Pradeep Mundre: Hello everyone, welcome to this episode of the UEG podcast. It's Pradeep Mundre here and I'm your host for this podcast. This is the part two of our discussion on MASLD, metabolic dysfunction associated steatotic liver disease. In part one, we covered the terminology, we covered the diagnosis, how to monitor such patients. And in this episode, we'll focus on the management, we focus on the current, the future, drug therapies,

Pradeep Mundre: and a bit on career. So I'd like to welcome Professor Sven Francque back to the studio. Sven is a professor of gastroenterology and hepcology at University of Antwerp in Belgium. He has hugely contributed to the field of MASLD and is also one of the guideline committee members who wrote the guideline on MASLD, which was published two years ago, which is a multi-society guideline from EASL and Diabetic and Obesity Society.

00:00:59: Welcome, Sven. Thank you, Pradeep. Happy to be back.

Pradeep Mundre: Sven, I want to move on to treatment. I just want to ask you, what would be the treatment targets? What are we aiming to achieve when we treat patients with MASLD? You know, a bit of fat, bit of fibrosis, it doesn't really matter from my point of view. So what are we aiming to prevent? What's the end game here?

00:01:23: You're highlighting an important point, I think, and it makes a little bit of difference between

00:01:28: what the goals of treatment and what the goals of treatment are in the developmental program of pharmacological therapies and the endpoints with the regulators on the one hand, and what we want to achieve in routine clinical practice on the other hand.

00:01:43: As you rightfully say, if there is some liver lipid accumulation, there might be a little bit of fibrosis, but if there is no disease progression and you can halt disease progression, as a clinician, that's already an important goal.

00:01:56: However, in terms of drug development, the bars have been put higher and it's really about regression of fibrosis and resolution of the steatohepatitis. The resolution of the steatohepatitis is obviously inspired by the fact that it's the underlying inflammation and damage of the liver that drives the fibrogenesis.

00:02:18: And then the regression of fibrosis, obviously fibrosis is, in terms of liver disease, the most important predictor of adverse outcomes. So regression of fibrosis, although it's still not validated as a surrogate for clinical improvement on the long run, it's highly plausible, of course, that if you can regress fibrosis, you will prevent liver-related outcomes on the long run.

00:02:40: Okay, we're using resolution of steatohepatitis and regression of fibrosis as surrogates for long-term outcomes. And I'm assuming the long-term outcomes would be decompensation and HCC?

00:02:57: Yeah, in terms of drug development, it's a little bit more complicated because even going from advanced or lower degrees of fibrosis to cirrhosis is a potential endpoint.

00:03:16: And then also in terms of the development of varices, getting from a situation where you have no varices at all to a situation with varices that need treatment is also one of the endpoints in clinical trials for the advanced stage.

00:03:32: So it's not just decompensation events or hepatocellular carcinoma, which is also a part of it. It's a little bit more complex than that, but of course, it's all part of the same concept.

00:03:44: Yeah, okay. And they're very important. So let's move on to the non-pharmacological treatment. It's clear that, you know, dietary adjustments play a role. Weight loss and physical activity are the three main ones that we talk about.

00:04:00: You know, maybe I'll ask you a practical question on this. You know, it's easy for anyone, any clinician or gastroenterologist to say to the patient, yeah, I lose weight, do some exercise, change your diet.

00:04:11: I just want to specifically ask, is there anything in your practice that you do that would enhance the effectiveness of this? Are there any specific type of weight loss program, psychological treatment, maybe? I don't know.

00:04:26: Is there anything that is more effective than just simple advice, go lose weight?

00:04:30: Sure. I mean, it's clear that the better the support is for the patient, the more result you can achieve. Support the patients with wearable devices or just the monitoring on their smart phone or smart watch can already be very helpful.

00:04:46: So, regular support by a dietitian or somebody else who can coach the patients, it will increase the results of that kind of intervention, motivational interviews. I mean, this is all very, very helpful. But of course, the systems are usually not built to support people in that way, unfortunately.

00:05:06: So, in your practice, do you have access to these multi-disciplinary type interventions and things or do people have to seek out another place?

00:05:17: It's limited to multidisciplinary consultations with other colleagues, obesity physicians, endocrinologists. Yes, that is something that we have. And also the support of a dietitian is something that we have, but it's limited to that.

