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for the invitation and also for having the courage to true slows
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to topics and for the full room for uh uh uh those two
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excel pick topics as you said i mean the diseases are not that common but they extremely challenging
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and i think uh uh really uh make up more and
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more for clean compared nulls mean academics and so these are my
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disclosures and uh that in contrast to p. p. c.
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where we have effective first line treatment or so and
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also now established second line treatment with a better call
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i guess it and vibrates based on the reasoning in trial
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in in prime is closing contract is there's no established medical therapies reuse of
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or so is really very controversial some countries which have the highest prevalent such as
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for example we don't use arose at all but we of course let's say
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in central europe probably already also feel like also is whistle from other christopher presentation
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uh we have i. b. d. uh which has a specific uh phenotype with this uh
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right side it uh collide this backwards i like this a rectal sparing certain is symptomatic deceased
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and let's say i mean the i. b. d. persons i'm very much of a yeah that patients can develop p. c. but
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i'm often surprised when i see patients who've a p. c. and
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were followed in let's say all set of of centres that they
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never had a call an oscar but despite the very height you murray's can really find a high rate of this places and
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even you know cancers that the initial column ask appears in the
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those early and patients which we have sold is a scope that
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and uh the malignancy risk of course that's not only the call and
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it's also mainly uh the other coming to sell a carcinoma gall bladder cancer
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and there's a lot of clinical heterogeneity which makes is deceased uh difficult to
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treating also so difficult to run clinical trials because it's really a very mixed fat
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and then you actually look at the person i think this is
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nicer reflect when you look look at liver transplant numbers i mean
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they've kind of a level bottom in here in the u. s. u. c. p. c.
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p. p. c. the numbers really uh i've calmed down and
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we think this me billing to the use of or so
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similar data from the u. k.'s big blue line here is p.
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b. c. little in office and n. p. c. kind of uh still
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increasing your let's say reaching higher a stable level as many other new
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mediated diseases and then you look this is data from your nose in the
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united states me ray at the seas searches p. c.
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quite stately makes up about seven percent of transplant complications
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inelastic and in some sense to slow the normal you know
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it's twenty percent also in b. and it's in the range of fifteen percent on the one i think also in homework
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uh if you'd look at all not p. c. long but let's see p. c. b. b. c. envelop him yet but that is the new
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needed to this season i think it's between ten to twenty percent and that's quite a burden
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when you think from finding effective treatments pairing organs preventing
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with the transportation so i think we also have to think about the p. c.
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and uh uh this also reflects our ineffective medical
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treatment anyway saturated he sees a count of course those
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uh good indications in every day on patients there's always the question that they already have cancer or not but
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uh let's say it also reflects off a or ineffective will understand in treating this disease
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so at the moment we still use arose and there was a little bit they will buy with the sole source
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of this continuation study from poland and that was a
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collaborative study which show that when you stop hers actually symptoms
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and biochemistry gets worse so movie keep linda wrote the very nice editor also when it gets worse
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when you stop it maybe it works when you between uh that's kind of complex already did an option
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my plane but this is actually from and it tore love
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keep linder uh who in the city guideline for some time actually
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uh advised against the use of rose because of his ineffective or detrimental hydro study so in his
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one of his reason and it was an actual so the current guidelines still allow
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or in cars to use of or so and monitor elk fossil though that's not
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that well established as a marker liking p. p. c. for example we still look
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with the may patients so sure reduction of elk falls by more than forty percent and by that
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this magic cup of one of one point five fold up a limit of normal we know the patients were below
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uh that a threshold have a better programs is than those who stay a buff that some patients
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could not hit this threshold at least also
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patients were you should consider additional mobile experimental therapies
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and uh consider including these patients in clinical trials
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so what's on the horizon here at the moment
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on the one hand we have voice like in many other colours that it this is the f. x. are
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with us there why pixar wide and such as a
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better call i guess it and also monster latex ally against
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and uh the interesting thing is uh the also vibrates maybe
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an optional goal briefly touch on that like in p. p. c.
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uh the interesting option here is that you may also hit the cup with that because i know that have exactly very
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importance signalling recounts did you to maintaining got integrity
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country of control and got my corpora up and actually
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the absence of bile acids and all the detrimental effects which you see also in advanced liver disease
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is basically due to absence of ethics are
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signalling and uh reduce the gap integrity and
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increased information so maybe it's a one stop shopping for both the liver and they got
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then of course we have strategies which treat the microbial up as
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the noting evidence about two sparrows are also will touch on that
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uh in a l. p. c. which is different from the two spews is which we see i. b. d.
