Q2 2022 Alnylam Pharmaceuticals Inc Earnings Call

Good morning.

I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam.

With me today on the phone are Yvonne Greenstreet, Chief Executive Officer, Tolga Tanguler, Chief Commercial Officer, Akshay Vaishnaw, President, and Jeff Fulton, Chief Financial Officer.

Okay.

For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, investors.alnylam.com.

Hello, Thank you for standing by and welcome to the island.

The island Pharmacy next quarter.

Two earnings conference call.

This time all participants are in a tell me mode. After the speaker presentation there'll be a question and answer session to ask a question. During the session you will need to press star one one on your telephone please be advised that today's conference maybe recorded I would now.

During today's call, as outlined in slide 2, Yvonne will offer introductory remarks and provide some general context.

To hand, the conference over to the company. Please go ahead.

Good morning, I'm, Christine Lindblom, Senior Vice President of Investor Relations and corporate Communications that'll nylon with me today on the phone or Yvonne Greenstreet, Chief Executive Officer until the Taylor Chief Commercial Officer attributes now President and Jeff Poulton Chief Financial Officer.

For those of you participating via conference call. The accompanying slides can be accessed by going to the events section of the investors page of our website and that sort of thought on island dotcom Bosch that.

During today's call as outlined by to a bundle offer introductory remarks and provide some general context talk about providing an update on our global commercial progress Akshay will review recent clinical and preclinical updates and Jeff will review, our financials and guidance followed by a summary of upcoming milestones before we open the call for your questions.

Please note we are in a quiet period with regard to the upcoming Apollo B result, and therefore, therefore will not be addressing any questions on that map.

I would like to remind you that this call will contain remarks concerning Alan island's future expectations plans prospects, 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.

Recent quarterly report on file with the SEC.

In addition, any forward looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views of any subsequent date, we specifically disclaim any obligation to update such statements.

I'd like to turn the call over to upon demand.

Thanks, Christine and thank you everyone for joining the call today.

We're very pleased with our second quarter results and the progress we've made towards our near and long term goals.

Commercially we achieved 14% product sales growth.

Compared with the first quarter as we continue to drive a steady increase in patients on therapy across our portfolio of marketed products, including on Patrick If lari amdocs.

And we're excited to have expanded our portfolio with the recent U S approval and positive.

Empty opinion sure I'm route trucks for <unk> amyloidosis patients with Polyneuropathy and we're looking forward to executing on our mutual launch and the potential for further global expansion.

Five ordinary therapy, six from our organic platform approved and under four years. It is truly remarkable.

Yeah.

In addition to our growing commercial portfolio, we continue to make great strides with our RNA therapeutic pipeline progress.

Includes our progress on establishing our TTS franchise, where we are tracking towards plan and are on the cusp of seeing results from the Apollo B phase III study of <unk> in patients with ATT amyloidosis with cardiomyopathy.

We've announced today that we expect to share top line data within the next three weeks with full data to be released their offsets at the medical Congress.

In addition to these highly anticipated results also continue to make exciting progress across numerous other programs with in our pipeline.

And continue to innovate a part of what we believe to be one of the most productive organic and self sustainable platforms of bottleneck, which has the potential to deliver meaningful value, creating therapies for rare and prevalent diseases in the years to come.

But that said there are many recent and upcoming milestones underscore the breadth and scope of our pipeline.

With <unk>, we reported positive top line phase II results in patients with Iga nephropathy, kidney disease with significant unmet medical needs.

Tolga will provide an update on our global commercial progress.

Akshay will review recent clinical and preclinical updates, and Jeff will review our financials and guidance, followed by a summary of upcoming milestones before we open the call for your questions.

We're now working with Regeneron to finalized phase III plans and potentially initiate the program by the end of this year.

Please note we are in a quiet period with regard to the upcoming Apollo V results, and therefore will not be addressing any questions on that matter.

I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995.

We're also excited to see positive data presented by foreign fee from the Phase III Atlas PBX study of <unk> in patients with hemophilia, which met its primary endpoint and demonstrated that the troops around prophylaxis significantly reduce bleeding episodes compared to prior factor.

While bypassing agent prophylaxis.

Looking through to the end of this year.

To have updates across our pipeline, including the potential for top line results from <unk>.

Early studies.

HFC in Nash.

And ex the <unk> goals and ATP and early onset Alzheimer's disease, our first CNS and depth.

Taken together this all highlight software.

These three key driver for our new items growth over the next several years.

What is the potential near term expansion of our TCR franchise opportunity, where we aim to become a global leader in delivering impactful and highly differentiated metrics to phase III.

The second key growth driver is our expansion beyond strategy, it's a prevalent diseases.

And the third growth driver for the company comes from our sustainable innovation engine comprised of new platform enhancements opportunities with extra hepatic delivery and our ability to find new genetically validated targets, which can drive further pipeline expansion to 2025 and beyond.

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 quarterly report on file with the SEC.

In addition, any forward-looking statements represent our views only as to the date of this recording, and should not be relied upon as representing our views of any subsequent date.

We specifically disclaim any obligation to update such statements.

We believe all of this positions us well to deliver on our nylon piece effect by 'twenty five goals, making on nine of the top biotech company developing and commercializing transformative medicines for rare and common diseases for patients around the world driven by high yielding pipe.

With that, I'd like to turn the call over to Yvonne.

Yvonne?

Brian of first and best in class product candidate from our organic product engine.

Thanks, Christine, and thank you, everyone, for joining the call today.

All while it's a different exceptional financial results with that let me now turn the call over to talk us through a review of our commercial performance Koga.

We're very pleased with our second quarter results and the progress we've made towards our near and long-term goals. Commercially, we achieved 14% product sales growth compared with the first quarter, as we continue to drive a steady increase in patients on therapy across our portfolio of marketed products, including Onpatria, Givlari, and Oxalumin.

Thanks, Bob and good morning, everyone Q2 was a strong quarter for our commercial portfolio with 14% quarter over quarter growth as <unk> highlighted.

We're also excited about the FDA approval and launch of <unk> in June .

We're encouraged by early promising signs of a new drop tick I'll have.

More details to share share on that shortly.

As anticipated we also experienced improved market conditions. Following COVID-19 impact in Q1, as we saw increased promotional activities improved patient flows healthy demand and improve patient compliance across our portfolio.

I will now provide details on the performance of each of our products.

We continue to see growth for our Petro achieving $153 million in global net product revenues in the second quarter, representing a 12% increase compared with the first quarter and 35% growth compared with Q2 'twenty one.

At the end of Q2 over 2400 patients were on commercial loan Patrick treatment worldwide up from over 200 patients at the end of the first quarter, representing a steady 9% quarterly patient growth.

In the U S sales of our collateral increased 14% versus the first quarter and were primarily impacted by an increase in patients on therapy and improve patient compliance following Q1, which was negatively impacted by COVID-19.

In our international markets, our Petro Q2 product sales increased 10% versus Q1, 'twenty two primarily due to an increase in patients on therapy, and the timing of orders and distributor as part of your markets.

Important to note our global results continued to be challenged by foreign exchange headwinds with one Patrick year over year reported growth of 35% being held back seven percentage points by the strengthening U S dollar.

As you are aware we.

We received U S approval for a blood draw at the end of the second quarter.

We're very pleased with the initial launch so far as our teams continue to execute in line with our plans.

We received 133 start forms from launch through July 20, <unk> shipping demand generation on track with approximately one third of start forms generated from patients new to online all either and two thirds from switches from one Patrick.

Over 20% of those start forms came from new prescribers, which we believe is an encouraging early sign of potential market growth.

We hit the ground running reaching over 61000 key stakeholders within 48 hours of launch serving as a catalyst for field engagement.

We have also been engaging with health systems and the formulary process processes has been started in over 60% of the priority delivery networks.

Firstly from an access standpoint, our teams have been engaged in feedback feedback has been positive to date.

In fact, there's one national policy published with a large national payer covering 24 million lives.

The first patient has also been treated and were looking forward to continuing this rollout and updating you further on our Q3 call.

Moving to our ultra rare disease franchise first with you Laurie.

We shipped 45 million global net product revenues in the second quarter representing.

Representing a 28% increase compared with Q1, 'twenty, two and 47% growth versus Q2 'twenty one.

At the end of Q2 over 420 patients who are on commercial <unk> treatment worldwide up from over 400 at the end of the first quarter, representing a 5% quarterly patient growth.

In the U S sales of <unk> increased 25% versus the first quarter and were primarily a result of the following.

Healthy demand growth of 12% driven by an increase in patients on therapy and improve patient compliance following a soft Q1, primarily impacted by Covid.

Inventory stocking dynamics, which favorably impacted reported growth by 8% and.

A decrease in gross to net deductions in the quarter, which favorably impacted reported growth by approximately 5%.

In our international markets, we've largely delivered 34% growth compared with the first quarter with the growth primarily driven by new patient adds including a strong launch in the UK and favorability in gross to net deductions.

Finally, global give our year over year reported growth of 47% was also helped by held back by six percentage points due to onshore our favorable foreign exchange rates.

Moving now to our second ultra rare disease product <unk>.

We achieved $15 million in global net product revenues in the second quarter, representing a 2% increase compared with the first quarter.

At the end of Q2 over 200 patients were on commercial treatment worldwide.

From over 116 at the end of the first quarter.

Representing 25% quarterly patient growth.

In the U S sales of <unk> increased 32% versus the first quarter and were primarily impacted by an increase in patient demand as well as inventory stocking dynamics and a decrease in gross to net deductions during the quarter.

And we're excited to have expanded that portfolio with a recent U.S, approval and positive EMP opinion for Ambutra for HATTR amyloidosis patients with polyneuropathy. And we're looking forward to executing on Ambutra's launch and the potential for further global expansion.

In our international business, despite an increase in patients on therapy during the quarters Q2, <unk> sales decreased by 15% compared with Q1.

Primarily due to an increase in gross to net deductions during the quarter and the timing of orders in our distributor and partner markets.

Five RNAi therapeutics from our organic platform approved in under four years is truly remarkable.

On a year over year basis global <unk> sales decreased 9%, despite an approximately double that of patients on therapy.

The decrease was primarily due to a higher proportion of patients on the monthly loading dose portion of their treatments.

