker to be i did to be able to identifypatients for treatment so patients for

treatment today if you think about theface three program okay these are nationally agents within a score of four more withf2f 3 fibrosis so this is the question we want addressed with a biomarkerdiscovery program so what we have been able to identify is an algorithm whichis the score came what we had been defined as if a patient comes in we putthat story the algorithm if they are above a certain score they are nice formore 2003 fibrosis they should be treated if they're below that score theydo not need to be treated this is what we have in hand today this is just aquick look at if you look at the a rock

and here which is comparing theperformance of our two algorithms so using our approach wedding we measuredover a different parameters using two different approaches and at the endusing these two different approaches they both identify the same fivevariables which we used an armored rhythms right now we have two differentalgorithms you can see here to performance and to the question ofidentity by occasional patients for treatment clearly are two other isperformed much better than any other scores significantly better than theothers courts which exists today so here are the five parameters are on the lowerright hand corner

tonight is most of them member the liver manifestation of metabolicdisease not surprising to see hp's is important component the other one is theprocollagen type 38 2 a.m. is out for mac program as a marker of liverdiseases as well as liver fibrosis and then the two other variables are veryimportant to think this is a major innovation which we bring to the fieldis to measure mir anees as some of you may know mrnas are related or involvedin the progression of various chronic diseases cancer metabolic disease and soon so these two mrnas mir 348 200 a has

been already been demonstrated to beinvolved in liver disease liver fibrosis as well as metabolic aspects of nationallevel d ok so this there are five parameters in our two algorithms we havean abstract has been accepted for presentation will be presented by aaronsanyo as many of you know is one of the leaders in ashfield so i invite you allto come out and the cat that poster we will be providing quite a bit moredetail about that program so here's a quick overview of where you are whereyou want to be going plan to be going so right now i mean we do have the score inhand we will be further validating the score in collaboration with herdifferent experts say they have their

own cohort so we will be furtherverifying these two algorithms it's also important that you know that we will beusing the samples of a phase 3 program defining the verified this algorithmit's important that you also know that what we will be doing this using thefirst phase of recruitment so he talked about re-try about and patients were thefirst endpoint once we have those patients recruited we will have theirblood samples we will have their by their biopsies and so on so we will beable to are ready for fire scored that stage we don't have to wait until the the end of the trial moving forward itwould be important to be able to develop

a kid to be measured these differentvariables i think jen fit very good at analyzing samples and and so on we are thinking maybe the best way foris the partner with a company to develop the kids and so on so these are thingsthat were thinking about as you for it in terms of timing we're looking at theability to be able to have this on the market to make it available to patientsin the positions at about the same time will be on the market so with that gone and so few will talk a bit about 45min or program abc already nobody inside the left side ofthe graph year of the image on whether

by dogs because of inflammation scarringto shoot you know really affected and you can see that damaged its importantlythe diagnosis is through on you have three types of diagnosis and usuallyhave to have two of those three criteria to have the disease so the main factorthat is its elevated of hospitals alkaline phosphatase you also have thepresence of anti by artists and these are the na dnt mitochondrial and i buythose bodies and you have liver histology again that shows the lesionsthat are specific to keep the prevalence of the disease it's a rare disease it'sonly up 2.05 percent of patients who have bbc importantly you do have apatient profile around eighty percent of

the patients are women that are around40 to 60 years olds you have for a long time tbc can also be asymptomatic butwhen it does become symptomatic it's mostly through fatigue very high fatigueand also provided so those other main symptoms of the disease for the patientsand like i said it starts off as being a symptomatic before the symptoms come inand i'm so the price is very important in these patients i mean it is one ofthe major symptoms and that is very young invalidating to the patient's youalso have abnormalities that could find in different clinical exams and bloodsampling so you do have increased damage et and immunoglobulin you have thehyperlipidemia actually in the stations

is you have to understand it's a highhdl meaning it's the elevated good cholesterol so they do have acardioprotective profile with the hdl that is raised in this patient's so you want to keep thatcardioprotective in these patients they have also vitamin deficiencyosteoporosis elements of the clinical disease that you could find pbc butglobally the specific symptom is parade is the fatigue like i said it's veryimportant you do have 78% of patients with fatigue so it's important for thequality of life of this patient's parade is in 15 really make it difficult forthem on a day-to-day basis to have you

know the quality of life that can be onthat can i mean the british can become invalidating because of that you do haveassociations with other other autoimmune disease in the stations and veryimportantly this is a very serious disease that leads to cirrhosis in usedto be called the pbc used to bc for cirrhosis know it's cholangitis becauseall these patients when the treatment does not work in today there's only oneapproved treatment which is udca they just invariably progress to cirrhosisand liver failure and they died i mean it's really a very severe disease todaylike i said we have the treatment with udca importantly the unmet need is stillvery very present because you have among

