Q4 2022 PTC Therapeutics Inc Earnings Call
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Okay.
Good day and welcome to the PTC Therapeutics fourth quarter 2022 corporate update.
The call at this time, all participants are slowly mode. After the speaker's presentation there'll be a question answer session and instructions will be given at that time.
As a reminder, this call's being recorded.
I would now like to turn the call over to call. The Oki Chief Commercial officer, you may begin.
Yeah.
Good afternoon, and thank you for joining us today to discuss PTC therapeutics fourth quarter 2022, corporate update and financial results.
Im joined today by our Chief Executive Officer, Stuart Peltz our.
Chief operating officer Matthew climb.
Our Chief Business Officer, Eric Palace, and our Chief Financial Officer Emily Hill.
Today's call will include forward looking statements based on our current expectations. Please.
Please take a mine that Turkey, the slides posted on our Investor Relations website in conjunction with the call which contains our forward looking statements.
Our actual results could materially differ from these forward looking statements.
Such statements are subject to risks that can materially and adversely affect our business and results of operation.
For a detailed description of applicable risks and uncertainties. We encourage you to review the company's most recent annual report on Form 10-K.
With the Securities and Exchange Commission as well as the company's other SEC filings.
We will disclose certain non-GAAP information during this call infill.
Information regarding our use of GAAP to non-GAAP financial measures and a reconciliation of GAAP to non-GAAP are available in today's earnings release.
With that let me pass the call over to our CEO Stuart Peltz.
Thank you Skyler.
Good afternoon, and thank you for joining the call.
I'm proud to share.
Fourth quarter and full year results and our expectation for continued strong performance in 2023.
PTC treat rare diseases by markedly.
And protein expression.
Our strategy is to discover develop and commercialize products to build a robust pipeline of potential new therapy.
Our goal is to deliver one new therapy every two to three years.
I'm honored to report that PTC has been named the winner of the 2023 Youre warranted Black Pearl Company Award for innovation.
This award recognizes and celebrates companies who have undertaken groundbreaking science to advanced rare disease research and development and is a testament to the mission and strategy RPG.
We're planning a very exciting year in 2023, including the celebration of our 20 <unk> anniversary.
And we're proud of what we've achieved to date.
Our commercial portfolio as five marketed products.
Fixed product for which we collect collaboration and royalty Robert.
In 2022, we achieved $699 million in total revenue, which is a remarkable 30% growth over total revenue in 2021.
This revenue achievement was quite.
Substantial FX headwinds.
Calculated at constant exchange rates it was $740 million.
Representing a 37% year over year growth in the fourth quarter of 2022, we achieved $167 million.
Total revenue.
We expect our growth to continue to accelerate in 2023.
As announced in January we expect our total revenue guidance in 2023 to be between 940 million to $1 billion.
Which would represent more than.
30% year over year growth.
We are continuing to advance our broad and deep pipeline of new therapies that we expect to provide substantial growth through our commercial portfolio in the coming years.
I'm proud that these efforts have led to seven promising.
Development programs focused on treating rare disease.
<unk> from.
From which we will have four important readout in the first half of 2023 three of which are registration directed studies.
We expect results from the affinity diving for separate Taryn for PKU.
No wonder, but mitochondrial disease associated fees.
And the 12 week data for PTC, five ordinary and Huntington's disease.
We're going to lift in more detail shortly.
Very excited about part one data for affinity Saturday Saturday.
After him and look forward to the results from part two shortly.
In addition to these studies.
We continued to progress enrollment in our Sunrise LMS trial via net Bowen and <unk> sarcoma patients and our cargo AOS trial for ultra electric debt for ALS patients.
With solid growth across our commercial portfolio and many new therapeutics advancing in our pipeline, we continue to generate strong momentum for many years to come.
I'll now hand over to Matt for an update on our development programs Matt.
Thanks to our teams continue to make progress in advancing important new therapies from our pipeline to patients in need.
As you noted in the first half of 2023, we will have results from four of our ongoing clinical trials three of which our registration directed study.
Let me begin with an update on affinity our global phase III trial of <unk> in patients with PKU.
As a reminder, affinity is a double blind placebo controlled study in which subjects are randomized to receive <unk> or placebo for six weeks with the primary endpoint being reduction in blood phenylalanine levels.
To enrich the randomized population for Cepheid, Karen responders, there as a running phase during which all screen subjects received Serbia taryn for two weeks.
Only those subject to demonstrate a reduction in federal alanine levels of 15% or more from baseline will be randomized with the primary analysis population consisting of those who have greater than 30% reduction.
Importantly, all subjects entering the placebo controlled phase will undergo a washout period of at least 14 days.
In January we shared data from the part one running phase for the initial cohort of subjects with greater than 30% reduction in federal OE levels I will now provide an update on part one preliminary data for all subjects.
Overall 156 subjects passed screening and completed the part one running phase of these 156 subjects 102, or 65% greater than 30% reduction in phenylalanine levels from baseline.
Very high responders over three times, the responder rate recorded in Kuban Responder study.
When looking at the magnitude of fee reduction in that 30% that would be a tailing responder group. There was a mean reduction of 66% which is more than twice that recorded in the <unk> placebo control phase.
Also I want to point out that the 30% Responder group includes 15 classical PKU patients who had a mean phenylalanine reduction of 61, 5%, which is a very impressive result.
But there are an additional five classical PKU subjects, who had a 15% to 30% reduction in fee levels during the run in phase.
These part one results, including high responder rate and the mean phenylalanine reduction and non classical and class of patients continue to support the premise that <unk> can potentially meet the persistent unmet medical need of PKU patients.
With the high proportion of subjects, achieving an over 30% panel alanine reduction in part one the primary analysis population for part two will be over enrolled by approximately 25% beyond the initial target of 80 subjects given the time required for these additional subjects to undergo a washout and complete.
The placebo controlled portion of the study.
Patient last visit is planned to occur in March and we expect results of part two in May.
Let me now move to the two registration directed trials in particular leidy and move the.
Maybe you can move that these studies are based on both a strong scientific rationale as well as data from several previous studies in which we have recorded evidenced treat and benefit across key disease endpoints.
<unk> study is a global registration directed trial of particular note in patients with mitochondrial disease associated seizures.