As well as lower net pricing in our international markets in Q2 'twenty two.

Additionally, as with on petrol and give Laurie.

Changes in foreign exchange rates also negatively impacted ocular Q2, 'twenty two results with reported year over year growth.

Minus 9% held back by.

Five percentage points due to the strengthening U S dollar.

In conclusion, we are pleased with the growth in revenues and patient demand achieved in Q2 and look forward to our Q3 results, which will include the first full quarter of <unk> launch.

With that I will now turn it over to Akshay to review, our recent R&D and pipeline progress Akshay.

Thanks, Tom and good morning, everyone.

I'll start with our assets in <unk> amyloidosis, where we are advancing two clinical stage product candidates <unk> and Butros Ryan.

<unk> is currently approved in multiple markets around the world to treat the polyneuropathy associated with hereditary <unk> amyloidosis, where.

We're committed to expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild type <unk> amyloidosis patients.

Excuse me.

To this end, we're conducting the Apollo B phase III study and as announced this morning, we expect to report top line results within the next three weeks.

We're also advancing Boutris horizon, which is delivered by quarterly subcutaneous injection and was recently approved in the U S. Under the brand name and boot trucks to treat the Polyneuropathy of <unk> Amyloidosis. In addition to receiving a positive <unk> opinion in the EU.

In addition to our growing commercial portfolio, we continue to make great strides with our RNAi therapeutic pipeline programs. This includes our progress in establishing our TTR franchise, where we are tracking towards plan and are on the cusp of seeing results from the Apollo B phase 3 study of Batista M in patients with ATTR amyloidosis with cardiomyopathy. We have announced today that we expect to share top-line data within the next three, weeks with full data to be released thereafter at a medical congress.

Two we are committed to expanding the label for the treatment of cardiomyopathy inherit tree and wild type patients.

In addition to these highly anticipated results, we also continue to make exciting progress, across numerous other progress within our pipeline.

Patricia is also in development for startup disease.

He'll say evaluating butros around in <unk> amyloidosis patients with Polyneuropathy form the basis for our regulatory submissions and recent U S approval of that route truck.

In April 2021, we presented positive results from the study at the AAN meeting, which showed the study met its primary and secondary endpoints at nine months.

We continue to report results from this study and recently presented new 18 month results from exploratory cardiac endpoints at the ESC HFF meeting.

These findings show that in a variety of pre defined.

So that in a predefined cardiac subpopulation of <unk> amyloidosis patients with Polyneuropathy treatment with <unk> was associated with improvements in exploratory cardiac endpoints relative to external placebo, including levels of empty pro BNP and a trend towards improvement in cardio graphic parameters.

These findings in the cardiac sub population with consistent with the previously reported results in the ITT population.

Additionally, in our planned cohort of patients from the ITT population, which was surrounded treatment reduced cardiac uptake of technicians in <unk> relative to baseline and a majority of assessable patients, including those with pair genie, Greg greatly greater than equal to two at baseline.

Suggesting that patients with the highest degrees of cardiac amyloid burden may recognize benefits from modernize our beauty.

<unk> also continued to demonstrate an encouraging safety and tolerability profile.

As mentioned this is just the start for <unk> as it is also being evaluated in the Helios B phase III study for the treatment of patients with <unk> amyloidosis with cardiomyopathy, including both hereditary and wild type <unk> doses.

Helios B, which is fully enrolled as of 30 month endpoint of all cause mortality and CV events with many patients followed up to 36 months and we expect the full results in early 2024.

The study design includes the potential for an interim analysis and we will consider this following results from Apollo B and engagement with regulatory authorities.

In addition to our late stage clinical programs. We believe we've also been making great progress without early and mid stage programs.

We have and continue to innovate upon what we believe to be one of the most productive, organic, and self-sustainable platforms in biotech, which has the potential to deliver meaningful, value-creating therapies for rare and prevalent diseases in the years to come. To that end, there are many recent and upcoming milestones that underscore the breadth and, scope of our pipeline.

For Sandeep Saran, we reported positive top-line phase 2 results in patients with IgA nephropathy, a kidney disease with significant unmet medical needs.

Notable highlights in the second quarter was our announcement of positive top line results from our phase II study of some <unk>, an investigational <unk> therapeutic targeting the C. Five component of the complement pathway and is in development in collaboration with Regeneron for the treatment of Iga nephropathy.

We're now working with Regeneron to finalize phase 3 plans and potentially initiate a program, by the end of this year.

We were also excited to see positive data presented by Sanofi from the phase 3 ATLAS, PPX study of Fetusran in patients with hemophilia, which met its primary endpoint and demonstrated that Fetusran prophylaxis significantly reduced bleeding episodes compared to prior factor or bypassing agent prophylaxis.

Looking through to the end of this year, we expect to have updates across our pipeline, including the potential for top-line results from early studies of ARMHSC in NASH, ARMXCH in gout, and ALMAPP in early onset Alzheimer's disease, our first CNS endeavor.

ICANN.

In this study at week 32 treatment with <unk> resulted in a 37% mean reduction from baseline in the 24 hour urine protein creatinine ratio relative to placebo.

Taken together, this all highlights our focus on these three key drivers for our NILM's, growth over the next several years.

The primary endpoint of the study and an important prognostic marker of disease progression.

The results of secondary endpoints were also consistent with the therapeutic benefit of some of this ramp in <unk>.

There were no significant drug related safety signals and we believe these collective efficacy and safety data to support continued clinical development development of <unk> monotherapy in patients with ICANN.

We now look forward to gaining alignment with regeneron to finalize plans for phase III and hope to initiate a program at the end of this year pending regulatory agency feedback.

Moving on our key growth driver for our <unk> in the years to come will be our organic product engine driving sustainable innovation.

The second quarter featured a new highlights in this regard in.

In nature Biotechnology, we published data from preclinical research on the delivery of like for like S. RNA conjugates extrahepatic tissues, including the CNS.

These data provide early evidence of the potential role of two prime or Hexadecile, <unk> conjugates, Thats Rnas and treating diseases of the CNS.

Alright and lung.

With further exploring the potential for lipid conjugate to help take delivery to other organs.

In another publication in nature Communications at this time, we published research findings identifying mutations.

EG associated with protection against abdominal obesity, and metabolic syndrome, a condition impacting more than 20% of adults worldwide.

Finding support the potential of inhibiting <unk>, which was previously referred to as gene X to be evaluated as a novel therapeutic treatment for the treatment of cardio metabolic disease since inhibits <unk> loss of function improves waste the hit ratio and is associated with an improved lipid profile.

We plan to pursue a development candidate for inhibit Ian as gene product activity leveraging our carrier clients.

As you can appreciate we have an incredibly broad and innovative platform that continues to advance and these are just a few recent highlights we look forward to updating you on a number of these programs in the coming months with that let me now turn the call over to Jeff to review, our financials and upcoming milestones Jeff.

Thanks, Akshay and good morning, everyone I am pleased to be presenting a summary of our items Q2, 2022 financial results and an update to our full year guidance.

Starting with a summary of our P&L results for Q2, 2022 total product revenues for the quarter were $214 million or 33% growth versus Q2 2021.

It's also worth noting that year over year growth in combined product revenues was held back by approximately 7% due to the foreign exchange impact of a strengthening U S dollar, which reached a 20 year high recently and given that approximately 50% of our product revenues are generated via sales in international markets.

Net revenue from collaborations for the second quarter was approximately $9 million, representing an 85% decrease compared with Q2 2021, primarily due to reduction in revenue from our regeneron collaboration which is subject to quarter to quarter variability, depending on a variety of factors, including the level of work completed during the.

<unk>, which is reimbursed by regeneron.

Do you expect an increase in collaboration revenue and royalties in the second half of the year, primarily driven by increased activity across our regeneron programs as well as from an increase associated with <unk> royalties and sales milestones as Novartis is U S launch progresses.

First is the potential near-term expansion of our TTR franchise opportunity, where we, aim to become a global leader in delivering impactful and highly differentiated medicines to patients.

The second key growth driver is our expansion beyond rare diseases into prevalent diseases.

And the third growth driver for the company comes from our sustainable innovation engine, comprised of new platform enhancements, opportunities with extra hepatic delivery, and our ability to find new genetically validated targets, which can drive further pipeline expansion to 2025 and beyond.

We believe all of this positions us well to deliver on our NILM piece-of-fit-by-25 goals, making our NILM a top biotech company, developing and commercializing transformative medicines for rare and common diseases for patients around the world, driven by a high-yielding pipeline of first- and or best-in-class product candidates from our organic product engine, all while delivering exceptional financial results.

Our non-GAAP R&D expenses increased 15% in the second quarter compared to the same period in 2021, primarily due to increased spend on early development activities increased head count to support the growth of our pipeline.

Our non-GAAP SG&A expenses increased 19% in the second quarter compared to the same period in 2021, primarily due to increased head count and other expenses to support the growth of our commercial portfolio.

Our non-GAAP operating loss for Q2, 2022 was $161 million, representing a $47 million higher loss compared with Q2, 2021, which was primarily impacted by the reduction in collaboration revenue during the quarter.

With that, let me now turn the floor over to Tolga for a view of our commercial performance.

Tolga?

Continue to believe our current cash balance is sufficient to bridge us towards self sustainable financial profile.

Now I'd like to turn to our full year 2022 financial guidance.

Thanks, Yvonne, and good morning, everyone.

Q2 was a strong quarter for our commercial portfolio, with 14% quarter-over-quarter growth, as Yvonne highlighted.

Following the strength of our operating results in Q2, we are reiterating the financial guidance, we provided on our Q1 results call in April .

Starting with net product revenues, we anticipate combined net product revenues for our four commercialized products will be between 870 $930 million.

I'm also excited about the FDA approval and launch of Amutra in June, and we're encouraged, by early, promising signs of Amutra uptake.

However, given the continued strengthening of the U S. Dollar since we issued our guidance in April and the fact that approximately 50% of our global product sales are generated in international markets. We are currently trending towards the lower half of our $870 million to $930 million guidance range.

I'll have more detail to share on that shortly.

As anticipated, we are also experiencing improved market conditions following COVID, impact in Q1, as we saw increased promotional activities, improved patient flows, healthy demand, and improved patient compliance across our portfolio. I'll now provide details on the performance of each of our products.