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and uh stretches such as frank uh my sin and also
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other antibiotics and there's even a reason to vicki microbe realtor transportation
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a study actually has shown some promising results and also palaces strategies such
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as ethics are control micro products so uh this maybe you'll be fine
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theme the question is should we treat the got to treat everyone is really got information associated
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with a live information terms of intensity we think it is
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not but it may be at least she up pathogenic cough works
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this of course is very attractive uh olympus at home have
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bad hypothesis that basically he somehow men from the got to deliver
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maybe be very uh to go in this uh uh can be treated with uh
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for example in to crimp walkouts with little it some up or more brought out
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it actually some up and other strategies which basically
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a target t. cell harming uh perhaps i would say
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shay at inflammatory cough race in the got and in that letter
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an interesting strategists any pretty rock which is a macrophages strategy chemo coming receptor
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which is really necessary for a rectify show a recruitment that
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seems to be not only important to nash but also in p. p. c. and there's an ongoing
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clinical trial seem to sum up the locks up when he
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did identify product track negative trial i mean one of the
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many failures uh in the big studies which
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below to stand in the past targeting directly
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for pros is uh i think this tells us approach rational of targeting directly for pros is
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in any leave it this is not only nash but also in a
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t. c. maybe a very high aim uh which is terrific difficult to reach
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and the study was negative and we have north of the arctic probably gas it
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which is a very good people for also undergoing call it but diction by well
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touch a little bit on that because that at the
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moment is the most advanced medicinal product which is currently undergoing
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of phase i three studies so nora so is inside change
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short the really diversity ox a colleague asked so it's lacking
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a method group and uh the name of more although we all know it from
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more i turn away no more i printed for in and uh at inner frame
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it causes a lot of confusion so people constantly makes up more also with ross or
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and actually it's going to be changed by a real cold new recall we guess that all know little bit makes
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it better to to keep you know are there better call it yes it this is the a. w. h. o.
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nomenclature so no no so this uh no stands for nitrogen without credit on
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this is all a tram in chemistry nomenclature so it's liking this methyl group
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and this method group is exactly the group ever buy less become conjugated with price and or
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and this makes a bile acid restricted to the enter patrick
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circulation does conjugation so when you have to buy less it
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which is not a conjugated this file is the champagne
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between the bile ducts and they paddle sites within the liver process cold calling a petty chanting
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and this call it that dick chanting is actually more
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or so was originally synthesise down hoffman nearly thirty years ago
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just to prove the concept of colour protection thing over conjugation resistant
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by less than than it was sitting on the shelf for twenty years
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and then revisiting the concept of colour protection thing and bile duct out hard
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getting experimentally now's model such as the india to model sparrows in cullen tried this
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uh no it's a restart was the phenotype and one of the mechanisms actually is
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that this call it that the chanting is at generating pack up and then pick on it
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is explained important to contact bile acid toxicity humans folk slicing contributed by
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less it's it's as important as a uh the formation of mixed mess else
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in addition or so also has an to proliferate differently
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for pop again tirade anti inflammatory and we think even you
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know model or tory effected also inhibits intro signalling in c.
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d. four in c. d. eight uh t. cell also the
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maybe a complex mechanism but very important feature is
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that no worse in the long and the goes to call it that
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fiction and things through the got but is and uh the enter patrick circulation
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so they got but is undergoing this call hypnotic chanting
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within the labour so a apart from generating pick cotton it
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which is protecting the bile the good with the the um there's also in richmond
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within the liver and i think this is a very important from a call dynamic feature
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and in addition and uh from the concept of
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into green a signalling uh this may be important
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for example the bile back to be filament this is preclinical data the engine bile duct
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is expressing a teasing molecules such as we can and also when you stimulate clench asides with yet
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they express high levels of weekend which helps a recruitment aside to evade at
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poses that's very nice mechanism a demonstrated but david adams and actually more or so
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is reducing uh we can expression within the by like b. b.
