Q4 2022 Alnylam Pharmaceuticals Inc Earnings Call
Thank you for standing by and welcome to the in Ireland pharmaceutical scorecard of 2023 find natural results conference call.
As a reminder, today's conference call is being recorded.
<unk> had a conference over to the company. Please go ahead.
Good morning.
Senior Vice President Relations and corporate communications that on an island with me today on the phone or Green Street, Chief Executive Officer told the <unk> Church to.
Too commercial officer.
Guard Chief Medical Officer.
<unk> Chief Financial Officer.
For those you participate in a conference call will be accompanied by its gonna be accessed by going to prevent infection.
Faster pace of our website investor's dot on an island dot com slash events.
Today's call is outlined in five to provide introductory remarks and general contact.
<unk> will provide an update on our global commercial progress.
For school will review pipeline updates and clinical progress.
Just to review our financial some guidance followed by a summary of upcoming milestones before we open the call for your questions.
I'd like to remind you that this call will contain remarks concerning on an island Street your expectations plans in prospect, which constitute forward looking statements for the purposes of the safe Harbor provision under the private Securities Litigation Reform Act 1995.
Actual results may differ materially from those indicated by these forward looking statements as a result of various important factors, including those discussed in our most recent periodically report on file with that these days.
In addition, any forward looking statements representative you only have the date of this recording it should not be relied upon as representing are viewed as any subsequent date with specifically disclaim any obligation to update such statements.
With that I'd like to turn the call over to Ivan Ivan.
Thanks, Christine and thank you everyone for joining the call today.
2022 is an excellent to hear what's on the island, where we delivered impressive commercial performance and made significant advancement across a broad pipeline.
Therapeutics.
Commercially as pre announced in January we achieved full year 2022 next product revenues of $894 million, which represents year over year growth.
<unk>, a 35% 40.
43% with confidence exchange rates and 17% growth between the third and fourth quarters.
A tailwind to the success with the approval and launch a food truck and the U S, Germany, and Japan for hereditary atti amyloidosis patients.
Where rapid uptake among physicians and patients reflects it's attractive product profile.
With our pipeline notable progress during the year included the exciting results from a polar B R. Phase three study <unk> for ATT amyloidosis patients with cardiomyopathy.
The S M. B a based on these results have been accepted with a producer date of October the eighth and we look forward to the F D as review and potential approval later this year.
<unk> will provide more color on this later and Nicole.
Among our audio programs a highlight for the year with the initiation of the first human study of Ironized therapeutics of the CNS with a L. N. A P. P for Alzheimer's disease. We also completed three CCA filings advancing to the clinic promising programs such as a O N K H K for type two diabetes.
<unk> <unk> and <unk> for ATT amyloidosis, and will be announcing today that does things has started in a phase one study with this program.
Looking forward to the rest of 2023, we're excited for several important pipes blind milestones, including 10 clinical Readouts from Alnylam and partner led programs such as phase one results from the aforementioned alien ATP study in phase two results from the cardio hypertension studies of <unk>.
This execution is in line with our focus on the following key drivers from items growth over the next several years.
First is the potential need some expansion of our ATT, our franchise opportunity, where we aim to become a global leader and delivering impactful and highly differentiated medicines to patients.
<unk> is our expansion beyond rare diseases to also address more common disease areas.
And the third growth driver for the company comes from a sustainable innovation and Jenna comprised of new platform enhancements opportunities with extra hepatic delivery and our ability to find new genetically validated targets, which could drive further pipelining expansion to 2025 and beyond.
We believe all of his positions as well to deliver on a nylon pizza fifth by 25 goals, making an item of top tier biotech developing and commercializing transformative matched us for rare diseases and beyond for patients around the world driven by a high yielding pipeline of first.
And or best in class product catheters from our organic products engine, all while delivering exceptional financial results with that let me now turn the call over to Tolga for a review of our commercial performance toga.
Thanks, Ivan and good morning, everyone.
Our commercial operations had a strong close to 2022, delivering 262 million and combined net product sales in queue for which you presented 13% growth compared with Q3 2022.
The strong growth was driven by an increase in patients so commercial therapy across both are GTR annual career franchises.
We remained particularly encouraged by several signs indicating that this ongoing launch of on Butcher for <unk> doses patients with Polyneuropathy both in the U S and now also in Germany, and Japan is expanding the size of a dual portrait for our city our franchise.
Now I will turn to our specific results.
With our TCR franchise.
We saw robust growth in our city our franchise in queue for achieving $191 million in global net product revenues for on petrol and <unk>, representing a 12% increase compared with the first quarter and a solid 48 per cent growth compared with two four.
2021.
The year over year growth in Q4 was driven by the strength of which are launching the U S with the U S market delivering an impressive 72% growth compared with Q4 2021.
At the end of 2022 over 2975 patients were on commercial and personal aura of what's our treatments worldwide an increase of nearly 400 patients from the end of Q3, which your presents a doubling of the quarterly trends that existed prior to the launch of.
<unk>, a clear signal of accelerating ctr franchise growth.