It includes a 24 week placebo controlled phase with a primary endpoint of change in observable motor seizures from baseline.
The placebo controlled phase will be completed in March and we now expect results in the second quarter to allow for data cleaning and database lock.
The move FAA trial is a global registration directed study of <unk> in patients with <unk> ataxia.
Study includes a 72 week placebo control phase and the primary endpoint is the change in the validated and Fars rating scale from baseline.
Last patient last visit for the placebo controlled phase will also be in March and we continue to expect result of the move that base study in the second quarter.
Moving to our PTC five eight Huntington disease program enrollment is ongoing at our global sites for the phase III pivotal HD trial.
As a reminder, pivot HD at the 12 month placebo controlled trial engine parts.
Part one is 12 weeks in duration and focuses on PTC, five pharmacology and pharmacodynamic effects as well as bio distribution.
Two is nine months in duration and focuses on blood based CSF based and radiographic biomarkers of disease.
The study initially includes two dose levels five milligrams and 10 milligrams with the ability to include a third dose level of up to 20 milligrams leveraging the tight trade ability of a molecule.
As we shared at the Jpmorgan Conference in January we have initiated additional five milligram and 10 milligram dosing cohorts in early stage three patients. We expect results from the 12 week portion of the trial in the second quarter of 2023.
Turning now to Trans Lara, we recently had an informal meeting with the FDA during which we discussed the potential path to an NDA resubmission.
Based on the meeting discussion we plan to request another type C meeting to review the totality of data collected to date.
<unk> district, and other mechanistic data as well as additional analyses that could support the benefit of <unk> <unk>.
To preparing a request for this meeting in the near future.
Lastly for data as we've previously shared the FDA requested additional bioanalytical data in support of comparability analyses between the drug product using the clinical studies and the commercial drug product. We have completed these analyses and have provided the results to the FDA for review ahead of a BLA.
Mission, which we continue to expect will occur in the first half of 2023.
I will now hand, the call over to Eric to provide an update on our commercial portfolio Eric.
Thanks, Matt It is exciting to see the great progress of our late stage clinical pipeline and the global commercial team is certainly ready to leverage our expertise and broad geographic footprint to bring these important treatments to patients.
Our global customer facing team has delivered yet another strong quarter continuing the significant momentum built throughout the year and closing out what has been a very remarkable year for PTC.
Our lots of ups stays in Europe is building momentum at global DMD franchise continues to strengthen.
We see our global commercial expansion delivering significant growth.
With a fifth product added to our commercial portfolio, we delivered $128 million of revenue in the fourth quarter and an impressive $535 million for 2022, which represents 25% year over year growth for our marketed products.
Let me start with ups data, we are pleased with the initial launch that stater.
Following the approval in the EU.
Last year, we treated commercial patients in Germany and patients in France through the early access program.
Fortunately, we are pleased with the initial interactions with health technology body in France, and Germany, which will further support pricing and reimbursement in the future.
We anticipate continued growth in 2023 by treating patients in other European countries.
Also enabling cross border treatment options.
Lastly to continue the growth.
Will further focus on geographies outside of Europe with additional registration submission and named patient program in Latin America, the Middle East and Asia Pacific.
Our DMD franchise continues to deliver robust results with $140 $14 million in revenue in the fourth quarter.
Which brings our 2022 DMD franchise to $507 million, an impressive 20% year over year growth over 2021.
This remarkable achievement is despite strong FX headwinds.
When calculated in constant exchange rates, it is $539 million and 27% growth.
The fundamentals of the employer business continue to be solid.
Revenue in the fourth quarter of 2022 foreign plot that was $58 million.
This brings total annual and plaza revenue to $218 million, which is a remarkable 17% growth over 2021.
Operational excellence drove continued new patient starts.
Broad access and continued focus on high can play and lower treatment discontinuation.
Turning to Trans Lauder, we achieved $56 million in revenue this quarter, which brings our 2022 revenue to $289 million.
Which is an outstanding 22% growth over the previous year.
Again, despite significant foreign exchange headwinds, we continue to see growth in our main markets now that trend, Florida is in its eighth year of commercialization. Additionally, we continue to push forward with our geographic expansion into new markets in Latin America Middle East North.
Africa and Asia Pacific.
Now turning to take steady and with Libre and Latin America.
The focus we've had on building the foundation of these therapies is delivering results.
We have strengthened our position in Latin America as the pioneers in rare diseases with a recent approval in Brazil for the second indication for we libre and familial partial lipodystrophy.
For FPL.
This is the first treatment for FPL in Brazil.
The first approval globally for Libre for the FPL indication.
As a reminder, we Libra was previously approved for familial.
Carlo Micronesia syndrome, and received category, one innovative drug pricing in Brazil.
<unk> steady we have received our second group purchase order from the Brazilian Ministry of Health, which we expect to fulfill in the first half of this year and our discussions with context continues to progress.
Across the region. We also continue with our geographical expansion with MAA filings for both <unk> and White Libra, and we continue to support and grow our patient base through early access programs.
2022 was a fantastic year for our global customer facing team.
He has set us on a solid trajectory for 2023.
This has been a transformational year as we continue our launch efforts for our spacer Lodge FPL in Brazil, and continue to grow our DMD franchise ahead of our near term pipeline readout.
Now, let me turn the call over to Emily for a financial update.
<unk>.
Thank you Eric I will take a few minutes to review, our fourth quarter and full year financial results. Please refer to the earnings press release issued this afternoon for additional detail.
Beginning with top line results total revenues for the fourth quarter were 167 million. This consisted of net product revenue across the commercial portfolio of 128 million and <unk> royalty revenue was $40 million.
<unk> net product revenues in the quarter were $56 million, reflecting strong growth in most geographies.
Despite significant foreign exchange headwinds.
Plaza had net product revenues of $58 million, representing 22% growth year over year.
non-GAAP R&D expenses were $175 million for the fourth quarter of 2022.
Excluding $14 million in noncash stock based compensation expense.
Compared to 136 million for the fourth quarter of 2021, excluding $13 million in noncash stock based compensation expense.
This year over year increase in R&D expenses reflects additional investment in research program and advancement of the clinical pipeline.
non-GAAP SG&A expenses were 79 million for the fourth quarter of 2022.