00:05:31: So, we can unfortunately not offer in a multidisciplinary way psychological support or somebody that can coach people for physical activity, for example. Unfortunately, we don't have it in the ideal world. We would need it, but it's not foreseen in the system.

00:05:47: I guess it's a problem of outside the method, you know, our medicine, the Western allopathic medicine. So, Sven, going on to the weight loss, just is there any particular cutoffs or is there anything that is clinically meaningful in terms of weight loss for such patients to prevent progression?

00:06:04: Yeah. Well, based on relatively limited data, because still it's based on paired liver biopsy studies and obviously these are not always very large numbers of patients.

00:06:15: And it's based on the endpoints that we just discussed, resolution of C-H and regression of fibrosis.

00:06:21: But for the resolution of C-H, on average, you need at least a 7% weight loss.

00:06:26: And for the regression of fibrosis, you need 10% weight loss.

00:06:30: But of course, some people will need more to achieve the same results and other will have already with 5% also an improvement.

00:06:38: So, this is just the average number that can help you guide a little bit the management.

00:06:44: Yeah. So, that seems meaningful.

00:06:46: And that numbers do help, I think, at least.

00:06:49: We as humans, I think we'd love to see these.

00:06:52: And it's a goal.

00:06:53: And if you achieve, it's, let's say, inspiration for patients and doctors to achieve.

00:06:58: So, I think these things do help.

00:07:00: Yeah, absolutely.

00:07:02: And you need some anchor points to help.

00:07:05: Great.

00:07:05: So, moving on to sort of other type of, any other non-pharmacological treatment, you know,

00:07:12: food supplements and microbiome modifiers and coffees and things.

00:07:17: I think there's some reference in the guideline about these.

00:07:20: But I couldn't quite, there was nothing that stood out at the end.

00:07:24: No, well, there is nothing that has very strong evidence to really support it as a formal guideline.

00:07:32: Of course, you have the data suggesting that coffee, for example, is beneficial, but you need substantial amounts of coffee to really demonstrate a benefit.

00:07:44: So, probably it's, what most of the data suggests is whatever way you achieve that weight loss in a sustained way has a benefit.

00:07:54: And there's probably little difference between the different ways of achieving it.

00:07:58: What is also important is to mention that physical activity is very important because that can give a shift in body composition.

00:08:07: It can strengthen your muscle mass, which is also very important for the liver condition and for your metabolic health in general.

00:08:14: And it's not always translating into a lot of weight loss, but it's just the body composition.

00:08:20: So, it's more than weight loss.

00:08:21: But as you rightfully said, you need some anchor points or guidelines to have goals that you can set in daily practice.

00:08:29: Yeah.

00:08:29: Essentially, you build your muscle mass and you lose your fat mass.

00:08:33: Lovely.

00:08:34: I just want to move on to the pharmacological treatment.

00:08:36: I want to talk about resmedurone specifically because that's the only pharmacological therapy that's shed in a positive light or recommended by the guideline committee.

00:08:46: Could you please talk us about what this is?

00:08:49: Because this is the first time I heard, you know, I'm not a hepatologist, so I don't know this drug.

00:08:54: How does it work?

00:08:56: What's the evidence?

00:08:58: How strong is the evidence maybe?

00:09:00: And who has access to this drug?

00:09:03: Yeah.

00:09:03: Before answering your question, perhaps an important point.

00:09:05: As you said, the guidelines are now already two years old and the world has changed in between.

00:09:11: Okay.

00:09:11: There's also now semaglutide that has presented positive phase three results and has approved at least already in the U.S.

00:09:19: And we will have an update of the guideline very soon just because of that changing landscape.

00:09:26: Great.

00:09:26: But at the time of the writing of the guidelines, we were about to have the positive results of resmedurone in phase three.

00:09:34: So that's why you have only there a formal recommendation.

00:09:37: But that's something that is going to change.

00:09:39: Now, resmedurone is a liver-targeted thyroid hormone receptor beta agonist.

00:09:44: So selective for beta, which means that you do not have the alpha action related to the thyroid hormone receptor, which is important in terms of potential side effects for a THR agonist.

00:09:57: And it's liver.

00:09:57: It's liver-targeted and quite liver-specific.

00:10:00: So it changes the lipid handling inside the hepatocytes.