In the U S combined sales of armed patrols and I will try to increase 12% versus the third quarter.
We're primarily impacted by the following.
And robust 19 per cent increase in demand growth, which was driven by the strength of the what's your patient uptake, which should be driven both by switches from El Paso and more importantly from increases in patients new to therapy.
On Patrick inventory Destocking and the channels during the fourth quarter reduced reported GTR growth by approximately 5%.
This was anticipated the demand for on pets or in the U S continues to decrease as more patients switch to Alberta.
In our international markets combined sales of home Petzel, and which are also increased 12% versus Q3 2022.
Primarily driven by the success of initial international.
Launches in Germany, and Japan with growth favorably impacted both by increased patient demand and initial launch Starkey.
Finally, our global results continue to be challenged by foreign exchange headwinds with total teach our year over year reported growth of 38%.
<unk> the foreign exchange impact off 10 percentage points due to the strengthening U S dollar.
Now I would like to provide you with some additional color on our ongoing Butcher U S launch progress as well as an update on initial international launches in Germany and Japan.
In the U S. We've received more than 750 or with restart forms in the six plus months since launch with more than 50% of the start forms representing new patients and the balance or presenting switches from one petzel.
Consistent with what we share that Q3, the monthly average of new tariff yawn with restart forms.
Haynes at 60 per month.
Which is double the rate of <unk>, new to tariff restart forms that we were receiving prior to the launch of <unk>.
Furthermore, in the U S or demand generation has been healthy and balance between community accounts and centres of excellence, we have and we have seen in approximately 30 per cent increase in our prescriber base since launch a clear signal that arbitrators expanding the opportunity.
For our T T R franchise.
Additionally, our patient base has broadened.
Include a variety of newly and previously diagnose patients starting on <unk>.
With significant enthusiasm being expressed around with this product profile, including quarterly subcutaneous Dawson.
Meanwhile, on the access France, given a clarity launch pricing, we have not faced any significant excess headwinds.
We've also made significant progress with formulary approvals supporting smooth access to patients that are prescribed <unk>.
You don't want international markets. The initial launches of which are in Germany, and Japan in queue for experienced robust demand with new patient starts coming from both switches from on petrol.
As well as new to Tennessee patients that were closest friend with what we experienced in the U S. In our initial launch quarters.
The new to therapy patients included a healthy mix of naive to Cherokee and switches from the competition and <unk>.
Our next anticipated international launch is expected in the UK in Lake Q1 2023.
So is that problem without withdraw we are pleased with our initial launch progress and are encouraged by the early signs that we're expanding the market opportunity for our teacher our franchise.
Moving to our ultra rare disease franchise first give lori.
We achieved 47 million dollar and global net product revenues in fourth quarter, representing a 3% increase compared to compared with 232022.
16% growth versus Q4 2021.
At the end of 2022.
520 patients were all commercial July treatments worldwide.
Hops from over 460 at the end of the third quarter, representing 13% quarterly patient growth.
Reported 16% increase in year over year global net product revenue growth of Laurie reflected a foreign exchange impact of six percentage points due to the strengthening U S dollar.
In the U S sales of give logging were flat versus the third quarter, primarily due to the demand growth of 3% driven by an increase in patients on therapy, which was offset by changes in inventories talking during the quarter.
Or international markets give large sales increased 10% compared with the third quarter, primarily due to the growth in patients on therapy, and the timing of orders and partner markets.
Why now to our second ultra rare disease product <unk> we.
We achieved $24 million in global net product revenues in the fourth quarter, representing a 45% increase compared with a torch quarter.
At the end of 2022 over 280 patients were on commercial similar treatments worldwide up from over 230 at the end of the third quarter, representing 22% quarterly patient growth.
In the U S sales of Oxalyl increased 38% versus the third quarter due to a growth in patients on therapy add an increase in everage patient utilization during the quarter driven by more patients or the monthly loading dose portion of their initial treatments.
You know our international business sales of similar increased 50 per cent compared with the towards quarter due to an increase in patients on therapy and due to the timing of orders and partner markets.
Additionally, as with all pets or I can give lori changes in foreign exchange rates also never negatively impacted <unk> 242002 results.
With reported year over year growth of 24%.
The foreign exchange impact of nine percentage points due to the strengthening U S dollars.
In conclusion, we are pleased with the growth in revenues and patient demand achieved in Q4, and particularly with our early signs of strong performance associated with the embouchure launch, which we believe are the presents.
Holding tear up the option for H T. T. R M. The dios's patients with Polyneuropathy and an accelerated growth opportunity for our T. T R franchise.
With that I will now turn it over to push call. So review, our recent R&D and pipeline progress pushed call.
Thanks, Toga and good morning, everyone.
Let me begin by updating you on our efforts in ATT are amyloidosis, where we are advancing three clinical stage product candidates for <unk> <unk> and his I'll update in a in a moment <unk>.
First because you've heard from Yvonne we are delighted that our supplemental new drug applications for <unk> for the cardiomyopathy of ATT or Emily doses has been accepted by the FDA with a standard review and if the Doofer date of October 8th.
