Q3 2022 Mirum Pharmaceuticals Inc Earnings Call
Presentation, you will have the opportunity to ask a question by pressing star followed by the number one on your telephone keypad I'll now turn the call over twice and Clement CFO Mary. Please go ahead Ian.
Thanks, Anthony and good morning, everyone.
Like to welcome you to Mirror Pharmaceuticals third quarter 2022 conference call.
I'm joined today by our President and CEO , Chris <unk>, our Chief operating officer, Peter out of it.
Head of R&D, Pam Vig and Professor Richard Thompson from King's College, London.
Earlier this morning minimum issued a news release announcing the company's results for the third quarter of 2022.
Copies of this news release and SEC filings can be found in the investors section of our website.
Given that we have professor Thompson, our call today to discuss the exciting full results from our phase III March <unk> study as presented earlier this week at <unk>, we intend to hit the rest of our base brief.
Full details on updates from the quarter can be found in our news release and the 10-Q issued this morning.
Before we begin I'd like to remind you that during the course of this conference call, we'll be making certain forward looking statements about <unk> and that program is based on management's current expectations.
Statements regarding the business brands development programs strategies prospects market opportunities and financial forecasts and guidance.
<unk> is under no duty to update these statements and are subject to numerous risks and uncertainties and actual results could differ materially from the results anticipated by these statements.
Investors should read the risk factors set forth in <unk> 10-K for the year ended December 31, 2021, and any subsequent reports filed with the SEC.
With that said I'd like to turn the call over to Chris Chris.
Thank you Ian.
And good morning to everyone joining us on the call today.
The last quarter for Marin was packed with major milestones.
As we continue to realize our vision of bringing life changing medicines to patients suffering from rare diseases around the world.
The live Marley launched in the U S continues to track well with $47 2 million in net sales year to date on track for an estimated $70 million and net product sales in 2022 for a strong first full year of approval.
Setting the stage for growth outside the U S. We recently received a positive <unk> opinion for <unk> in Europe for treatment of cold static pruritus and hours Youll syndrome, two months of age and older.
And our launches in key European countries next year, we will also be supplemented by further approvals and demand from partner markets like the recently announced approval in Israel.
And we're excited about the potential for label expansion based on the positive results of the <unk> Phase III study.
These data build on the years of treatment experience, we have in our <unk> syndrome and Piecyk with.
With a broader genetic type and higher response rates in earlier studies.
Showing the potential for improved outcomes for patients.
It is a moment, where the Marin team is hitting its stride on both commercial performance and realizing the value of our pipeline.
Great advances, we've made that mirrors are only possible with the participation of patients and dedicated researchers.
On that note we are delighted to have professor Thompson join us today to share. The recently presented details from the March <unk> Phase III study.
And with that I'll pass the call over to Peter for a couple of brief remarks on the commercial business before diving into the new clinical data Peter.
Thanks, Chris today, I'll share additional color around live mileage third quarter net product sales and upcoming plans for the commercial business.
We are happy with the continued quarterly growth with $18 8 million in <unk> net sales in the third quarter and.
And we are raising full year net product sales guidance estimate for <unk> to $70 million.
We continue to observe high levels of compliance and persistence to loop mildly and maintained strong reimbursements.
Coming into the fall, we've seen an acceleration in new patient starts on live Marley and continue to believe we're early in BG. The full addressable eligible syndrome patient population in the United States.
Our commercial business is strong and profitable, which positions us well as we turn to launches and in international markets.
Germany will be the first European country to come online in Q1 of 2023 with others. Following over the course of 2023 and into 2024.
Beyond our core U S and EU markets. We also expect to see contribution in 2023 from our partner markets with several approvals occurring over the next 12 to 18 months.
And outside the United States over 130, <unk> patients are currently receiving live Marley from clinical and expanded access programs. These patients will be eligible to transit transitioned to commercial <unk> upon local approvals.
On that note I will turn the call over to Pam Pam.
Thanks Peter.
Over the last few months our team has continued to take major strides in advancing with Marley for pediatric prosthetic behavior.
We've just we're trying to fund the ASR being liver meeting where we are.
With that an exciting late breaking data.
First we reported on PK safety and Tolerability in infants with Alex <unk> from two months of age to one year of age.
These yourself of therapy were similar to those observed in children with greater than one year ago.
We also showed real world safety, and Tolerability data, which demonstrated a profile that was well tolerated with only 8% Gi related disorders.
Including diarrhea, and no Gi related discontinuation from this analysis.
And this aligns with feedback from the commercial use of the product where the Tolerability profile has been very well received.
This profile along with the efficacy observed in allergy all including the six year outcomes data that had been previously presented really highlights the ability of <unk> to make a meaningful impact in these patients' lives.
Now we are most thrilled by the late breaking presentation of our March <unk> Phase III study by Professor Thompson.
At March 30, <unk> 93 piece of patients, which is the largest study conducted the study met its primary endpoint and secondary endpoints and included pizza types that have not previously been studied.
