Q1 2022 Alnylam Pharmaceuticals Inc Earnings Call

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Good day and thank you for standing by welcome to the on Island Pharmaceuticals first quarter 2022 earnings Conference call.

Operator: Good day and thank you for standing by. Welcome to the Alnylam Pharmaceuticals first quarter 2022 earnings conference call. At this time, all participants are in listen-only mode.

At this time, all participants are in listen only mode.

Operator: After the presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star, then 1 on your telephone keypad. Please be advised, today's conference may be recorded. If you require operator assistance during the call, please press star then zero.

After the presentation, there will be a question and answer session.

To ask a question during the session you'll need to press Star then one on your telephone keypad.

Be advised todays conference maybe recorded.

You require operator assistance during the call. Please press Star then zero.

Operator: I'd now like to hand the conference over to your host today, Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communication. 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, Pushkal Garg, Chief Medical Officer, and Jeff Poulton, Chief Financial Officer. Akshay Vaishnaw, President, is unable to join the call today due to a personal conflict.

I'd now like to hand, the conference over to your host today, Christine Linden Baum Senior Vice President of Investor Relations and corporate communications.

Good morning, I'm, Christine Lindenberg, Senior Vice President of Investor Relations and corporate Communications at an island with me today on the phone are along Greenstreet, Chief Executive officer until the tangle, our chief commercial officer.

Chief Medical Officer, and Jeff Felton, Chief Financial Officer.

Actually that's now president is unable to join the call today due to a personal complex.

Christine Lindenboom: 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 event. During today's call, as outlined in slide two, Yvonne will provide some introductory remarks and general context. Tolga will provide an update on our global commercial progress. Pushkal will review recent clinical and preclinical updates and Jeff will review our financials followed by a summary of upcoming milestones before we open the call for your questions.

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 web site investors thought on island Dotcom Flash then.

During today's call as outlined in slide two upon will provide some introductory remarks and general context.

So who will provide an update on our global commercial progress.

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

Christine Lindenboom: 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 Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recently quarterly report on file of the SEC. In addition, any forward looking statements represent our views only as the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'll now turn the call over to Yvonne. Yvonne?

I would like to remind you that this call will contain remarks concerning all islands future expectations plans and prospects, which constitute forward looking statements for the purposes of the safe Harbor provision under private Securities Litigation Reform Act of 1995.

Actual results may differ materially from those indicated by these forward looking statements as a result of various important factors.

Putting those discussed in our most recently quarterly report on file with the SEC.

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

With that I'll now turn the call over to Bob.

Yvonne Greenstreet: Thanks, Christine, and thank you, everyone, for joining the call today. The first quarter of 2022 was another quarter of continued progress at Alnylam across our commercial and pipeline portfolios. First, despite an expected quarter-on-quarter decrease in combined product revenues from our commercial portfolio of Ompatro, Givlari, and Oxlumo, we observed a steady increase in patients on therapy. Alongside that commercial progress, our RNAi therapeutic pipeline programs continue to advance. With the TTR franchise, we presented positive 18-month results from the Helios-A Phase III study of Butrysia.

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

The first quarter of 2022 was another quarter of continued crude glass, that's all nine of them across our commercial and pipeline portfolios.

First despite an expected quarter on quarter decrease in combined Cobalts revenues from our commercial portfolio of them part true give laurie and oxygen that we have.

The steady increase in patients on therapy.

Alongside that to muscle mass.

And the only therapeutic pipeline programs continue to advance with a cheeky all franchise. We presented positive 18 months results that he gets a phase III study of <unk>.

Yvonne Greenstreet: The NDA for Plutusran is under review, with a new PDUFA date of July 14, 2022, following the three-month delay we announced earlier in April, to allow for the review of newly added information related to a new secondary packaging and labeling facility. We also brought new programs into the clinic with the initiation of two Phase 1 studies. And today, we announce that the phase one study of ALN-XCH in patients with gout has been initiated.

The NDA for <unk> under review with a new producer date of July 14, 2022. Following the three months delays, we announced earlier in April to allow for the review of newly added information related to a new secondary packaging and labeling facility.

We also put new programs into the clinic with the initiation of two phase one studies.

And today, we announced that the phase one study is a L. M X P. H patients with gas has been initiated.

Yvonne Greenstreet: Additionally, the first on nylon RNAi therapeutic targeting a CNS disorder, ALN ATP, has entered phase one, a very exciting milestone for our platform, and initial top-line results from both of these programs are expected in late 2022. Looking further out, we believe Alnylam is poised for significant growth based on three key drivers. Success is the potential near-term expansion of our TTR franchise, where we aim to become the global leader in delivering impactful and highly differentiated medicines to patients.

Additionally, the first on myeloma.

Therapeutic targeting a CNS disorder.

T and the phase one a very exciting milestone for our platform.

And initial top line results from both of these programs are expected in late 2022.

Looking further out we believe our model is poised for significant growth based on three key drivers.

Yvonne Greenstreet: Second is our expansion beyond rare diseases into prevalent diseases. And the third key growth driver for the company comes from our sustainable innovation engine, comprised of new platform-enhanced, Opportunities with extra hepatic delivery and our ability to find new genetically validated targets which can drive further pipeline expansion. 2025 and beyond.

First is the potential near term expansion the bulky tea all franchise, where we aim to become the global leader in delivering impactful and highly differentiated medicines to patients.

Second is our expansion beyond rare diseases into precedent diseases.

The third key 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 side the pipeline expansion to 2025 and beyond.

Yeah.

We believe all of this positions us well to deliver on our Mylan pizza fifth by 'twenty five goals, making all nine of them are top biotech company, developing and commercializing transformative medicines for rare and common diseases for patients around the world driven by a high yielding pie.

Yvonne Greenstreet: We believe all of us positions as well to deliver on our Alnylam P4-5x25 goals, making Alnylam a top biotech company, developing and commercializing transformative medicines for rare and common diseases for patients around the world, are 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. With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga, Thanks, Yvonne, and good morning, everyone.