the patients are treated with udca youhave about 50% of patients who are actually well balanced with udca theothers can either be non-responders they can be partial responders or they can beintolerant also you know to to to the drug or have other providers also withthese drugs so when we look at where elephants can come in and i'll explainwhy we believe that there's a very strong russia now for everyone or toaddress this unmet need in pbc the target population remains you know gobeyond the partial responders and non-responders and the intolerantpatients 22 effective treatments i will not go into detail but this is importantto us because we have clinical data

which i will show with other foreign oilthat is very interesting for the pbc feel but there's also the mechanism of a and as you know elephant or it is apeople are often delta a good news and the people are elvis there's been asense of work you see you the number of studies evaluating the ppl fatherfibroids in pbc and their different mechanism of actions actually hope thetransport of the bile acids out of the hepatocyte and that also detoxify thebile acid and invalidates you know the bile acids therefore you have lessdamage to prevent the damage to to the collages sites you know provoking dodamage in the baltics so this is well

known this has been several studies andthen we can look at also what we had in our clinical trials with the forbiddenor and like we should be four on the site of an all the feast to results wedo have a significant and important reduction in calc false and you see thatin that short we had visits every two months and you see the two lines on thebottom rd and 120 milligrams so the decrease in elp is very quick and itremains low throughout the treatment and you see that placebo does not move orrather even know increases little bit on alkaline phosphatase and this isaccording to the different quartiles meaning the levels initial levels ofbaseline for a place where you see that

the efficacy is always there with thethe doses of indian 120 milligrams compared to placebo so this is takenfrom from the data from our phase 2 trial so when we look at this and thisis why we have thought this through and we are starting the bbc program here wehave the clinical evidence of our own data but we also have the fact that thisunmet need still remains very serious condition and we do not have adequatetreatment today to treat the pbc we have year period option that was proven inour trials not only the face to enough we also had previous face to a programin different metabolic populations and we always consistently had thissignificant decrease in alkaline

phosphatase he's we have the peopleralph activity on bile acids that is well known and demonstrated we also haveno pride us with oliver below which is veryimportant in these patients whether major symptom is already provided andthere was some trials also that have shown with a cunt people are a decreasein providers in pbc patients so this is why for us you know where we'relaunching this bbc program with other former north and to give you an idea onthe timelines we are launching this song the first pilot study the feast to studythis year in 2016 and it will be followed with a longer faced withretrial once we get those first results

of course the regulatory input is veryimportant we've done this with our nash development always discussing in aparallel with the agencies and we're working in the same way with experts andauthorities on the ppc field or so we will have this input as you know therewill be on input from regulatory bodies very soon on on surrogate endpoints inapprovals in the pbc for foreign drug so this will be important for us to him tocontinue working in the same way that we've always done with jen fit talkingto authorities as a parallel process of of our development on the other studieswith this deal with elephant or we do have and i think we've spoken of thatalready quite a few times but we are

launching this year as well the firstpediatric trials so we will start with the pkp d meaning you knowpharmacokinetic and pharmacodynamic study more on metabolic aspect ondecrease of but also on metabolic metabolic activity in a pediatricpopulation so this will be from 8 to 17 years old and we will launch this year's1 2016 around junior july for this study and this will be followed by a long-terma long-term study once we get all these did on ppg which will be more you knowthe long-term biopsy trials and this is again as i said we're discussing this ofcourse with the top experts in pediatric nash also deliver forum is no there'salso were participating as well on to

make sure that we follow through withthe correct and points in development in projector x and importantly in children themetabolic of the disease is also very important most of them are prettydiabetics and that is very important to have that metabolic treatment as well asthe histological treatments with oliver brown orange population and for chronictreatment you know that children they will start the treatments are they willstart the treatment very early so of course the safety and tolerability isalso a very important factor for children even more so in the industrythe other study that we're starting now

is the so its civil suits but of coursenational do cirrhosis trial and we will launch a pilot study because we will belooking at the first effect on each ppg which is currently the surrogate markerfor the cirrhosis trials so this pilot services trial or not you know not avery large population but to get the first information on each ppg beforeprogressing to a face three cirrhotic trial and this will be done the secondhalf of this year for the pilots erotic trial you're going to talk about things so just come back to nashville for a fewminutes this is something that we are looking into for quite a while now and ithink is going to be something that's