The postulation that higher doses will translate to a greater magnitude of response and high response rates have played through and the magnitude of effect observed across the pizza types.
Our expectation.
And we're so excited about what this means for <unk> patients in the sleep dataset will help answer questions that are until now gone unanswered on and we're looking forward to digging even deeper.
And with that said it is a pleasure to hand over to Professor Thompson Professor.
Thank you very much indeed.
IEM.
Pediatrician, who looks after children with liver diseases conduct research.
So the underlying causes of these diseases.
Really pleased to be able to.
Present, these data because I think lay off.
<unk>.
And.
Following introduction I think we can jump straight through to slide four.
Talks about <unk>, which is progressive familial intrahepatic cholestasis, which is actually a group of genetic disorders.
Characterized by a multitude of vital composition of slip.
The consequence of this.
Genetic abnormality as these children have progressive disease.
But clinically the most important thing is that it happens to have this.
Intense April pruritus.
And other consequences thereof in particular this impact on the quality of life.
And not just to them.
<unk>.
The most.
Frequency of the types of PSC is Basel export on deficiency patients with this disorder royalty.
Off the primary cohorts in this particular study.
But as you will see from the slide the number of other subtypes of also described particular efficacy one deficiency and up 3% efficiency.
<unk> and <unk> five be deficiencies all of which are in the other <unk> cohort of our challenges today.
Previously we've treated these patients with a variety of off label drugs, which will have some benefit mainly on the pruritus rather than the liver disease.
But we have historically used surgical interruption of the antiemetic circulation.
Assets clause the formation of a stoma external bio drainage everyday.
Which we do believe has helped approximately 50% of patients who've been treated in that way.
Sadly major surgery.
I believe as a consequence.
Many patients have not been also that one surgery, because that's quite a high threshold, you'll sign a form of surgery with I guess, 50% chance of a significant improvements.
As a consequence of our limited repertoire of treatments.
Currently the majority of patients have ended up with liver transplants in childhood.
Which isn't effective form of treatment, but obviously is a major undertaking.
Uhm considerable risk.
So im delighted that <unk> inhibitors are now becoming available as an alternative pharmacological treatments for.
These conditions.
Slide five youll see that concept, which is the.
It sounds like the central market speculation from being simplifies and delivered a completed and filed the.
They used in the small intestine absorbing our fastener division.
But those that have not used.
And each cycle are reabsorbed in the terminal volume by the ideal.
Acid transport, which is the second couple of transport.
But they are absorbed into from the intestine.
Through the portal vein straight back to deliver from weather expected and they go round that cycle and normal healthy individuals.
Patients with <unk>, however, reduced transport capacity in the liver.
They have lower levels of therefore balancing demand tested but most importantly, they have accumulation of bile acids in the liver wet.
<unk> strongest ACI Jubilee pruritus, but also with progression of liver disease.
You will see from on the license side from previous studies.
So have you seen that Netflix has been capable of improving pruritus, reducing the pool size as measured by the peripheral serum bile acids.
And we have in our phase II study has shown that those who do respond are associated with prolonged nature to the survivors neighborhoods of transplantation.
Slide six shows you the schema of this randomized.
<unk> study initiatives in children with <unk>.
A lesson out to 12 months of age randomized 50, 50 to either receive <unk> or placebo.
This dose of <unk> is considerably higher than the dose we used in the initial phase two studies and I think that probably is causing.
Difference in results we've seen in the study.
Patients on entry has to have persistent pruritus, which has to be a mortgage Australia persistently elevated serum bile acid side of the market spaces.
The majority of patients went on into the open label Phase III study a phase II study.
But they got drug for the phase III study drug and the marks on the study.
Page.
Slide seven shows you the distribution of patients of the whole study cohort as Pam said with 93.
On the top right hand corner as the primary cohort those with <unk> deficiency.
Which was the non fund casings.
Majority, 90% of patients with lease up deficiency fall into this category.
But they have the potential to some residual function.
Combined with the other payer box below those as the other cohorts.
Cohort.
Obviously, the <unk> MTR three T. J P. Two amassing five lead efficiency. So the data are all present today around the primary kind of holds.
<unk> cohorts, which combine to form the.
<unk> cohorts.
The group on the bottom right.
The other thing thats volumes with clinically important but more heterogeneous.
I haven't got.
Endpoint data on those today, but they are included in the safety data that Joe discussed.
Slide eight shows you the details of endpoints of this study in particular on the left hand side. The primary endpoints was improvements in pruritus as measured by the <unk> tool.
<unk>.
Previously published.
And that is an improvement.
In the <unk> cohort.
A number of clinically and biologically important secondary endpoints as shown on the right hand side.
In particular some of the changes in pruritus, we look for in the rest of the <unk> cohort.
Biologically improvements in serum bile acids as a marker of cholestasis have looked at the different groups along with a responder analysis on a patient by patient basis, which I'll show you something else as well.
Okay.