<unk>, the first and best in class product candidate Tomorrow, Gamic product engine, all while delivering exceptional financial results.

With that let me now turn the call over to Toga, who will review of our commercial performance Tioga.

Thanks, Ivan and good morning, everyone.

Tolga Tanguler: The first quarter reflected steady progress as we increased the number of commercial patients on therapy across our three products by nine percent. In spite of this increase, Q1 reported revenues decreased by 6% compared with Q4 2021, as Q4 benefited from a variety of non-recurring stocking and gross net benefits. Additionally, we did experience some headwinds from COVID in the early part of Q1, particularly in the US, where we saw a decrease in patient compliance, across our portfolio in January and February when Omicron cases were at their.

The first quarter reflected steady progress as we increase the number of commercial patients on therapy across our three products by 9%.

In spite of this increase Q1 reported revenues decreased by 6% compared with Q4 'twenty 'twenty. One is Q4 benefited from a variety talk me out nonrecurring stocking and gross to net benefits <unk>.

Additionally, we did experienced some headwinds from COVID-19 in the early part of Q1, particularly in the U S where we saw a decrease in patient compliance across our portfolio in January and February when Omicron cases were at their peak.

We are encouraged by improved market conditions that developed in March that have extended further into April .

Tolga Tanguler: We are encouraged by improved market conditions that developed in March, that have extended further into a and we're cautiously optimistic that COVID will have minimal impact on our commercial operation, for the balance of the year, recognizing that the course of the pandemic remains uncertain. I will now provide details on the performance of each of our products. For Ompatro, we achieved $137 million in global net product revenues in the first quarter, representing a 1% decrease compared with the fourth quarter and 34% growth compared with Q1 2021.

And we're cautiously optimistic that Covid will have minimal impact on our commercial operations for the balance of the year recognizing that the course of dependent market remains uncertain.

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

Foreign Petro, we achieved $137 million in global net product revenues in the first quarter.

Presenting a 1% decrease compared with the fourth quarter and 34% growth compared with Q1 2021.

Tolga Tanguler: At the end of Q1, over 2,200 patients were on commercial on-patron treatment worldwide, up from over 2,050 patients at year-end 2021, representing steady 7% quarterly patient growth. In the US, sales of Home Patrol increased 4% versus Q4 2021 and were primarily impacted by the following.

At the end of Q1 over 'twenty 200 patients were on commercial loan Patrick treatments worldwide up from over 2050 patients at year end 2021.

Representing steady 7% quarterly patient growth.

In the U S sales of <unk> increased 4% versus Q4 2021.

And were primarily impacted by the following.

A 7% increase in demand driven by an increase in patients on therapy, which was negatively impacted by a decrease in patient compliance primarily in January and February I know mccrone cases were at their peak.

Tolga Tanguler: 7% increase in demand, driven by an increase in patients on therapy, which was negatively impacted by a decrease in patient compliance, primarily in January and February, when Omicron cases were at their, Inventory Stocking Dynamics contributed to a 6% decrease in reported growth and a modest decrease in gross to net deductions in the quarter contributing to a 3% increase in reported growth. In our international markets, Ompatra Q1 product sales declined 5% versus Q4, despite an increase in patients on therapy due to an increase in gross net deductions following Q4, which included several non-recurring benefits, along with an unfavorable foreign exchange, impact due to strengthening U.S. dollar in Q1, which impacted results across all three commercial products.

Inventory stocking dynamics, which contributed to a 6% decrease in reported growth and a modest decrease in gross to net deductions in the quarter contributing to a 3% increase in reported growth.

In our international markets on Petro Q1 product sales declined 5% versus Q4, despite an increase in patients on therapy due to an increase in gross to net deductions. Following Q4, which included several nonrecurring benefits along with an unfavorable foreign exchange <unk>.

Due to strengthening U S dollar in Q1, which impacted results across all three commercial products.

Moving to do Laurie, we achieved $35 million in global net product revenues in the first quarter.

Tolga Tanguler: Moving to GiveLary, we achieved $35 million in global net product revenues in the first quarter, representing a 13% decrease compared with Q4 2021 and 43% growth versus Q1 2021. At the end of Q1, over 400 patients were on commercial Givlari treatment worldwide, up from over 350 at year-end 21, representing robust 14% quarterly patient growth. In the U.S., sales of Tivlari decreased 22% versus Q4, 21, and were primarily impacted by the following.

Representing a 13% decrease compared with Q4 2021.

And 43% growth versus Q1 2021.

At the end of Q1 over 400 patients were on commercial give laurie treatment worldwide up from over 350 at year end 'twenty one.

Presenting robust 14% quarterly patient growth.

In the U S sales of give Laurie decreased 22% versus Q4, 'twenty, one and were primarily impacted by the following.

Black patient demand, despite a 5% increase in patients on therapy due to reduce patient compliance, which was negatively impacted by Covid in January and February .

Tolga Tanguler: Flat patient demand. Despite a 5% increase in patients on therapy due to reduced patient compliance, which was negatively impacted by COVID in January and February, Inventory stocking dynamics, which negatively impacted reported growth by 15% and an increase in gross net deductions in the quarter which negatively impacted reported growth by 7% following the fourth quarter which included several non-recurring gross net benefits. In our international market, Givlari delivered 11% growth in Q1 compared with Q4 21 with the growth primarily driven by new patient ads across key markets and geographic expansion including an initial contribution from the UK following Q1 commercial launch.

Inventory stocking dynamics, which negatively impacted reported growth by 15%.

And an increase in gross to net deductions in the quarter, which negatively impacted reported growth by 7% following the fourth quarter, which included several nonrecurring gross to net benefits.

In our international markets give Laurie delivered 11% growth in Q1, compared with Q4 'twenty one with the growth primarily driven by new patient adds across key markets and geographic expansion, including an initial contribution from the U K following Q1.

Commercial launch.

Moving now talk Shlomo, we achieved $50 million in global net product revenues in the first quarter, representing a 24% decrease compared with Q4, 'twenty, one and 59% growth versus Q1 2021.