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c. and so it also maybe another level apart from having direct
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uh and probably for the v. effects on on t. cells that also the recruitment
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to the bile duct tape if the limit the maintenance of uh uh lymphocytes closed to the public the p. t. loom
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may be interrupted at least based on a preclinical data
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and you uh probably way off the face to data showing it those dependent
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reduction of alkaline of foster basis primary readout
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uh compared to placebo with different those is really
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is often more so with the about or twenty
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five percent with the highest those within twelve weeks and then or so was discontinued that was a relapse
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of liver enzymes and then this effect occurred independent of the
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previous response through the arctic probably guess its own this trials
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the patients who've been top or so but there there there's a respond as in previous as a non responders and both
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responded equally which is i think an important feature because no h. so good safety profile and
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based on the state to a phase three trial has been initiated a long time trial which
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we'll have a combined and point of reduction pelican foster days
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and a stabilisation of a liberal histology uh uh basically it's it
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makes the a square or uh and it includes biochemical he's the logical
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and also clinical endpoints with about three hundred patients to be recruited
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another think they're fifths it's we've sent dozens with so and so
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y'all recruit actively to this trial really need to have updated
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every patient counting those p. c. trials it's really fight for every
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in the little patience because uh it's really really yeah the seats
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so i should point out that no uh so which also
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may be effective in another colour static diseases which are not yet
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a test that the moment we published a reason thoughts while in nash that was it
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so they import the thing is that no it's it's not a a like and for
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the classic bile acid receptor such as f. x. are in teacher five and this is
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but we can't resting another strategy which is
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currently holding those uh nuclear receptor targeted therapies
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targeting efforts are or for example of uh people are in the
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case of vibrates and the interesting thing with those nuclear receptor is ah
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that nuclear receptor satellite and activated transcription factors
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which are for example activated by by last it
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well by a fatty acid or white rock which of course is high affinity
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and this then in uses utterance workshop program which
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is really very part so they have a very productivity
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the control metabolism not only by less it but also clue clothes and lip metabolism
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and they also control inflammation immunity and fibrosis in t. should repay
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so i would see those nuclear receptor is is immune water it rocks
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which control both metabolism in this case bile acid metabolism and information
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and and that applies to both affix our and and keep our
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and these nuclear receptor targeted strategies now have emerged the second
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line therapy in p. p. c. is you're probably way off
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with a stairwell uh f. x. out like an such sabbatical i guess it with the new england paper
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people lie against the the reason pacified with data
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from the french trial by a crystal for copy show
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and also took a copy good reset to specify is more than just an immune to suppress if it's of course
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a are too quick to reset dragon is but it
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also you come and uses a or or modify spout composition
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and that was the reason try was put as a night uh uh in in
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p. c. so the question is could those tracts also be effective in p. c.
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there are trials with a better call i guess it announced or what life exile against
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and know that the french uh based on you know small case here is that that's a fibre it was
00:15:13
also effective in p. c. also initiated phase three trial
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similar to the p. p. c. trial in the french network
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and put last night the questions i know that homework and we all may have some discussion
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i think is using steroids in in p. s. c. and it always depends a little bit
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you know it's of course in overlaps income christopher's talked about that that's a clear indication first their rates
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and then uh it depends do you really look for
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information in liver histology usually do it in the context
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of having a suspicion of overlaps income and then you see inflammation their interface
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appetite is of course your going to treat it right so see and treat
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inflammation than others in yeah raise the overlap but i touchy
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for the ten percent of the p. c. patients have elevated
00:16:01
she for level so there is a they overlap with i. g. forty seasoned op immune hepatitis about
00:16:07
ten percent of patients and those uh certainly candidates a formula suppresses treatment
00:16:12
and the question is at least and you see and uh inflammatory infiltrate
00:16:17
only the histology there's one opinion that this is the consequence of colour spaces
00:16:22
because colours diesels isn't using opinion phenomenal so you wait
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what is colour static therapy doing for example to trends
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i mean is is are you treated right away that i think there's a we can discuss that later sissy country
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information also is a topic in a college steady little diseases such as in p. f. c.
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so uh what about those nuclear receptor is uh i mentioned
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earlier that this may be a a stretch either you basically
00:16:50
to read both the lever and the cap and their stated
00:16:53
both affix ah and for people of course first there it
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that you are going to hit both the liver and they
00:17:00
get and then this is i think an interesting concept especially
00:17:03
the ethics ally against but also for vibrates we also know that there
00:17:07
was a strategies treating i. b. p. with people or a small molecules
00:17:12
which i've got restricted and uh recently a uh
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face to trial that'll better call the gas it the second line treatment in p. p. c.
00:17:22
was also contacted in p. c. s. s. u. c. with much lower those is then in p. b. c.
00:17:28
it was effective in reducing outlined faster pace but even with a low
00:17:31
doses of this is point five to three and five to ten really plan
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you see very high rate of pride 'cause my inspiration is it's even higher then e. p. p. c.
00:17:41
and uh the setback occurred independent of the previous response or use of or so
00:17:47
and having the i think also that phase uh to be you or perhaps
00:17:51
even face re trial is planned for better call i guess it at the moment
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uh recently a a a study with the not sure
00:18:00
what life excel like endless i love facts uh was performed
00:18:04
which also showed with that have outlined pasta baseball thing uh so exposed us in these patients also
00:18:10
channel up and if i brought a gun point one battery marcus will improve then the important thing is
00:18:16
that these non story life excel lie against it not decorate
00:18:19
right so it may be the no longer look like bile acids
00:18:23
but maybe something to build a compound has a power structure not that they didn't use the sprite does
00:18:29
and also here face at three trial is already on the way
00:18:34
so basically when you think of affix ah kind of policies i would see then
00:18:39
s. stairway to hormones which circulate between the liver and they got that
00:18:43
all sink use other factors in the intestine such as active nineteen which also
00:18:48
control by less at home is stacey is so in addition
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to affix ah and the ice display g. of having those morale
00:18:55
not restricted or even got selective non suffer with latex out
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like in such a set of facts which worked mainly the got
00:19:02
or having more broad compounds such as a better call i guess it would even
00:19:06
and they're going to babbitt separation because they are by less iterate the if the continue
00:19:12
to circulate within the enter patrick circulation and uh stimulate both the
00:19:17
liver and uh they got the in a continuous way i mean
00:19:20
they're both arguments for both i mean it also has a danger
00:19:24
of course menu from oracle circulating around all the time in the think
00:19:28
you all the way up there all the dozing issue instead what the patient this happens when you have a compound which is kind of
00:19:34
trapped inventor patrick circulation so i would say it's safer to just hit the got and have a comp what which man is gone
00:19:40
and maybe from the concept in p. c. tweaking the let's really
00:19:44
caught me by modify my proper order this is still conceptual speculation
00:19:49
shoes this could be a way how to approach indices such as p. c.