Our guidance for net revenue from collaborations and royalties is a range between $175 and $225 million.

And our guidance for combined non-GAAP , R&D and SG&A expenses as a range between $1 390, and $1 $450 million.

Let me now turn from financials and discuss some key goals and upcoming milestones on back through the end of 2022.

We continue to see growth for Ompatro, achieving $153 million in global net product revenues, in the second quarter, representing a 12% increase compared with the first quarter, and 35% growth compared with Q2-21.

We will continue executing on our global commercialization of on Petro give Barry and <unk> as well as the launch of <unk>.

Next our TCR franchise will have important updates with Petite Saran topline results from the Apollo Phase III study are expected in the next three weeks.

With <unk>, we plan to report results on a biannual dose regimen and initiate a phase III study in Stark heart disease, both in late 2022.

At the end of Q2, over 2,400 patients were on commercial Ompatro treatment worldwide, up from over 2,200 patients at the end of the first quarter, representing a steady 9% quarterly patient growth.

In the U.S., sales of Ompatro increased 14% versus the first quarter, and were primarily, impacted by an increase in patients on therapy and improved patient compliance following, Q1, which was negatively impacted by COVID.

In our international markets, Ompatro Q2 product sales increased 10% versus Q1-22, primarily due to an increase in patients on therapy and the timing of orders in distributor and partner markets.

Important to note, our global results continue to be challenged by foreign exchange headwinds, with Ompatro year-over-year reported growth of 35%, being held back 7% of Q1-22 sales by the strengthening U.S. dollar.

As you are aware, we received U.S. approval for Amutra at the end of the second quarter, and we're very pleased with the initial launch so far, as our teams continue to execute in line with our plans. We received 133 start forms from launch through July 22nd, keeping demand generation on track, with approximately one-third of start forms generated from patients new to Alnylax, and two-thirds from switches from Ompatro. Over 20% of those start forms came from new prescribers, which we believe is an encouraging, early sign of potential market growth.

Lastly, we plan to file an IND and initiate a phase one study for <unk> <unk> in healthy volunteers by the end of the year.

And our mid stage portfolio. We are looking forward to milestones include completion of enrollment in the phase II study of <unk> in patients with recurrent renal stones by year end.

Completion of enrollment in our phase II cardiac study in Sotheby's saran at or around year end.

And results from a phase II study of <unk> in combination with monoclonal antibody beer $34 34, which our partners expect to report later this year.

Wrapping up we have a few early stage readouts coming as well. These include top line results from part B of the Phase one study of <unk> in patients with Nash expected in mid 2022.

We hit the ground running, reaching over 61,000 key stakeholders within 48 hours of launch, serving as a catalyst for field engagement.

We have also been engaging with health systems, and the formulary process has been started, in over 60% of the priority delivery networks.

Further, from an access standpoint, our teams have been engaged and feedback has been positive, to date.

In fact, there is one national policy published with a large national payer covering 24 million, lives.

The first amputee patient has also been treated, and we're looking forward to continuing this, rollout and updating you further on our Q3 call.

Moving to our ultra-rare disease franchise, first with Givlare, we achieved $45 million, in global net product revenues in the second quarter, representing a 28% increase compared with Q1-22 and 47% growth versus Q2-21. At the end of Q2, over 420 patients were on commercial Givlare treatment worldwide, up, from over 400 at the end of the first quarter, representing a 5% quarterly patient growth. In the U.S., sales of Givlare increased 25% versus the first quarter and were primarily, a result of the following, a healthy demand growth of 12% driven by an increase in patients on therapy and improved patient compliance following a soft Q1, primarily impacted by COVID.

Preliminary top line results from a phase one study of the <unk> ATP in patients with early onset Alzheimer's disease expected in late 2022 and.

Inventory stocking dynamics, which favorably impacted reported growth by 8%, and a decrease, in gross net deductions in the quarter, which favorably impacted reported growth by approximately, 5%. In our international markets, Givlare delivered 34% growth compared with the first quarter, with the growth primarily driven by new patient ads, including a strong launch in the U.K., and favorability in gross net deductions.

Finally, global Givlare year-over-year reported growth of 47% was also held back by 6 percentage, points due to unfavorable foreign exchange rates.

And preliminary topline results from a phase one study of <unk> in patients with gout also expected for late 2022.

Moving now to our second ultra-rare disease product, Oxlumo.

We achieved $15 million in global net product revenues in the second quarter, representing, a 2% increase compared with the first quarter. At the end of Q2, over 200 patients were on commercial Oxlumo treatment worldwide, up, from over 160 at the end of the first quarter, representing 25% quarterly patient growth. In the U.S., sales of Oxlumo increased 32% versus the first quarter, and were primarily, by an increase in patient demand, as well as inventory stock dynamics, and a decrease in gross net deductions during the quarter.

In our international business, despite an increase in patients on therapy during the, quarter, Q2 Oxlumo sales decreased by 15% compared with Q1, primarily due to an increase in gross net deductions during the quarter and the timing of orders in our distributor and partner markets.

Let me now turn it back to Christine to coordinate our Q&A session. Christine. Thank you, Jeff Operator, we will now open the call for questions. Those dialed in we would like to ask you to limit yourself to one question each and then get back in the queue. If you have any additional questions.

On a year-over-year basis, global Oxlumo sales decreased 9%, despite an approximately doubling, of patients on therapy. The decrease was primarily due to a higher proportion of patients on the monthly loading, dose portion of their treatments, as well as lower net pricing in our international markets in Q2-22.

Additionally, as with Ompetra and Givlari, changes in foreign exchange rates also negatively, impacted Oxlumo Q2-22 results, with reported year-over-year growth of minus 9% held back by 5 percentage points due to the strengthening U.S. dollar.

In conclusion, we are pleased with the growth in revenues and patient demand achieved in Q2, and look forward to our Q3 results which will include the first full quarter of Armutra's launch.

As a reminder, we are in a quiet period with regard to our Apollo B study and will not be responding to questions on that topic.

Thank you as a reminder to ask a question you will need to press star one on your telephone.

Our first.

Question.

Comes from Paul Matteis with Stifel. You May proceed.

Hey, good morning, Thanks, so much for taking my question.

Just on <unk>.

Just a two part question the commercial dynamics I guess, one can you talk about the initial prescribing for patients new to a silencer and how much of that is coming.

With that, I will now turn it over to Akshay to review our recent R&D and pipeline progress.

From Cardiologists and then just curious on the economics have been office dosing appropriate tresor in and how does that compare for a physician versus our versus on patch horizon infusion. Thank you.

Thanks, Paul.

Without question I'd, just like to start off by saying that you really are the license to have our therapeutic.

Therapeutic.

And that's the full year with Oscar it's great to have additional upselling for patients.

<unk> talked about on the call the initial signs, but also very very encouraging.

I'd like to hand over this question to you. So it's around that is the <unk>.

Commercial dynamics with respect of <unk>.

Sure.

Initial.

Launch how much from cardiology.

And then any commentary on the economics with respect to Patrick and Patrick.

Akshay, thanks Tolga and good morning everyone.

With respect to the Copa absolutely.

Paul.

I'll start with our efforts in ATGY amyloidosis where we are advancing two clinical phase product candidates, Petitseran and Voutriseran. While Petitseran or Onpatro is currently approved in multiple markets around the world, to treat the polyneuropathy associated with hereditary ATGY amyloidosis, we're committed to expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild-type ATGY amyloidosis patients.

It is really exciting time.

Launch the product in reporting the information that's available to us.

Within the five weeks in that five weeks, we were able to receive 100 over 130 start forms and of those one third of those were exited naive patients. There are new so on island and and Thats actually a very good robust number it's early for us.

And these are only start forms patients need to go through the system and make sure that they exited get get the product in.

But as an early sign one third is new.

E patient dynamic is very encouraging.

In terms of the economics.

Essentially the product is part B therefore.

It is still a buy and bill and those patients that are.

Going to be looking at a very similar dynamics.

We see in <unk>.

What we're also excited about us.

Frankly, 20% of our prescribers in this very short period.

Excuse me.

Our new prescribers of <unk>, new prescribers of <unk>. So that's also a very exciting.

To this end, we're conducting the Apollo B phase 3 study, and as announced this morning, we expect to report top-line results within the next three weeks.

We're also advancing Voutriseran which is delivered by a quarterly subcutaneous injection, and was recently approved in the U.S. under the brand name Ambutra to treat the polyneuropathy of HAT amyloidosis in addition to receiving a positive CHMP opinion in the EU.

Alex.

Sure.

Thanks, Bob and Thanks, Paul next question. Please.

Thank you one moment for questions.

Here too, we're committed to expanding the label for the treatment of cardiomyopathy, in hereditary and wild-type patients.

Voutriseran is also in development for Stargardt disease.

Our next question comes from David Lebowitz with Citi. You May proceed.

Helios A evaluating Voutriseran in HAT amyloidosis patients with polyneuropathy, formed the basis for our regulatory submissions and recent U.S. approval of Ambutra. In April 2021, we presented positive results from the study at the AAN meeting, which showed the study met its primary and secondary endpoints at nine months. We continue to report results from the study and recently presented new 18-month results, from exploratory cardiac endpoints at the ESC-HF meeting. These findings show that in a variety of predefined, show that in a predefined cardiac subpopulation of HAT amyloidosis patients with polyneuropathy, treatment with Voutriseran was associated with improvement in exploratory cardiac endpoints associated to external placebo, including levels of NT-proBNP and a trend towards improvement in ex-cardiographic parameters. These findings in the cardiac subpopulation were consistent with the previously reported results, in the MITT population.

Additionally, in a planned cohort of patients from the MITT population, Voutriseran treatment reduced cardiac uptake of technetium on centigraphy imaging relative to baseline in a majority of assessable patients, including those with perigene greater than or equal to two at baseline, suggesting that patients with the highest degrees of cardiac amyloid burden may recognize benefit from RNA therapeutics.

Voutriseran also continued to demonstrate an encouraging safety and tolerability profile.

As mentioned, this is just the start for Voutriseran, as it is also being evaluated in the Helios B Phase III study for the treatment of patients with AT-triamyloidosis with cardiomyopathy, including both uretery and wild-type AT-triamyloidosis.