Tolga Tanguler: Moving now to Oksluma, we achieved $50 million in global net product revenues in the first quarter, representing a 24% decrease compared with Q4 2021 and 59% growth versus Q1 2021. At the end of Q1, over 160 patients were on commercial oxlomoid treatment worldwide, up from over 140 at year-end 21, representing 14% Quarterly patient growth. In the US, sales of Oxluma decreased by 5% versus Q4 2021 and were primarily impacted by the following.

At the end of Q1 over 160 patients were on commercial so what treatment worldwide.

From over 140 at year end 'twenty one.

Presenting 14%.

Quarterly patient growth.

In the U S sales of bulk shipment decreased by 5% versus Q4, 2021 and were primarily impacted by the following.

Tolga Tanguler: A 6% increase in patient demand, driven by an increase in patients on therapy, and an increase in gross to net deductions in the quarter, which more than offset the demand growth, and negatively impacted reported growth by 11%. Oksuma sales decreased in our international markets by 32% during the first quarter compared with Q4, despite an increase in patients on therapy during the quarter, primarily due to an increase in gross net deductions following Q4, which included several non-recurring benefits as well as the timing of order in partner and emerging markets.

A 6% increase in patient demand driven by an increase in patients on therapy.

And an increase in gross to net deductions in the quarter, which more than offset the demand growth and negatively impacted reported growth by 11%.

Well from a sales decrease in our international markets by 32% during the first quarter compared with Q4.

Despite an increase in patients on therapy during the quarter.

Primarily due to an increase in gross to net deductions following Q4, which included several nonrecurring benefits.

As well as the timing of ordinary in partner and emerging markets.

Tolga Tanguler: In conclusion, As expected, despite the reduction in reported revenue growth during the quarter and challenges from COVID in the early part of the quarter, we remain encouraged by the steady growth in patients we achieved across three products, particularly our performance with Om Patra during the quarter. Additionally, even though we were disappointed by the three-month PDUFA delay for Wutrisran in the U.S., we are poised to launch the product upon potential FDA approval by the new July 14th PDUFA date, and we remain confident that this will continue to represent an attractive option for TTR polyneuropathy patients and an incremental growth opportunity for our TTR franchise. With that, I will now turn it over to Pushkal to review our recent R&D and pipeline progress. Pushkal.

In conclusion.

As expected despite the reduction in reported revenue growth during the quarter and challenges from Covid in the early part of the quarter.

We remain encouraged by the steady growth in patients we achieved across three products, particularly our performance we don't Petro during the quarter.

Additionally, even though we were disappointed by the three months produce a delay for which we see that in the U S. We are poised to launch the product upon potential FDA approval by the New July 14th producer date, and we remain confident that this will continue to represent an attractive option for T T. Our polling raw.

With your patients.

And an incremental growth opportunity for our TCR franchise.

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

Pushkal Garg: Thanks, Tolga, and good morning, everyone. Let me begin by updating you on our efforts in ATTR amyloidosis, where we are advancing two product candidates, Patisseran and Butreceran, across a number of clinical indications. While Patisran or Onpatro is currently approved in multiple markets around the world to treat the polyneuropathy associated with hereditary ATTR amyloidosis, we are committed to expanding the product's label to the treatment of cardiomyopathy in both hereditary and wild-type ATTR amyloidosis patients.

Thanks, Tom and good morning, everyone. Let me begin by updating you on our efforts in <unk> amyloidosis, where we are advancing two product candidates <unk> and <unk> across a number of clinical indications.

Pushkal Garg: To this end, we're conducting the Apollo B Phase 3 study, and we remain on track to report top-line results in the middle of this year. We're also advancing Butresran which is delivered by a quarterly subcutaneous injection and is also in development for ATTR amyloidosis as well as Stargardt disease, and ATTR Amyloidosis, we're conducting two phase three studies. The first is HELIOS-A, which is evaluating vitreous serine in hereditary ATTR amyloidosis patients with polyneuropathy.

While the <unk> or on Patrick is currently approved in multiple markets around the world.

Neuropathy.

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

To this end, we're conducting the Apollo B phase III study and we remain on track to report topline results in the middle of this year.

We're also advancing <unk>, which is delivered by quarterly subcutaneous injection and is also in development for <unk> amyloidosis as well as Star Guard disease.

In <unk> amyloidosis, we're conducting two phase III studies.

The first is Helios, a which is evaluating <unk> in hereditary <unk> amyloidosis patients with Polyneuropathy 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.

Pushkal Garg: 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. Those data form the basis for our regulatory submissions to both the FDA and EMA, which are currently under review. As we announced a few weeks ago, the FDA has extended the review timeline of the NDA to allow for the review of newly added information related to a new secondary packaging and labeling facility.

Those data form the basis for our regulatory submissions to both the FDA and EMA, which are currently under review.

As we announced a few weeks ago. The FDA has extended the review timeline of the NDA to allow for the review of newly added information related to a new secondary packaging and labeling facility.

Pushkal Garg: Specifically, we submitted an amendment to our NDA upon learning that the original third-party secondary packaging and labeling facility we planned to use for the Boutry Strand Lodge was recently inspected as part of a routine CGMP inspection, This inspection was unrelated to the Buttrey Strand application, but as its outcome was unknown, it nevertheless could have resulted in Buttrey Strand receiving a complete response letter, with uncertainty regarding the timeframe for resolution. While our amendment resulted in a three-month extension, we believe that this approach offers the fastest path to a potential approval.

Specifically, we submitted an amendment to our NDA upon learning that the original third party secondary packaging and labeling facility. We plan to use for the <unk> launch was recently inspected.

Very routine cgmp inspection.

This inspection was unrelated to the <unk> application, but as its outcome was unknown. It. Nevertheless could have resulted in <unk> receiving a complete response letter.

With uncertainty regarding the timeframe for resolution.

While our amendment resulted in a three month extension, we believe that this approach offers the fastest path to potential approval.