00:10:05: It also changes, it improves mitochondrial function and has also some effect on some of the inflammatory mechanisms.

00:10:11: And by that combination of impact on metabolic and inflammatory pathways, it also has an impact on the fibrosis.

00:10:19: So what was clearly seen in the phase three trial is that after one year of treatment, you have a significantly higher proportion of patients compared to placebo that achieve resolution of steatohepatitis and that also achieve regression of fibrosis.

00:10:36: So in that regard, it's not just halting disease progression.

00:10:40: In the number of patients in whom you really have regression of diseases is not 100%.

00:10:46: So the effect size is about 12% compared to placebo if you need, if you look at the stringent endpoint of fibrosis regression.

00:10:55: But overall, you have to be mindful that it's not just fibrosis regression that matters in routine clinical practice.

00:11:02: Already halting disease progression is important.

00:11:05: So it's significantly better than placebo even if you take those stringent endpoints.

00:11:11: Okay.

00:11:11: And is there any long-term, I guess this was two years ago, is there any more data, long-term outcome data?

00:11:19: I guess it's still early.

00:11:20: It's too early.

00:11:21: It's too early.

00:11:22: So the trial, the phase three trial goes on because as I mentioned, those endpoints are just surrogate endpoints and even not validated,

00:11:31: but only what they call a reasonably likely surrogates of clinical outcomes on the long run.

00:11:38: So the trial goes on and there's a separate trial in patients with fibrosis also ongoing.

00:11:44: So there's still a lot of data that we are waiting for, but that are upcoming.

00:11:49: Is this drug available?

00:11:51: It is available, but not in all countries.

00:11:54: So yeah, that's the particularity of the EU that, of course, it's now with a positive recommendation from the market authorization by the commission.

00:12:04: But then it still needs translation into the different countries.

00:12:07: So it's available in some countries.

00:12:09: I think it's, for example, in Spain, Germany, Portugal.

00:12:12: It's available.

00:12:13: In other countries, the procedure is still ongoing.

00:12:17: And I'm assuming that these should be used in early phases of when they're in a state of a hepatetic or you can't use these drugs when they're cirrhotic already.

00:12:26: Well, you're right.

00:12:27: For the time being, the trial in cirrhosis is still ongoing.

00:12:31: So we don't know in patients with cirrhosis.

00:12:33: The approval is only for patients with F2 and F3 fibrosis.

00:12:37: So not the very early stage.

00:12:39: There needs to be at least what we call significant fibrosis.

00:12:42: So F2, F3, that's the indication.

00:12:45: So two advanced disease in terms of cirrhosis for the time being is not an indication.

00:12:50: It's considered a contraindication.

00:12:52: We'll see what the results in cirrhosis will be.

00:12:56: And finally, are there any adverse events or are there any major concerns in terms of adverse events at all with these?

00:13:04: Well, it's generally very well tolerated.

00:13:08: And there were very little issues in the phase 3 trial in terms of safety.

00:13:14: We need to be mindful, of course, and follow up carefully the function of the levels of the thyroid hormones for sure.

00:13:23: But in the end, to date, we have very little indication of a safety issue there.

00:13:29: And classical side effects like some gastrointestinal side effects, usually minor and rarely moderate, can occur.

00:13:37: But it's usually a very well tolerated drug.

00:13:41: Excellent.

00:13:41: Sven, let's move on to the GLP-1 receptor agonists.

00:13:47: The somatidotide, tisapetide, osambic, VCOV seem to be the trending terms these days.

00:13:53: And I did a podcast with Professor Karl LaRue from Dublin nearly one and a half, two years ago, I think.

00:14:01: And he was very positive about the outcomes in MASH and kidney disease and heart disease and things like that at that time.

00:14:10: And as you mentioned, the guidelines seem to be neutral on these drugs so far.

00:14:15: But you mentioned things have changed when you're revising the guidelines.

00:14:19: Can you give us the latest viewpoint on where these drugs stand, particularly in relation to progression or helpfulness in MASH treatment?

00:14:29: Well, the guidelines were conservative as two years ago we didn't have the data that we have today.

00:14:34: And at that time, we could not recommend it as a specifically anti-MASH treatment.

00:14:39: Of course, it's indicated for obesity, diabetes, cardiovascular disease because it has really an impact on the metabolic syndrome as a whole.