00:19:55
in addition uh to uh f. x. ah we also had f. chief nineteen
00:20:00
which is a whole morning cues benefits are repressed as powerless censuses and also
00:20:04
look at synthesis and you may have heard of f. t. f. nineteen
00:20:08
agony is in uh the feel of a nash the same also applies
00:20:13
two p. c. and p. c. they're very current ching face to
00:20:17
date in p. p. c. with a reduction of alkaline foster days
00:20:21
eighteen q. c. interestingly alkaline phosphate days has not improved as a lot of discussion at
00:20:27
the moment is alpine foster is a good market are in p. c. we know that
00:20:32
a significant proportion of patients have normal act one
00:20:35
fall off apace despite having c. viewer probably injured graphic
00:20:39
at the melodies there's a lot of fluctuation and actually in the
00:20:43
study an improvement of opposes mark that's non invasive marcus actors poses three
00:20:48
and alf test was seen without improvement of alkaline phosphate they so they
00:20:53
hit a direct and departed effect of active nineteen which also was seen
00:20:58
in nash trial i think this is an interesting concept it's an intractable part so
00:21:03
we'll see whether this is accepted by patients is with p. c. as long term treatment
00:21:09
then in addition we also can interfere at up points invented that dick
00:21:13
circulation which is basically still preclinical data but they also for example by last
00:21:19
entry block us into the little you know that they uh my absolute
00:21:23
takes a they had but that is your that but that is the rock
00:21:27
basically a n. t. c. p. the palace transport the volume tower coloured coat transporter
00:21:33
uh taking up by lessons into the new ways to popping side for the hepatitis b. virus and
00:21:38
block us off this um viral entry also blocked by less up take of course
00:21:43
and there's preclinical data that this may uh reduce the buttons of
00:21:47
bile acids by interrupting their interpublic circulation and you also can do that
00:21:52
uh in the in testing either with raisins or with more uh more selective
00:21:57
re uptake inhibitors indian testing such as a speedy inhibitors and this is going
00:22:03
to a shift at the signalling in they got by
00:22:06
also model lighting the micro broader because if increased exposure
00:22:10
often been testing in this case the colon to buy less it's the question is do you want to have that in the context of i.
00:22:16
p. d. and potential cancer it's it could be posted could be anti
00:22:19
inflammatory or it could be per customer training we don't know what that is
00:22:24
at the interesting aspect is that didn't uses she'll be want production and she'll be one not only has
00:22:30
those well known metabolic defects but is also complains you're protected actually probably
00:22:35
clinically we could demonstrate that you can fuel bile back injury bind using she'll
00:22:41
be one production for example by giving is p. d. inhibitors arises we
00:22:45
get a concept of chewing the labour through the got maybe this is something
00:22:49
which will follow us in the future that also i think uh have apologised have to
00:22:54
have a comprehensive view of pestering probity and have apology and also always look at the cup
00:23:01
and they have more so which is a totally different concept i mean this is a comment that take a a
00:23:06
track which is undergoing this colour but the chanting but not
00:23:10
targeting within the entered but except collections a lot of options
00:23:14
and let it would visit the got little access that day and i've mentioned this particular p. c. i.
00:23:20
b. d. phenotype i personally think this is an separate type of i. b. d. maybe the third or fourth
00:23:26
depending determine it polite is uh not uh it's in
00:23:30
independent type of a call like this i would say
00:23:34
and you have basically the concept of despair houses and the loss
00:23:37
of got the area function which may be a pathogenic and they are
00:23:42
it's a lot of uh uh let's say that a good rationale to target the cat litter axes
00:23:47
e. p. c. i've talked about the lymphocytes homing i mentioned disposes
00:23:52
if it changes in micro brought up but of course he they are that the clinical
00:23:56
course of p. c. and i did the is the second the most explains an on and
00:24:01
its manifestation of p. c. after collect i mean this is actually not
00:24:05
better and i was very surprised seeing this speech data that two hundred five
00:24:10
out of two thousand five hundred a p. c. i. b. p. patients develop you
00:24:14
see after collector i mean of course this is about back knows is a manifestation
00:24:20
it's not the same thing but i think it's not a rare thing there's certainly a disconnect
00:24:25
i think yeah i'd be the pipeline of products is very
00:24:28
inspiring i think those guys trying draw it doesn't have apologised realist
00:24:32
look what's going on in room apology in term apology
00:24:36
or step apologises was going on in the i. t. field
00:24:39
who's taking you know they do sticking on lap although it was disappointing
00:24:43
in p. d. c. there will be a pool in alternative politely so
00:24:47
although most of what you showed with the th seventeen x.