Pushkal Garg: The updated PDUFA goal date to allow for this review is July 14th, 2022. I'd like to reiterate that the inspection issues raised at the original facility were not specifically related to Patrice Rant, there have been no questions with regard to the safety or efficacy of the product, and there have been no additional clinical data or trials requested. In addition to these nine-month results, we also presented positive data from the 18-month analysis of the study in January of this year at the SFNP meeting in France.

The updated <unk> goal date to allow for distribute as July 14th 2022.

I'd like to reiterate that the inspection issues raised at the original facility were not specifically related to <unk>. There have been no questions with regard to the safety and efficacy of the product and there have been no additional clinical data or trials request.

In addition to these nine months results. We also presented positive data from the 18 month analysis of the study in January of this year at the <unk> meeting in France.

We are delighted that he will stay met all secondary endpoints measured at 18 months, including statistically significant improvements in neuropathy as measured by the modified neuropathy impairment score or <unk> of seven <unk>.

Pushkal Garg: We're delighted that Helios A met all secondary endpoints measured at 18 months, including statistically significant improvements in neuropathy, as measured by the Modified Neuropathy Impairment Score, or MNIST Plus 7, quality of life, Gate Speed, Nutritional Status, and Overall Disability. Relative to external placebo data from the Apollo Phase 3 study. Further, at 18 months, Boutristran also demonstrated improvement compared to external placebo in the exploratory cardiac endpoint NT-PROBNP and trends towards improvement in echocardiographic parameters, as well as improvement compared to baseline in cardiac uptake of technetium on scintigraphy imaging.

Life.

<unk> speed nutritional status and overall disability.

Relative to external placebo data from the Apollo Phase III study.

Further at 18 months <unk> also demonstrated improvement compared to external placebo and exploratory cardiac endpoint NT pro BNP.

And trends towards improvement in echocardiographic parameters as well as improvement compared to baseline in cardiac uptake of technetium <unk> scintigraphy imaging.

We believe that taken together these data along with the exploratory cardiac data from the original Apollo study provide evidence to suggest the GTR silencing <unk> and blue tree strand treatment and potentially improve the cardiac manifestations of this disease.

Pushkal Garg: We believe that, taken together, these data, along with the exploratory cardiac data from the original Apollo study, provide evidence to suggest that TTR silencing by Petit-Seran and Houtri-Seran treatment may potentially improve the cardiac manifestations of this disease.

Pushkal Garg: Patrice Rand also demonstrated an encouraging safety and tolerability profile as shown by the data on this slide. We're very pleased with the totality of the results and the profile of the tree strand that continues to evolve. We believe that based on these data, Rutrystran, if approved, will present an exciting commercial opportunity, providing an attractive treatment option for patients with HHETR amyloidosis with polyneuropathy. In addition, I'll also remind you that we are seeking to further reduce the burden of treatment for patients by evaluating an every six-month regimen of a tree strand in the extension period of Helios A, with data expected later this year.

<unk> also demonstrated an encouraging safety and tolerability profile as shown by the data on this slide.

We're very pleased with the totality of the results and the profile of <unk> that continues to evolve we believe that based on these data <unk>. If approved will presents an exciting commercial opportunity, providing an attractive treatment option for patients with <unk> amyloidosis with polyneuropathy.

In addition, I'll also remind you that we are seeking to further reduce the burden of treatment for patients by evaluating it every six months regimen of <unk> and the extension period appeal, you'll stay with data expected later this year.

Of course this is just the start for <unk> as we are also conducting another phase III study Helios B, which is our ongoing phase III Kartik outcome study with Vitry strand in hereditary and wild type amyloidosis patients with cardiomyopathy.

Pushkal Garg: Of course, this is just the start for Vutrisiran as we are also conducting another phase 3 study, Heliospeed, which is our ongoing phase 3 cardiac outcome study with Vutrisiran in hereditary and wild-type amyloidosis patients with cardiomyopathy. Helios B, which is fully enrolled, has a 30-month endpoint of all cause mortality and CV events, and we expect the full results in early 2024. The study design includes the potential for an interim analysis and will consider this after reviewing the results from Apollo B and engaging with regulatory authorities.

Helios B, which is fully enrolled has a 30 month endpoint of all cause mortality and CV events and we expect the full results in early 2024.

The study design includes the potential for an interim analysis and we'll consider this after reviewing the results from Apollo B and engaging 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.

Pushkal Garg: In addition to our late stage clinical programs, we believe we've also been making great progress with our early and mid stage programs. As we've highlighted for some time, a key growth driver for alnylam is our expansion beyond rare diseases into prevalent conditions. A great example is our program in hypertension. Zalbisteran is our investigational RNAi therapeutic targeting angiotensinogen, or AGT, which is in development for the treatment of hypertension.

As we've highlighted for some time a key growth driver frown xylem is our expansion beyond rare diseases into prevalent conditions are Great example is our program in hypertension.

<unk> is our investigational <unk> therapeutic targeting angiotensin agent or AGP, which is in development for the treatment of hypertension.

Pushkal Garg: Zalbistran is being evaluated in the Phase 2 Cardio Program. The first of these two studies, CARDIA-1, is designed to evaluate the efficacy and safety of Zalvisiran as a monotherapy in patients with mild to moderate hypertension. The second of these studies, CARDIA 2, was initiated late last year and is designed to evaluate the efficacy and safety of Zalbisteran as an add-on therapy in patients with hypertension despite treatment with standard of care agents.

<unk> is being evaluated in the phase II cardiac program. The first of these two studies Carty. One is designed to evaluate the efficacy and safety of <unk> as a monotherapy in patients with mild to moderate hypertension.

The second of these studies cardiac <unk> was initiated late last year and is designed to evaluate the efficacy and safety of <unk> as an add on therapy in patients with hypertension, despite treatment with standard of care agents.

We've announced this morning that we are experiencing enrollment delays in cardio one in part due to impacts of the situation in Ukraine as well as the ongoing pandemic.