Thank you very much for taking my question.

First on <unk>.

This does not with respect to any details on the data I just wanted to as far as presentation I know historically in the past for top line releases, you put out key values.

Wanted to confirm that.

Is that we would likely see P value is certainly on the primary endpoint.

But also the secondary endpoints as well and one little.

Add on here as far as pricing goes.

Can you please give us perspective on what type of shift we might see.

<unk> cardiomyopathy gets added to the label.

Great.

David Thanks for that question I think the first one access.

Yes.

Just clarifying Dave that you sell boutris rent, but I suspect <unk> with respect to the Apollo B results of our correct. Indeed of course, yes.

And Youre right, we will present top line results in the form of a PR.

With.

P values as we.

The primary and secondary in a hierarchical OPEC.

That's as much like film at the present time.

Maybe talk a it could.

The second question with respect to pricing and any shifts that we.

To answer the cardiomyopathy.

We're excited about.

Thoughtful Joe survey cardiomyopathy patients, but as you can appreciate it's a little too soon for us to.

To share any information because it's a little too soon.

But we will obviously.

Appropriate when we make those decisions alright.

Alright, Thanks, David next question please.

Thank you.

Our next question comes from Salvino, Victor with Goldman Sachs. You May proceed.

Good morning. Thank you for taking my question could you just speak to the dynamics with regard to switching and combination thats playing out between.

North GTR franchise, and pfizer's to fit with us. Thank you.

I think we talked about that question ex Australia this year.

Yes.

Switching wise obviously.

In the U S. We're.

We see similar rates.

We've seen in the past it's about anywhere between.

15% to 20% what.

What we see what we're excited about switching dynamics as in ex U S.

Particularly in Europe , and Japan were both of those products and available with Polyneuropathy. We've seen a significant source of our business is really built by the switch is obviously, we continue to add new naive patients both in Europe , and Japan, but early on we've seen a good strong dynamic which allude.

To us that.

The physicians believe that there is actually probably more opportunity to move into to use on petro as a silencer.

In the earlier part of the disease to get adequate treatments.

Thanks next question.

Helios B, which is fully enrolled, has a 30-month end point of all-cause mortality and CV events, with many patients followed up to 36 months, and we expect the full results in early 2024. The study design includes the potential for an interim analysis, and we will consider the following results from PoliB and engagement with regulatory authorities.

In addition to our late-stage clinical programs, we believe we've also been making great progress with our early and mid-stage programs. A notable highlight in the second quarter was our announcement of positive top-line results from our Phase II study of Semdyseran, an investigational RNA therapeutics targeting the C5 component of the complement pathway, and is in development in collaboration with Regeneron for the treatment of IgA nephropathy, or IgAN. In the study, at week 32, treatment with Semdyseran resulted in a 37% mean reduction from baseline in the 24-hour urine protein to creatinine ratio relative to placebo.

Thank you.

Our next question comes from Ritu <unk> with Cowen you May proceed.

I was hoping for just a follow up to Paul and <unk>, just a little more detail on the new patients.

You mentioned that prescribers, but are you seeing less severe patients.

Are you seeing more mixed phenotype patients.

And does this sort of bolus imply that theres, some theres sort of warehoused patients to work through as we look at the new patient question.

<unk>.

This was the primary end point of the study, and an important prognostic marker of disease progression. The results of secondary end points were also consistent with the therapeutic benefit of Semdyseran in IgAN. There were no significant drug-related safety signals, and we believe these collective efficacy and safety data support continued clinical development of Semdyseran monotherapy in patients with IgAN.

Yes, it's a great question. Thank you.

We now look forward to gaining alignment with Regeneron to finalize plans for Phase III, and hope to initiate a program by the end of this year, pending regulatory agency feedback.

Moving on, a key growth driver for alnilam in the years to come will be our organic product engine driving sustainable innovation.

The second quarter features a new highlight in this regard.

As I indicated before it's little too soon for us to really give a lot of specific dynamics, it's an area where we're obviously.

In Nature Biotechnology, we published data from preclinical research on the delivery of lipophilic sRNA conjugates to extra hepatic tissues, including the CNS. These data provide early evidence of a potential role for 2'-OH-C16-conjugated sRNAs in treating diseases of the CNS, eye, and lung.

We're further exploring the potential for lipid conjugates to help achieve delivery to other organs.

In another publication, in Nature Communications this time, we published research findings identifying mutations in the inhibin E gene associated with protection against abdominal obesity and metabolic syndrome, a condition impacting more than 20% of adults worldwide.

Findings support the potential of inhibin E, which was previously referred to as gene X, to be evaluated as a novel therapeutic treatment for the treatment of cardiometabolic disease, since inhibin E loss of function improves waist-to-hip ratio and is associated with an improved lipid profile.

We plan to pursue a development candidate for inhibin E and its gene product active in E, leveraging our ICARIA platform.

As you can appreciate, we have an incredibly broad and innovative platform that continues to advance, and these are just a few recent highlights.

We look forward to updating you on a number of these programs in the coming months.

Closely monitoring what.

What we're encouraged about is the early signs indicate that we do see some.

Younger patients, but again, it's difficult to generalize at this point, we're only five weeks into the launch.

<unk>.

But we're again excited about is the fact that we are seeing a broad range of patients.

Either switched or may even being treated part of it I'm sure there's going to be a little bit off the warehousing, but but it is important to highlight that in Q1, we had a great strong robust strong pass through growth with what we originally thought was probably the patients and physicians would be.

With that, let me now turn the call over to Jeff to review our financials and upcoming milestones.

Jeff?

<unk> and warehousing some of those patients for a good drug.

It didn't exactly happen, but I'm certain that part of the the uptick that we've seen in the first five weeks.

Thanks, Lakshay, and good morning, everyone.

Might be contributed to the warehouses.

Yes, no. Thanks, Bob It really does look at the introduction of <unk> is helping us will help us grow the overall TCR franchise going forward, which I think is very encouraging.

Thanks, Richard next next question.

Thank you.

Our next question comes from <unk> <unk> with Bank of America You May proceed.

Hi, Good morning. Thank you for taking my question Mike is on.

On Helios B, so you've reiterated your confidence stopped early 2020 or target for data readout is something that you feel confident about.

I'm pleased to be presenting a summary of Alnylam's Q2 2022 financial results and an update to our full-year guidance.

Starting with a summary of our P&L results for Q2 2022, Total product revenues for the quarter were 214 million or 33% growth versus Q2 2021 It's also worth noting that year-over-year growth and combined product revenues was held back by approximately 7% due to the foreign exchange impact of a strengthening US dollar which reached a 20-year high recently and given that approximately 50% of our product revenues are generated via sales in international markets Net revenue from collaborations for the second quarter was approximately 9 million, Representing an 85% decrease compared with Q2 2021 Primarily due to a reduction in revenue from our Regeneron collaboration, which is subject to quarter-to-quarter variability, Dependent on a variety of factors including the level of work completed during the quarter which is reimbursed by Regeneron We do expect an increase in collaboration revenue and royalties in the second half of the year, primarily driven by increased activity across our Regeneron programs as Well as from an increase associated with LECVIO royalties and sales milestones as Novartis's US launch progresses, Our non-GAAP R&D expenses increased 15% in the second quarter compared to the same period in 2021 Primarily due to increased spend on early development activities and increased headcount to support the growth of our pipeline, Our non-GAAP SGA expenses increased 19% in the second quarter compared to the same period in 2021 Primarily due to increased headcount and other expenses to support the growth of our commercial portfolio, Our non-GAAP operating loss for Q2 2022 was 161 million Representing a 47 million dollar higher loss compared with Q2 2021, Which was primarily impacted by the reduction in collaboration revenue during the quarter Finally the end of the quarter with cash cash equivalents and marketable securities of, 2.1 billion compared to 2.4 billion at the end of 2021 Continue to believe our current cash balance is sufficient bridges to a self-sustainable financial profile, Now i'd like to turn to our full year 2022 financial guidance Following the strength of our operating results in Q2.

We are reiterating the financial guidance, We provided on our Q1 results call in April Starting with net product revenues we anticipate combined net product revenues for our four commercialized products, Will be between 870 and 930 million 930 million, however, given the continued strengthening of the u.s dollar since we issued our guidance in April And the fact that approximately 50 percent of our global product sales are generated in international markets, We are currently trending towards the lower half of our 870 to 930 million dollar guidance range Our guidance for net revenue from collaborations and royalties is a range between 175 and 225 million, And our guidance for combined non-gap r&d and sg&a expenses is a range between 1 billion 390 and 1 billion 450 million Let me now turn from financials and discuss some key goals and upcoming milestones on deck through the end of 2022, We will continue executing on our global commercialization of on patro give lorry and ox lumo as well as the launch of ambutra, Next, our TTR franchise will have important updates.

With Patrice Seran, top-line results from the Apollo Phase 3 study are expected within the next three weeks.

With Lutris Seran, we plan to report results on a biannual dose regimen and initiate a Phase 3 study in Stargardt disease, both in late 2022.

Lastly, we plan to file an IND and initiate a Phase 1 study for ALN TTR SCO4 and healthy volunteers by the end of the year.

Just wondering is there at all a scenario in which you would opt to extend the observation period that allows for a higher chance of being at the nextgen and towards men a mortality benefit.

In our mid-stage portfolio, we are looking forward to milestones that include completion of enrollment in the Phase 2 study of Blumasterin in patients with recurrent renal stones by year-end, completion of enrollment in our Phase 2 Cardia 2 study of Zaldivar-Seran at or around year-end, and results from the Phase 2 study of ALN HPV02 in combination with the monoclonal antibody FEAR3434, which our partners at FEAR expect to report later this year.

Wrapping up, we have a few early-stage readouts coming as well. These include top-line results from Part B of the Phase 1 study of ALN HSD in patients with NASH expected in mid-2022, preliminary top-line results from the Phase 1 study of ALN ATP in patients with early-onset Alzheimer's disease expected in late 2022, and preliminary top-line results from the Phase 1 study of ALN XTH in patients with gout also expected for late 2022.

Let me now turn it back to Christine to coordinate our Q&A session.

Christine?

Thank you, Jeff.

Maybe I'll start by reiterating our confidence in early 2024 data readout from our <unk>.