Excluding $13 million in noncash stock based compensation expense compared to 74 million for the fourth quarter of 2021.
Excluding $13 million in non cash stock based compensation expense.
Our total revenue for the full year 2022 was 699 million for year over year growth of 30%.
This was impacted by significant FX headwinds.
<unk> calculated.
Dr with $740 million and 37% year over year aircrafts.
This included DMD revenue of 507 million, which represented 20% year over year growth.
27% growth at CER.
I have received royalties for the year grew 108% to $114 million year over year.
Cash cash equivalents in marketable securities totaled approximately $411 million as of December 31, 2022.
Compared to $773 million as of December 31, 2021.
I will now turn the call over to the operator for Q&A.
Operator.
As a reminder to ask a question. Please press star one one.
Taking my question was answered and you'd like to remove yourself from the queue. Please press star one again.
While we compile the Q&A roster.
Our first question comes from Eric Joseph with Jpmorgan. Your line is open.
Hi, Good afternoon, Ms. Hannah on for Eric Thanks for taking the questions. Just a few from US. So first can you breakdown just some of the revenue components in your full year 'twenty three revenue guidance outside of your.
DMD franchise.
Just wondering how youre thinking about the balance of risky NFC that I have a follow up after that.
Yes. Thanks.
Thanks for the question.
Emily you wanted to take that.
Yes, sure I'm happy to take your question. Thanks for looking forward to our guidance for 2023 of $9 $40 billion to $1 billion.
And that obviously reflects continued growth expected in the DMD franchise as you alluded to also growth in that space.
Steve both royalty and milestone there was a $100 million milestone expected for.
<unk> net sales thresholds for Brinci, and then continued contribution of <unk>.
We haven't broken out specifically the contributions of upstairs.
But obviously you know you can see now that Roche has a bursty approved in over 90 countries quickly, becoming the standard of care in SMA, and we expect significant growth going into next year.
Okay. That's helpful and then just moving onto affinity.
Thanks for providing updated data from the running portion I'm, just wondering if you're able to speak to the variance of blood phenylalanine lowering that youre seeing in that run in study and then should we expect any stratification mechanisms or criteria in place based on the magnitude of fee reduction as part of the phase two patient randomization.
Yeah I.
I think thats a good point I mean, one of the things that we always say is that.
The nice thing about.
Endpoint is the biochemical marker so we measure.
And it's relatively stable.
Sure Matt.
Matt do you want to talk a little bit about the stratification.
Okay.
Yes, absolutely.
Thanks for the question. So first just obviously, we're really excited about the updated part one data from what we reported in January we are seeing the overall response rate up from 61% to 65% and the magnitude of reduction for both be nonclassical optical PKU patients is also higher which continues to give us a lot of confidence.
Going into part two in terms of your question about genetic variance I believe that was your question that the enrollment includes really the full spectrum of genetic variance nonclassical classical we didn't do any specific stratification or exclusion based on any.
<unk> genetic subtypes in terms of the stratification for part two we did stratify the randomization for above and below 600 micro multiple leaders. So that was the one strategy as well as stratify for greater than 30% response in the run in phase and 15% to 30% response in the running phase.
Of course, the greater than 30% population being the primary analysis population for the study.
And within the greater than 30%.
Patients now moving on to the primary analysis population should we assume that there is no further stratification based on what <unk> seen and Brendan Horgan.
Correct, we pre defined the strategy that was greater than 600 at baseline for a below 600 at baseline as they enter the placebo control phase.
Great and maybe just one more if I could just wondering about the need or the interest and over enrolling the study relative to your initial study design I wanted to know if that was born out of feedback from any regulatory agencies.
Yes.
Okay.
Go ahead.
Yes.
That had nothing to do with regulatory interactions. There was agreed upon protocol is agreed upon with the FDA at ebay prior to the start of the study is really reflected significant interest on the part of the patients and the physician.
I think as we've talked about this clear unmet medical need and desire for safe and effective therapies and what we saw was just really significant interest from centers throughout the world and as the over enrollment and the delays in getting to data really comes from the fact that <unk> had and it was still a large number of investigators key kols who had patients.
We want them to get into the study and of course, we believe that the greater number of patients only strengthens our heightened probability of success in the trial.
Okay very helpful. Thanks for taking the questions.
Thank you. Our next question comes from Kristen <unk> with Cantor Fitzgerald. Your line is open.
Hi, everyone. Thanks for taking my questions and congrats congrats on the 25 year milestone.
First question I had was for PKU can you give us your son or preliminary thoughts on what the payers response might be whether there might be a generic kuban step edit or perhaps how it could differ across different populations doses classical.
Yes.
Yes.
Yes, a good point and I think you need to remember that well.
Yes.
The first drug it ahead.
Large patient population then it was ineffective to and what we see is that approximately if you look at maybe <unk> Z Kuban together, it's still probably.
Close, but not not exactly 10% of the overall population.
You have a huge patient population of patients.
Are not satisfied with the current treatment right. So the 58.
PKU patients globally.
That makes it a really pretty significant.
Opportunity to be able to to be able to bring these to bring a new therapy.
That is that we believe is much highly effective you could see that.
Getting 60 over 65% in the overall patient population.
61, 5% of the classics.
There are nearly the same just.
Showing you how effective.
When you consider what PKU.
Before we didnt even function.
Classical patient.
We think it's pretty clear that.
A superior product.
So I think.
So many patients where the drug effect that we think we're in a really good Bob.
For this and so we don't think we don't expect any.
Step edit.
Classical PKU.
So well known.
Sure Greg.
And even if there is.
Step edits.
Patients.
Walk through proven there's already.
A fair number of those patients who've already tried and failed.
And well documented and even if even if they haven't.
It's a very short period of time.
Got it.
Function.
So I think.
You have a real.
Yes.
I don't think thats going to be cumbersome or difficult.
Yes.
To be able to handle.
Kind of if you have anything to say also.
You've done a fair bit of work on payers.
Yeah. Thanks, Kristen for the question I think it's a really important one and as Jay said, we really do believe in the substantial unmet need that exists in the PKU market place.
And I would stay with talking to we started to begin a number of different payer engagements to ensure we understand sort of how they're looking at a data package and from that perspective, It's David Chang.