Pushkal Garg: We've announced this morning that we are experiencing enrollment delays in Cardio One in part due to impacts of the situation in Ukraine, as well as the ongoing pandemic. We're expanding the geographic footprint of the study and are also streamlining certain aspects of the protocol to facilitate enrollment. As a result, we now expect a complete enrollment in Cardio One in early 2023. Top-line results expected in mid-2023. We are implementing similar measures in CARDIA 2 as well, so as to complete enrollment at or around year end.

We're expanding the geographic footprint of the study and are also streamlining certain aspects of the protocol to facilitate enrollment.

As a result, we now expect to complete enrollment in cardio one in early 2023 with topline results expected in mid 2023.

We are implementing similar measures in cardiac too as well so as to complete enrollment at or around year end.

Pushkal Garg: Another key growth driver for Alnylam in the years to come will be our organic product engine driving sustainable innovation with the goal of bringing two to four new molecules into the clinic each year. Here, we achieved some notable progress in the first quarter. We announced this morning that the phase one study of ALNxDH in patients with gout has been initiated. This is an exciting program based on our work with the UK Biobank, where we found that heterozygous loss of function of xDH was associated with significantly reduced serum urate and a lower risk of gout.

Another key growth driver from the island in the years to come will be our organic product engine driving sustainable innovation with the goal of bringing two to four new molecules into the clinic each year here, we achieved some notable progress in the first quarter.

We announced this morning that the phase one study of <unk> in patients with gout has been initiated this.

This is an exciting program based on our work with the UK Biobank, where we found that heterozygous loss of function of <unk> was associated with significantly reduced serum <unk> and a lower risk of Gal.

Pushkal Garg: We expect top-line results in late 2022. We also achieved a major milestone with the initiation of our Phase 1 study of ALN-APP, our first RNAi therapeutic targeting a CNS disorder. ALNAPP is an innovative program with the potential to address both Alzheimer's disease and cerebral amyloid angiopathy.

We expect topline results in late 2022.

We also achieved a major milestone with the initiation of our phase one study of <unk>, our first RNA therapeutic targeting a CNS disorder.

<unk> is an innovative program with the potential to address both Alzheimer's disease, and cerebral amyloid angiopathy and.

Pushkal Garg: Initiating this program is a key step towards expanding our pipeline into extrahepatic tissues, and we look forward to top-line results in late 2022 here as well. These are just a few highlights among the many exciting programs we're advancing to address important unmet needs for patients. And we look forward to updating you on our progress throughout the year. With that, let me now turn it over to Jeff, to review our financial results and upcoming milestones. Jeff.

Initiating this program is a key step towards expanding our pipeline to extra hepatic tissues, and we look forward to top line results in late 2022 here as well.

These are just a few highlights among the many exciting programs, we're advancing to address important unmet needs for patients and we look forward to updating you on our progress throughout the year.

With that let me now turn it over to Jeff to review our financial results.

<unk> and upcoming milestones Jeff.

Jeff Poulton: Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting Alnylam's Q1 2022 financial results, and I will also provide an update on our 2022 financial guidance. Turning now to a summary of our full P&L results for Q1 2022. Total product revenues for the quarter were $187 million or 38% growth versus Q1 2021, with all three marketed products contributing more than 30% year-over-year growth, is also worth highlighting that year-over-year growth in combined product revenue was held back by approximately 5% due to the foreign exchange impact of a strengthening U.S. dollar, and given that approximately 50% of our product revenues are generated via sales in international markets.

Thanks push call and good morning, everyone I am pleased to be presenting on the island Q1, 2022 financial results and I'll also provide an update on our 2022 financial guidance.

Turning now to a summary of our full P&L results for Q1 2022.

Total product revenues for the quarter were $187 million or 38% growth versus Q1, 2021, with all three marketed products contributing more than 30% year over year growth.

It's also worth highlighting that year over year growth in combined product revenue was held back by approximately 5% due to the foreign exchange impact of a strengthening U S dollar and given that approximately 50% of our product revenues are generated via sales in international markets.

Jeff Poulton: Net revenue from collaborations for the first quarter was approximately $26 million, representing a 38% decrease compared with Q1 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. Our non-GAAP R&D expenses decreased 2% in the first quarter of 2022 compared to the same period in 2021, primarily due to modestly reduced clinical trial expenses across the portfolio.

Net revenue from collaborations for the first quarter was approximately $26 million, representing a 38% decrease compared with Q1 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 quarter, which is reimbursed by regeneron.

Our non-GAAP R&D expenses decreased 2% in the first quarter of 2022 compared to the same period in 2021, primarily due to modestly reduced clinical trial expenses across the portfolio.

Jeff Poulton: However, we do expect an increase in the year-over-year R&D expenses for the balance of the year, primarily driven by an increase in spend associated with our plans to increase enrollment in our Zolpysiran Cardio I and Cardio II Phase II studies. Our non-JAF SG&A expenses increased 18% in the first quarter of 2022 compared to the same period in 2021, primarily due to increased legal expenses, charitable contributions, and other expenses to support our strategic growth.

However, we do expect an increase in year over year R&D expenses for the balance of the year, primarily driven by an increase in spend associated with our plans to increase enrollment and our resolve these saran cardio one cardio two phase III studies.

Our non-GAAP SG&A expenses increased 18% in the first quarter of 2022 compared to the same period in 2021, primarily due to increased legal expenses charitable contributions and other expenses to support our strategic growth.

Jeff Poulton: Our combined non-GAAP R&D and SG&A expenses were approximately $295 million in Q1 2022, representing 6% growth versus Q1 2021, as we continue to advance our pipeline and deliver strong top-line growth while maintaining discipline in how we invest in our operation. Our non-GAAP operating loss for Q1 2022 was $117 million, representing a $13 million improvement compared with Q1 2021 as we continue to progress on our journey towards building a self-sustainable financial profile aligned with our P to the fifth by 25 goal. Finally, we ended the quarter with cash, cash equivalents and marketable securities of $2.2 billion compared to $2.4 billion at the end of 2021.