very important for the whole nationalyou the whole population of nash patients i mean this also comes back tothe the objective argenta to really consider the whole global clinicalmanagement of the national patients in the left hand side are we talked aboutthe fact that the compound of the fireworks both of his knowledge esaspects i talked about another important aspect for the patience of course anon-invasive biomarker to identify patients for treatment but the otherimportant aspect to really you know how it's what's the best way to consider thewhole population of nash patients i think we all know that the nashpopulation of patients is somewhat

herald genius and this is not all not atall surprising again every pete nash's the liver manifestation of metabolicdisease and we know made up disease by and large are multifactorial differentmechanisms involved and so on so what's clear is that if you really want toconsider and treat the maximal the largest population of nash patientspossible you should be considering combination therapies again this is whatwe have been doing what's important is that you think about combinations onpaper it's not that difficult to think about being able to combine twodifferent compounds you think about complementary mechanisms of actionhoping that you know the effect will be

added to and even better a synergistic game thatwould be on paper i think the most important aspect this you have to testthese both in vivo models and ultimately in the clinic of course and this is whatwe have been doing both using compounds which we have in-house proprietarycompounds of jan fit but also importantly we are discussing withdifferent groups as two compounds which are in the nash pipeline with the othercompanies which are also working on nash here i'm just showing the progression ofof nash from from early-stage disease alleged agencies think it's alsoimportant to note that you consider a

low fiber nor gate which is able totreat a wide spectrum of patients ok fairly early patients because thecompound does work in histology but that car to metabolic benefit that we seethat's also be beneficial for early-stage patients as well as latestage patients ok but having said that i think you think about combinations weshould be think about the whole spectrum and where these different target genesor therapeutic targets left early in the process that could be later in theprocess and i think we have to consider the whole spectrum of these differentpossibilities and this is what we are doing i think is also important thoughtoday you know i love five min or is

well aligned to be first light treatmentwhen i say first-line treatment when you think about the different programs arein this space think the clear differentiation of ella five min orbeyond the efficacy ecology is the other important aspect of course is thecardiometabolic benefit and also the tolerability no side effects notolerability issues with the compact case of this i think clearly puts us in position of first-line therapy andbecause of that position i think we can take the lead and think seriously beproactive considered what we should be concerned it's considered combining ellafiber nor with so having said that like

i said before this is a programconsidering both in-house proprietary compounds as well as with compounds it'sa competitive landscape or talk to different groups and this is what we aredoing in that space now with that what i want to do now is just move on a talkabout some of the other programs which we have ongoing at jen's hit the first 1i'll talk about is our program in five boroughs casey fibrosis our focus ismainly on the gastroenterology space liver fibrosis we all know theimportance of addressing liver fibrosis and nyc roses is not only nationaldealer fibrosis there are other things you know fibrosis alcohol abusedisorders leading to fibriles and so on

so in our fight in our program i thinkthe idea and this is clear that you want to go in there g two patients withwell-established fibrosis could be somewhere in the middle before they hitsoros is ultimately in that stage you want to prevent them from progressingthis arose but you can also treat patients later on cirrhotic patients and prevent the compensation for examplehaving said that our focus of course is on liver fibrosis but the programs thatwe are working on the compounds which we have in hand is important to know thatthey can be considered for other disease areas of fibrosis things like lungfibrosis other disorders or fibrosis is

important component this these arethings to be considered these are not our areas of strong expertise gained sowhen we have these things in hand we think it'd be interesting to drive witha proof of concept lisa preclinical proof of concept look to partner some ofthose programs and they're interesting aspect that we are considering is thearea of fibrosis in crohn disease in ibd ok it's clear that crohn's disease rightnow is a strict dress me with anti-inflammatories but we know thatalthough the anti-inflammatory compounds do have good efficacy it is not today decreasing the number of intestinalresection is not decreasing the number

of patients and so in our discussionswith the chaos i think this is quite innovative is that there is the fibrosiscomponents of these patients in this could be the key really to prevent these patientsundergoing surgery to do their disease i think this is an innovative part of ourstrategy to think outside the box and some of these disease areas and here'sthe addy fibrotic compound can make a big difference so in our fibrosisprogram just surrender to it very quickly what we did was we went wedeveloped a screening assay it's easy to look you know here is represented in oneslide but this took quite a bit of time

to optimize basically the cells involvedin fibrosis beyond its stately sell there there are they are quiet sincethen if they're induce with with different cytokines that teach youbetter for example they then differentiate into myofibroblasts oractivated t cells in this is the cell type which secretes extracellular matrixand leading to fibrosis in the tissue so we optimize the screening assay and andthe readout aside somewhat a phenotypic screening assay and read out here is asemi which is a protein intimately part of the fibrotic pathway so two parts ofthis program one part he had considered profiles and screen proprietary and seesk compounds belonging to general and