In their final acceptance letter the FDA stated that they have not identified any review issues.
The agency also noted that they are planning to hold an advisory committee meeting to discuss the application.
If approved this will allow us to extend the potential benefits of an RNA therapeutic to the many patients with wild type and hereditary <unk> Emily doses with cardiomyopathy.
This filing is based on the pivotal Apollo beef study, which demonstrated improve functional status and quality of life in patients with ATT or cardiomyopathy, given pretty strange for 12 months relative to placebo.
The efficacy is also supported by encouraging safety profile and exploratory data, indicating that <unk> treatment can favorably impact disease progression.
With the <unk> now accepted I'd also like to share some details on our global filing plans for <unk> and a teacher amyloidosis credit myopathy.
We are planning to submit an essay da in Brazil in early 2023.
However, we do not plan to pursue label expansion in other regions.
This is a result of the earlier than anticipated enrollment completion of the <unk> study combined with the timelines for regulatory approval and obtaining market access in these countries.
As a result, we will focus our efforts in other regions to submitting an S. MBA per <unk>, assuming positive results from the ongoing <unk> study.
As a reminder, Helios b is studying a similar population as Apollo B, but are designed for a primary outcomes endpoint of all cause mortality and recurrent C V events.
We remain on track to share topline results in early 2024.
As you know we have been evaluating a biannual dosing regimen of <unk> as part of the Helios, a randomized treatment extension or Rte, which was performed after the main portion of the study is completed.
Our objective has been to see if we can provide a more convenient dosing regimen versus the already excellent profile of the 25 milligrams every three months regiment.
Maintained efficacy.
The primary endpoint of the R. T E was noninferiority of TCR lowering with the 50 milligram biannual regiment versus the 25 milligram quarterly regiment as well as an acceptable safety profile.
Today, we are reporting topline results of the randomized treatment extension three months nine.
As expected Noninferiority of the 50 milligram biannual dosing regimen was indeed established is demonstrated by means serum TCR reduction over nine months.
However, we did note some recovery of serum TCR reduction in the 50 milligram arm towards the very end of the dosing interval at six months.
Illustrates this at month, 680% of patients on the 25 milligram quarterly regiment achieved 80% knocked down or greater.
Whereas on the 50 milligram biannual regimen, 63% of patients achieve that same degree of knockdown.
In other words.
37% of patients did not get to 80% teacher knockdown with the biannual rentschler.
<unk> also continues to demonstrate an acceptable safety profile.
No safety signals regarding cardiac a paddock arena events were observed.
And the <unk> studies that were six deaths of which five occurred on the 50 milligram buying your alarm and we're in occurred on the 25 milligram quarterly arm after the patient dropped out of the study.
None was considered related to the study drug and the majority of occurred in patients with notable preexisting cardiomyopathy baseline in the context of known aggressive mutations.
We are planning to present more details on these results in a scientific Congress in early 2023.
Despite the supportive efficacy data and safety data from the Rte, we've made the strategic decision not to move forward with regulatory submissions for the 50 milligram buying you won't dosing regimen Dimitri strength as previously planned.
Real factors played into that decision.
First is the dynamics of serum teacher recovery observed towards the very end of the biannual dosing interval, which we believe is suboptimal in terms of a product profile, where we see clamped pharmacology in order to achieve maximal efficacy for patients.
Second as you heard from told them the very strong initial commercial performance of Amdura in his first two quarters on the market.
Given it's compelling therapeutic profile with quarterly subcutaneous dosing.
Along with the extremely positive feedback it has received from patients and physicians allows us to exercise greater selectivity in advancing an innovative offerings.
And finally, we now have a new molecule targeting TCR ctr SCO for which I am proud to announce that has entered the clinic and begun dosing phase one study.
<unk> is an investigation of RNA I therapeutic based on our I carry a platform and offers the potential for more durable and potent teacher silencing with the possibility for an annual dosing.
As such we will focus our continued innovation on advancing <unk>, which may offer a transformative profile, we expect topline results from the phase one study in late 2023.
In addition to our late stage clinical programs. We believe we have also been making great progress with our early and Midstage programs are notable highlight includes lb's around our investigation on in a therapeutic for hypertension, which we believe could transform the treatment of this disease and offer a highly differentiated profile from all existing anti hypertensive.
<unk>, including Ras inhibitors, we're thrilled to have announced that are cardio in phase. Two study was fully enrolled as of December and on track to deliver topline results in mid 2023.
We also look forward to cardiac two top line results at or around here in 2023.
We're also working.
To expand delivery of RNA therapeutics to tissues beyond the liver.
That and we are on the cusp of seeing important data from <unk>, which is our first investigational earn AI therapeutic directed to the CNS and in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy.
<unk> has the potential to offer a highly differentiated approach and Alzheimer's disease by targeting ACP upstream of where antibodies currently target and has the potential to excellent intracellular and extra solely to reduce disease, causing peptides.
We believe these initial clinical data with <unk>, if positive will be an important milestone not just for this particular program.