If you look at the classical PKU patients Kristen there has been no effective therapies in that space and so from that perspective, we don't see any types of step edits the requirements to be able to put these patients on treatments and I assume the doses.
The space, where they've previously tried to them even if they were step edit to generic <unk> plans and the cases preventing generic.
We don't see this as a major hurdle because in many cases, they try it and say, okay that and therefore, the documentation has been established and even if it needed to be re establish it as a quick and efficient Scott and the sensitivity of blood based biomarker.
But to put the patients on treatment established treatment isn't working.
Based on line some are more effective therapy, and so from that perspective.
We're very confident going into the commercial landscape that we have the right dataset and the right data package, assuming success with infinity to hit the ground running.
And we don't we don't we don't look at them.
Even with the generic.
<unk> with a drug that had a very small window of patients to treat.
But most of it.
The patients were successful and so we plan on.
Bringing.
A new therapy.
These patients.
Hey.
Well it will be more successful on this therapy, it's very different than fighting with it.
You guys have a generic and youre trying to get.
A piece of that pie.
We're actually.
We believe that we'll be able to treat patients were able.
Able to be treated before.
Okay. Thank you Sue and Kylie.
I think of your late stage candidates Mdas, perhaps gets less attention compared to you, especially like PKU in Huntington's disease.
Maybe can you reiterate for US why you remain excited about the program potential here and how you think about the commercial opportunity in <unk>.
Ease of finding some of these patients should it be successful and ultimately approved thank you.
Yes, we think we think particularly known for very important.
A new therapy in part because it really does echo.
A new area in terms of the <unk>.
<unk>.
And that is really sort of mitochondrial dysfunction.
Consequence of that.
Think about.
Uh-huh mitochondrial dysfunction, when you think about that.
The amount of ETP that's produced.
No.
It looks like 15.
ATP molecule.
And if things go awry.
This regulation.
Enhanced.
Free electron.
All sorts of stress on the cell.
That causes of both.
It can cause havoc.
<unk>.
Booking neuro inflammation and things like that and the consequence of the.
The consequence of that.
Yes.
It's big and when you think about quickly.
Like in the brain.
It's the only a three Portland, Oregon, but.
About 20%.
Of the overall.
Within the body it can be quite dramatic effects and you can see that.
Congress.
With associated seizures, So I think.
Having a drug that can modulate.
Through.
Novel, and New Mexico.
Martin.
Excited about that because it can be really quite broadly.
Do you want to talk a little bit about maybe.
So excited about it.
Yes, Christine Thank you again for the question.
Well, maybe it's not getting as much attention. This is a population thats.
No Nick has over 20000 patients worldwide with mitochondrial disease associated seizures and as Steve mentioned this is just the beginning.
A population that could benefit from a drug that targets. These fundamental excess oxidative stress inflammation pathways that are causing disease.
We have confidence in the study it's built on a number of previous studies showing that we can have an important effect on seizure activity. Both in terms of seizure frequency and other seizure related morbidity and we believe that this can be a very important therapy not only from our concho to these patients patients with future taxes, but many others.
Thank you.
Thank you and our next question comes from Brian Abrahams with RBC. Your line is open.
Hey, guys. Thanks for taking my question and my congratulations as well on 25 years.
I was wondering if you guys could expand a little bit more on the nature of your discussion with the agency on Trans Laurence.
Curious to learn a little bit more about I guess, what their reaction initial reactions were to the the full four one data plus the stride registry.
Seems to be the sticking point and I guess, what gives you confidence that dystrophin and some of the other analyses would support approval and is this something that would be a potential accelerated approval, perhaps thanks.
Yeah, So yeah, we recently.
Yeah.
Formal discussing that will allow us to lead.
Setting up a meeting with them and it really was the notion of.
Okay.
About <unk>.
The overall package and the mechanism of action as well as why we think we have clinical benefit as a consequence.
Matt you want to go through this a little bit.
Yes sure.
Alright. Thanks for the question so just to take a step backwards.
I think most of it.
Most of you recall after we had the trip.
Ofer one data we have requested a type C meeting with the FDA to discuss <unk> 41, as well as stride in the pooled analysis from including study 770 <unk> 'twenty.
And the agency informed us that we would have a meeting with written response only we had asked to be able to have a live meeting given the volume of data and they said that they would provide written response only comments, but we would have the ability to talk to them. Afterwards, if we still have questions.
We did have questions. After the initial feedback which seemed to focus mostly on study <unk> hundred one itself not meeting the bar up substantial evidence of effectiveness, but clearly there is evidence of benefit in that study and when combined with 77 study <unk> see highly statistically significant and consistent improvement on the key functional end points of disease and then as you mentioned also the <unk>.
Stride registry.
This meeting was a live meeting offered as a clarification of the comments that were made in the type C. Written comments and again a lot of that discussion.
It was about why 741 wasn't believed to have substantial evidence of effectiveness, we talked about totality of data and it was suggested that we could request.
Type C meeting to discuss totality of data, including the mechanistic dystrophin data because the comment in our meeting with me that we had shared those data, which as you. All know we had those data, but actually focus on the functional benefit that was at <unk>, one and Kim afterwards, so we see this as an opportunity to again highlight not only 41% to <unk> 41.
Alongside the other placebo controlled studies from the stride registry have benefits.
Demonstrated in the course of a clinical trial are translating into long term meaningful benefit as far as delay and to keep more of a transition states. The disease lots of emulation lots of pulmonary function and then bring it all the mechanistic data we have from 745 in the laboratory gains as well, which really confirm that we have.
Novel mechanism of action in terms of nonsense suppression and that's yielding dystrophin production, which is also associated with the clinical benefits recorded in all of these studies.
That's really helpful. Thanks, Thanks, so much and if I could just squeeze in a quick follow up.
The PKU program I think the ways to measure that.
I don't mean levels in modern studies are more reliable and.
But I was wondering if you could maybe just clarify the way C is being measured in the phase III relative to the <unk> studies and your confidence that the assessment of fees.
<unk> robust enough such that you wouldn't have pseudo responders, whose reductions might drop off between the open label run in the randomized portion has had happened with some of the old Kuban studies. Thanks.
Yes.
Go ahead.
Yes, Brian we are using blood spot.