then the other aspect was to go intopharmacol peel and stream the former compared using this assay and really toidentify compounds which can be repositioned to be used as an attyfibrotic so these are compounds which originally not developed for fibrosisand we're able to identify seven different compounds which haveimpressive 85 productivity's to give you an idea of the 85productivity which we have been able to demonstrate with the sec that we have inhand basically you can see the dots they'rejust represents a subset of the different compounds which we had screenand you can see that there are quite a

few the darker ones coming from thepharmacopoeia you can see that there are able to inhibit the secretion of smethis marker with a good potency kbc 50 ic 50 that's in the low double digitanimals which is quite potent compounds and we also have a few compounds in thatspace as well here is a result looking at the 85 productivity and a model offibrosis without getting into any details here you can see the two grassyknoll looking at the other college in norwich the gene encoding collagenscleary you can see at the compound decreases the level of fibrosis and thenyou look at this ecology top panel control middle panel you can see thefibrosis induced on the bottom sixty

effect of the compound which is clearlyidentified broad ok so this is just to give you some top-line data as to whatwe we had been able to demonstrate with the compounds we have in so having saidthat this is where we are with the two subprograms international india fibrosisspace so in terms of the nce is a proprietary generally compounds we areready to go into preclinical development as of today this is something that bobis working hard on and then we're moving forwardwith that program and the other program which is the repositioning of thepharmacol p.m. we should be ready we will be ready to move into a face toprogram did because this is compounded

the market there's this it has a strongdossier already and we have in vivo testing which is in the process of beingfinalized and we will be able to move in the face to towards the end of this yearand of course very important aspect of the repositioning strategy of compoundsis the intellectual property of course these things that we consider it veryearly in the process and so this program also has an intellectual propertycomponent to it which ended has applied for patents for the protection of ofthis particular compound in the space of fibrosis with that i'm gonna move on and speakabout their program which is very

exciting for us which is a program intospace of autoimmune diseases or chronic inflammation and this is targeting anuclear receptor remember jennifer has a very strongexpertise and you receptors in our target is to nuclear receptors peopleoutside and delta scientific expertise coming from our scientific co-founderand marc staal is one of the pioneers receptor space so our organic tea is anuclear receptor bob has been working on this very carefully and so are damagedhe targets i'll 17 pathway is only you me know i'll 17 pro-inflammatorycytokine there is clinical proof of concept there's antibodies out there ifyou decrease i'll 17 you have the

anti-inflammatory read out on the streetin the clinic and compounds on the market and so on so this is one of themechanisms of targeting our organic tea because that leads to increaseexpression of all 17 the secretion of bile 17 i guess it was inflammatory andother pro-inflammatory another important aspect of tearing up our our communitiesthat it is involved in the commitment of t cells kbt 817 cells and t reg cells sot reg cells on the right hand side here tv shows are will just be simple is theanti inflammatory phenotype on the right and the left and said he had 17ourselves which are inflammatory and what he is able to do is to effect thisbalance between the t regs the teat

seventeens like a favor to t reg over the 817 therefore favoring theanti-inflammatory populations of these cells now the indication that we arereally addressing with with this program manager at the beginning is anautoimmune diseases autoimmune hepatitis it is a progressive disease right nowthere are compound they are being treated with anti-inflammatories casetheir rights and so on we all know steroids over long-term treatment dohave side effects related to it so there is this very large unmet need to be ableto treat these patients and the long-term this is very long term is notchronic treatment of these patients and

so what what we think that we should bedoing is able to identify compounds which inhibit inhibitors over oregon btwto be able to keep these patients on treatment and in there and they'rerepressed state in the long term he raised we know are important to me thinkabout human hepatitis is important for your self tolerance in maintaining thatin the liver also we know that on it in a mean but i is patience and number andfunction of t reg cells come down and also that they do these loser functionin terms of the ability to be a suppressive k and is also clear thatwill clear one hypothesis and this is going to burn out based on our resultsis that if you're able to inhibit our

organic tea in the cells that you shouldbe able to increase the number of t-rex as well as a function of tv excel sothis is their reasoning moving forward just to give you a little bit of resultshere we're looking at the tissot skewing as cbc booking at the racial between treg cells again gave the the anti inflammatory cellsversus 8817 the pro-inflammatory cells so basically i won't get into thedetails here when you look at one cell populations you hit with inhibitory lookat seventeen you can see this compound is able to repress it and then on thebottom sign the green there if you start with a notice of populations of cellscan get with compound there you're able