Our combined non-GAAP R&D and SG&A expenses were approximately $295 million in Q1, 2022, representing 6% growth versus Q1 2021, as we continued to advance our pipeline and deliver strong top line growth, while maintaining discipline in how we invest in our operations.

Our non-GAAP operating loss for Q1, 2022 was $117 million, representing $13 million improvement compared with Q1 2021, as we continued to progress on our journey towards building a self sustainable financial profile aligned with our peers by 'twenty five goals.

Finally, we ended the quarter with cash cash equivalents in marketable securities of $2 2 billion compared to $2 4 billion at the end of 2021.

Now turning to our financial guidance, despite steady progress in adding patients across our three commercial brands in Q1, we have decided to reduce our combined product revenue guidance for two primary reasons first as we announced earlier this month, our FDA <unk> date for <unk> has been delayed by three months.

Jeff Poulton: Now turning to our financial gui, Despite steady progress in adding patients across our three commercial brands in Q1, we have decided to reduce our combined product revenue guidance for two primary, First, as we announced earlier this month, our FDA PDUHA date for Vutrisirin has been delayed by three months. Secondly, a strengthening U.S. dollar has created a foreign exchange headwind for our international operations, which today comprise approximately 50% of our global sales.

Secondly, a strengthening U S. Dollar has created a foreign exchange headwind for our international operations.

Which today comprise approximately 50% of our global sales.

Jeff Poulton: As a result, we have reduced our full-year combined product revenue guidance from an original range of $900 million to $1 billion, to a revised range of $870 million to $930 million, representing a 5% reduction at the midpoint of the range.

As a result, we have reduced our full year combined product revenue guidance from an original range of $900 million to $1 billion to a revised range of $870 million to 930.

Representing a 5% reduction at the midpoint of the ranges.

Jeff Poulton: This updated guidance assumes approval of Utrecht Saran in the U.S. by the revised PDUFA date of July 14th. As well as foreign exchange rates as of April 18th that are footnoted at the bottom of our guidance. Additionally, we have also reduced our non-GAAP combined R&D and SG&A expense guidance from an original range of $1.4 billion to $1.5 billion to a revised range of $1,390,000,000,000, to $1,450,000,000 as we seek to partially offset the reduction in our top-line guidance.

This updated guidance assumes approval a good free stranded in the U S. By the revised Paducah date of July 2014.

As well as foreign exchange rates as of April 18 that are footnoted at the bottom of our guidance slide.

Additionally, we have also reduced our non-GAAP combined R&D and SG&A expense guidance from an original range of $1 4 billion to $1 $5 billion to a revised range of $1 $390 million to $1 billion to $450 million as we seek partially offset the reduction in our topline guidance.

Let me now turn from financials and discuss some key goals and upcoming milestones on track through mid 2022.

Jeff Poulton: Let me now turn from financials and discuss some key goals and upcoming milestones on deck through mid-2022. To start, we will continue executing on our global commercialization of Onpatro, Givlari, and Oxfam. On the R&D side, we have an exciting clinical readout coming up with SIMD-SARAN, where we plan to report Phase 2 monotherapy results in IgA nephropathy in early 2022, plan to continue advancing our TTR franchise. Petit Saran.

To start we will continue executing on our global commercialization of on Petro give Laurie and Auxilium.

On the R&D side, we have an exciting clinical readout coming up with some D serine where we plan to report phase II monotherapy results in Iga nephropathy in early 2022.

We plan to continue advancing our GTR franchise.

Jeff Poulton: We look forward to top line results from the Apollo B Phase 3 study in mid-2022. With Nutriseran, we look forward to the potential approval and U.S. launch of our fifth RNAi therapeutic with a new PDUFA date of July 14th. Approval in the EU is anticipated mid-year, with subsequent launches in key markets to follow, pending finalization of pricing and reimbursement.

<unk>, we look forward to top line results from the Apollo B Phase III study in mid 2022.

The interest and we look forward to the potential approval and U S launch of our fifth Arnie I therapeutic with a <unk> date of July 2014.

Approval in the EU as anticipated mid year with subsequent launches in key markets to follow pending finalization of pricing and reimbursement.

Jeff Poulton: With ALN-HSD, we expect to report top-line results from Part D of the Phase I study in patients with NASH in mid-2022. Let me now turn it back to Christine to coordinate our Q&A session. Christine.

The airline HFC, we expect to report top line results from part D of the Phase one study in patients with Nash and mid 2022.

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

Christine Lindenboom: Thank you, Jeff. Operator, we will now open the call for your questions. To those filed 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. If you'd like to ask a question at this time, please press the star, then the number one key on your touchtone telephone. To withdraw your question, press the pound key.

Thank you Jeff Operator, we will now open the call for your questions 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.

If you'd like to ask a question at this time. Please press. The Star then the number one key on your Touchtone telephone to withdraw your question press the pound key.

Our first question comes from David Leibowitz with Citi.

David Lebowitz: Our first question comes from David Lebowitz with Citi. Thank you very much. When you look at the on Patro performance in the quarter, did you happen to notice any different dynamic? Describer, a cardiologist versus neurologist to start, So thanks for that question, Dave.

Thank you very much for taking my question.

You look at the on Petro.

<unk> in the quarter did you happen to notice any different dynamics in the prescriber, a cardiologist versus neurologist.

To start.

So thanks for that.

Yvonne Greenstreet: Look, we're pleased with the growth that we're seeing with respect to patient demand with Onpatriot. But I'll turn it over to Tolga to answer your specific question. Yes. Hi. Good morning.

David look we're pleased with.

The growth that we're seeing with respect to patient demand with <unk>.

But I'll turn it over to told US answer your specific question, Yes, hi, good morning.

Tolga Tanguler: Look, at the end of the day, this is a multisystem disease. And we do we do know that both neurologists and cardiologists play a very important role in the treatment. We have not really seen any change in the way the product is prescribed across the globe.

At the end of the day. This is a multi system disease and window, we do know that both neurologists and cardiologists play a very important role in the treatment, we have not really seen any.