Range of biologically and clinically important secondary endpoints, including changes in bilirubin.
<unk>.
<unk>, which I'll show you some preliminary data on that as well.
Slide nine shows the distribution of the patients.
The time of enrollment in terms of the visa cohort the <unk> cohort and then the photo on the right hand side you can see these rule children, mainly in the first decade of life.
We will have significant provides us on the scale of it goes from zero to four.
They were extremely elevated serum bile acid you'd see the pizza.
Around 300 compared to a normal range in the general population of less than 14, one four microphones per region.
The vast majority of patients will be treated with.
Obviously, Celtic acid, which is widely available and very happy to used.
<unk>, which is perceived to have some small improvements.
This condition and.
And approximately 50% of our own rifampicin, which is again an off label use of <unk>.
To biopsy, which foolish.
Some patients to pick you up a small benefit.
Patients are left on those notes.
Modified <unk> study.
As you can see.
Iot is a reflection of the fact that they've got liver disease raised.
Transaminase is suggesting the ongoing liver damage of onset.
The majority of patients with jaundice measured by within ILUVIEN in particular director Ruben.
Although not all patients.
Yes.
That patient actually would not Jones as Stefan said.
Reuben is an intrinsic part of it as a marker.
While deliveries functionally the secondary consequences.
As you can see at the bottom.
But the scope.
Overall this cohort.
But.
Failing to.
To thrive.
Height and weight.
Baseline.
Slide 10 shows the.
Details of the primary endpoints and all of these variables were assessed using the mixed model repeated measurements.
Neat analysis.
Which entire against all of the data from 15 weeks.
Six.
As compared to baseline on the left hand side of this slide Youll see.
The changes observed in the primary cohort in the <unk> patients.
Who achieved a very significant improvement in pruritus cohort.
And it was with some.
Placebo change in the placebo group, which we expect.
We will get significant improve.
Proven and placebo patients enrolled in studies such as this but the difference between the treatment group only.
Placebo group was March and highly statistically significant.
On the rental side you can see the same data represented longitudinally.
With a clear separation of late treatment group and placebo group very early on.
Approximately two weeks of exposure.
The pruritus response continued to improve over the first few months and the pace to reach steady state by about three months of treatment.
And then persistent for the duration of the 26 week study.
Slide 11 shows you.
Some of the data for the other <unk> cohort with these other diseases listed top that.
And in fact, if anything if anything the separation.
The patients with treatment with <unk> and placebo was greatly.
Obviously highly significant.
In these patients.
Patients.
On the license side those patients are shown in the dark red and Blue Bloods and superimposed.
In the pilot color all the results that I showed you just now.
<unk> cohort and as you can see.
Really effectively cupric plausible.
Not surprisingly therefore on slide 12, when we combined <unk> cohort, which.
Previous to the types of data combined we get significant improvements and a very nice.
Plots on the right hand side to try and clear separation and persistence of the effect between the.
Treated and untreated patients.
Slide 13 shows some of the biochemical data and domestic importantly, the changes in serum bile acids over there.
After.
12 weeks of the study.
There was a and the B CEP cohorts shown here there was a marked improvements in serum bile acids.
<unk> hundred 76 market most litre compared to the baseline of approximately 300.
As a cohort in the.
The treatment group, but <unk>.
The change from baseline in the placebo group and again those figures are shown on the right hand side loan excuse me.
And here I think it's pretty clear that not only was the significant improvements in two weeks, but we pretty much achieved steady state.
In the first month.
<unk> treatments.
Probably not surprising with the changes in serum bile acids predates the changes in <unk>.
Because this is really closer to the actual biological change, which you're hoping to achieve with the drug.
Slide 14 shows you the same data announced that the other cohorts.
Cohort and in parallel to the previous data, which I showed you for pruritus.
These data.
<unk> policy changes, which were much greater in the treatment group and really no change in the placebo group and again on the right hand side, you'll see the other <unk> areas marquee superimposed upon me.
The couple of infrastructure due to the previous slide.
On slide 15, again, those cohorts are being combined in the <unk> cohort III site.
Very clear distinction between the treatment group and the placebo on the left.
Now onto Q2 on the right, which is either duration of action.
Reduced Airbus content from the accretive effects in emerging data.
On 16 shows a.
<unk>.
Responder analysis, which obviously is extremely important because I want to be able to tell patients have elected the algebra to response.
On the left side is the <unk> responses and methods.
Measuring and improvements of greater than one point on the <unk> scale and previously.
Published data the change of greater than one point, just being associated with a clinically meaningful improvements in breakfast and as you can see.
96% over placebo group responded that 64% of the treatment group responsive Tuesday.
Hey.
Highly significant difference.
On the marketing side.
Look at the response in terms of serum bile acids.
As in the <unk> cohort.
And the council is used here.
Based on the customer ops, which we derived statistically.
<unk>.
Surgical retrospective analysis.