00:24:50
that type of opinion hepatitis but i think in p. c.
00:24:54
it plays a role they don't eat some not the uh the into playing partners is an interesting approach
00:25:00
and i think we also have to keep in mind that the and the colours that big rocks the f. excel
00:25:04
likens it even that vibrates also work on crap information
00:25:08
or in the case of ethics are on my copy op
00:25:11
so there's this help like one of i. b. d. marks
00:25:14
which continuously all was still in the uh uh p. c. field
00:25:19
and to an actually the the recent example above middle it somehow
00:25:23
and that was a bit disappointment i must say i mean there's no perspective trial
00:25:27
unfortunately probably based on those more discouraging results
00:25:32
from three retrospective series from the shit ted
00:25:35
uh and also from the international p. c. a study group and also
00:25:40
i uh mayo clinic and and australian experience basically the take home message
00:25:45
is that there's no improvement of act one faster pace in some serious
00:25:49
a significant proportion of patients even showed deterioration so we don't know is this the natural fluctuation
00:25:55
of elk fascinate rock which is not that effective and it comes
00:25:59
back to the discussion is alkaline faster these it good weed out
00:26:03
to town for example or stop a t. c. track i think this is an interesting question at the moment
00:26:09
but perhaps too many potentially a effective treatment options account because that didn't
00:26:15
work on out fast because for example don't look sufficiently uncle enjoyed brands
00:26:20
or on opposes markets but basically delete some not disappointing
00:26:25
uh no all changes so my outline faster pace but
00:26:28
in terms of id activity of course in p. c. i. b. d.
00:26:32
it's effective and this is for example the international p. c. study group
00:26:37
a recently published by caitlin she see there's basically no change in liver enzymes
00:26:43
still like answered is intriguing i mentioned uh uh uh actually it some of which a
00:26:48
little bit well uh the inhibiting beat the seven also another intake when i saw forms
00:26:53
and uh of course not delete some up is not an issue because the side effects and the net can walk past
00:26:59
uh the tosca trial positive and also just collide this i think
00:27:03
locking net can resting between partner also maybe an option e. p. c.
00:27:08
and the the interesting candidate is bad want which is a bit enhance
00:27:12
sign which basically in uses indirectly net can expression and the interesting thing is
00:27:18
that uh uh this enzyme uses big the already arrived and
00:27:22
nine says substrates which basically drive this process the maybe the link
00:27:26
between the cat micro papa microbial product promoting net can
00:27:31
expression and perhaps the up whitey some homing in this approach
00:27:35
uh it's still has a number that's it i try which is currently contacted by the pending in university
00:27:41
and uh the study still recruiting in a that one and monoclonal antibody
00:27:46
a little bit elite sum up a study the the randomised controlled through a trial was the strongest and
00:27:51
then you look at biological seem to sum up i mentioned earlier there and if a product like negative
00:27:57
and send it to a rock actually is on the horizon with a a pass size trials
00:28:02
yeah i don't know whether of the data basically could be because i think they should have data
00:28:08
at the moment and the interesting thing is that a cynic critter ah you'll probably
00:28:12
oh like they have to pay to nash but also in colour spaces there's recent interest
00:28:18
that macrophages infiltration of brown cloud parts plays a key role
00:28:22
so it's not just about lymphocytes also about in that community
00:28:26
is about known aside to write macrophages and with this this
00:28:29
year to see see five blah you basically bach marker fashion
00:28:33
recruitment to the liver and to parasites trial was actually
00:28:36
completed some perhaps uh we're going to see data here
00:28:40
very soon as well and then you remember the nash baited had burned and different topic
00:28:45
than anti inflammatory signatures i'm very curious to see what that means for a p. c.