Operator, we will now open the call for questions.

And I'd say any perspective on.

To those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have any additional questions.

No.

How we might think about that going forward.

We've revisited the study designs.

Thoroughly assessed how robust is the study.

Is it structured and powered in a way to help us meet the primary endpoint and the secondary endpoints and we are comfortable with the study design and so.

<unk> designs on altered.

The only thing we will consider is the interim analysis of course.

In due course and the other thing I would say by the way is that.

And as we as.

Patients come in over a long period in the study in a large study like that so many of them will have gone to 36 months.

And that provides additional.

Also, as a reminder, we are in a quiet period with regard to our Apollo B study and will not be responding to questions on that topic.

Coverage in terms of the robustness of the studies. So we're comfortable and we would reiterate data early 'twenty four and looking forward to positive results.

Thanks Akshay.

Next question please.

Thank you.

Our next question comes from Joseph Stringer with Needham You May proceed.

Yes.

Hi, Thank you for taking our question.

Thank you.

As a reminder, to ask a question, you will need to press star-one-one on your telephone.

Our question was for.

In vitro I know, it's early days, but how do you anticipate.

Our first question comes from Paul Matisse with Stiefel.

The time from start form to getting patients on drug.

Do you think this compares relative to your <unk>.

You may proceed.

<unk> with on macro thank you.

Yes, that's a great question, and clearly with Enbridge or being second products.

Hey, good morning.

And the GTR franchise, we're really building on.

The very robust in a commercial operation that we have under <unk> leadership, but perhaps you could talk a little bit about that.

Now I'm going to have that book so to speak.

Okay. Thanks, Bob obviously, we're very well positioned to be able to maximize the opportunity for <unk>, given our experiences with Arturo and on which was really attractive profiles being subcutaneous injectable.

Every every three months in regards to.

In regards to the how the timing is going to work is.

Look I mean agenda today, we do have the right capabilities right patient services.

Benefit verification and so forth already in place within this category and what we have so far done.

<unk> is working very closely with not only with major national and regional payers, but also with integrated delivery networks and other health providers to make sure that formularies are in place.

Given the fact that we actually also set the price despite.

It's very attractive profile at parity with on Petro we have not so far seen any significant headwinds.

Nevertheless, like any new product. It does take time for the health care system to absorb and make sure. The TNT committees and so forth are in place to get the product approved.

Very pleased with the early signs of what we have so far done and how the health care system XI reacting, but I'm sure we're going to see.

No.

Some some delays early on and eventually get to a place where I think is going to be.

At parity with our portfolio, even though it may be a little faster approvals, but it's a little too soon for us to.

Thanks so much for taking my question.

To share where we are in that regard I think good progress thus far.

Just on Butreserin, just a two-part question on the commercial dynamics.

So next question please.

Thank you.

Our next question comes from Maury Raycroft with Jefferies. You May proceed.

Hi, good morning, and thanks for taking my questions.

I was going to.

Ask a question on <unk> for hypertension.

Wondering if you can elaborate on steps you've taken to streamline the protocol to speed up enrollment and.

What the status is on that.

I guess, one, can you talk about the initial prescribing for patients new to a silencer, and how much of that is coming from cardiologists?

And then just curious on the economics of in-office dosing for Butreserin and how does that compare for a physician versus on Patra as an infusion?

Yes.

<unk>.

A reminder, we unfortunately experienced some delays with arcata.

One of the risks and southeastern primarily.

Due to the fact that we selected sites in the Ukraine and obviously.

The ongoing more.

No.

The sites were unable to move forward we've expanded.

Site footprint and are very pleased with progress. We also took the opportunity to.

Yes, just refine the protocol to make it an easier study to.

To execute efficiently.

Thank you.

Thanks, Jay do you want to add any.

Now ill cover the Avon.

Thanks, Paul, you know, for that question.

Yes.

More specifically on the streamlined with inevitably more in these protocols.

One tries to capture as much scientific innovation is one cab.

You know, I'd just like to start off by saying that we really are delighted to have our 5th RNI therapeutic for patients in less than four years with Amputera.

And it's great to have an additional option for patients here.

But given the needs of the program.

We were able to reduce some of the.

Your assessment.

Don't take anything away from the core issue downtown hypotensive effects and safety insight.

And yet maintain two large robust protocols, which will be easier to accrued one in monotherapy and combination therapy. So between the site expansion and these payments the peripherals for op risk.

How about Readouts next shift.

Great and just to add that were expected to complete enrollment in <unk> II.

At the end of this year Thats right.

Thank you next question please.

And, you know, as Tolga said on the call, the initial signs for launch are very, very encouraging.

Thank you.

Our next question comes from.

<unk> with RBC capital you May proceed.

Oh, great. Thanks, so much for taking my question congrats on the quarter, maybe one on PPR Polyneuropathy, how youre thinking about the competitive landscape here, obviously <unk> has reported successful phase III and they seem very confident they can compete commercially given the astrazeneca global footprint I know, we don't have the full data at this point, but how are you thinking about.

But Tolga, I'd like to hand over this question to you.

The implications of that launch for your franchise. Thanks, so much.

Thank you.

Regarding the primary question about how we believe that we're going to compete in the TCR space, particularly with.

So it's around the commercial dynamics with respect to the initial launch, how much from cardiology, and then any commentary on the economics with respect to Patra compared to Butreserin from a physician's perspective.

Potential new competitors coming on stream.

With Astrazeneca.

Thank you Ivan.

Look first of all we are always excited to bring new module medication different alternative treatments to patients because theres a lot of woods to chop when it comes to <unk> prevalence and what the patients that are currently being treated we anticipate.

Thanks, Tolga.

Absolutely.

Hi, Paul.

Prevalence numbers around 25% to 30000 patients worldwide.

And we are a very small fraction of that that we've been able to deliver so while we have seen in similar categories. A good expansion of diagnosis and treatment rates going on in regards to.

Where we are.

The major driver.

<unk> that is also being promoted by our important company.

This is a really exciting time.

One of the important I think.

Drivers of our growth is going to be obviously, the making <unk> available worldwide and we are well positioned to do that we have.

Europe , and Japan, the geographic puts footprint and available in over 50 markets through other partners and distributors.

Given the fact that we're going to be.

A year ahead already offset competition and plus again, a very attractive profile that upwards.

Ultra for the patients with the subcutaneous injectable over three months, then and soon with six months if those trials work.

We really like our chances in terms of how we are well positioned to be able to make this product available in and continue to be a leader.

As our portfolio leader.

But again I just want to reiterate having said that there are going to be products available and that's good for patients and we're excited about that.

Access to want to say anything about <unk>.

Yes.

Yes, no answer to that.

Proposal four which.

Thanks, a lot of sense, but in terms of the data themselves I think we've got a very comprehensive base.

Got it.

Which was around around Boucher <unk> across the primary showing improvement in Europe .

Which is exciting in terms of the other endpoints secondary but not to the exploratory cardiac endpoint impacts on the hard and <unk>.

On slide the right spot transports, but still notable particularly with new observation.

Reducing technetium scan uptake and that's very exciting for patients and physicians.

And so along with the convenience Q3, and then hopefully in Q six monthly dosing of <unk>.

Very differentiated product in a market that is tolga explained we've been leaders in.

And ultimately I will add that.

Whilst patients made good options in this space.

We won't see the full data package associated through without contrast.

Recalling that the first time round within a test and there were some safety issues of note.

Including <unk> injection site reactions platelet effects.

<unk> Bay of everybody is keen to note that the safety is good so let's see but I think we're off to a great start with equity.

Okay very helpful. Thanks.

Okay.

Thank you next question. Please thank you.

Our next question comes from Gary Nachman with BMO you May proceed.

Okay, great so back to <unk> and the start forms in the two thirds switches from on Petro what's the profile of initial patients that are switching from a petro are you getting a sense, if it's more patient or physician driven do they stay on on patch up until they get and if that takes some time.

And how do you expect that split between new and switches.

Just over the next couple of quarters. Thank you.

So I think that let's be lots of interest than the absolute.

Yes, I mean look at.

At the end of the day.

We're really excited about is our neutral profile is giving to us stability and physicians the ability to be able to actually treat.

Diagnose and treat more patients.

And what we've so far seeing the early signs.

In terms of initiations, it's both when it comes to switches as well as naive patients.

Have a good robust patient services and our patients has been informed about the availability and some of those patients proactively reached out to their physicians, but we've also seen is as I indicated earlier.

Good new prescribers coming into.

Treatment.

Of this condition and excited to be actually providing this medicine to those patients.

That probably were on the fence given that it was in <unk>.

Infusion with on pass through earlier profile.

Woodrow tends to offer a very convenient option with great safety and efficacy data.

Therefore, we do what we so far seen in the 133 start forms is a good broad range of both patient prescriber base as well as patients.

Demographics that ranges across yogurt as well as <unk>.

Our traditional.

Demographics.

Thanks, Tom let's let's take on I think your question.

Thank you.

Our next question comes from the line of Palm Rama with Jpmorgan you May proceed.

Hey, guys. Thanks, so much for taking the question.

Maybe following on the last question on <unk>.

On switching dynamics, what has your market research suggest on the timeframe in which you would expect switching to kind of peak or where most patients that are going to switch have made the switch I think thats what were trying to understand many of us. Thanks. So much.

Hi, Adam.

Great question and thank you.

We launched the product and reporting the information that's available to us within the five weeks. In that five weeks, we were able to receive over 130 start forms. And of those, one third of those were actually naive patients. They are new to aniline.

Putting a forward buy precisely.

And that's actually a very good robust number.

I think told that's a specific question here around that.

Our market research is telling us right about the time to sort of peak.

Cheng.

What we're really interested at this point is really to make sure that.

The overall category is growing so our focus is actually right now is really to make sure that we are bringing as many as new patients as possible.

It's early for us.

Given this new option.

The switches what we believe is going to play out a little more organically.

And we will obviously update the street for about a year about the switch and naive patients.

And, you know, these are only start forms.

Patients need to go through the system and make sure that they actually get the product in.

We expect that to Acacia to organically happen is most patients will end up with <unk> given its profile. However, we also know that in.

But as an early sign, one third is new.