00:14:50: But the data, we didn't have phase three data, so we couldn't recommend it as an anti-MASH treatment.

00:14:56: Meanwhile, we do have the data showing indeed that with the high dose of semaglutide, the dose that is used for the treatment of obesity,

00:15:03: you do have a resolution of steatohepatitis, quite impressive percentages.

00:15:08: And you also have some regression of fibrosis after a year and a half of treatment because that was the time point it was evaluated in the phase three trial,

00:15:16: which is what you would expect.

00:15:17: I mean, there's a substantial and sustained effect on body weight, which goes at those 10% or more that we mentioned in the first part.

00:15:30: So if you have that sustained effect on body weight, only that would already translate into significant liver benefit.

00:15:38: Some discussion if there is more than just the weight loss to explain the liver benefit, statistical analysis suggests that there is more than just weight loss.

00:15:48: There are also recent data about effects on the endothelium and the vasculature that might contribute beyond just weight loss to the liver benefit

00:15:57: and also other benefits of this type of or this class of drugs.

00:16:02: So for sure, it's such an impressive metabolic improvement that it also translates into liver benefit, probably mostly indirect,

00:16:11: but we have increasing suggestions that there might be some direct intrahepatic effects also.

00:16:17: So let's move on to the other drugs.

00:16:20: Is there any evidence for use of other medications for mazal-D, you know, beta-colic acid or so?

00:16:27: Obedicolic acid has positive phase 3 results.

00:16:30: So that's on, it was in fact the first drug that had positive phase 3 results for the treatment of MASH

00:16:38: in the same indication as we have now for resmeterone or semaglutide.

00:16:42: It has never been brought on the market specifically with MASH as the indication in the label,

00:16:48: probably for risk-benefit balance issues, but there is a cholesthetic component to the pathophysiology of mazal-D

00:16:56: and it has some benefit and it induced some fibrosis regression.

00:17:00: But I think in general, probably it has not a specific place in the treatment of mazal-D.

00:17:08: What also works are drugs like pyoglitazone, for example,

00:17:14: because it drastically improves adipose tissue dysfunction.

00:17:18: It also has some other benefits, potentially also some effect on the stellate cells.

00:17:23: So that also induces resolution of steatohepatitis.

00:17:26: Not a very strong signal on fibrosis regression, but probably also there on the long run,

00:17:32: that could have a benefit.

00:17:34: And that's the reason why the American College of Endocrinology even included that in their guidelines.

00:17:41: We did not propose that specifically as an anti-MASH treatment,

00:17:47: again, because we do not have proper phase 3 data.

00:17:51: But in the global management of metabolic syndrome,

00:17:53: it could be a treatment that also benefits the liver,

00:17:56: just like drugs like aspirin or anticoagulants might have a minor effect.

00:18:03: They're not powerful enough to cure the disease,

00:18:06: to meet the endpoints that we discussed.

00:18:08: But on the very long run, they might also improve the evolution of the disease,

00:18:15: just like statins, for example.

00:18:16: So in the optimization of the metabolic comorbidities,

00:18:20: there are some drugs that also have sometimes minor,

00:18:23: but still some benefits for the liver.

00:18:25: Span, I want to move on to other surgical treatment,

00:18:29: you know, bariatric surgery or endoscopic anti-obesity treatment management.

00:18:35: Are they recommended in MASH specifically outside the obesity management?

00:18:40: Outside the obesity management, no.

00:18:42: They're not recommended for the time being.

00:18:45: What I personally would consider is that within the medical indications for those therapies

00:18:51: as anti-obesity treatments or metabolic treatments,

00:18:55: I think you should take into account the liver also as a comorbidity

00:18:59: and not just look at the ones that are classically in the indications now.

00:19:04: So it justifies or it supports the medical indication for bariatric surgery.

00:19:10: But for the time being, outside the context of its proper indications,

00:19:14: I don't think you can, in isolation, just say that this is a liver treatment.

00:19:20: You will not apply that in, we discussed also about lean patients.

00:19:23: You will not specifically for the liver disease apply that in people that otherwise are not living with obesity.

00:19:31: Yeah.

00:19:31: There's definitely huge benefits from bariatric surgery, I'm assuming,

00:19:36: in terms of outcomes from muscle D or changes in the histology.