00:28:51
what about moderation of not microbial i i mentioned the antibiotics
00:28:55
most of the data out there for bank uh my scene
00:28:58
but we have to keep in mind that might come bank uh my son is not just an on
00:29:02
it all the way antibiotic it's also very potent immutable
00:29:05
auditory bracket model it's you read a activity in composition
00:29:10
it's it's interesting to see that uh then you look at antibiotics and mean a metal night
00:29:16
assault tetris cycling positive trial from finland but but a lot of side effects i don't think
00:29:22
this is going to be uh they it's interesting to
00:29:25
see that's office hours nine see some revival there's no
00:29:29
oh that tool randomised controlled trials in the us so this is basically this whole file a cellphone i might
00:29:35
uh and mess on asylum mine component combine so maybe
00:29:39
you can anti inflammatory antibiotic got michael brought the model waiting
00:29:44
approach and actually a my experience and i've talked
00:29:48
about that with with other investigators there are individual patients
00:29:52
who respond to uh to the l. p. c. i. b. c. right back
00:29:55
out to the old fashioned sort of our sign i don't know whether you've made
00:29:59
similarly experience and that's also data that's all purcell assigned also sent in to port and they enter
00:30:04
and get a pop topic in the liver so it's also very all right but very interesting product
00:30:10
which is where was that at the moment with tax i mean was disappointing and actually there's a lot of tape down
00:30:16
by one ally in p. c. i think this is basically
00:30:19
just the signature of little so roses or advanced liver disease
00:30:23
and they're a new address for example so little mice in is about an ally
00:30:28
uh the specific antibiotics which which uh maybe tried in the future
00:30:33
i think no interest isn't the clips it gets a love story at the moment which is a pool forming tapes yellow
00:30:39
a species which was identified in p. c. i. b.
00:30:42
d. patients basically contributing to got permeability and a little information
00:30:48
uh but yeah except been disappointing and josh course and make a from how they actually
00:30:53
recently completed a f. m. t. trial which was safe
00:30:56
and a very small proportion you know intend passions you can't
00:30:59
say much showed an improvement of outline faster this but i think you see the the feel this going in the moment
00:31:06
so at the end it then we we think of p. c. you know we
00:31:10
have this information with this structuring and then you look at the combine chip ran
00:31:14
you have to see the inflammation in structuring
00:31:17
actually combine geographical it looks or colin just copy
00:31:21
collate it looks more think phones theses so i would say it's the currencies of the got
00:31:26
associated with polite is maybe this is telling us something
00:31:29
but uh personally i think that a new clothes all healing
00:31:34
isn't important uh aspect but then you see this really
00:31:38
by look into the paper thingy i'm i'm wondering how
00:31:41
can a few and imply mayor pro or anti inflammatory approach
00:31:46
we still have lacked integrity so i think in the future when you think about combination simply iffy
00:31:52
we not only will have any colour static kind
00:31:55
of bile duct protective attracts which maybe the backbone
00:31:59
but uh we don't have to add a email mulatto it lacks probably we
00:32:03
have to uh diagnosed disease early i think many of them you know mahler tori
00:32:08
biologics did not work because we're just simply diagnosing the disease much too late
00:32:13
basically when it is for product and giving this colin should graphics a clearance
00:32:18
and adding appropriate channel differ perhaps also santa let the cracks because in essence and this was a question
00:32:24
a different context yeah they spy objects in essence probably
00:32:28
con computing to bile duct uh it it's sealed best
00:32:32
and as analytic tracks of course the question all this is with
00:32:35
this height you more receipt risky you really want to stimulate regeneration
00:32:39
it's actually the season maybe things like g. l. p. one
00:32:43
through the got the kind of mild form of approaching that
00:32:47
of course uh out there a lot of uh you know concepts
00:32:51
for combination therapies but when you look at those diapers basically it's
00:32:55
combining everything at the same time i think this doesn't make sense probably we need
00:32:59
sequential therapy depending on t. c. stages or individual acerbic
00:33:04
depending whether a part that protected in one the model editorial perhaps probably generative
00:33:10
and if the product approaches make more sense i think the key question one of the key questions is by that
00:33:17
clicking the cat is really instrumental in terms of treating p. c. than says we don't really
00:33:23
know because it appears to be a a slightly disconnected and this is hey it i think with
00:33:29
many conceptually it peeling approaches i think the near future will be nora so
00:33:35
and affix ah like ends and people likens vibrates perhaps also the f.
00:33:39
f. nineteen men ethics which are most advanced in clinical trials at the moment
00:33:45
yeah i think the michael brown is promising with frank um i seen the the tragedy with frank uh
00:33:50
my son is that the hotly would control trials a
00:33:53
lot of small or partly very large case the rest
00:33:57
but no control trials i think email model of tori tracks
00:34:01
ah interesting they have so far been disappointing for the question
00:34:05
which we have to ask is the concept wrong or i'll be
00:34:08
too late in the the seasons out diagnosis i think the late uh
00:34:12
is the case and as i mentioned uh i think one of the enigmatic questions is
00:34:17
whether we really have to treat underline i. b. d. we're just simply to reach up
00:34:21
passes in the live when they got which i think also would be good i think
00:34:25
but that knows is essential we have learned a lot
00:34:28
from the scandinavian trial putting you know i. b. d. patients
00:34:32
in this can and basically detecting high prevalence of p.