to maintain a level socks which is amarker of t reg cells so basically the take home message here is that thecompound and inhibitor organic compounds is able to affect the ratio between thet-rex regurgitate seventeen's which is a very important point of course this iswhere we are with his program today we are moving forward with a lot of focuson this and we will be ready to go into preclinical developments in the secondhalf of this year with this program so with that i'll stop all headed backto drop from what i dunno review session i would like to give you some to summarize what we did you read thelast i would first of all that remains

our primary focus as you can imagine andwe consider tougher brian or as a first-line putting children and explainwhy we we believe strongly in the face three resolve it we have already involves first passionsand as we are said we we think in the next 12 certain amounts we will have thefirst thousand passion that we need for the support age and for nda and on thediners diners field we consider that a biomarker program with the same deadlineand we'll see with an approval round the approval of the drug is the only way tounlock the market and unlock the market not only for four life of brian oh butfor all the drugs in this field

you understand that today we we aredifferent things in the national and particularly we we consider it veryimportant what we are doing in the field of advanced week because it's it'sreally a very big has burden and particularly in this country but notonly and we we consider is that we will do that when perfect collaboration withacademic and regulatory agencies to be sure to address correctly thispopulation with no solution today as well as for either but i think it's avery strong motivation for dnc to be involving and this budgetary career ithink he knows as described that come better wraps recipes is something thateverything is everybody's thinking about

and we want to be proactive in thisfield we do not want to have in some years just i we'll see people trying to the whole recipes tocombine his drug use is one in soon want to provide proof of concept or synergybetween some drug was different and complementary mechanism of action it'swhy we are stronger working on that and of course i think you you you understandthat we will discuss ways different companies to see what we could dotogether to be proactive in this direction generators as announced today a new pbcprogram but you have understood that we

have done that after many months ofthinking about and after please call data and clinical evidence we havediscussed with a lot of care when the field and it's a decision which is takenbecause of the people outside activity on the relevant ppc targets and thesecond aspect is that we are seen in all the face to that we have a realpotential to read use i p which is one of the main factor for getting approvalin the field of pbc of course in pbc we know that many things will happen in thefollowing days mount and we will be very very big attention to what what is theconclusion of the different meetings with every year in this field and wewill i sofia said we will be very close

to say regulatory agencies to progressin the pbc in the bbc program so we we want to continue to target unmet needseither says beginning we want that to be incoherence with what we know the bestin genfit time in metabolic disorders metabolic disease autoimmune disease andnow we consider that still many unmet needs in the gastroenterology field andwe want to be very present in this field not only r&d company but also as acommunity company now what's important to us tospeak about this agenda because you know many people seeing that now face reallynice we have to wait two three years no i think it's not a turner we will have alot of things very strong news flow in

2016 in the following months in 2070 andi think it will be done of of course the progression of enrollment for about ageand expectation of 1000 passions in h1 2017 unexpected ending in 2019 was abiomarker nash we also will take the profit of face 32 validated and 22accelerates regulatory pathway to go for an approval approximately the same timeas the support page for the drug pvc as we are said we are starting to rollmeant in h2 2016 we will launch pad rhetoric nash in h2 2016 also and thestart of human testing for a leading company that they not just described fewminutes ago in liver fibrosis will also begin in 2016 and zero gravity we'll bein a preclinical development at the same

time so we do that in parallel withassessing potential initiatives in licensing and decoherence what with thepipeline we're going to build and all of this thing i will say it will be myconclusion is a result of many years of big force already filled but also thefact that we have decided a very clear strategy for years now and that we arecontinuing to progress on this route of course we as you knowwe are very resilient company we we consider that even if they're alsoordeals it's not a problem and we will pass over that sothank you for that i think we are going now into cuban association i don't knowsure if some question from the room or

if we are some papers coming from theroom also so then if you want to to be the chairman of that for those who question is for thebiomarker program whether we think that additional validation will be requiredfor the pediatric population versus the adult population and considering thatwhat we have done so far of course is from the face to be which is the adultsi would think at this point that this is something that should be considered andlooked at before it can be used in pediatrics at that says my take on thisbut i think i can let sophie chime in on that you cannot do that but it is a veryimportant question and i think it goes

beyond the biomarker just the fact thatpediatric novelty or not is different even histologically you know it's notdefining the same way so it seems logical that you're not going to addressthe same specifics with biomarkers as well because you have to link it tobiopsies of first stage yet this is from yahoo's separate validation that needsto be done pediatric population yeah i agreecompletely i think there are very unique histologic features in pediatric nashthat we do not see any adult nash and the mechanisms underlying pediatricnasher somewhat different even physiologically particularly with thealterations that may occur during