Rare diseases. There are patients who are pleased with their existing treatment. So if these patients never had any new treatment before almost solely on Petro was available. So we do expect some patients to remain on therapy.

The naive patient dynamic is very encouraging.

In terms of the economics, essentially the product is Part B.

Similar dynamics that we've seen.

Sure.

Is.

Similar dynamics that we've seen in other other categories patients tend to gravitate towards a more better option, which we believe.

<unk>, what I also wanted to take the opportunity to remind everyone that.

Therefore, it is still a buy-in bill.

And those patients that are going to be looking at a very similar dynamics as we see in Onpatra.

We're going to be updating on this.

What we're also excited about is, frankly, 20% of our prescribers in this very short period are new prescribers of TTR, new prescribers of Onpatra.

The dynamics for <unk> in two to three quarters, just one other comment.

From a modeling perspective, as a matter of phenomenon patch or a neutral at the same price same value per patient per year. So just a reminder, on that point great point.

So that's also a very exciting dynamic that I'd like to understand.

Good Okay, let's take.

Thank you.

The next question.

Q.

One moment for questions.

Our next question comes from Tom <unk> with Barclays. You May proceed.

Our next question comes from David Lebowitz with Citi.

You may proceed.

Thank you very much for taking my question.

Hello.

Actually can you hear me.

Yes, we can hear you.

Ed.

Gena Wang from Barclays, Yes, So I have a question.

Maybe follow up the stock from the 133 staff from you said 34, new two I'll now Owen just if you can give a little bit more clarity what percentage of these are the switcher from tech savvy and versus truly naive patients and then quickly on <unk> I just wanted to.

Some maintenance check last time, we discussed to fathom is dropping maintaining at the low single digits any change in the dropping rate.

First, I'm Patrice Seran.

Okay, let's start with that.

Targa.

The answer to your question on that and then access of the <unk> question.

We really appreciate the excitement around the strong launch of <unk>.

This is not, with respect, any details on the data.

Yes, we saw the <unk> data so we wanted to make sure that the.

I just want to, as far as presentation, I know historically in the past for top line releases, you put out P values.

We all recognize that the granularity of the data we're providing is as good as we possibly can at this point are those 34, new patients are <unk>.

I just want to confirm that we would likely see P values, certainly on the primary end point, but also the secondary end points as well.

And one little add on here, as far as pricing goes, could you at least give us perspective on what type of shift we might see once cardiomyopathy gets added to the label?

<unk> to us.

And.

In terms of your own modeling one should also remember that the <unk> city.

Great.

David, thanks for that question.

Is it remains a very small portion of the overall overall category.

So we wouldn't necessarily index.

Patients just only on switches from an alternative treatments.

Yes.

Great opportunity to grow exactly.

New patients coming into.

And future.

Access TV speed fast drop in rates, yes, thanks gene.

I can reiterate the drop in rates to remain well within expectations.

Didn't discuss before we obviously had.

Put in a buffering the sample size to account for top drop ins were well within those estimates were comfortable with the design gena. Thank you.

That's great.

Next question.

Thank you.

Our next question comes from <unk> <unk>.

Merrill with UBS you May proceed.

Hey, guys. Thanks for taking my question I guess, not an easy question, but on the pipeline for master and renal stones.

I think the first one, Akshay, is for you.

Yeah.

Maybe just with the phase III phase II, finishing enrolling later this year and thinking about phase two data next year I mean, how should we think about what you are looking to see here. It's obviously a much broader population.

Just clarifying, Dave, that you said Patrice Seran, but I suspect you meant Patrice Seran with respect to the Apollo B results. Am I correct? Indeed, of course.

Yeah.

I guess, what could we learn in terms of the relationship between oxalate reduction and reduction in stone formation in this broader population and your confidence in the biology, there and then I guess thinking about sort of the regulatory pathway from there like what a potential phase III could look like and any types of like patient segmentation and comes out.

And you're right, we'll present top line results in the form of a PR with P values as we test the primary and secondaries in a hierarchical order.

So that's as much as I can say on that at the present time.

Thanks, Akshay.

And maybe, Tolga, you could take the second question with respect to pricing and any shift as we hopefully enter the cardiomyopathy.

Thank you.

Relationship.

Yes.

Actually I'm not sure if you caught all of that yes, I think it's around the recurrent.

Studying what we're looking to see phase two data on how we're thinking about.

Oxalate reduction and then I think.

Plans for for moving forward that study yeah. So.

Thanks for the question so the alumina recurrence to inflammation studies ongoing as obviously, a very large population globally numbering in the billions.

Quickly.

And.

What we want to see a reduction in urinary oxalate.

Now in the Th one population of course, we saw very substantial reductions in urinary oxalate. They have an enzymatic defect in the liver.

Go one leads to.

70, plus percent reduction in urinary oxalate.

This is the hypothesis, we're testing one of the interesting things is we may not need to achieve levels like that to see a reduction in stone events and so let's look at the data as it comes out next year and see and I say that because the.

The important thing is once oxalate becomes a saturating levels.

In the year and that has been spent inflammation occurred. So you may not need to take it all the way back down to normal you might just need to get it out of the Super saturation range by some relatively modest margin to prevent stone formation and so lots more work to do here and we will update you as we get data, but this is a very exciting opportunity with an approved drug that.

Looks very safe so far in the ph population and that just reminds me except for safety, but also have been seeing the RFS population, but we are optimistic with what we've seen so far.

In ph file.

<unk> access.

If program in our pipeline, which is orientated around patients with <unk>.

Much more common diseases banker and exciting.

Development.

On either next question please.

Thank you.

Our next question comes from Myles Minter with William Blair You May proceed.

Thanks for taking the question just on license.

We're adding the RJ nephropathy died off can you just sort of discuss where you're saying you'd like the complement inhibitor.

Serology sitting in the launch of therapy, and I guess, how it relates to the data that we're seeing from the Endothelin receptor antagonists.

And I guess is that a K consideration fair regeneron and how that would potentially design a pivotal study and that pops up.

Patients that you would enroll.

In our pivotal study thanks.

So quite a few questions. There I mean really just I think startup by any weird iterate things that we were really pleased for the phase III without.

These are patients with Iga nephropathy very common condition.

That reduction in price scenario. This is great and I think.

It's another potential phase III program for <unk>. So we're very pleased to be working with our partner Regeneron and moving forward. The next steps.

Sure.

And that I think a much more specific around how we think.

So yes, we're very excited by the phase II result, with a 37% reduction in dairy area.

And are busy working with Regeneron right now we take the lead in this program and the study.

Study design.

We're sort of very busily looking forward to engaging regulatory authorities and hopefully kicking off the study by the year end the specifics.

Where complement Orient complement approach has said and the interesting thing is the fundamental underlying pathology here, our iga immune complexes that deposit mix amount listen activate complement that activated complement damages the glomerular basement membrane and per unit results.

Additional aspect of the disease I don't think anyone really understands how this occurred as hypo filtration in the kidney and so blood flow dynamics change through the glomerulus. So we havent opportunity here or formally to impact two key pathogenic factors with anti complement approaches we can get at the fundamental under.

Lying immuno pathology and we've seen the preliminary results wechat. So this will have a foundational role I believe in the future and what will end up being.

Polypharmacy situation, where there'll be anti inflammatory purchase and complement some of this ramp would be a great fit for that and it could be a once a month. Once every three months type of infection.

And then in addition to that.

Things that ultra blood flow, so endothelin antagonist ace inhibitors, ace inhibitors, or arbs, etcetera, and so youll see trucks from both classes antihypertensive type drugs and <unk>.

And to complement the drugs being combined.

We'll see if steroids will also become part of the picture, but there's more work to do that although they are rather general months specific agents.

Have a lot of side effects and just to add up.

These favorable results open up.

And the potential for <unk>.

This estimate the patients with other <unk>.

The web we're enthusiastic in moving forward here.

Thank you for the question.

One more question I think we have one more question before we place last question. Please thank you.

Our last question comes from Olivia Brayer with Gen. Sir you May proceed.

Hey, good morning, guys. Thanks for the question I know you are in a quiet period with respect to Apollo B, but I wanted to ask if there are any monitoring requirements applications reached that 12 month Mark.

That our Belgium study and then I've got a follow up on sequencing for Mexican anticipation is there anything you can do to improve access for patients that could move on to on hot shower Andrew.

After Canada. Thank you.

So I just want to say you pointed out we are in a quiet period. So we're not going to be taking any questions on Apollo b, but I didn't actually quite catch your second question I think it was something to do with that is mature, but I didn't hear probably could you repeat the question. The second the second part of the question, Yes, sure. It's just about mixed phenotype patients right and whether there is anything you guys can do to shrink.

The payer access for patients.

Good sequence onto on pace of RMB chalk area after to animals.

You mean polyneuropathy mixed phenotype patients.

Yes.

Yes, I mean look we certainly have the right capabilities to support those patients. The fact that we've been able to position this at parity pricing.

It will certainly be we believe help.

Increased access so far we haven't really had any.

Headwinds around the access access fees.

We are indicated for polyneuropathy and in the U S.

<unk> is indicated for cardiomyopathy. So in terms of providing any breach strategy for access would not be something we would consider like any.

Our new patients, we have great support of benefit verification in and patient access support which those patients.

Certainly be eligible if they go through our patient services.

Thanks silica okay. So thanks.

Thank you everyone for joining us on this call.

Very happy with the progress that we've made in the second quarter and first half of 'twenty three we delivered strong commercial results.

We've advanced our diverse pipeline programs in development, a number of exciting catalysts on back in the coming months.

Look forward to updating you along the way, while we continued to deliver on.

Yes.

So thanks, everyone and have a great day.

Goodbye.

Thank you. This concludes today's conference call. Thank you for participating you may now disconnect.

Well, we're excited about the possibility of serving cardiomyopathy patients, but as you can appreciate, it's a little too soon for us to share any information because it's a little too soon.

But we will obviously update appropriately when we make those decisions.

Thanks, David.

Next question, please.

Thank you.

To raise your hand during Q&A, you can dial star 11.

Our next question comes from Salveen Richter with Goldman Sachs.

You may proceed.

Good morning.

Thanks for taking my question.

Could you just speak to the dynamics with regard to switching and combination that's playing out between your TTR franchise and Pfizer's Terfamidus?

Thank you.