So that is done at home.
This has been very well validated as a robust measure I think we have confidence that obviously, we're using the same methodology and both the run in phase in a placebo controlled phase and also it's important to note. The way we measure these fee responses, which in a running phase they are treated for 14 days, but we're averaging three different.
Time points, 510, and 14 days, which gives us the value of production. So it's averaged over three points, which is another effort to ensure we're getting an accurate and precise.
Assessment of the fee reduction so this is Tim.
Method thats been well well designed well validated and we have a GOP laboratory consistent measurement in both the run in a placebo controlled phase I can't comment on specific differences to the methodology that was used with <unk> that can provide the confidence that we have a very well.
The validated method that can provide both accurate and precise assessment of the fee.
Changes over time.
That's super helpful. Thanks, Matt.
Yes.
Yes.
Thank you. Our next question comes from Joseph Thome with Cowen Your line is open.
Hi, there. Thank you for taking my questions.
Maybe just one we're going to see some registrational data set here in the first half, which is great and hopefully some of these are more all of them are successful, but as you did.
Bringing these in is there anything else that you would need outside of the Registrational data before a regulatory submission. So essentially can you just comment on your comfort with the CMC as it stands right now.
And the size of the safety database for.
Sort of the next three that are coming up here that'd be great. Thank you.
Yes.
You want to take that.
Yes sure. Thanks for the questions Joe So obviously all both compounds.
Cepheid taryn for PKU as well as particularly on have been in development for a number of years, which has really given the opportunity for the other components of the package. When you think about CMC and you think about non clinical claims farm for those portions of the package to get sold out.
Obviously, you had conducted a fairly large study in PKU now reset the tariff to that and we believe based on this trial on the other data.
Had been collected Secretary studies that will have the sufficient database to support submission with positive trial and it was particularly low and I think one of the.
Clearly foundations of that therapy is the extensive safety record that you recorded in kids over the past decade, including patients who were on drug continuously for over a decade with very strong safety profile.
Are you seeing together for both therapies. We believe we have all the components of the package, obviously well with positive data, we will meet with the agency to rely on the details of the <unk> submission and then move forward as quickly as possible.
Great and then maybe just a quick follow up maybe on the financial side in terms of the financials and guidance for 2023 is there any additional build in the U S.
Marketing force anticipated this year or that would be more of a 'twenty 'twenty four spend item. Thank you.
Yes.
Emily.
No sure.
Take that one on the spend side and then commercial lines Jonathan.
Infrastructure, we're pretty well sized on the commercial question.
There is no significant change in the.
And on the U S.
South Florida.
Great. Thank you very much.
Thank you. Our next question comes from David Lebowitz with Citi. Your line is open.
David Lebowitz with Citigroup your line sorry.
The name.
It.
Sell out for a moment.
I guess question number one on the <unk>.
<unk> three data.
How should we benchmark response rate.
Compared to <unk> given that.
Patients were on a fee restricted diet.
Which would be expected to deepen the overall response.
Yeah. So.
I think what we're asking for is for people.
Direct selling.
Of what they're on.
I think overall, what youre seeing within the.
The results are.
Pretty dramatic results.
Greater than 60% both in the classical as well as.
The other forums.
<unk>.
So I think you're seeing.
Okay.
Tiffany.
Thank you.
Hi.
I feel we're in a.
And if it's deeper than the other way.
I think youre still seem pretty high response rate that you have.
Yeah.
Yes.
Got it.
Yes.
Thank you for the question and there are these patients all tend to be on fee restricted diet and the key in both studies, obviously is to have them on <unk>.
System diet, so that's not a confounding variable, but I think what we're seeing in terms of differences in magnitude of effect is quite impressive if you look at the.
Phase, one which was that the Kuban responder study when they recorded a greater than 30% change in 20% of the patients and obviously now we're looking at 65% in the study. So I think this is clearly a.
Much higher response rate and again, what we've talked about is really what you would expect from a mobile available co.
Cofactor.
Obviously in the phase two you said.
A continuous diet.
Thank you for that and would you be do you do you expect to specifically report.
Response rates for classical PKU patients.
Yes, you mean overall will be at the end of the day, we'll break that out as well.
Excellent. Thanks for taking my question.
Thank you. Our next question comes from Kelly <unk> with Jefferies. Your line is open.
Thank you so from meta data now in Q2 could you have two set of expectation.
Kind of a reduction of seizure frequency would it be considered a clinically clinically meaningful and what Adam errors. We should also focused on to evaluate the clinical benefit.
With Docomo.
And then lastly.
Given that the mitochondria disease is a very heterogeneous disease.
What do you expect this time Gustaf for patients with Mr. Tadlock, Gino Todd just a greater benefit.
Based on the mechanism of action of <unk>.
Thank you.
Sure Hey, Matt you want to take that.
Sure. Thank you again for the question. So when we talk about benefit in these patients.
First we have to think about the disease itself. So obviously mitochondrial disease associated seizures are highly morbid common aspect of the disease about half the patients by the Congress have.
<unk> seizures and these seizures don't tend to respond the typical anti epileptics, because the typical anti epileptic don't.
Target the energetic pathways that cause seizures in those patients in fact, many of the traditional anti epileptics are mitochondrial taxes. So they actually make the disease worse. These kids have seizures that are refractory to typical meds. They can tap tens hundreds even up to thousands of months. So.
High seizure volume, it's a highly morbid aspects of the disease, which frequently leads to aspiration pneumonia and other infections often can be the cause of death in these patients.
So when we think about the meaningful reduction there most of the physicians, we seem to think that even at 20% to 25% reduction in seizure frequency. These patients can be important we've powered the study for a 40% differential reduction between the treatment group and placebo group.
A hypothesized reduction of 50%.
His seizure frequency and the active population and 10% of the placebo population.
In terms of differences between genotype and response.
Given the fact that particular, one is targeting 15 lipoxygenase, which is a common response pathway.
<unk>.
Outside of the mitochondria the treatment effect.
Should be agnostic to underlying genotype and might there be other patient characteristics, such as age and stage of disease that could contribute to differential therapeutic response, that's possible, but one of the things we've observed in previous studies.
No specific.
Recently sonship between genotype of Disney subtype in response again, because we're targeting element comment response pathway comment to all different causative genotype.