<unk> in the way the product is prescribed across the globe, we certainly had seen some.

Tolga Tanguler: We certainly had seen some, as we indicated on the call, some softness in January and February, particularly in the adherence compliance rates. But we are very encouraged by what we've seen in March. And the Omicron impact obviously is dissipating, as we also seen in April, got it and and we're looking at the shift in guidance as you you cited, Reduction relative to the vitrecer ampidufidate being put off or delayed. How are we supposed to look at it as a component of that change that the trees ran delay for the overall guidance? and I guess I'm trying to level in on how should we view expectations for the drug. Yeah, hi, this is Jeff.

As we indicated on the call some softness in January and February , particularly in the adherence compliance rates, but we are very encouraged by what we've seen in March and the <unk>.

Omicron impact obviously is dissipating as we also have seen in April .

Got it and then when looking at the shift in guidance as you cited.

Reduction relative to the <unk> being put off.

Delayed.

Uh huh.

How are we supposed to look at it as a component of that change that the <unk> delay for the overall guidance change.

And I guess I'm trying to level and then how should we view expectations.

The drug for this year.

Yes, Hi, this is Jeff.

Jeff Poulton: We updated our guidance, as I said, on the call for two primary reasons. One is the FX strengthening US dollar given the percentage of revenue that we generate from ex-US markets. And secondly, because of the delay in the PDUFA date for Boutriseran. And the thinking there is that, you know, we've talked about Boutriseran being a growth driver overall for the TTR franchise for, I would say, for three primary reasons. One is that we think it'll be very attractive, attractively positioned for those mixed phenotype patients.

We updated our guidance as I said on the call for two primary reasons. One is the FX strengthening U S dollar given.

Percentage of revenue that we generate from ex U S markets and secondly, because of the.

Delay on the <unk> date for <unk>.

And the thinking there is that we've talked about <unk> being a growth driver overall for the GTR franchise for I would say for three primary reasons. One is that we think it will be very attractive attractively positioned for those mixed phenotype patients, we think for potential switches from competitive products.

Jeff Poulton: We think for potential switches from competitive products. And then lastly, for patients that have been diagnosed, but not yet on treatment. We think Boutriseran will grow our overall franchise as a result of its profile. So the guidance just reflects the fact that we'll have, you know, assuming approval by July 14th, that we'll have the product on the market for one less quarter than we originally anticipated when we got it in February. Tolga, anything you'd like to add? Yeah, I mean, look, we're really excited about Woodtree.

And then lastly for patients that have been diagnosed but not yet on treatment. We think Patrice ran will grow our overall franchise as a result of its profile. So the guidance just reflects the fact that we will have assuming approval by July 14th that we'll have the product on the market for one last quarter than we originally anticipated when we guided in February .

Okay.

Anything you'd like that.

Tolga Tanguler: It clearly provides another growth opportunity for the TTR franchise. We've built what we'd like to think a good, strong growth engine within the TTR franchise across our key markets. And Woodtree Surround will be a great addition to that.

Yes, I mean look we're really excited about with <unk>. It clearly provides another growth opportunity for the GTR franchise, we've built what.

What we'd like to take a good strong growth engine within the TCR franchise across our key markets and which we certainly will be great.

Addition to that what we've also seen as a.

Although anecdotally patients are excited about this there is a group of patients that actually.

Are going to be making an important decision they're early in their disease progression. So theyre not they may not be willing to get them to start with your infusion and it's going to be a really great treatment option for those patients who would then be able to take advantage of our subcutaneous quarterly injection.

Tolga Tanguler: What we've also seen is, although anecdotally, patients are excited about this, there is a group of patients that actually are going to be making an important decision, their early in their disease progression. So they're not, they may not be willing to get a start with the infusion. And it's going to be a really great treatment option for those patients who would then be able to take advantage of our subcutaneous quarterly injection. Thanks, Tolga. Moira, does that answer your question?

Does that answer your question.

Christine Lindenboom: Thank you very much. And I guess just one more question on the delay and the proof of date itself. Can you just reiterate what information the FDA has asked for and versus what information you have elected to send them thus far? and you also spoke that there was no other areas of discussion.

Thank you very much and I guess, just one more question on the <unk>.

On the delay in the <unk> date itself.

Could you just reiterate what information.

The FDA has asked for and versus what information you have elected to send them thus far.

And.

You also spoke that there there was no other areas of discussion.

Pushkal Garg: I expect that that won't change going forward. Yeah, so I think it look in terms of I'll probably have to reiterate a little bit of what I said on the on the call already. This is really all a result of a third party secondary packaging and labeling facility that had a routine CGMP or current good manufacturing practice inspection, just a routine inspection, it was not related to Boutry Saran.

I expect it that wont change going forward.

Pushkal Garg: But this was a facility that we were going to we had proposed for to help with the launch of Boutry Saran. But as a result of that, there were some inspection findings. And the FDA has a has a timeline by which they have to sort of classify that determine what actions necessary. That timeline was beyond the PDUFA date, the April 14 PDUFA date for Boutry Saran.

Yes.

So I think look in terms of I'll, probably have to reiterate a little bit of what I said on the call already.

This is really all a result of a third party secondary packaging and labeling facility that had a routine cgmp or current good manufacturing practice inspection just a routine inspection it was not related to the tree Saran, but this was a facility that we were.

We have proposed for to help with the launch of <unk>.

But as a result of that.

There was some inspection findings.

Pushkal Garg: And so as a result, if it wasn't classified, we ran a risk of getting a complete response letter. And you know, the timeline for resolution of that, as you know, can be somewhat uncertain. So based on that, we had discussions with the FDA, and we were expected to file an amendment to bring on board a secondary, a different facility. And we were able to do that quickly, and file an amendment to the existing NDA.

And the FDA has the timeline by which they have to reclassify that determined what actions necessary that timeline was beyond the Paducah date. The April 14th <unk> date for <unk>.