adolescence hormonal changes throughpuberty and so i think it's going to be essential to have independent validationin pediatric nash we made come to learn that the biomarkers are comfortable tothose in adult nasha but i think finding the further validation and independentcourts we won't know the question for the bbc program what are some of the other end pointswhich which should be considered and i think that's an important again for theendpoints and we're looking to have been all who actually treat with keith lindersure she can act with that to david the question around pdc is you know thequestion about 10 points and legs

officer was saying we do need to haveyou know the first feedback from the authorities will have a very very soonfollowing the advisory committee early april on the on the trials with oc and ithink that's very important for the field of pbc to know what the reactionwill be from the fda approvals a surrogate markers so we're just talkingabout what i mention he was a primary surrogate marker to start with with youbut of course you know the other end point that you mentioned that spread ofthe disease and that's part of what we looked at but for to start off with forthe you know the the pilots the proof of concept just to make sure that we haveall this you know needed decrease email

but of course the longer-term bbc trialwill include all these other in specially with pvc this early phase ofit treatment program improvement in liverbiochemistry predominantly alkaline phosphatase ggt alterations in and outof control antibody changes are are are in to to justify the proof of conceptkeep in mind that the fda's regulatory authorities even in pbc will payparticular attention to alterations and quality of life measures so even for aphase 2 study early face study if patients it's less feel better andcertainly survive longer which would be proven in subsequent studies that

itself is a significant measurable the question is for the programmingfibrosis where we are positioning comp repositioning compounds in a former copay for targeting diseases in fibrosis whether the ip should should alsoconsider it to your freedom to operate definitely these are things that has tobe considered we consider this very early on in the process and the strategyof of gender fits around this basis something of course this is consideredand we'll be happy we will have room to operate on this particular compound inthe area of fibrosis just one word when you are working onwith positioning strategy i we see fifty

percent of workers to to work on themedical aspects scientific aspects proof of concept but fifty percent of the workis to work on the intellectual property it's sort of big part of the sleazy we are some questions from the paperscoming back to national to question on that question is nash face free program with other fibernor why we considering only patients with af 235 roses and why not the f1 patients i think that's a verygood question what i can try minute then i think i handed off to sophie in andgrab them a leak though this much better

than i do what i can say for sure thatwouldn't you talk to patient advocacy groups is something that they reallywant they want to be able to dress / pieces with f1 fibrosis that with theunderstanding that they would rather have a treatment to address thesepatients before they later stage disease so that's just my top line input on thisi know i think we've come to learn that at least as it pertains to deliverrelated morbidity and mortality the primary predictor and no other primarypredictor not a confirmation but the primary predictor for outcomes fibrosisso in keeping with the goals of the fda and trying to alter the natural historyof the disease would make sense to

enrich a study cohort with patients mostlikely to develop the disease progression so we a priority or selecting thosepatients at high risk which would allow us in the capacity of a phase 3 study todiscern measurable outcomes and associated morbidity and mortalityfrom the liver disease standpoint by selecting out patients with stage zeroeven stated one disease you're actually in reaching the page the patient cohortfor those less likely to develop those outcomes because the natural history ofthe disease progression from one stage to another is on average about seven toten years so at this early stage it

makes sense to certainly enrich thecohort with patients who are kind of developed develop such outcomes are athighest risk for alcohol and at the same time as we learn more about the spacethese therapies and we would certainly want to be able to treat all patients atrisk and open up this face to face with fibrosis 2813 in this was discussed withthe authorities so we are adding an extra toying with the f1 patients butimportantly dia 1 patients will be enrolled in recruiting our study andfollow to the ends are enriched with metabolic risk factors and anothersevere et that is higher so we have criteria for the f1 patients in ourstudy that make them you know how i

regressors to to evolve faster to chooseto the end stages of of evolution of roses no questions coming from here that'swritten down here is a good one what about the pricing and/or consideredbbc great question as he knew we we are for the end the i think we will getthrough these approval potentially approval for nash and approval for ppcwould succeed in this field is roughly the same time so i would say that we wecannot envision to have a different price for ppc or for national was noreason for that and i think it would be interesting for bbc passions which aremore rare disease and usually companies

can get better price was odd but becausewe will get to drugs approved the same time we will have the same price and thesame price will be probably the price for nash so it's not sure deforest theprogram because of the agenda of course i can imagine that it could be moreconcerned for some companies with different agenda for sap ecc approvedfor a national problem but it's not okay going back to the biomarkers whytransferred so confident that you'll be able to bring something new or better tothe market's good question i think different aspects to that question ithink the first of all when we say we want anonymous have our markers toidentify patients for treatment i think