00:19:41: There are several studies with biopsies after one year and five years

00:19:46: showing a very pronounced effect on seatosis, theatohepatitis,

00:19:51: and in the longer, in the studies with the longer duration.

00:19:54: So at one year, there's not so much effect on fibrosis,

00:19:57: but at five years, you clearly see also a regression of fibrosis.

00:20:01: Not in all patients, and specifically those with cirrhosis at baseline.

00:20:05: Part of them remain at the cirrhotic stage,

00:20:08: but there's anyhow a substantial improvement in liver histology.

00:20:13: And on the long run, we do have some data suggesting that they reduce also liver-related events on the long run.

00:20:20: But that's not, I mean, this is more real-world evidence

00:20:24: and not properly designed trials to demonstrate that.

00:20:29: Sven, in terms of liver transplant for mesoledipal, mesoled cirrhotic patients,

00:20:34: is your approach to such patients any different from other cirrhotic at all?

00:20:38: In terms of indication, no,

00:20:43: but there is, of course, a difference in the profile of these patients.

00:20:47: They have metabolic syndrome.

00:20:49: They have, quite frequently, cardiovascular disease,

00:20:53: impact on the renal function.

00:20:55: So they have sometimes a more complex comorbidity profile.

00:20:59: And they also tend to be, because of the slow evolution of the disease,

00:21:04: they tend to be older at the time they put forward the indication for liver transplantation.

00:21:09: So that makes it a challenging population in terms of liver transplantation.

00:21:15: But the indication is the same as in other liver diseases.

00:21:20: What is important in the management, I think,

00:21:23: is that if you, in follow-up, see that the patient is slowly deteriorating

00:21:28: towards what could become an indication for liver transplantation,

00:21:32: you have to tackle those comorbidities early on,

00:21:36: specifically the cardiovascular disease.

00:21:38: Because if you only start to investigate it very thoroughly,

00:21:42: at the moment you are wanting to list a patient for liver transplantation,

00:21:45: and then they go for coronography, stenting, dual antiplatelet therapy, etc.,

00:21:51: it's making things complicated.

00:21:53: So because they tend to be older,

00:21:56: you have to tackle those comorbidities even more aggressively

00:21:59: than you would probably do in general,

00:22:02: just to optimize their chances for liver transplantation.

00:22:06: Yeah, cool.

00:22:06: And so are there any new targets of treatment?

00:22:11: Are there any new drugs in development at all

00:22:13: that we could be aware of things to come out in the next few years

00:22:17: that would be relevant clinically?

00:22:19: Yeah, there's a large pipeline of drugs

00:22:24: with a lot of different modes of action.

00:22:27: In terms of the incretins,

00:22:29: there's the triple incretins that include the glucagon component,

00:22:33: because there you have, for sure,

00:22:35: direct intrahepatic effects on the glucagon pathway.

00:22:39: The FGF21 is also an interesting FNU

00:22:45: with very promising phase 2 data.

00:22:47: The same for the PAN-PPAR approaches.

00:22:51: We discussed PIO, which is a P-PAR-Gamma,

00:22:53: but there's also a PAN-PPAR approach

00:22:56: with very promising results in phase 2 and now in phase 3.

00:22:59: There's a bunch of other drugs with other modes of action.

00:23:03: Interesting is also the genetic approaches.

00:23:06: There are some genetic PNPLA3s,

00:23:09: obviously the most well-known,

00:23:11: but there are others in different pathways that are involved

00:23:14: and that clearly have an impact on disease progression.

00:23:17: And also there you have approaches

00:23:19: with silencing RNA, for example,

00:23:24: small interfering RNAs,

00:23:25: that change the metabolism in the hepatocytes

00:23:30: that might benefit some of these patients.

00:23:34: So interesting times, but not easy to study, of course.

00:23:38: Okay.

00:23:38: Sven, in terms of,

00:23:40: there are a lot of young trainees out there

00:23:42: who want to pursue a career in hepatology.

00:23:45: How do you think a doctor in hepatology,

00:23:48: a role of a hepatologist,

00:23:49: would change in the future,

00:23:51: either in terms of research

00:23:52: or in terms of the clinical practice,

00:23:54: just so that we can inspire them?