Deepak.
Thank you Super helpful.
Yes.
Thank you. Our next question comes from Zain Ahmad with.
Bank of America. Your line is open.
Hi, good evening, Thanks for taking my question.
Maybe one.
Point of clarification for transplant.
I think that you've talked about the totality of data as being the premise for a lot of discussions recently with the agency, but I guess as it relates specifically to dystrophin.
If the agency for dystrophin.
Dystrophin is part of the package can you just remind us when the last time, Mr. Finn was measured in any of your trials to date and how many patients worth of data you might have on that.
Yeah sure so.
So the way.
Obviously the way.
You got to remember all of the dystrophin.
When we measure we measure.
W O four.
Which was the first.
Got it that we did take a look to see.
Proof of concept study, where we showed that the <unk>.
Published paper.
Where we showed that you saw increased level.
Of dystrophin.
And that was it was a small study I think.
15 16.
Patient somewhere around there and then we did study 45.
Did it again steady at 45.
How many patients worth of minutes you remember.
So we had 20 overall and they were <unk> 18 in the analysis population population.
Okay. So we have those that yeah.
Soon.
And then we have obviously from a clinical point of view.
Studies from <unk>.
Seven.
<unk>.
741.
A large number of patient.
In the ICT population.
Especially in quarter, one we saw a clinically significant.
Results and then not only was it.
As Matt said before.
Not only was good.
Not only not only.
Pause there, but it was also positive in the North star at the time function.
And that was true also in study one.
And as well as multiple endpoints.
Seven.
There is a large body of data that demonstrates.
Trends lagonda as activity in terms of <unk>.
So thats been consistent with.
The stride registry.
<unk>.
<unk> looked at harder endpoints.
Loss.
Ambulation loss of getting awful.
Being able to get all the stand from the ground.
And la for.
Pulmonary activity and then all those Grupo demonstrating thank you.
Sure.
The ability to walk that preserves the ability.
Get off from the ground by year end.
Preserves the ability.
To preserve pulmonary function.
You put all that together.
I have not seen a better clinical package.
And then the one we'd have.
We believe it's pretty clear that patients.
Benefits from it and you can see that patients have been on it for now.
Quite a long time, so we believe.
Have patients from.
From around the globe get a trend, Florida, and we only think it's.
Appropriate.
Fair.
That does that.
Should work.
Getting patients in the United States this drug.
We're really asking for.
Look we'd like to.
We think that we have a strong package, let's review it.
Pfizer's Committee.
At least give us.
Jim and not just for us but.
Patients and their families.
Or fear here so.
The folks who've been and frankly, many of them do not it broke.
Over a decade now.
Yes.
Yeah.
To give them their due on what we think is a highly active drug.
Okay.
Okay. Thanks for all of that color.
At this point, what do you think needs to happen to get the agency over the finish line for them to say that you should apply for our profile.
They looked at all of this data already as part of your written interactions.
Yes, so were.
Look.
Thank you.
We've had years now.
Of working with the agency.
Not talking to them and.
And it has not kept up its been Oh.
Whole community.
Holy had written discussion.
And uncomplicated result.
With a large body of data.
And they have plenty of new people.
There may not understand the whole picture.
And not to actually I simply don't understand but not to have.
Interaction, where you have communication.
Can you talk through it and just like everything else.
That we do in life.
You need to be able to go back and forth.
To your point of view that and that's how you can change people's minds or at least have a shot at it.
One doesn't have to be sure.
If it's every three months you get the right response.
Two questions right. So.
That at least what we.
We need to do it.
Have a conversation and see where that goes.
Okay, and do you think that that will be sooner rather than later or do you have to wait the extra three months just as Scott Your line.
It takes time this is the.
The nature of regulatory discussions you put it in and there is time for them.
Two.
Okay.
Got it thanks for that appreciate it.
Sure.
Thank you. Our next question comes from Gena Wang with Barclays. Your line is open.
Thank you for taking my questions I have two questions regarding affinity study.
First is just a clarification regarding the HUD your 56 patients.
What these patients actually pass 50% reduction.
Screening test.
156 patients as a total patient screen, if it's March 56 patients across 15% fee reduction what is the total patient numbers.
Okay.
Matt do you want to take that one yes.
Yeah, sure Hi, Gena.
156 refers to all those who went to screening and then completed the running phase. So that's 156 subjects or received two weeks of Cepheid taryn.
<unk> hundred 56, 102, or 65% had a greater than 30% reduction.
So out of 156, how many of Ge's achieve 15% reduction.
So of the 100, so that 102 had over 30% and 13 had between 15 and 30%. So in total that would be 115 or about 75%, 70%, 75% at 15.
<unk> reduction at above, but obviously far and away. The majority of those 102 of those were greater than 30% reduction okay.
Okay very good very helpful. And then my second question is can you remind us the rationale of dose escalation.
Two weeks each of the 20 milligram 40 milligram 60 milligram part two study.
Okay.
Yes sure.
One of the things we're studying obviously at the agency always likes to understand his exposure response relationship. So by doing that two weeks at 20 milligram per kilo two weeks 40 milligram per kilo 'twenty two weeks at 60 milligrams per kilo, we can have a very nice curve and understand the relationship between exposure and response, which is important for regulatory purposes, we believe that.
Dose will be 60 milligrams per kilogram and we're also very confident that two weeks is sufficient to understand what the effect at each dose level will be.
Thank you very much.
Thank you. Our next question comes from Jeff Hung with Morgan Stanley . Your line is open.
Hi, This is Mike <unk> on for Jeff hung. Thank you for taking my questions first one once the upcoming affinity data readout in May can you remind us how youre thinking about the cadence and timing of regulatory events and we have a follow up after that.
Sure.
Our goal.
As we will get the returns.
<unk>.
And then based on that we'll obviously report out through both so publicly and then as rapidly as possible.
Set up meetings and get ready.
Sure.
For the product.
Ready for regulatory guidance.
Possible, obviously, we'll do a pre NDA.
Maybe.
And while we're doing that we'll be getting all the documents ready to go.
Yes.
I think as Joe.
Finishing up.
Last patient out Matt do you have any thoughts on that.
Yes, yes.