But for our overall CNS platform to show that RNA I can achieve clinically relevant degrees of target knocked down in the CNS with a safety and dosing profiled that supports for the development.
We remain on track to report topline results from the Phase one study in early 2023.
These are just a few highlights from abroad and innovative pipeline driven by our underlying organic product engine that we expect will deliver sustainable innovation and represents a key growth driver for alnylam in the years to come.
To wrap up these highlights we're excited to have submitted a cta filing for Alan K, H K and type two diabetes with a phase one start expected imminently.
In addition, our partners that regeneron have begun dosing in a phase one trial of am and PM P and Nash.
With that let me now turn it over to Jeff to review, our financial results in upcoming milestones.
Yep.
Thanks push call and good morning, everyone I'm pleased to be presenting Alnylam Q4 in full year 2022 financial results, which underscore on the island strong commercial capabilities and operational excellence.
After commenting on our fourth quarter and full year results by will also provide our financial guidance for 2023.
Turning now to a summary of our bowl P&L results for the fourth quarter and full year.
Total product revenues for 2022 or $894 million or 35% growth versus 2021 or 43% on a constant exchange rate basis with growth contributions from all for commercial products.
Net revenue from collaborations for the fourth quarter was approximately $71 million, representing an 18% increase compared with Q4 2021, primarily due to increased revenue from our collaboration with Regeneron from increased manufacturing activities in the quarter.
For the full year net revenue from collaborations was $135 million, representing a 25% decrease compared with 2021, primarily due to a decrease in revenue recognized in connection with our collaboration agreements Regeneron in Pierre attributed to reduced research and manufacturing activities and timing of reimbursed for activities.
Or non-GAAP R&D expenses increased 16% in the fourth quarter of 2022 compared to the same period in the prior year, primarily due to increases in head count to support our R&D pipeline and development expenses associated with the cardio one in cardio too so I'll be surround phase two studies.
Or non-GAAP SG&A expenses increased 15% in the fourth quarter of 2022 compared to the same period in the prior year, primarily due to increased head count and other investments in support of the global launch of <unk> and other corporate expenses to support the scaling of our business.
Ah combined non-GAAP , R&D, and SG&A expenses, where approximately $1.4 billion for the full year 2022, representing 14% growth versus 2021, as we continue to advance our pipeline and deliver strong top line growth, while maintaining discipline and how we invest in our operations.
Or non-GAAP operating loss for 2022 was $554 million or approximately flat versus 2021.
We do anticipate reducing our non-GAAP operating loss in 2023.
You will hear when I provide our 2023 financial guidance as we remained focused on achieving a self sustainable financial profile by 2025 align with our pizza by 25 calls.
Finally, we ended the year with cash cash equivalents and marketable securities of $2.2 billion compared to $2.4 billion at the end of 2021 with the decreased primarily due to our operating loss in 2022, which was partially offset by approximately $265 million received from employee option Award exercises.
And approximately $135 million from a convertible debt financing.
We continue to believe that our current cash balance will bridges to financial self sustainability, an enviable position in today's market environment.
Now turning to our financial guidance for 2023.
Starting with net product revenues, we are providing combined net product revenue guidance from Patrick give Laurie <unk> and <unk> are.
Our guidance assumes the San da for <unk> for ATT are amyloidosis with cardiomyopathy in the U S will be approved by the produce the date on October 8th 2023, and also assumes foreign exchange rates as of December 31, 2022.
We anticipate combined net product revenues for these four products will be between one and two and 128 5 billion with the projected reported growth range versus 2022 of 34% to 44%.
As you can see we are also providing constant exchange rate growth guidance for a net product revenues. This year with a projected range of 34% to 44% highlighting no current difference between our reported and constant exchange rate growth guidance.
Our guidance for net revenue from collaborations in royalties as a range between 101 hundred $75 million with the mid point of the range of approximately flat versus 2022.
We anticipate the collaboration revenue associated with our partnership with Regeneron and like feel royalties from Novartis will drive the majority of our collaboration royalty revenue in 2023.
Our guidance for combined non-GAAP , R&D and SG&A expenses as a range between one and 575 and $1.65 billion. The midpoint of the guidance range represents a projected 13% increase compared with 2022.
Growth highlights for R&D expense in 2023 include increased investment in Selby surround as we progressed the cardio one according to phase two studies initial.
Initial investment and <unk> as well as growth and previous C and IMD, enabling efforts across are preclinical portfolio as we continue to invest in creating new organic growth opportunities for the future.
Growth highlights for SG&A expense in 2023 include increased medical and commercial investment as we prepare for the potential launch a patese ran in the U S for ATT are amyloidosis with cardiomyopathy.
Let me now turn from financials and discuss some key goals in upcoming milestone slated for early 2023.
We will of course be executing on the global commercialization of our products on Patrollers boot truck give Laura <unk> limo.
We expect a completed enrollment in the cardio to phase two study of <unk>.
Topline results from our phase one study of Alan ACP in patients with early onset Alzheimer's disease is on track for early 2023.