that in itself is something that'sdifferent than what other groups have been doing and those groups are manygroups are able are trying to find biomarkers to represent the wholespectrum of national detach pieces which is not an easy thing to do i think therelevant question for from a clinical standpoint is to have a biomarker toidentify the patient for treatment and this is what we were presenting heretoday we are addressing at least for now k the have a biomarker toilet to identifypatients with ask for more with f2f 35 bros so so i think that's an importantdistinction i think another innovation

which we bring to this field is that weare measuring important parameter type of primaries which is the mrna imentioned briefly that mrnas are involved in the disease process in manydifferent chronic diseases and this has been also been demonstrated for now thein dash so this i think is important when we think about non-invasive ourmarkets and we all know that you know i'm ironies released into circulation different tissues or stressed and thisis also could be part of the path of physiological process i think is alsoimportant that as we think and move forward to stay on the team of mrna forthat at the moment we are still looking

at additional not all described are allof them have been described to be involved in liver diseases either so wedo have the sample sets in hand we compare those patients who should betreated versus those should not be treated we know there's a whole seriesof mrnas which are upregulated for done regularly represents could be imputed into the algorithm toimprove even further the algorithm scores so i think these are differentaspects why we think that we will be able to be successful and before that ithink the sample said that we have is also reporting this is we do have thishappen said from the face to be trial

and this is a rare sample sets applescoming from interventional trial got a double biopsy controlled trial and theguy said samples collected throughout the process a one-year treatment processwhere significant proportion of patients ball from nash 29 national i know thisis an enviable samples that we do have very different groups who's beencontacting us over the last few months many months trying to access thosesamples to help them verified what they have in hand terms of biomarkers so i think right nowto strategy of course is to use these samples for owned by market discoveryneed to partner and and provide those

samples as well tonight i'm in with thecomment i think we sometimes lose sight of the fact that matches a veryheterogeneous disease and and if i were to envision where we will be inhopefully another five to 10 years from now we're not gonna have one mile markone size will not fit all and we will not have one therapy will have alandscape of treatment options and i think the biomarker discovery for gentlewill be uniquely poised potentially one of course to discern those with highestrisk for disease progression discern those with national pipe roses but alsoto land predictors for cardiometabolic risk there are patients who walked intomy clinic who may be five hundred pounds

we have no lack of liver disease andothers that block in moderately obese whose primary cause of death maybecardiovascular as opposed to cirrhosis progression of patients who progressedto services you never have heart disease and others who died of their heartattack and have little or no eyebrows so ideally as we put therapies intopractice discerning who's at risk for what personalizing the treatment identifyinguser risk and potentially predicting responders from non-responders in anycold war treatment is gonna be ideal and so i think to implement biomarkerdiscovery in the context of these

studies is visionary and actually plans head for defining the most idealpopulations to treat with that unique there be in that unique space todecrease a unique patients overall risk for morbidity and mortality withwhatever inflammatory cardiometabolic and/or liver related markers may be inwhatever panel is defined for that i have here a related question doctorabnormally can convey be further addressed this in no hurry addressed itduring your presentation question is what more can we say about the metabolicconditions of nash patients conditions nash patient's characterized by truncalobesity the apple paradigm as opposed to

the pair so adiposity distributioncentrally with that comes increased risk for hypertension diabetes highcholesterol and ldl cholesterol hdl phenomenal so what has been thechallenge for metabolic syndrome in general you also see patients as theyprogressing years will have higher risk for fibrosis progression so we willtypically see fibrosis patients who are older than 45 to 50 years of age withthe highest risk predictor of fibrosis at least clinical being the presence ofall established type 2 diabetes which may carry anywhere from six to thirteenfold increased risk for fight vs thank you very much i think we ought to lastquestioner on ppc and then we will

who will say hello to everybody yeah igot two questions here on ppc combined them but you can start thinking about itdoes have one question is in the space of pbc think about people are out therewhich is really good target to address for the treatment of ubc position thatversus the five rates which today can be used off-label and then a relatedquestion bbc what differentiations are expecting with a laugh or other drugs soi think for the first question yes there are five great up there which havedemonstrated efficacy in different models even in the clinic thinkdefinitely when you think about the treatment paradigm something that isagency approved for something that's not

something that's prescribed by labour'sis off the table i think that does have a major impact i think that's the easypart of the answer there something else iwant to raise when you think about all the fiber nor we spoke about this in thepast 15 min or undergo center appendix likely the fact that it does and they'regoing products like thing we do know is that there is a concentrated a higherlevel of the compound found in the bile ducts ok so when you think about bbc ofcourse bile ducts having compound which targets people out in delta which has ahigher concentration in the intermatic cycle in the biotech i think this issomething that's important and we can