00:34:35
c. in patients with spoke when normal out point faster pace
00:34:39
the think the current strategy baking until at one foster these races
00:34:43
at least in high risk patients such as i. b. t. pages long we have to treat
00:34:48
the disease really maybe we have to do we define the disease that defining the disease
00:34:53
on complains your colouring geography which basically is proposes in scaring
00:34:58
my commands refers to this liver cirrhosis of the of the bile duct and would be like
00:35:02
defining upper rank come up with a disease based on the fact that there's a
00:35:06
rose is just simply doesn't make sense i think we have to redefine the disease
00:35:10
tweak it earlier and want issue is and
00:35:13
this is a unifying a perspective basically fall a
00:35:17
pack the pinnacle bile duct diseases is that when you have purposes and you've lost the facts
00:35:23
it's difficult to get the ducks back and this is totally different
00:35:26
for example from viral hepatitis and nash where you can get ripped off
00:35:30
uh they propose and still have the uh architecture which
00:35:34
with the rich works in p. c. and in even more
00:35:37
in p. p. c. uh when you lose the bile back
00:35:40
to have a disconnect and even getting rid of the prototype roses
00:35:44
probably won't help service complimentary and synergistic options and i think a complex disease
00:35:51
such as p. c. very likely will need a combination therapy
00:35:56
but it's not combining everything we have at the same time
00:35:59
but it's more a sequential therapy the problem will be hard to really test that clinically
00:36:04
in patients which in terms of number a slightly a
00:36:09
limited supplies recruit to clinical trials i think that's the most
00:36:13
important take home message thank you very much yeah
00:37:06
yeah i think it's fibrosis and probably non invoice aggressive approaches marcus
00:37:11
i think in terms of imaging we're not good good enough to really
00:37:15
you know quantified reliably or even though what we're looking at should we look at bile duct volume should
00:37:20
we look at a you know a stiffness or
00:37:23
should we look at the information in a diffusion sequences
00:37:28
but i think at the moment would be be probably have
00:37:30
made the mistake of not integrating for pros is enough yeah
00:37:34
i mean the compromises that at least in the ongoing phase
00:37:38
three trials we have those accomplice it endpoints improvement of colour spaces
00:37:42
at least without deterioration in some studies even improvement of approaches a little bit
00:37:48
like what you know from national improvement of nephew thought deterioration
00:37:52
of approaches or improvement of for profit without the duration of match
00:37:56
and this is uh this is really a problem also
00:37:59
in terms of uh uh encouraging industry in engaging in
00:38:03
large files and we have i think the little form next week or are these rules will be discussed i think
00:38:08
i think mandate effect potentially effective products has been killed
00:38:13
because the didn't reduce alkaline phosphates i think this was one of the
00:38:16
mistakes which would probably made in the past we do agree on that or
00:38:40
the problem is that those markers i mean it's great you know to to
00:38:44
to a face to trial showing proof of concept pocket the cage with everything
00:38:48
then you go with the same concept to the phase three and this or they ask what's
00:38:53
the evidence that this is linked i'll come and then you have to say we don't know
00:38:56
and then you're back to the start this is this is the real problem uh
00:39:00
no but we just simply don't have the evidence at the moment but it really those
00:39:06
sorrow get parameters that linked all upcoming p. c. it's even more
00:39:09
an issue like a game you know of a national another liberties so
00:39:52
because i'm reminded that i have to repeat the question not show was a
00:39:56
endoscopy of the bile duct where the the use your common interest copy also
00:40:01
in terms of requiring samples i mean the problem is uh the invasive next yeah otherwise we would be much more
00:40:07
advanced we would do it like an i. b. d. kind of also isn't really also from the convent we could do
00:40:14
colin joss could be as easily and safely like on oscar p. b. would run a lot filed
00:40:19
with nicole for healing and just see what works within or or eight weeks or something like that
00:40:24
that would be the perfect endpoint the product by hope is that in the chain
00:40:29
maybe good enough you know a high resolution m. r.
00:40:33
uh also with the fusion imaging and things like that
00:40:36
uh but i think it the you answer the question
00:40:39
itself clinical practised it will remain humour surveillance that human suspicion
00:40:43
and uh i didn't mention that the list and a
00:40:46
trial because it was focusing on a pharmacological therapy basically
00:40:51
pilot aviation uh with outstanding is uh by the same if because the
00:40:56
ratings less side effects and complications and drop them stand yeah but we
00:41:00
still do it's in some cases for the think it from stereo and
00:41:03
it was only or in patients who who were who haven't if if
00:41:43
oh absolutely absolutely
00:41:48
i mean the humble groove based on many studies also directed looking at the bile
00:41:53
including microbial up our also i'll six o. also help protect and i think you know
00:41:58
that may actually be a mark i think which is on the estimated because you often have the phenomenon
00:42:03
of having those sky high cal protecting levels
00:42:07
with hardly any endoscopy delusions and then we've
00:42:10
uh uh ask maybe it's his logical information i think this is coming from the bile duct
00:42:15
and i think cal protecting could be i mean certainly you know uh
00:42:19
they also put use a lot of or help protect it could be
00:42:23
maybe it should be studied more i know that uh for colours to do in your
00:42:28
directing file put you interviewed surviving behold to passage maybe that's a good income that information mark
00:42:38
or from the u. c. p. a right of course that's what the above come through through e. e.