A reduction when we use surgical interruption identified circulation reduction of 75% from baseline or a reduction to the level of 102 <unk> per liter was strongly associated with the avoidance of transplantation.
A follow up.
So.
We hope that.
These will be.
Reproducible.
Follow up studies using <unk>, we believe that serum bile acids are intrinsic to the nature of the.
The bonuses are possibly the actual fundamental metrics of disease, we believe that the changes in certain balances will be.
Representatives of changes in the natural history of the disease and as you can see.
There was a very small response this parameter in the placebo group, but 52% of the opioid by Ctrip Board met this change in serum bile acids, which <unk>.
Previously as I say.
<unk> patients with long term native liver survival avoidance of transplantation.
Retrospective surgical study.
Yes.
Slide 17 goes on to look at some of the other biochemical data and this is the <unk>.
<unk> did a rubin.
Its intrinsic to the disease, but it is a good marker of liver health and there was an improvement which was just significant in the modeling about group compared to placebo and longitudinal debates over the license side and this is despite the fact actions.
Currently cohorts with Hudson.
The majority of that bilirubin direct bilirubin, which is what we expected liver disease and those data are shown on slide 18.
On Slide 19, you will see the changes in serum transaminase.
China's.
Millions of transfer rate.
Which a baseline where in the range of 100 200, and there was a very smooth.
Deterioration in increase in the amount of <unk> group and that price will decrease in the placebo group and these are very small compared to the parameters.
Baseline, but clearly something which we are very keen.
To observe.
Would potentially be a safety signal, but.
The changes are small as you can see on the right hand side.
By the end of the study actually day treatment group and placebo group of Petro converged again.
And as I said growth is a very serious complication of <unk>.
<unk> disease like this and here.
'twenty, we can see the changes in the way.
These core elektron side, which was <unk>.
Markedly Bachelor and the treatment group.
The there was a trend in the same direction Lavazza on slide for Heights improvements Hi, Tobey.
It's delayed over improvements in growth.
Slide 21, just summarizes some of the safety data, which is now live.
So the whole cohort <unk>.
Cohort and explores tables is holding 93 patients enrolled in this study these were sick children as you can see those treatments.
Emergent adverse events in <unk> treated group and the placebo group.
Patients.
There were some significant adverse events as you would expect in treating patients with severe liver disease.
The difference between the two groups is probably summarized at the bottom of that slide with the gastrointestinal side effects of the highlighted in particular increased stool frequency and diarrhea, which is an expected consequence of.
Diverting bile acid the colon.
None of this was deemed Savannah vast majority was mild.
It did lead to one discontinuation, one teenager, who had deemed mild diarrhea was unhappy with this and that was the only discount.
Discontinuation as a result of side effects observed in study.
The one side effects.
All manageable mainly.
The mild and usually.
Usually outside the JV result after.
Early in the studies.
Slide 22 summarizes written most of what I've just told you. This study a phase III study.
Which is the first <unk> Sebastian <unk>.
It does include the patients not just with <unk> deficiency.
Bronchial <unk> subgroups.
<unk> demonstrated the primary and secondary endpoints were met.
Quite comfortably.
And it does look like thinks about is capable of producing but.
Bye bye biologically and clinically significant improvements.
Particular and provides a serum bile acid across the types tested.
I do think we've seen much.
Greater improvements in this study compared to the phase two study that was undertaken some years ago.
With <unk>.
Where the responder rate was less.
And.
The difference between the studies really is that I think we have now optimized the dosing patents.
These patients ended up on that.
<unk> is a drug in the previous studies.
Equivalent.
Sure Les.
As I also said.
The academic community.
Pulled together study called the method study, which was looking at the surgical interruption of entropic circulation of bile acid.
And clearly in that academic.
Study, we showed that improvements in serum bile acids.
Through through surgical interruption enterprising circulation deposits.
Is.
Correlated with <unk>.
Native liver survival and the importance of transplantation.
On the basis of the cutoffs.
Previously identified in that study it looks like the amount of capacity capable of producing similar changes across all the different types of <unk>.
In the study.
The wholesale channel I think with significant improvements in their Rubin late schools and a trend in the right direction and height.
No.
It looks like <unk> is well tolerated all side effects that manageable.
Music trends in some early.
Disease, and there is no new safety signals.
Using this large cohorts of patients.
It does.
I'm extremely grateful to all my colleagues who are.
Our recruiting patients in the study and collected data but of course.
Most grateful to all the families.
We.
Collected data.
<unk>.
What's up with the increased monitoring and things with two necessary before a complex study of this nature.
So there is a yes.
Yes.
So far from the study.
Clearly as I said at the beginning.
Pediatrician, who looks after these patients.
I'm delighted that we've now got tools, which will help us pick patients.
Probably.
Yes.
Important reflection from my point of view is that single patient.
Involved in the phase two study would not alone.
Seven years follow up.
Certainly the patients that sticks out in my mind.
Because she had an internal controlled in the sense of the system.
Some years ago for the quality of life and maintain pruritus.