With our partner programs Veer expects additional results from phase II combination trials avail in HBO too and Regeneron plans to initiate a phase two study avail in HSV in patients with Nash.
Now turn it back to Christine and coordinate our Q&A session Christine.
Thank you desk, operator will now open the call for your questions to those style then we'd like to ask you to limit yourself to one question each and then get back in the queue. If you have additional questions.
Well at this time in order to ask a question. Please press star one one on your telephone.
Need to be announced to withdraw your question. Please press tier one once again.
Taken as a reminder, he need only ask one question. Please.
Please turn violent compiled acuity roster.
Our first question comes from the line <unk>, calling your line is now okay.
Good morning, everyone. Thanks for taking the question.
Even.
To ask about just the potential topics of the Advisory Committee meeting what do you think at this point, what what is on an island planning on addressing.
The Advisory Committee meeting, it's <unk> <unk>.
I'm sorry, no review issues have yet been identified in the.
Communication or are there points during the S N da.
View that by law interaction is required between.
<unk> and the regulator to help you set that out thanks.
So thank you very.
Very much for that question I mean as as you know we were very pleased with the results of the <unk>.
<unk> study and I'm pleased with the FCA exceptional application.
And as you point out did not identify any.
<unk> wishes to date.
Whether you have an AD calm or not is entirely up to the <unk>.
We have no indication at this point in time with respect to any specific areas to address as any potential advisory committee, but we look forward to engaging with the FDA through this process into sharing sharing our data beyond that says there's not a lot.
<unk>, we can we can we can say at this point in time.
No legal interactions required for the <unk> protests in the near future with you guys.
Well, we will get you know information is.
More details around the advisory committee at the points in time better at this stage. We have no further information that we can we can provide I mean do you have any update that we are required to provide the F. D. A is 120 day safety update.
Got it thank you.
Next question.
One moment for the next question.
And your next question comes from the line of <unk> from City. Your line is now open.
Thank you very much for taking my question with respect to the.
Six months dosing of those Andrew Ultra I'm, falling short and being discontinued.
What learnings are you taking from that too.
To the carrier program and.
And is it does it changing your strategy with respect to how you are looking at that particular therapy and just little tag on <unk>.
Do you think that the lack of be bi annual dose substantially changes anything for the future slash prospects.
Right. So I'll I'll I'll start off and then invite prescribed to contribute I think really the first thing to say is that the country Regiment of a temperature has has really been a game changer for patience Windsor TTL Polyneuropathy and we're really pleased with <unk> and you have some tolga area, you know how well.
The launch is getting so read the decision to not move forward with a six month your regimen with a strategic when we want to be able to focus on the quarterly.
And future regiment in the near term and then as you had and you touched on this uhm progressed T. T. R. I C. A for based on a car platform, where we believe that the real potential for knockdown TCR knockdown of Grace for 90%.
And potentially annual dosing as well, which we think is then a real step forward for for patients.
Prescribed any commentary on the.
<unk> I suppose what we've learned is you know more about the profile of the six months <unk> anything else to add yeah now that I think the only thing that I would add to what you said about us I mean, it's reaffirmed the potency and the power of the 25 milligram quarterly regimen, where we saw excellent clamped pharmacology with.
Quarterly dosing that reaffirms the profile that we saw in the original Hulio say study.
And I think Dave to your other point I think and as a on the highlighted we're really excited that SCO four is now in the clinic and.
And we will get data. Shortly later this year around what that's looking like in the phase one study and we're optimistic based on the preclinical data and the power of the I carry a platform.
But we will see more potent.
And more durable knockdown in.
Enabling possible annual dosing regimen with that so I think we're really in a fortunate position that our research engine has been able to bring forward. This this SCO four molecule that we can bring into the clinic. It allows us to progress intubation for these patients.
Thanks for the next question.
One moment for the next question.
Your next question comes from your line of <unk> Bank of America and your line is now okay.
Hi, good morning, Thanks for taking my question.
Any expected top line that.
In the beginning of this here can you just give us some color.
Dana exactly you're planning on for that thing.
We shouldn't interpret that data what would be clinically meaningful and you also.
Presenting any plat clearance data with that top line. Thanks.
We we didn't actually kind of hit all of the questions in mind, perhaps.
Repeating his and it may be focusing on just just one question.
Yeah. The question is on the left ear canal pretense at the top line. What should we include in that subset of what you are going to be presenting.
That's really cancer.
Yeah.
Data from the <unk> studying <unk> yeah. Thanks disease. So we're really excited about the <unk> program, it's our first foray into the CNS.
We're still on track to have top line data and the first half of this year.
Reminder, this is a study in patients with early onset Alzheimer's disease were in the single ascending dose phase of that study and what we are open to report out on will be safety and Tolerability, which is the primary endpoint. This the first time, we're giving interest equal injection with the C 16, conjugate and then looking for target.
Engagement and knocked down of soluble ABB a P P alpha and beta so we are very good.
Pharmacodynamic markers that complaint to target engagement and.