00:43:03
yeah yeah yeah yeah i mean quite honestly i think we should
00:43:09
put every i. b. d. patients i. b. d. more than a ten
00:43:12
years uh in the sky or even five years in the scanner i
00:43:16
mean it's easy to do in the centre but let's say to the
00:43:19
in the centre that's that's approach which i convinced my i. p. t. call work to do
00:43:25
and based on the scandinavian paper you detect a lot of abnormalities but here the question is is it really
00:43:31
p. c. so you have a normal colour ensure granting the patient has normal uh kind of off the base
00:43:37
but they also data suggest that there's radiological progression so
00:43:41
it's suggested that this may able to full blown p. c.
00:43:44
but the two and says we don't know whether that's true yeah but you
00:43:48
see early changes uh in i. b. d. patients with totally normal upon faster pace
00:43:53
and even you know patients who have a more local ensure grams we have some diffusion perry
00:43:58
portable correcting signals and the i mean something is going on in liver that maybe early p. c.
00:44:10
yeah that's the other downside yeah that's yeah
00:44:16
yeah that that's true i mean yeah
00:44:22
and probably should name it differently yeah we should i mean i i do not tell the patient
00:44:27
you have early p. c. because then they're just cool remote disputes yelled at a a uh huh
00:44:37
the it's a it's a difficult decision but i think at the end we we we need to have the courage
00:44:42
to change the definition of the disease otherwise you know remote window right now
00:44:53
yeah it's just so should survival benefit from i mean is that it's
00:44:59
a good for everybody really but this is right the this is the information
00:45:02
rich you seem to get there and the for profit and the cussing which
00:45:06
ended and the anti inflammatory i mean they're not directly into colours that it
00:45:10
actually um my group and was back in crowds or we're
00:45:13
running a a very early stepping trial in t. p. c. d.
00:45:17
because we thought it would be and the colours that approaches show that it's safe and that it's
00:45:22
lowering the profiles and there's the data from scandinavia the pages on staten switch you see
00:45:27
that's better outcomes due to those multi factorial steady effects i would
00:45:32
i would say i would not prescribe standards for p. c. but when there is the
00:45:36
slightest indication force that in user would encourage the use of stallions in such patients huh
00:45:43
even though you know that they have a increased prevalence or i. b.
00:45:46
p. patients of increased that the prevalence or don't know about you see
00:45:50
i don't think somebody showed the paper that maybe i think we you had one of your slides i think
00:45:57
we neglected many of our patients have all from ash and there will be on top of the immune or whatever
00:46:15
you know your i. e.
00:46:34
right i i think that
00:46:38
i think the evidence is that patients uh whether significant elevation
00:46:43
of a l. t. in addition to the out far off
00:46:46
also improve without your key to go with the with the oak for some also for example yeah
00:46:53
so i think those are second i mean but we for example in p.
00:46:55
p. c. it's better defined as as active t. b. c. or this interface
00:47:00
uh activity not plastic appetite is in p. p. c.
00:47:05
which purport to associate with pull a prognosis i mean
00:47:08
it's it's actually this let's say there's good preclinical beta
00:47:13
that by less it's in this medium range of about fifty
00:47:17
hundred mike from all you know fire away from this toxic detergent activity
00:47:22
isn't using it th seventeen response and ever yeah directly from the battle sites which for example but
00:47:28
use and c. p. one uh this is indeed you're one mediator of a of an ominous i'm wondering
00:47:34
whether it i would say from a clinical perspective those patients would interface activity
00:47:40
in p. p. c. uh don't automatic all you know if the don't fulfil
00:47:44
the fool or criteria of overlaps and numbers biochemical in several logical a lot of
00:47:50
i would i break i mean nowadays we don't put little histology in p. p. c. or in
00:47:55
p. c. outside of clinical trials but a lot of that interface activity i think a secondary phenomena
00:48:02
work clinically would wait until the p. l. p. improves i think that maybe
00:48:06
a take home message i think if that goes of overlaps animals made much of
00:48:10
i i'm shop you know even all uh institution how many overlaps syndromes are
00:48:16
in let us or diagnosis just because somebody's indigo p. with p. b.
00:48:20
c. which then goes down with us agreed but that's not a lot of
00:48:25
and um i think those are secondary phenomena and you could say it's file as a
00:48:29
proxy city or in a more more than him a logical few which i'm sure you
00:48:34
uh have high affinity to i would i would think about the new mechanisms by less of a totally new
00:48:40
remote whatever you clocks i think this is or agents
00:48:44
this is some this is a concept which i think we'll