And so consistent with strong sponsors and pieces I heard somebody well post trial thought that obviously is on <unk>.
Especially et cetera that you expect after transplant.
A patient who is involved in the phase two study and is now go.
Martin it's about the second.
Has normal liver biochemistry.
Normal Cerro Moro.
She takes matter of expense.
And she takes a small amount of it is indeed all of the vitamin levels are normal global growth spleen size gone back to normal and really if you were to meter. If you look at the biochemistry you would say if there was nothing wrong with Oracle.
And of course that does that.
Sort of endpoints, which we pay.
To be able to achieve and clearly long term studies are necessary, but all of the <unk>.
Our emitters that we've studied in the $6 two point, but we're moving in that direction.
I think at some huge equivalent total everywhere.
Our PVA is again.
So.
Very happy to take any questions.
I'll hand over to Chris Thank you.
Okay.
Thank you Professor Thompson.
As you can tell the results from the <unk> Phase III study show convincing promise for Love Marley.
We plan to begin regulatory submissions early next year to get with Marley to perfect patients as quickly as possible.
It was a great quarter from Europe and for families suffering with pediatric cholestasis and with that we'll open the line for questions for both Professor Thompson and the Marin team.
Operator, please open the line for questions.
Thank you.
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Our first question today comes from the line of Jessica Fye with Jpmorgan. Please go ahead Jessica your line is open.
Hey, there good morning, Thanks for taking my questions.
201 can management team and one for the physician investigator.
First for management I think in prepared remarks, you mentioned, an acceleration of new starts on with Marley and I may have missed the timeframe of when you saw the acceleration, but just wondering how to reconcile that with what looks like a <unk>.
Celebration and revenue growth that was reported and then for the physician can you talk about what you see is clear differences between with Marley and Bill day.
And if we fast forward to a time when with Marley is approved for <unk>, how you would select between those two agents for pubic patient. Thank you.
Yes.
Thanks, Jess for the question.
And it strengthened Peter to comment on the top line and then to the Professor Thompson for your second part, yes. Thanks, Jeff.
So in terms of the comments that we are seeing an acceleration in the fall continuing to see that acceleration in new patient starts with live mildly that's really what gives us confidence in the.
Raising of guidance to $70 million.
20%.
Over quarter growth that implies going in from Q3 to Q4.
Looking at the full Q3 picture to your question, we did see some softness in the summer.
Keep in mind in the U S.
Many of these children are seeing once every six or even every 12 months. So what kind of kind of a phenomenon, we observed as families going on vacation choose not to do.
Physician appointment, where nutrition starts typically occur in those summer months. So that's what we do.
Obviously, the summer months, where most of Q3, but the acceleration coming in into the fall and continuing now.
So Jessica.
Obviously.
As you note there are two.
<unk> inhibitors that are being studied in the.
Groups of conditions.
I'm delighted that we've got.
The positive response from both drugs.
Disappointingly of course, neither drug treats effectively all of the patients that are being studied.
Yes is there a distinction between the two drugs I mean, the honest truth is that.
Despite the fact that a similar studies, we haven't done a head to head comparison.
And I think if you tried to do that right. At this moment you would not find the statistically significant difference between the two drugs.
I do have a significant response rates of 52% is excellent manav to response rate 64%.
<unk> is an excellent.
Response rates in terms of pruritus.
Thank you.
The people sitting around the table would tell me that that is.
Greater than that shown in the VIX of appetizers I'm not sure that statistically significant I think from my point to do on an individual patient basis, we'll have to dig into these texture and see if we can see any differences between the response rates I believe the major determinant of whether a patient responds or lots in these conditions is the amount of.
Residual pilots and transport.
The best way, we have looking at just kind of look at individual mutations that these patients carrying something I don't want to do is to take.
Take those down into the data if there is any.
Chemical predictors of response any genetic predictors of response and only when we've done that can we really see whether there are any of these any clinically meaningful difference between these drugs.
There's other factors come into the availability of the drug the formulation of the drug.
And I'm sure at some in some territories.
The price of the drug.
An important factor.
But.
And deciding which drug to use so I think to that.
But we've got to learn the resort side or other factors, which.
Pharmacological and try natural neutral impact on it but that outside my.
Thanks.
Okay. Thanks, Jess for the question Greg.
Yes.
Our next question comes from Steve <unk> with Raymond James. Please go ahead Steve.
Hey, good morning. Thanks, so much just on the acceleration of patient starts again I'm wondering.
I'm wondering if you can comment is there any sense that that's being driven by repeat prescribers at this point or are you still.
Mostly gaining patients through new prescribers.
I think we see both.
The prescriber base in the U S.
It's pretty well defined I mean, theres only a certain number of pediatric herpetologist that take care of these patients quarter.
Quarter over quarter, we do see more come onboard, particularly from the medium or smaller centers that might not have as much volume.
But in terms of acceleration I think it kind of comes from across the board.
Okay and then.