We want to see evidence of target engagement there <unk>.
Being good pharmacology in the brain. So those are really the key things that will be reporting on later this in the first half of the year.
<unk>.
Next question.
One moment for the next question.
Mmm. Your next question comes from your line of <unk>. Your line is now open.
Hi, This is Tanya <unk>. Thanks, so much for taking your question for healing and can you remind us of the rationale behind using all colors mortality instead of cardiovascular mortality in the composite primary endpoint and is there one that's prefer advice physicians regulators. Thank you.
Thanks for being like assessor Crescent straight for your first call Yeah, So salve and I think when we when we look at when we designed the Helios be studied we really want to ultimately show the benefit of the drug Ah the totality of a big experience to patients with this disease and and all cause mortality and <unk>.
[noise] CV event endpoint really captures maximizes the the number of events that we can capture in the course of the study, which AIDS in the powering of this study and also becomes a very clinically meaningful effect certainly there can be.
Analyses that are looked at under that Ah secondaries or post topics that look at the various types of mortality events, but that's that's the basic explanation.
Next question.
One moment, Sir the next question.
The next question comes on the line.
More you may call from Jeffrey stay on line is now okay.
Hi, good morning, and thanks for taking.
Hi, Good morning, Thanks for taking my question I was wondering if if you. If you have a tentative date scheduled for the AD, Tom and you've mentioned, adding the 120 day safety data from Apollo be open Liberal extension, but I'm I'm wondering if you can discuss possible scenarios, where you may be able to supplement b S. MBA with edition.
Advocacy or safety data from Apollo be open label extension and or that Helio speech study.
Yeah, so more and maybe a couple of questions in there we don't have a formal date yet that's something again, we've released what we understand at the moment from the agencies corresponds with us. So we'll look forward to getting additional information on that.
In terms of the 18 month data.
We're in the process of getting in reviewing the Apollo be open label extension data as a reminder, everybody crosses over to active drug it at 12.
And we'll certainly share those data.
Scientific meeting and with regard to the agency will be supplying whatever they need to facilitate their review and so we're looking forward to sharing things the data with them. Both from the main study and as they need from the open label extension. The day 120 safety update is primarily focused on safety.
Sneaking safety update data so that will also be a parallel process.
Understood. Okay. Thanks for taking my question.
Sure.
Give me one moment for the next question.
Your next question comes from your line of <unk>. Your line is now open.
Hey, Thanks, so much for taking my question and congrats on the progress.
I was I I I thought it was really interesting that you included potential sales from <unk> cardiomyopathy in guidance given that it's under review given that there is an AD Tom and I guess is that the right interpretation of that decision that the company continues to have very high conviction at the Apollo.
Data <unk>.
Should lead to an approval and that was enough for you to plan financially and guide around that thank you.
Okay, well I'm in our thoughts and then hand it over to Jeff in terms of how we felt about planning I mean, clearly we we do believe that the caller.
Caller be study as delivered actually very impactful results first in terms of.
Health Health health status and.
Disease progressed, we've talked about the efficacy endpoints either in some detail and clearly we.
Planning for the Advisory Committee as as it is.
As as notified for IV Uhm FDA.
And obviously, we will have sir.
The fda's determination on our submission but.
We believe that we have an efficacy and safety package here that is pretty companion.
You have to have to speak a little bits of how we thoughts about mm Petra C. M. Yeah avenues, yeah, Paul you're right I mean, we flags out and the guidance on the slide that we assume that again, given the timing of that given that it's in the fourth quarter the impact of that from a from a revenue perspective. This year is going to be relative.
Modest and so now that doesn't really have a significant impact on the financial guidance, we've given for the year as a result.
If approved we would expect more significant impact next year.
Thanks, so much.
Mmm one moment for your next question.
The next question comes from the line.
N O N.
That's barkley's your line is now okay.
Thank you I have one question regarding the apes proclaiming all whoopi to click.
Clinical profiles regarding percentage of knocked down in the frequency of dosing Amy.
<unk> <unk> bye annual dose of data regarding frequency associate.
<unk>.
Yeah Gina Thanks for the question. So I guess a couple of things in there what's the ideal profile. So look I think this is the we've said before that we don't have the from genetic data we would imagine that we would want to get too close to about 50 per cent knockdown of Allen a P. P of Emily precursor pro.
<unk>, we think that's probably around the target range to get to a therapeutic effect, but at the end of the day no one really knows and so that's kind of where we're shooting for but this is again an initial single sending dose study will be providing some interim data and so I'll be working our way up to get to you know higher levels of knocked down as.
The data allow and so that's one in terms of the frequency of dosing look the preclinical data that we have suggested this may be a relatively infrequently dose molecule, we've seen knockdown lasting over six months and the nonhuman Primate studies that we've done with Alan a P. P. So we're very encouraged with the <unk>.
Angel that this could be a quarterly or potentially biannual when he dose drug in the CNS, but again the data will will inform that I don't think there's any particular readthrough from the boot tree strand randomized treatment extension, that's a different molecules and be given to a different space into different conjugate and as you know we continued to.