Yes, Michael it's really a question of having now knowing exactly when that last patient last visit is going to be which is going to be in March and then having sufficient time to do all the database cleaning the database lock and then getting to Dana. So it's really a refinement of the timeline now that we know the definitive last patient last visit date.
Okay.
Awesome. Thank you.
Thank you. Our next question comes from Paul Choi with Goldman Sachs. Your line is open.
Hi, Thank you good afternoon, and thank you for taking our questions I have two two pipeline questions. First is on affinity can you just maybe elaborate on the updated timing from may of this year versus your prior guidance.
And can you maybe speak to any geographical differences with regard to.
Practice in clinical treatment of PKU patients in the U S versus our U S that we might look for as your top line the results.
Later this year.
Sure.
So I'll just take the first one.
Talked about this.
The timing really has to do is.
At large.
Finally, the timing of when we would complete the trial had a lot to do with yes.
There were a lot of patients at the end of the.
When we are nearing.
The trial.
And what we've decided to do is the number of people that we wanted to make sure that some of their patients got it in some of the Kols.
Would be able to do that.
<unk>.
We actually brought in more than we thought.
And that extended the timeline to.
Getting the results, which we think nobody.
Everyone's in the trial now and so we were able to give a pretty good time.
On when we'd be able.
To complete the trial, so we feel pretty good about that.
Exactly where we're at.
We will complete the trial.
In terms of.
Geographical differences.
Matthew on any comments you wanted to make that known.
Yes.
<unk>.
Paul We really don't expect geographical differences, while there may be different guidelines in terms of target fee reduction and region to region. The practice is fairly consistent worldwide and obviously this is a disease, where the cornerstone of management is for now diet modification.
And that starts at birth newborn screening is in place.
In many places around the world. So we can certainly look at whether there's a differential response based on geography, but it's not one that we would expect our priority.
Okay.
For that and as a follow up on 518 for Huntington's can you maybe comment or update us on what.
Feedback our data you've provided to the FDA and just what your current expectation is for getting the clinical hold lifted there.
Yes.
As we've discussed in the past.
Go.
No.
Sure with them.
Some data that we're getting.
Current patients and go back to them with that.
We will be doing.
And we think that.
No.
Clinical data set of patients.
We can then go back and talk to them.
And so that's what we're doing.
In terms of that.
Opened up obviously.
A fair number of sites around the globe.
And.
So patients are coming in what had been expanded.
To take an additional cohort of patients.
So we feel pretty good about bringing a man.
And then well you know.
We will bring in at some point when we have it.
Set of data that we're going to talk to the FDA about and show them that we're in pretty good shape.
Mind, everyone, we're doing the 510.
Milligram data.
We will be able to the 20 milligram data and we'll be able to bring.
Okay.
Did the FDA at some point so we opened it up in the U S. That's our game plan.
Okay. Thank you and congratulations on 25 years.
Alright, Thank you Paul.
Thank you. Our next question comes from Danielle Brill with Raymond James Your line is open.
Hi, guys. Good evening. Thanks, so much for the question just a couple of clarifying ones for me.
Last month at Jpmorgan.
They did or key revenues for a day's worth $13 million is that number still accurate and should we be expecting the.
The spillover from the 20 to 40 million you previously guided for <unk> to be reflected and Q1and then just a clarification on translarna.
<unk> is well the type C meeting that you plan to request for this one be in person or are you expecting just written meeting as well. Thank you.
Alright.
Yeah. Thanks, Thanks for the question.
And so let me take it.
In Florida.
Uh huh.
We anticipate this to be.
<unk>.
It means that it will.
About 10%, so it's not going to be.
It's not going to be written.
And I believe it's going to be.
<unk> isn't that right.
We grew annual request.
Request, a live interaction, obviously and I know that the agency now started having in person meetings again, so the exact details.
Danielle whether this is doing whether its following whether it's live.
I wanted to do it another way obviously, it will be up to them and we'll know better once we submit any question and get their response.
Yes, obviously, we would be.
We believe that's the most effective form of discussion, but obviously this is going to be up to the agency and theirs.
Yes.
And then.
In terms of.
Obviously the.
Patient finding.
In terms of.
Most of what we do is focus.
Thanks for your patience.
And certainly we remain confident that.
Yes.
Good.
In terms of the number numbers.
I don't think there were any changes going into 2022 number.
And we'll probably provide more color.
How were doing.
Early with the launch right.
We will be able to provide more color on that.
Each of the quarterly calls.
Certainly I think Q1 earnings call.
We will provide more color on that.
Currently.
Do you have anything else to answer that one.
Thanks, Joe Yeah.
Daniela there was no changes to that.
The numbers that states what.
What it did.
Thank God, we're continuing to focus on patient identification.
Continuing to focus on securing pricing and reimbursement in a number of different countries across Europe .
As we told you that in January focusing on looking at named patient programs outside of Europe .
Renewing according to plan.
As Eric mentioned earlier, we're seeing strong engagement with payers a question number of different hedge to everybody's in.
We look forward today advocate continue that question around investments that to treat more patients and we plan to provide more updates.
Coming quarter earnings.
Yes.
That's helpful. Thank you.
Thank you. Our next question comes from Robyn Karnofsky Truest. Your line is open.
Hi, This is Alex on for Robyn.
We had a question on if there had been any updates into the patient finance are patients identified for ADC, perhaps days adds but it sounds like we're all going to wait till the first quarter.
To get some more results on that.
Correct me if I'm wrong. We also wanted to now turning towards the U S. Can you remind us of the pre launch initiatives are ongoing for <unk> and what additional initiatives may still be needed as we approach BLA submission and anticipated future launch. Thanks.
Yes sure.
Hum.
Eric do you want to take that one.
Yes, yes sure. Thanks I'll answer the question.
Currently are seeing the dynamics in Europe , but we're also preparing for the launch.
Some of it stays in the U S. In a similar way we have a dedicated team that's actually doing that we have focused on.
Key areas, including accelerated disease awareness, we have a number of key programs, including advisory Board symposia and publication of key publications and peer review that have been in.
In English is also a U S based journals.
We're talking to payers as well in the U S and preparing for this launch we're talking to a number of key payers.
The design, because we know that there are gene therapy.
Currently approved in the U S.
But many of them are replacing standards of care Philips days that will be the standard of care.