Pete I wanted to ask here because there is some data coming up for an interim analysis.
First half of next year. It seems like enrollment in that study has picked up after the some of the protocol changes you had talked about making.
Implementing earlier this year.
I was hoping you could just comment on.
Anything you're learning about just the number of patients seeking treatment with ICP unmet need.
So that demographic.
That you're enrolling in that study with respect to like is it mostly third trimester patients first or second pregnancy is just anything trending.
And that study that would be noteworthy dimension. Thanks.
Yes, thanks for the question on that.
Nothing.
Specific really to call out in terms of the demographics at this point it would be premature to comment on what that looks like until we get to the analysis cohort. We are on track for the first half of next year.
And have seen.
Patients come in with this updated protocol so all pointed in the right direction.
Okay.
Sorry, Steve sounds like you've got cut off did you have another follow up.
Okay, great. Thanks for the questions.
Yes, I was just asking about March pizza and the patient with the liver transplant, if you could share.
Details of why they ultimately elected for that.
Non responder just any color there. Thanks.
So I mean.
The reason for transplant and my understanding is that that was obviously the families choice.
And they were perceived to be.
<unk> non responders I think.
I haven't got all the biggest trend.
Pretty sure that there was the discontinuation of the <unk> were slightly greater there was certain there was four of them were in the placebo group three of them on drug.
And.
The majority of the ones that went to Trump bump, where non responders procedure as non responders on drug or deterioration into the function in the placebo group.
Obviously were in the placebo group.
But obviously the bile acids in the proactive scoring and everything.
Not hesitant.
Pivoting to the families that are making decisions on the physicians are making decisions on clinical grounds rather than <unk>.
Actual contents.
Thank you.
Great. Thanks for the question.
Our next question comes from Mani <unk> with SBB Securities. Please go ahead money.
Hey, guys. Thanks for taking the question.
That's what a little bit on patient dynamics and growth going forward have you seen any mix shifts and age.
Mean body weight et cetera for patients.
And this recent surge of additional fall patients coming on versus the initial the initial swags.
And as we start to see more.
More geography come on next year can you give us a little bit of detail on exactly how you account for Bob.
Revenue coming in from partners from partnered.
Youre, obviously as opposed to places where youre monetizing yourself.
Any nuances, we need to be aware of that as we look forward.
Thanks, Marty for the question I'll comment on the kind of broader international piece, and then pass it to Peter for the specifics.
In the U S to date.
And when we take a step back and think about the international markets. We are building and launching ourselves in western Europe and using distributors in some of the other geographies around the world licensing partners and.
Asia.
And what we expect for these distributor markets is that they will have.
Orders that may be kind of more and more.
Monthly for multiple patients at a time before a quarter at a time. So you could see more of an order based approach to how they are.
Comment.
<unk> will start to we could start to see some of that this year even.
But expected to come online with early access programs and approvals in some of those smaller markets.
Into next year.
And then when were.
Countries, where we're.
End market doing it ourselves.
Pretty standard for rare disease, where we'll recognize revenue as we sell it through to the pharmacy when orders come in for patients.
With that ill pass it to Peter to.
Diving, a little deeper sure on the on the patient mix in terms of age and body weight no changes there in recent months really consistent with.
The types of patients that were put on.
Connick pivotal study in the clinical program. So if you can always refer back to those papers and that'll get you in the ballpark of the average age.
But we see maybe the only other comment is similar to what we've talked about before kind of the perception of the phenotype.
Early days saw the patients are perceived to be most severe with their pruritus and other quality of life impact of the disease are the ones that we see physicians to kind of go forward one.
As they gain more comfort.
With the product and prescribing experience.
Then we see prescriptions broadened into patients that are perceived to be more moderate.
So we're seeing that phenomenon play out.
In the recent quarters.
Yes.
Yeah.
Great that's really helpful.
On the dynamic around monthly quarterly kind of.
Order structure for some of the distribution markets.
The more consumer that will introduce a little bit more tonnes units and choppiness into the quarterly quarter over quarter numbers or am I over reading that.
I'd say at this point, we don't know and we have to just kind of see the cadence of how the orders come in.
<unk>.
The one thing I'd note is that there are several different distributors several different countries. So we do expect it to be coming from a lot of different sources.
Which.
I think it would smooth out anything that that could be chunky kind of where our thinking is at this point.
Okay. That's very helpful. Thanks, guys.
Yeah. Thanks for the question.
Our next question comes from David Lebowitz with Citibank. Please go ahead, David Your line is excellent.
Thank you very much for taking my question.
Would you be able to comment on comparability with building given differences in the trials such as measuring in the morning versus measuring in the morning and night.
And just overall, how how efficacy was calculated in one study versus another.
Alright, Thanks for the question I think from a high level.
Okay.
We know our data how our endpoints were calculated thats really what we can speak to in detail.
So not in a position that we can really make.
Any kind of definitive cross study comparisons across drug comparison.