I think, Tolga, that question is straight forward to you.

Yeah, I mean, switching-wise, obviously, in the U.S., we're indicated for pulmonary opathy and Terfamidus is indicated for cardiomyopathy.

Therefore, we do not see any switching dynamics.

In terms of concomitant use, we see similar rates that we've seen in the past.

It's about anywhere between 15% to 20%.

What we see, what we're excited about switching dynamics is in the next U.S., particularly in Europe and Japan, where both of those products are available in pulmonary opathy.

We've seen a significant source of our business is really built by the switches.

Obviously, we continue to add new naive patients both in Europe and Japan.

But early on, we've seen a good, strong dynamic, which alludes to us that the physicians believe that there is actually probably more opportunity to use Ompatro as a silencer in the earlier part of the disease to get adequate treatment.

Thanks Tolga.

Next question.

Thank you.

Our next question comes from Ritu Baral with, Cowan.

You may proceed.

Good morning guys.

Thanks for taking the question.

I was hoping for, just to follow up to Paul and Salveen's, just a little more detail on the new patients.

Tolga, you mentioned the prescribers, but are you seeing less severe patients?

Are you seeing more mixed phenotype patients?

And does this sort of bolus imply that there's some, there's sort of warehouse patients to work through as we look at the new patient question for MBUTRA?

It's a great question.

Thank you.

As I indicated before, it's a little too soon for us to really give a lot of specific dynamics.

It's an area where we're obviously closely monitoring.

What we're encouraged about is the early signs indicate that we do see some, you know, a little younger patients, but again, it's difficult to generalize at this point.

We're only five weeks into the launch.

What we're again, excited about is the fact that we are seeing a broad range of patients quickly getting either switched or naively being treated.

Part of it, I'm sure, is going to be a little bit of the warehousing, but it's important to highlight that in Q1, we had a great, strong, robust Ompatra growth.

What we originally thought was probably the patients, physicians would be waiting and warehousing some of those patients for MBUTRA.

That didn't exactly happen, but I'm certain that part of the uptake that we see in the first five weeks might be, contributed to that warehousing dynamic.

Yeah, I know.

Thanks, Paul.

It really does look as though the introduction of MBUTRA is helping us, will help us grow the overall TTR franchise going forward, which I think is very encouraging.

Thanks, Richie.

Next question.

Thank you.

Our next question comes from Tazine Ahmad with Bank of America.

You may proceed.

Hi, good morning.

Thank you for taking my question.

Mine's on Helios B.

You've, reiterated your confidence that the early 2024 target for data readout is something that you feel confident about.

I'm just wondering, is there at all a scenario in which you would opt to extend the observation period, though, to allow for a higher chance of seeing a significant improvement in mortality benefit?

Maybe I'll start by reiterating our confidence in an early 2024 data readout, from Helios B. Akshay, any perspectives on how we might think about that study going forward?

Yeah, you know, we've revisited the study designs and thoroughly assessed how robust is the study, is it structured and powered in a way to help us meet the primary end point and the secondary end points, and we're comfortable with the study design.

And so the study design is unaltered.

The only thing we'll consider is the interim analysis, of course, in due course.

And the other thing I would say, by the way, is that You know as we as you patients come in over a long period in the study in a large study like that so, many of them will have gone to 36 months um and that provides additional uh coverage in terms of the robustness of the study so we're comfortable and we'd reiterate data early 24 and looking forward to positive results.

Thanks Akshay.

Next question please.

Thank you.

Our next question comes from Joseph Stringer with Needham.

You may proceed.

Hi.

Thank you for taking our question.

Uh our question was for um uh Ambutra.

I know it's early, days but how do you anticipate um the time from start form to getting patient on drug?

Uh how do you think this compares relative to your experience with Onpatro?

Thank you.

Yeah that's a great uh question and clearly with Ambutra being our second product um in the TTR franchise we're really building on um you know what's a very robust uh you know commercial operation that we have under Tolga's leadership but uh Tolga perhaps you could talk a little bit about that.

So yeah I mean how that looks naturally speaking.

Thanks.

Obviously we're very uh well positioned to to be able to to maximize the opportunity for Ambutra given our experiences and all with Onpatro and Ambutra's really attractive profile being subcutaneous injectable uh every every three months.

Uh in regards to um in regards to the the how the the timing is going to work is look I mean at the end of the day we do have the right capabilities, right patient services, uh benefit verification and so forth already in place within this category and what we've so far done uh is is working very closely with not only with major national and regional payers but also with integrated delivery networks and other health providers to make sure that formularies are are in place.

Um given the fact that we actually also set the the price despite uh it's very attractive profile at parity with Onpatro we have not so far seen any significant hazards.

Nevertheless like any new product it does take time for the healthcare system to absorb and make sure the PNT committees and so forth are in place to get the product approved.

We're very pleased with the early signs of uh what we've so far done and and how the healthcare, systems are reacting but I'm sure we're going to see uh you know some some delays early on and eventually get to a place where I think it's going to be uh at parity with Onpatro even maybe a little faster approval dynamic but it's a little too soon for us to to to share where we are right now with that.

Thanks Olga.

I think good progress thus far and we're very pleased.

So next question please.

Thank you.

Our next question comes from Maury Raycroft with Jeffries.

You may proceed.

Hi uh good morning and thanks for taking my questions.

Um I was going to uh ask a question, on uh zolbicerin for hypertension.

I'm just wondering if you can elaborate on steps you've taken to streamline the protocol to speed up enrollment and um what the status is on that.

Yeah, just for everybody as a reminder, we unfortunately experienced some delays with, Arcadia, one study with Zarbisraq, primarily due to the fact that we selected sites in the Ukraine and obviously, with the ongoing war, you know, those sites were unable to move forward.

We've expanded our site footprint and are very pleased with progress thus far.

We also took the opportunity to, you know, just refine the protocol to make it an easier, study to execute for physicians.

Akshay, do you want to add anything?

No, I think you covered it, Yvonne.

The only other thing more specifically on the streamlining, is, you know, inevitably, more in these protocols, one tries to capture as much scientific information as one can, but given the needs of the program, we were able to remove some of the assessments that don't take anything away from the core issue of antihypertensive effects and safety and so, and yet maintain two large, robust protocols, which will be easier to accrue, one in monotherapy and one in combination therapy.

So, between the site expansion and these changes in the protocols, we're optimistic about readouts next year.

Great, and just to add that we're expecting to complete enrollment in CARDIGA II, at the end of this year.

That's right.

So, we're looking forward to that.

Thank you.

Next question, please.

Thank you.

Our next question comes from Luca Issi with RBC Capital.

You may proceed.

Oh, great.

Thanks so much for taking my question.

Congrats on the quarter.

Maybe one on TTRPOL, and neuropathy.

How are you thinking about a competitive landscape here?

Obviously, IONIS has reported successful phase three, and they seem very confident they can compete commercially given the AstraZeneca global footprint.

I know we don't have the full data at this point, but how are you thinking about implications of that launch for your franchise?

Thanks so much.

Thanks.

Luca, I think the primary question about how we believe that we're going to compete in the, TTRPN space, particularly with potential new competitors coming on stream with AstraZeneca.

Yeah, thank you, Yvonne.

Look, first of all, we are always excited to bring new modes of, medication, different alternative treatments to patients because there's a lot of wood to chop when it comes to TTRPN prevalence and what the patients that are currently being treated.

We anticipate the prevalence numbers around 25,000 to 30,000 patients worldwide, and we are a very, small fraction of that that we've been able to deliver.

So what we've seen in similar categories, a good expansion of diagnosis and treatment rates going on.

In regards to where we are, look, at the end of the day, we have been able to actually establish ourselves in the last four years as the major driver, including in Europe and Japan, against the Sepamidis that's also being promoted by an important company.

One of the important, I think, drivers of our growth is going to be, obviously, the making Omvutra available worldwide, and we are well positioned to do that.

We have Europe and Japan, a geographic footprint, and available in over 50 markets through other, partners and distributors.

Given the fact that we're going to be a year ahead already of that competition, and plus, again, a very attractive profile that Omvutra offers for the patients with a subcutaneous injectable over three months and soon with six months if those trials work.

We really like our chances in terms of how we're well positioned to be able to make this product, available and continue to be a leader, as a portfolio leader.

But again, I just want to reiterate, having said that, there are going to be products available, and that's good for patients, and we're excited about that.

Thanks, Olga.

Actually, do you want to say anything about the effective profile?

Yeah, no, I'll just add to what Tolga said, which makes a lot of sense, that in terms of the data themselves, I think we've got a very comprehensive data associated with batrissera and rambutra in HATTRP, and of course, the primary showing improvement in neuropathy, which is exciting.

In terms of the other endpoints for the secondary, but not just the exploratory cardiac endpoints, the impact on the heart and the exploratory endpoints, but still notable, particularly with the new observation of reducing technetium scan uptake, and that's very exciting for patients and physicians.

And so, along with the convenience Q3 and then hopefully soon Q6 monthly dosing, this is a very differentiated product in the market, as Tolga explained, we've been leaders in.

And ultimately, I will add that Whilst patients need good options in this space, we'll want to see the full data package associated, with F1 test and recalling that the first time around within a test there were some safety issues of note, including renal effects, ejection site reactions, platelet effects, and you know I'm sure they and everybody is keen to know that the safety is good.

So let's see, but I think we're off to a great start with Ambutra.

Very helpful.

Thank you.

Next question, please.

Thank you.

Our next question comes from Gary Nachman with BMO.

You may proceed.

Okay, great.

So back to Ambutra and the start forms and the two-thirds switches from Ampatro, what's the profile of initial patients that are switching from Ampatro?

Are you getting a sense if it's more patient or physician-driven?

Do they stay on Ampatro up until they get Ambutra, if that takes some time?

And how do you expect that split between new and switches to shift over the next couple of quarters?

Thank you.

Well, I think that will see lots of interest in the Ambutra early dynamics.

Again, I mean, look, at the end of the day, what we're really excited about is Ambutra's profile is giving us the ability and physicians the ability to be able to actually treat, diagnose and treat more patients.

And what we've so far seen early signs in terms of initiations, it's both when it comes to switches, as well as value patients.

We have a good robust patient services and our patients have been informed about the availability and some of those patients proactively reached out to their physicians.