Our scientists continue to own our chemistry, all the time, but a lot of that is also a molecule and target dependence. So.
We're very encouraged by the data we'd have so far non clinically I'm really looking forward to the clinical data emerging shortly.
Thank you very much thanks Gina.
Alright, So your next question.
Your next question comes from the line of <unk> R. P. C capital Your line is open.
Alright. Thanks, so much say my question and congrats on the progress I have a quick one on Helios B I think there's a few docs out there that are convinced that actually the drug is making a new pact with their patients received your card myopathy, but they're just worried at this trial is not logged enough to actually show a convincing separation of the curves.
Their scenario, where you can amend the protocol. So you don't read out the primary point with the last patient to reach the 30 months, Mark but router after a pre specified number of events.
They're much appreciate it.
Yeah look I think there's there's first of all.
It's great that you're getting that sort of feedback. We're obviously encouraged overall by the profile of the trees trend that we're seeing.
From patients.
Out there in terms of the study design you know I think we've a I'd just remind you we have a track record of working in this space for quite a while and executing successful studies. Our teams have gone through and we feel very good about the design of the study in the execution of this study.
As a reminder, we've got variable follow up for 30 to 36 months in this study builds upon the success and what we've seen in terms of encouraging data coming out of Apollo B, where we saw positive impacts on functional end points quality of life.
Evidence of potential delays and disease progression.
[noise] favorable impacts on.
Echocardiographic parameters technicians, and there's a lot of positive data there <unk>.
Twice as large in about three times as long. So we feel good about the design and execution of that study and we're not planning at this point to make any changes.
Spot on prescribing right now we're focused on.
Execution in bringing this home and sharing results with you in adding 2024.
Got it Super helpful. Thank you guys.
Next question.
One moment for your next question.
And your next question comes from the lineup Jessica J P. Morgan Your line is now open.
Hey, Good morning. This is jail for just so two questions on us on the.
San Diego on patrol in the case that the F. D. A will request and the new data or in the case that you might want to some more data.
Do you expect any type of tissue for extension because of the new data submission.
And then secondly.
Note that the cardiovascular outcome based off from British pilots a tribute <unk> will be available in July . So just curious would you.
You be watching for a dictator from Detroit.
And it's.
And you thought you can share with us regarding the potential impact on distribute data on your thinking of you know the changing patient population and anything along those lines. Thank you very much.
A few questions for you really here <unk> one on the S. N da we don't Petro and.
Climate for new data and potential extensions the dates and then I think some questions around our perspectives on.
Richard Pryor cardiomyopathy.
Uhm outcome study yeah. Thank you look in terms of the impact if we if we're asked to supply. Additionally, I really can't speculate.
Certainly we will provide whatever data the agency requires to facilitate their review.
And we look forward to sharing that data in the course of questions that come from the agency N. At the Advisory Committee <unk> declared a could do for date of October 8th and I know there'll be striving to achieve that and we'll update if there's any changes to that based on on their requests in terms of the <unk>.
We look forward to seeing the results I think it's scheduled for the middle of the year, but I don't think that really changes anything for us in the context of the Apollo B S. N da that studies completed and under review and and so we will certainly be looking for those results but.
And watching them, but I don't see any really particular impact on the Apollo B S.
<unk>, yeah, so informative for the field, yeah, but uhm.
Kind of consequences.
Specific programs correct yeah.
Next question.
One moment for the next question.
And your next question comes from the line of Michael's with Morgan Stanley . Your line is now.
Good morning, and thanks for taking the question maybe just a quick one on M. Leuctra in poly neuropathy I noticed you got a J code in early January just curious what impact do you think that could have on a trajectory of the launch and as a potential we could see an inflection there.
Yeah, that's a nice.
Question for <unk> implications of the.
Receipts of such acres.
Right Hi, my Thanks for the question, we're very pleased with the fact that the J codes visa signature quote is it on the due date.
To the J code, we already had a generic J code that allowed us to be able to have access to to to provide the right access to our patients in the U S. Therefore, we wouldn't necessarily be expecting.
Any significant change now in terms of.
The the uptake is already itself has been as as if I'll put it has been a game changer, we have a double number of start forms that we would normally receive in a steady state of all my own Petro. Therefore, we're very pleased with the accelerated growth that are you know parrots.
Pricing at launch.
Those are good to evaluate his exit strategies that we were able to establish prior to the launch that's really allowing us to have a sewage sailing in terms of the axis wrong and and the growth is really coming from thanks for the profile of the the the product as well as our efforts and expanding the prescriber base for the poll neuropathy.
Across the U S is whether it's now in Japan and Germany.
Got it thank you.
Thanks Toga next.
Next question please.
One moment Clinton next question.
And your next question comes from the line of <unk>. Your line is now open.
Hi, Thanks for taking the question just on the Helios extension and assist you make by and you're saying that the five patients that passed away in that all its shave the Ivy percent JCR knocked down or did I not and type all die from cardiomyopathy that just again, thanks debating balance between Maultasch.