I'd say just on the morning versus evening measurements, what we see in our study is that that is effectively the same results. So that's something we've looked at.
Across all of the Readouts we've had.
Haile.
Consistent whether you look at morning evening.
Average worst et cetera, so that.
That holds up.
That to be a difference for the measurement of that point.
Got it and when you look at the data and compare what you see in <unk>.
Any thoughts on extrapolating.
How they might compare in lgs.
Okay.
Well, what I can say is what we see from these <unk> results and kind of what we've walked through here on the call. If you step back and look at the <unk> program over history as we've taken a huge step forward and the impact for patients and the response rates are much higher here when you look at the proportion of <unk>.
Days of proportion of scores that are a zero or one one of the FDA preferred analysis.
62% of the scores.
In the treatment arm.
Yes.
It's a great step forward in terms of what we see for.
Activity.
Great response rate and results coming out of the study.
Got it.
Thanks for taking my question.
Thank you.
Our next question is from the line of yes, mainly Amy with Piper Sandler. Please go ahead.
Good morning, Tim.
My question is actually directed to that.
Thank you so much for being with us.
First question for you.
When you look at the data from box piece Tech.
Sir.
The result that you think are absolutely critical to belong into the label that could drive stronger adoption. That's question one.
And then a question for you is we recently saw allergy Hal data with BIOLASE and would love to hear.
I appreciate your comments about.
<unk> two products and March pizza and perfect, but if you could share your thoughts on these two I bet inhibitors compare in contrast to one another and allergy or that would be really helpful. And then the third question is as you know me I Miss working on box about a number of other indications from.
ICP to PSC and PBC any comments, there where you think the mechanistic rationale stronger may have a high probability of success.
Sorry for asking so many questions that really wanted to take advantage of having.
On this call this morning.
At that time Sam.
Right. So I mean I think.
<unk> got the last two questions sort of merge in a way because.
Clearly I do believe that bile acids.
Causing the deposit of liver damage.
<unk> contributing indirectly to the pruritus.
In LNG.
LNG and these other phenotypes, which youre talking about PBC PSC, etc.
Kenny.
Sure.
The OLED conditions are very different from <unk>.
The product is not just important parts of the damage and symptom production, but are absolutely key to the initial.
Initiation of the disease as well so it's much easier.
Dror.
Connection between Offloading bile acids and.
The the.
The natural nature of the disease, and therefore, I think earlier signals that we're changing something in the natural history of the disease.
As opposed to.
Improving the clinical features.
So I think a big piece.
These studies in a sense is it a short will show you clear distinctions in <unk>. Some of these other phenotypes.
I do believe that an OLED is kind of a static phenotypes.
Bile acid as an important driver of our liver damage.
Retention of monarch is an important driver of pruritus.
And then I think.
Thinking about the pre.
Previous amount, it's about studies eligible that I was involved with.
I missed the initial studies were disappointing and I think the change came when the iconic study.
We're in a much higher dose of <unk> was used and I think that's what we're seeing in the study now is the reflection compared to the early <unk> studies.
Studies.
And the iconic company. So the original randomized studies that with Jonathan Boldt, where the higher dose of <unk> achieved a much greater response.
And obviously from a patient point of view I mean, it is still disappointing that we're not.
Perfect response in terms of bile acids or more importantly for us is.
And all of the patients.
And clearly as I said are already I think we need to learn to work out if we can predict which patients.
To respond.
And the next few years once we start using the <unk> doesn't.
Real life, whether we can actually find any way of improving on the responses that we get it.
Clearly from the patient's point of view.
<unk> to us asking about.
Provides us because of that interesting that dominates that life and clearly if we can pay off.
If we can get 64% of patients getting a process responds.
Thats extremely meaningful to them and Thats, what they want Tonight.
From my point of view.
Im equally interested in the Barnett assets because.
As I've shown you that I do believe because it is.
So at the heart of these diseases.
Logically.
Transitioning into a reduction in rate.
The tonnage to deliver Ramsey.
<unk> have long term.
Da Vinci, such as transplants and.
I would say that.
What we're expecting to happen based on our previous experience. So I think.
Your first question was what's the clinically meaningful aspects of the one that most important but from my point of view and as I say I'm less interested in the cohort analysis that combines.
Responders and non responders and seen that is by customers.
What is important is how good that responses and the responders on whether we can then maintain leverage in the long term.
Our response.
Tom.
Avoid transplantation.
And as I've also said, obviously, we've got patients now in the who didn't respond, particularly when the dose was increased in the original <unk> study, who now on a long term responses seven years now.
But even with the increased dose they are still on the lower dose.
Then the dose we're using in the study.
Do you believe there was quite a significant number of patients in those original studies failed to respond because it is getting close to an upfront.
Okay.
Am I right in.
Thinking of.
Some sort of attempt to respond to your questions. Please Tony.
No no that's very helpful. Thank you.
You talked about the Max.
Alright, thanks, guys. Thank for the question.
Our next question is from Brian <unk> with Baird. Please go ahead.