What we've also seen is, as I indicated earlier, good new prescribers coming into the treatment of this condition and excited to be actually providing this medicine to those patients that probably were on the fence, given that it was an infusion with Ampatro earlier profile.

And Ambutra tends to offer a very convenient option with great safety and efficacy data.

Therefore, we do what we so far seen in the 133 start forms is a good broad range of both patient prescriber base as well as patient demographics that ranges across younger as well as more traditional demographics.

The conference will begin shortly to raise your hand during Q&A you can dial star one one.

Thanks, Tolga.

Let's take the next question.

Thank you.

Our next question goes from Ramanu Palmarama with JP Morgan.

You may proceed.

Hey, guys.

Thanks so much for taking the question.

Maybe following on the last question on Ambutra, switching dynamics, what is your market research suggest on the timeframe in which you would expect switching to kind of peak or where most patients that are going to switch have made the switch?

I think that's what we're trying to understand, many of us.

Thanks so much.

Hi Adam Pham, that's a great question and thank you for putting it forward very precisely.

Yeah.

So I think Tolga, there's a specific question here around what our market research is telling us about the time for peak switching.

Yeah.

What we're really interested at this point is really to make sure that the overall category is growing.

So our focus is actually right now is really to make sure that we are bringing as many as new patients as possible given this new option.

The switch is what we believe is going to play out a little more organically and we'll obviously update the street for about a year about the switch and net naive patients.

What we expect that to organically happen is most patients will end up with Amutra given its profile.

[music].

However, we also know that in rare diseases there are patients who are pleased with their existing treatment. Some of these patients never had any new treatment before Amutra, sorry Ompatra was available. So we do expect some patients to remain on therapy.

But in similar dynamics that we've seen in other categories, patients tend to gravitate towards a better option which we believe Amutra is.

But I also wanted to take the opportunity to remind everyone that we're going to be updating on this dynamics for two to three quarters.

Just one other comment.

From a modeling perspective it doesn't matter if you're on Ampatra or Amutra, they're the same price, same value per patient per year.

So just a reminder on that point.

Great point.

Good.

Okay, let's take the next question.

Thank you.

Our next question comes from Tong Lu with Barclays.

You may proceed.

Hello.

Actually, can you hear me?

This is Gina.

Yes, we can hear you.

Okay, good.

This is Gina Nguyen from Barclays.

Yeah, so I have a question.

Maybe follow up the start form, 133 start form.

You said 34 new to Alnalen.

Just if you can give a little bit more clarity, what percentage of these are the switcher from texeti versus a truly naive patient?

And then quickly on Helios B, I just wanted to, as a maintenance check, you know, last time we discussed the texetimus dropping rate maintained at a low single digit.

Is there any change in the dropping rate?

Okay, let's start with Tolga for the Amutra question and then to Akshay for the Helios B question.

We really appreciate the excitement around the strong launch of Amutra, yet it's only five weeks of data.

So we wanted to make sure that we all recognize that the granularity of the data we're providing is as good as we possibly can at this point.

Those 34 new patients are naive to us.

In terms of your own modeling, one should also remember that, you know, the Tick-City remains a very small portion of the overall category.

So we wouldn't necessarily index our naive patients, just only on switches from an alternative treatment model.

Yeah, good opportunity to grow, you know, new patients coming into Amfutra.

So Akshay, TDSB, TAP drop-in rate?

Yeah, thanks, Gina.

You know, I can reiterate that the drop-in rates, remain well within expectations.

And I think as discussed before, we obviously had put in a buffer in the sample size to account for TAP drop-ins.

We're well within those estimates.

We're comfortable with the design.

Gina, thank you.

Thanks, Akshay.

That's great.

Next question.

Thank you.

Our next question comes from Ellie Merle with UBS.

You may proceed.

Hey, guys.

Thanks for taking the question.

I guess not an ATTR question, but on the pipeline for lumasaran and recurrent renal stones, I guess maybe just with the Phase 2, finishing and rolling later this year and thinking about Phase 2 data next year, I mean, how should we think about, what you're looking to see here?

It's obviously a much broader population.

I guess what could we learn in terms of the relationship, between oxalate reduction and reduction in stone formation in this broader population and your confidence in the biology there and then I guess thinking about sort of the regulatory pathway from there, like what a potential Phase 3 could look like and any types of patient segmentation in terms of accessing this much larger population?

Akshay, I'm not sure if you caught all of that.

I think it's around the recurrent renal stone study, what we're looking to see from the Phase 2 data, how we're thinking about, you know, oxalate reduction and then I think, you know, plans for moving forward that study.

Yeah.

So thanks for the question.

So the luma recurrent stone formation study is ongoing.

It's obviously a very large population globally, numbering in the millions probably.

And, you know, what we want to see, is a reduction in urinary oxalate.

Now, in the PH1 population, of course, we saw very substantial reduction in urinary oxalate. They have an enzymatic defect in the liver, and the targeting of GO1 leads to, 70 plus percent reduction in urinary oxalates.

This is a hypothesis we're testing.

One of the interesting things is, we may not need to achieve levels like that to see a reduction in stone events.

And so let's look at the data, as it comes out next year and see.

And I say that because the important thing is, once oxalate becomes at saturating levels in the urine, that's when stone formation occurs.

So you may not need to take it, all the way back down to normal.

You might just need to get it out of that, super saturation range by some relatively modest margin to prevent stone formation.

And so a lot more work to do here, and we'll update you as we get data.

But this is a very exciting opportunity, with an approved drug that looks very safe so far in the PH1 population.

And that just reminds me to say, of course, safety will also be important to see in the RSF population, but we're optimistic with what we've seen so far with LUMA in PH1.

Thanks, actually.

And, you know, another, you know, program in our pipeline, which is orientated around, you know, patients with much more common diseases, I think an exciting potential development for Arnheim.

Next question, please.

Thank you.

Our next question comes from Miles Minter with William Blair.

You may proceed.

Thanks for taking the question.

Just on some disarray in the IGA nephropathy data, can you just sort of discuss where you, see like the complement inhibitor methodology sitting in the lines of therapy and I guess how it relates to the data that we've seen from the endothelial and reciprocal antagonists?

And I guess is that a key consideration for Regeneron in how they would potentially design, a pivotal study and the types of patients that you would enroll in that pivotal study?

Thanks.

So quite a few questions there.

I mean really just to I think start off by reiterating that we were really pleased with, the phase two results with these ramifications of IGA nephropathy, very common condition, 37% reduction in proteinuria.

We think this is great and I think kind of it's another potential phase three program, for our model.

So we're very pleased to be working with our partners, Regeneron, moving forward the next, steps.

Actually, I think there were a number of questions in there that I think are much more specific, around how we're thinking about the program.

We're very excited about the phase two result with a 37% reduction in urinary proteinuria.

You know, busy working with Regeneron right now.

We take the lead in this program in the ICANN study design and we're sort of very busily, looking forward to engaging regulatory authorities and hopefully kicking off the study by the year end.

The specifics of where complement or anti-complement approaches fit, you know, the interesting, thing is the fundamental underlying pathology here, our IGA immune complex is that it deposits in the glomerulus and activates complement. That activated complement then damages the glomerular basement membrane and proteinuria, results.

An additional aspect of the disease, I don't think anyone really understands how this occurs, is hyperfiltration in the kidney and so blood flow dynamics change through the glomerulus. So we have the opportunity here orthogonally to impact two key pathogenic factors.

With anti-complement approaches, we can get at the fundamental underlying immunopathology, and we've seen the preliminary results we've shared, so this will have a foundational role, I believe, in the future in what will end up being a, you know, polypharmacy situation, where there'll be anti-inflammatory approaches like anti-complement, Semdysran would be a great fit for that, you know, it could be a once a month, once every three month type infection.

And then in addition to that, things that alter blood flow, so endothelial antagonists, ACE inhibitors, ARBs, et cetera, and so you'll see drugs from both classes, the anti-hypertensive type drugs and anti-complement drugs being combined and we'll see if steroids will also become part of the picture, but there's more work to do there, although they're rather general non-specific agents and have a lot of side effects.

And just to add, of course, you know, these favorable results open up the, you know, potential, for Semdysran to, you know, get the needs of patients with other pneumonia diseases.

We're enthusiastically moving forward here.

Thank you for the question.

One more question.

I think we have one more question before we close.

Thank you.

Our last question comes from Olivia Bear with Cantor.

You may proceed.

Hey, good morning, guys.

Thanks for the question.

I know you're in a quiet period with respect to Apollo B, but I wanted to ask if there are any monitoring requirements after patients reach that 12-month mark, you know, that are built into the study.

And then I've got a follow-up on sequencing for mixed phenotype patients.

Is there anything you can do to improve access for patients that could move on to Ampatra or Ambutra after defamatives?

Thank you.

So I just want to say, you pointed out we are in a quiet period, so we're not going to be taking any questions on Apollo B.

But I didn't actually quite catch your second question.

I think it was something to do with Ambutra, but I didn't hear it properly.

Could you repeat the question, the second part of the question?

Yeah, sure.

It's just about mixed phenotype patients, right?

And whether there's anything you guys can do to improve payer access there for patients that could sequence on to Ampatra or Ambutra after defamatives.

You mean polyneuropathy mixed phenotype patients?

Yeah.

Yeah, I mean, look, we certainly have the right capabilities to support those patients.

The fact that we've been able to position this at parity pricing will certainly, we believe, help increase access.

So far, we haven't really heard any headwinds around the access piece.

But we are indicated for polyneuropathy, and in the U.S., defamatives is indicated for cardiomyopathy.

So in terms of providing any brief strategy for access would not be something we would consider.

Like any of our new patients, we have great support of benefit verification and patient access support, which those patients would certainly be eligible if they go through our patient services program.

Thanks, Tolga.

Okay, so thank you, everyone, for joining us on this call.

We're very happy with the progress that we've made in the second quarter and first half of 2022. We've had strong commercial results. We've advanced our diverse pipeline programs and development, and we've got a number of exciting catalysts on deck in the coming months.

So we look forward to updating you along the way while we continue to deliver on our near and long-term goals.

Thanks, everyone, and have a great day.

Goodbye.

Thank you.

This concludes today's conference call.

The conference will begin shortly.