<unk> on the 25 me every quarter and the 50 make biannual let me neither the <unk> quarterly as efficacious Sir.
I'm, just clarifying that would be helpful.
Thanks miles.
Maybe I can just give you a little bit of context of the of the depth events that happened in the study I mean, just to taking a step back the overall safety in terms of adverse events serious adverse events cardiac renal hepatic events laboratory that was all really quite balance between the arms. We did see this new miracle difference in terms of.
Deaths. They were all unrelated is deemed by the investigator.
They had multiple risk factors for poor prognosis in terms of advanced in YHA class elevated BNP or aggressive mutations as an example, three out of the five patients in the 50, Meg Biannual Regiment, who passed away had grew 89, Glen and serene 77, allowing mutations which are <unk>.
Typically aggressive.
You'll make the causes to some C V, but somewhere non C V.
As an example, one of the patients who passed away in the biannual Regiment diagnose.
Diagnosed with acute myeloid leukemia and.
And died after chemotherapy.
And then we'd love there was no relationship to pharmacokinetics or as you were asking pharmacodynamics I knocked down that we observed so will provide more details on upcoming scientific meeting.
But we were very reassuring from the the details safety analysis did not did not so are mine seem to be any relationship to the drug.
Right. Thanks.
Mmm moment for the next question.
On your next question comes from the line of Joseph <unk> from Needham and call. Your line is now.
Uhm. Good morning. This is Barbara on for Joey and I question is about the Big picture can you give us a sense of what you think <unk> and which was combined market penetration of the a T. T. R. Polyneuropathy and mixed phenotype says at this time.
Yeah, I think I think just kind of taking a step back and thinking about the.
ETR market as a whole I mean, there's no doubt.
It's a rapidly growing market with increased.
Physician awareness increase that diagnosis of patience and obviously that translating into increase the treatment of patients. So we're very excited that we have.
Two O nine therapeutics.
Participates in helping patients who have pizza amyloidosis at amendment would probably neuropathy and then of course, hoping to extend the label to patients who also have cardiomyopathy. We think it's a market that also has room for you know multiple players video is all about kind of.
<unk> growth, rather market share and I think what's particularly passionate with respect to Apple 30th.
Is.
D C.
Failure driving grocery overall.
Going forward.
For an island.
So.
Very pleased with our progress as far as you know we look to continue helping physicians.
Three patients as appropriate with <unk> and Andrew Trash talk is there anything you wanted to add in temperature stepping back and thinking about the <unk> yeah yeah.
Yeah, I mean, along the same lines, we're very pleased to be able to provide now we do have a franchise. We have two products that are available in the U S N.
Soon for the rest of the world.
Pulling her up with you and what we know is despite the fact that it's it's a rare disease. There are still significant <unk>, it's a devastating disease expectations are not treated.
I do end up with <unk>.
Timeframe in five to seven years and despite that the diagnosis and treatment is still a relatively low numbers and what what's your launches demonstrated to US is the fact that having a very compelling product profile and with the the convenience store subcutaneous injectable every quarter really does change the.
Hang in terms of how it allows us to be able to reach more patients through by actually finding more more physicians. So we do have this prevalence number that's anywhere between you know 40 to 50000 across the world, including the make sure you're not citations, we're still scratching.
The surface and has evolved indicated with these products coming into the market.
<unk> actually increase the awareness both on the physician side as well as on the patient Guy then the most recent launch no problem, what's clearly demonstrates though.
Thanks focus so we've got time for one last question.
A moment for the last question.
And your last question comes from the line of Aline Rally with ETS. Your line is now open.
Yeah. Thanks for taking my question just.
<unk> I guess just from the interactions and feedback from the active so far <unk> add comments more specific to the Apollo P data such as being a 12 months or do you think it sort of is more probably about the a T T R landscape and cardiomyopathy clinical significant.
<unk> and I mean, I guess like in other words, how much do you think the outcome what impact and the trust potentially applying discussion personal testing more than a pile of beef a setback unrelated discussion at the outcome.
Thanks for your question.
As we've said at the beginning we don't have any particular feedback from the agency on the specifics of what the outcome will be or the questions. There certainly look forward to hearing more from the agency we're committed to supporting their review in any way we can.
I do expect that the outcome is going to be focused on the Apollo B data. However, that's the San da that we filed and that would be the subject of the review those would be the data that we'd be sharing and talking about in the context of that the review and and the advisory Committee as well, but again, we'll look forward to seeing more from the agency when they when they get back.
What's with details and again I think Justin underscore.
<unk>.
Uhm has demonstrated a hypothesis that sir.
Therapeutics can have a meaningful impact on patients with that teacher amyloidosis with cardiomyopathy. So we shall stop that thank you everybody for joining the call. We're really happy with the progress that we've made in the fourth quarter and the full year 2022 is sort of a strong commercial resolved to continue to advance the best pie.
Crime programs and development and you've also got a number of exciting cashless on back in 2023. So we look forward to updating it along the way S. B a continues to deliver on these calls so thank you everybody and have a great day.
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