think about having increased efficacywith a compound like that differentiation between a low fiber norany other compounds and p&l top guns are you all now thatpeople around highly involved in bile acid metabolismnot different from the other findings the differentiating part is probably thecheapest adult activity which is highly involved in the management ofinflammatory disease and you know that pc has high entire confirmatorycomponent and since our draw this actually nicely expose about in theliver and bile system with think that this is probably going to be the majordifference as opposed to the fibroids we

we have received by my email questionfrom the european and that is yes i think this is a question addressed to drabdul malik and and sophie menu as well so the question is on slide 13 we referto an updated definition resolution of nash basically we focus is on ballooningand information if we can say a few words about where did that come from we are right that we we we we came fromcarter initial understanding two decades ago we thought that was completelybenign we came full circle to think that the presence of fat was detrimental tolearn more in the space that really had no prediction for progression offibrosis the presence of necro

inflammation and blood parasites werethe predictors not only for fibrosis progression but for increased risk ofcardiovascular risk that we also learned can floods in and out of the liver veryquickly and very readily so if one could funded amount of calories fast food youcan get to me at the boxes of fat in and out of liver and that's touringtriglycerides is actually a safe way to store anywhere in the body when youdevelop a stress response whether it's inflammatory you in the presence of badyou develop necro formation balloon to parasites and that presence of recordformation is the primary predictor for fibrosis so we moved away from thephilosophy that battle is important but

that the jury subsequent to the fact insome patients and not all patients was the primary predictor of outcomes andthat's been shown over and over again that that in and of itself can block thefat enough of itself can be stored safely isolated steatosis without anymeasure of injury carries no increased risk for morbidity mortality and so wemoved away from the philosophy of worrying about the fat and posed to befocusing more on injury maybe sophie you can chime in with thisendpoint acceptability by the agency and just you know so he's also a part of theliver forum is co-chairing one of the working groupson disease definition and end points and

so on so i think deliver forum and anational basis very important organizations maybe you can see a fewwords you know how the agencies as well as lower form is implicated in thisupdated definition always saying and she's part of the well and we've beenworking on this so i mean the liver forum that you know the construction ofthe endpoints for clinical trials in this look at this new definition allthis has been you know moving forward look for the past two years with a lotof these changes in the liver forum with the presence of you in the evening withyou sell diesel the academic persons but also industry stakeholders as well soall these discussions you know any

concerns sure way with working groupsworking in like manner was saying what is isolated state houses or not outcomes what is ballooning is in thegarage outcomes what is information than what is national what is resolution ofnational always has been really really discuss with all the major stakeholdersto deliver forum and not only the meetings but external discussions inworking groups in in conference that we've been having andplus there's a collection of data that's coming out as a forward and you you knowwith the relationship to the outcomes remember the important long-termclinical benefit is what counts for all

the regulatory bodies and his men alwaysthing for the young endpoint of the feast to trial that was modified withhis definition this game is a request is not just that he was accepted by theauthorities it came as a request from the authorities to look to go back toare faced with it out to look at this new more stringent modified definitionand two applied for the face three so so it's really something that we've beendoing gather all along and it was a requestfrom the authorities in the new line of course to be used with the face regionfor most of the new trials coming on board that are taking ballooning is themajor you know the major driver of

disease or the one that we want to haveto treat the underlying thank you we have one last question that came in and i think it's an answer only is heyour can answer so what's a skin and provide the answer the question what isthe question me that somebody was raising questionsabout financing the biplane i think it's a good question i we see that we haveraised recently money so as you know we are about one hundred and thirty milliondollars in back that means that we are money for the next two years but ofcourse we we we do not consider that it's sufficient to develop also companyin the next three four yrs do we expect

to raise more money yes why not but it'snot a question of today in new we we plan to be on the nasdaq but it's aquestion is only when the market conditions would be better we are not ina hurry facades we were just expecting good conditions but you remember that wehave repeated very often that we are discussing with pharma companies we wantto be president of the market but not alone of course and we are thinkingabout could ever meant was thinking about commercialization retaining somerights in some territories but that means that we need partners and we needpartners to prepare the commercialization and not the week ofthe year just to think about a partner

so i confirm we are ongoing discussionwas partners with different partners about the gst 4054 brainer in nationalof course so that means that we will probably get more money from thesciences to continue to finance the development of genfit and to continue toprogress in the strategy we have decided and we have presented this morning soit's the best conclusion for me is to say thank you again for attending inthis room thank you again sicilians for webex session and you will have a slight headache i don'tknow if it's ten minutes showing two hours but we had a slight headache weare presented here with some added

slides even more details in the day today okay thank you very much