Hi, This is Luke on for Brian I, just have a couple of billion.
Her management have you had any recent discussions with the FDA around embarked in the path to approval in this indication.
And then FERC Professor Thompson.
Talk to some other physicians who've noted that maybe a third of patients who get vixen side.
I've had a partially successful procedure. So one that is security, but also doesn't require an immediate transplant using about one third is an accurate estimate and could you help us characterize the heterogeneity.
In other clinical markers among that subset.
Thanks for the question and comment on the first.
A portion of it and we discussed the.
Biliary Atresia program with FDA prior to initiating the study.
And are excited about what the.
The potential for patients are in the study when we have those results will go back to the agency and talk about.
Registration plans.
And quite excited about what.
If the drug can do what we think is possible in this setting.
The the potential to see real.
Strong impact at that six month primary endpoint next year.
I'll pass it over to Professor Thompson for the second question.
So in terms of response I think the.
Original studies the responder analysis was based on largely in particular.
We do now have these surgical data.
And the responder analysis I showed you for boxes was based on the observations you made in those studies.
I mean, it's interesting that obviously, we didn't appear to have to achieve normal serum bile acids to achieve long term nature liver survival based on those studies and I think that is telling us something about the fact that delivery is protecting itself on a loaded peripheral serum bile acids are not normal.
So got the levels are down and deliver low enough.
Not only just the <unk> improvements.
We don't compare to <unk>.
Progressive liver disease.
So the question is what sort of level of response rate and all of the partial responders actually going to avoid.
Transportation for instance.
Actually if you go back and look at the surgical data.
There was quite a wide separation between responded in August .
Some of the study, which we don't have to go look at those in detail.
And what it what it means is that actually whether you weigh exactly you put that cutoff that can be changed quite widely without really making a significant difference to the results and so although that cutoff over 75% reduction in or below a 102 micro most Lisa gave us the best distinction with <unk> respond to that.
Non responders.
Actually a lower level of responses lesser improvements made it difficult efforts to date.
Separation.
So obviously it remains to be seen by the values. So as a result can be.
Expected with the drug, but we believed it was actually the same when we believe the <unk>.
Sarah biologic marker as a reflection of.
Biological improvements is equally valid.
But at the end of the day, we will have to see whether those correlate but those are the data we have and obviously those are the data that we will be using for the time being to make clinical decisions.
Great. Thank you.
Thanks for the question.
Our next question comes from Ed Arce with H C H.
H C. Wainwright. Please go ahead.
Yeah.
Hi, Good morning, everyone. This is Thomas Yip asking a couple questions for Ed. Thank you for the final questions, perhaps first one for Dr. Thompson.
Sure.
Among the top 50.
Let's see in the March 30 in Q3.
Which attributes thrift model there.
Would you consider to be unique and most important to patients.
The attributes that are most important from patients I mean on the St.
It's about endpoints and I want to be able to say to a patient what are the chances that by getting too.
And a clinically meaningful improvement.
And also linked to that most of the chances that we're going to avoid.
Transplantation, and so I think there is.
As you've seen them, so im going to be sending patients.
John .
The gains against a clinically meaningful improvements in pruritus.
I am going to beside the moment it looks like there is approximately a 50% chance.
On this basis, but they will be able to avoid long term.
Liver transplantation in the long term.
Based on the results we have so far in our extrapolation from the data, which I've described.
Previous clinical studies.
But those are the two things.
I'll be discussing we found it.
And Mr Thompson, and perhaps a one question for the team.
Can you can you outline the key components are firm with moneys potential U S launch what are some overlaps and differences between.
The strategy between a piece again.
<unk> syndrome population.
Sure happy to comment on that and I think the.
In terms of the.
Commercialization strategy.
Physicians and health care pressures to take care of PV patients are largely.
<unk> two <unk>.
The patient the physicians to take care of lgs patients. So at the same centers that we're already in now promoting the Marley for ALS Youll syndrome.
Obviously upon an FDA approval.
The promotion will include both eligible syndrome <unk>.
Alex already available.
Working with the patient advocacy groups and other stakeholders and keep it for years right as you've heard today going back seven seven plus years. So.
Pretty pretty straightforward addition of Youre thinking about it from an SG&A perspective, maybe the only other comment to make is.
We have about 100 patients from our clinical and expanded access programs with Patrick who are currently receiving laboratory around the world. So a good part of our early effort will be.
Upon approval.
Hurting the patients receiving the clinical drug to <unk>.
<unk> growth.
Got it.
Again with a couple of questions.
Fourth European approval by year end.
Thanks, Tom for the question.
Thanks for all the questions. We have I'll now turn the call back to Chris for concluding remarks.
Thank you operator.
Thanks, everyone for joining today's call.
I'd like to thank again professor Thompson for joining us today, all of the investigators and families that made these steady results possible.
And hope everyone has a great day goodbye.
Thank you everyone for joining us today. This concludes our call and you may now disconnect your lines.