00:23:57: And if I, as a trainee, come to you and say,

00:23:59: I want to do hepatology,

00:24:00: what would you say my life would be different

00:24:02: compared to your life as a hepatologist currently?

00:24:05: I think it's very important that we realize

00:24:07: that this is not an isolated liver disease.

00:24:10: We are now embracing the CKLM concept,

00:24:14: cardio, kidney, liver metabolism,

00:24:17: really highlighting that this is part of a systemic disease.

00:24:20: And then you have the different end organ damages

00:24:23: in that context.

00:24:25: And we, as a hepatologist,

00:24:26: will take care of the liver,

00:24:28: whereas the cardiologists take care of the heart.

00:24:30: But we should have a basic knowledge

00:24:33: of systemic metabolic syndrome,

00:24:36: both in terms of understanding disease pathophysiology,

00:24:39: but also what we have to look at

00:24:40: and how we can treat it.

00:24:42: So having a solid background in general internal medicine

00:24:46: and specifically in metabolism

00:24:48: is something I think is a prerequisite

00:24:50: for a hepatologist to be able to take

00:24:53: part of that multidisciplinary measurement

00:24:55: and make sure that in the end,

00:24:57: we can still take care of the patients early enough

00:25:00: that develop more severe liver disease

00:25:03: because that's our core business, obviously.

00:25:05: We are not the physicians

00:25:06: that have to take care of the treatment

00:25:09: of the obesity as such,

00:25:10: but we should have a knowledge of it.

00:25:12: We should be able to work in a multidisciplinary team

00:25:15: where those aspects are managed

00:25:17: and we should be able to properly refer patients

00:25:20: to the appropriate colleagues

00:25:22: to take care of those specific aspects,

00:25:25: whereas we also ensure that they also incorporate

00:25:28: the liver in their thinking

00:25:30: so that we get the patients that we need to see

00:25:33: and that we can see them sufficiently early

00:25:35: in their disease course

00:25:36: and not just when they put forward the indication

00:25:39: for liver transplantation,

00:25:41: because obviously we can still then help them,

00:25:43: but that's the point that you would like to avoid.

00:25:45: Yeah, and are things happening in the clinic practice

00:25:48: when, you know, our IBD colleagues

00:25:50: already do some joint clinics

00:25:52: with, let's say, rheumatologists

00:25:53: or gynecologists or obstetricians?

00:25:56: Is somebody doing a multidisciplinary-type clinics

00:25:59: in such patients,

00:26:00: I think, really benefit such patients?

00:26:02: Yeah, absolutely,

00:26:03: and that's why it's very important

00:26:04: to really see this not as an isolated liver disease

00:26:08: and not something that we have to tackle

00:26:10: from day zero to the day they put forward

00:26:14: the indication for liver transplantation.

00:26:16: It's really something we need to,

00:26:17: we need to be part of it as hepatologists.

00:26:20: In the whole trajectory,

00:26:22: we did also quite an effort

00:26:23: and it's published now

00:26:25: on the SLD patient trajectory

00:26:27: with a large multi-stakeholder group.

00:26:30: Everybody has its role,

00:26:32: but also has to take his responsibility

00:26:34: in the global management of those patients,

00:26:37: but it's truly a multidisciplinary effort

00:26:39: because otherwise we will never,

00:26:40: we will never be able to help all those patients

00:26:44: that are walking around with this disease.

00:26:46: And Sven, any final thoughts or comments

00:26:49: before we end this episode?

00:26:50: Probably too many,

00:26:51: but if we can already have this disease

00:26:54: on the radar of the colleagues

00:26:57: that are seeing these patients

00:26:58: before we see them,

00:27:00: and if we already have in mind an algorithm

00:27:03: how we can accurately diagnose these patients

00:27:05: and make sure they are managed in a holistic way,

00:27:10: then I think we have made a big step forward.

00:27:13: Thank you for your insight.

00:27:15: Thanks for your time coming on this.

00:27:16: It was really helpful definitely for me

00:27:18: and I'm sure our trainees

00:27:19: or other gastroenterologists

00:27:21: would benefit from this podcast.

00:27:23: Thank you once again.

00:27:24: Yeah, you're welcome.

00:27:25: It was really a pleasure to be here

00:27:26: and thank you for having me.

00:27:27: Thank you.

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