So we're taking an approach to really understand how the payer view will be on that.
We have accelerated a number of patient finding activities, particularly in the high.
Enriched populations.
And looking at Barry I'd also ethnic type groups, we have.
Already.
Our target is to prepare somewhere between seven and 10.
Surgical centers to be ready at the time of launch and.
And importantly, this will be.
This will be timed any centers will be timed with the time to watch will be able to to work very closely to bring in these patients. So overall I think we're very pleased with the progress we're making outside of Europe , but we're also sharing a lot of the knowledge from the from the launch itself.
In Europe , and we're sharing that that continuous learning and execution that we have with the U S market.
Following the BLA approval, we'll be ready to launch the product in the U S.
Okay.
That sounds great and and.
And also on the same notes now that there have been patients treated.
In the real World setting do you find that the clinical results. The early still early clinical results that youre seeing and detailed lumped procedure matched that of the what you saw in the clinical trial or are there any key differences to note.
Yes.
<unk>.
Look.
The nice aspect of.
ADC deficiency in that.
Gene therapy.
Have as well.
It is truly a transformational.
A transformational therapy wear.
And as you've seen.
All of the patients have performed better in their patients.
Lee.
While they were growth arrested.
And weren't able to.
They're ahead of current turnover.
Standard thought.
And clearly you can see some patients.
We have one patient who speaks three languages.
So thats been exciting and.
We continue to see.
And a substantial improvement in these patients so there is.
As we always say that nothing more.
Ratify.
Then.
In part.
Or a drug therapy, and bringing it to patients.
Having such a transformational effect on it.
You bet.
It's great for the family to see what it does for the family.
<unk>.
For our own community for Jeff.
Just being part of <unk>.
So we're excited about it and it continues to be a transformational product.
Yeah that sounds fantastic.
Congrats and thanks for taking my questions.
Thanks.
Thank you. Our next question comes from Colin Bristow with UBS. Your line is open.
Hi, This is <unk> on for Connie Thanks for taking all the questions we.
We have two clarification questions. So the first one is on the PKU data.
Congrats on the <unk> data and could you. Please give us some more details colors on the primary reason for the top line data from H, we knew and like you have already.
You get a lot of stuff it looked like for the power one.
And gentlemen was as planned and it has a fixed timing endpoints. So I'm just wondering what the.
<unk> now behind it.
And the second question is on <unk>.
PTC filed by H Huntington's disease program.
I'm just wondering have you heard any updates on especially if the requirements from FDA, yet and how long will it take to get the data and also in terms of like X, you're asking gentlemen.
Have the high dose portion already start here. Thank you gentlemen.
Could you please clarify on that thank you so much.
I think if I.
It was a little muffled I think youre asking why.
Is it in May was that the question.
So I think the answer so I think.
Maybe just so we're clear the reason is it was.
The the end of the study really occurs when the last patient last visit.
Fleet at that aspect.
Got it and Thats when all the patients are completed.
And clean the data and ultimately get it annualized.
And really what happened is at the end of the road.
A large number of patients at the end of at the end of the study that we're going in and that's always.
In a way a little bit of an air traffic control nightmare that'd be able to.
To get to a bring in as many patients as you can and close it as rapidly as possible.
And so.
So that makes it.
Okay.
We're balancing.
Wanting to close.
Trial, but also wanting to make sure that.
Patients got it.
Got it.
Patients from multiple physician.
Get into the trial.
And so that we don't hang or anybody because they werent and part of it.
The trial and so thats that.
It's always a little.
It's difficult sometimes.
Precisely land the plane at the time, you think youre going to do it in this one.
In particular much more at the end has lots of patients and that's why.
The timeline move from where we thought it would be too.
It's a little bit longer, but we've gotten a lot of.
Okay.
We have a lot of the patients from.
People.
All of it.
Key opinion leaders and investigators so at the end of the day, the small chains, but well worth it because we have.
Everybody in this study and we feel good about it.
So I think that at the end of the day, that's what we're comfortable with.
And well worth the small amount of climate change to get everyone made it so that.
Okay.
Because the one eight.
We're now collecting data, we haven't said yet.
When we're going to clean the data and go back to the FDA, but we plan to.
To do this and when we do we'll let everyone know.
What our plans are but we haven't done that yet.
I don't think we've set it up.
Let's say when we're going to complete that anything else like that.
Right.
Yes, I would just add a couple of things.
All right.
Just as a reminder, this was feedback that came from the non clinical data that we had committed to the agency that was reviewed at the other agencies.
As we've said all the other countries have allowed us to start the study at five and 10 milligrams for a year and even start with 20 milligrams up to a year and the FDA simply ask for some additional data to support the dosing and duration that we wanted and as Steve said, we're in the process of collecting what we think will be the Puget data to do that which is clinical data so real data from.
Patients that can give them.
Comfort for the dosing and duration, we want to use in terms of your question regarding the initiation of the higher dose of 20 milligram cohort that Hasnt started yet as we said we want to look at the data from five milligrams to 10 milligrams and really make a data driven decision based on what we're seeing in terms of pharmacodynamic effect that is reduction in peripheral mrna.
Huntington and protein Huntington protein reductions were fully in the bio distribution in terms of CSF exposure. Once we have an understanding of what that looks like at five and 10 milligrams will then be in a position to make a decision regarding <unk> and the 20 milligram cohort and so we look forward to.
Having those initial five and 10% of our data to help inform that decision in the near future.
Yes.
Got it very helpful. Thank you.
Thank you there are no further questions I'd like to turn the call back over to Stuart Peltz for any closing remarks.
Okay. Thank you. Thank you operator.
In closing I'd like to thank all of you for.
Joining the call today, and your well wishes for 25 years.
Do you think about that.
Especially excited about.
Where we stand today and see where we are.
As you can see strong and accelerated in revenues from our product.
Portfolio.
We have four data Readouts first alco.
2023, including three.
Registrational study.
Clearly we're firing on all cylinders.
And we look forward to more updates for you over the.
Coming months.
Thank you for staying on.
Good evening.
Thank you for your participation you may now disconnect everyone enjoy the rest of your day.
The conference will begin shortly to raise and lower Johan during Q&A, you can dial star one one.
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Okay.
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