And so as a result, if it wasn't classified we ran a risk of getting a complete response letter in the timeline for resolution of that as you know can be somewhat uncertain. So based on that.

We had discussions with the FDA and we elected to file an amendment to bring onboard a secondary a different facility.

Pushkal Garg: That resulted in this three month clock extension and the PDUFA date. But just to reiterate, there was no request for additional clinical data of any sort, there's no more safety or efficacy data that were asked for, there's no new clinical trials, etc. This really just came about because of this inspection finding of this facility unrelated to Boutry Saran, and our decision to really find the most expedited path to get Boutry Saran approved into patients.

And we were able to do that quickly.

And file an amendment to the existing NDA that resulted in this three months clock extension and the <unk> date.

But just to reiterate there was no request for additional clinical data of any sort there is no more safety or efficacy data that were asked for Theres no new clinical trials et cetera is really just came about because of this.

Section finding at this facility unrelated to <unk> and our decision to really find the most expedited path to get <unk> approved and to patients and we think this was the best path to do that so that's what this is all about.

Pushkal Garg: And we think this was the best path to do that. So that's what this is all about. Thanks, Scott. We're absolutely ready to launch, you know, assuming FDA approval by the July PDUFA date. Thank you, Dave. Next question. Thank you so much. Our next question comes from Maury Raycroft with Jeffreys. Hi, good morning. Thanks for taking my question. I had a question about Apollo B.

We are absolutely ready for launch.

Are you meeting FDA approval.

The July <unk> date.

Thank you David next question. Thank you so much.

Pushkal Garg: So one difference between Apollo B versus BridgeBio's attribute phase three is inclusion of up to 30% stabilizer progressors. Can you elaborate on the criteria to classify patients as stabilizer progressors for the trial? Maybe talk about what gives you confidence the RNAi mechanism is going to work in these patients? Yeah, absolutely. Thanks, Maury, for your question. Look, I think we've talked about this at some length over the last several months since the BRIDGE-Bio results. We remain quite confident about the design and the execution of the Apollo B study for a variety of reasons.

Our next question comes from Maury Raycroft with Jefferies.

Hi, Good morning, Thanks for taking my question I had a question about Apollo B. So one difference between our Apollo B versus bridge Bio's attribute phase III is inclusion of up to 30% stabilizer progresses can you elaborate on the criteria to classify patients as a stabilizer progressing for the trial maybe talk about what gives.

Your confidence the RNA <unk> mechanism is going to work in these patients.

Yes.

Absolutely. Thanks, Marty for your question look I think.

We've talked about this at some length over the last several months since the bridge by our results we remain quite confident about the design and the execution of the Apollo B study.

For a variety of reasons both the criteria we're using to include patients with the disease.

Pushkal Garg: Both the criteria we're using to include patients with the disease, the clinical criteria that we require to show that they have disease that's likely to progress during the course of the study and likely to benefit from therapy. The sizing and powering of the study, the methods that we put in place in terms of the oversight and execution of the six-minute walk test. To your specific question, Maury, about the, we do allow, in Apollo B, up to 30% of patients to have been previously on tefamidis, assuming that they have been determined to progress based on the investigator's assessment. There's no formal criteria for that.

Clinical criteria that required to show that they have disease that is like.

<unk> progressed during the course of the study and likely to benefit from therapy.

The sizing and powering of the study the methods that we've put in place in terms of the oversight and execution of six minute walk test to your specific question Maury about we do allow in Apollo B.

Up to 30% of patients to have been previously onto <unk>.

The big.

Assuming that they have been determined to progress based on the investigators' assessment. There is no formal criteria for that that's really based on the investigators' assessment to the patient.

Pushkal Garg: That's really based on the investigator's assessment of the patient. And I think, you know, we powered very conservatively our study to allow for that. It's a global study, and so there was, we knew there was going to be some background to tefamidis use in the population. We certainly want to establish what the effect size of the drug is, both as a monotherapy and in combination, because we know that's some of the reality of what's going to be happening in the marketplace.

And.

And I think we powered very conservatively our study.

To allow for that.

Global study and so there was we knew there was going to be some background to famine as used in the population, we certainly want to establish what the effect size of <unk>.

The drug is both as a monotherapy and in combination because we know that some of the reality of what's going to be happening in the marketplace and we took very conservative powering assumptions and I'll remind you we actually over enrolled by 20% in the study as well. So I think we're very well positioned for that with regard to what gives us confidence.

Pushkal Garg: We took very conservative powering assumptions, and I'll remind you, we actually over-enrolled by 20% in the study as well. So I think we're very well positioned for that. With regard to what gives us confidence, you know, I think ultimately what gives us confidence is really the fact that we're targeting an upstream mechanism in every data set that we've generated, both Apollo as well as with Helios A, as well as external data sets that have been generated through investigator studies.

Ultimately what gives us confidence is.

Really the fact that we're targeting in upstream mechanism and in every data set that we've generated.

The pollo as well as with Helios, a as well as external data sets that have been generated through investigator studies.

Pushkal Garg: You know, there's an accumulating amount of data that suggests that silencing may have an important effect on the cardiac aspects of this disease, whether it's measured by biomarkers, whether it's measured by echocardiographic parameters, or even outcomes. So we look forward to the results in the middle of this year. . . . . I'm Ray.

Theres, an accumulating amount of data that suggests the silencing may have an important effect on the cardiac cardiac aspects of this disease, whether it's measured by biomarkers, whether it's measured by echocardiographic parameters.

Or even outcomes. So we look forward to the results.

In the middle of this year.

Okay great.

Okay.

Hi Marie.

Yes. Thank you for taking my question.

Pushkal Garg: Yeah, thank you for taking my question. Yes, yeah, very helpful. Thank you. Our next question comes from Salveen Richter with Goldman Sachs. Good morning, thanks for taking my question. Can you help us understand what the impact of COVID in the Ukraine are on the Cardio One study? On the latter, what proportion of the study is based in the Ukraine? And then just curious also on the lowered revenue guidance, are you comfortable with the FX assumptions for the Ford here? Thank you. Our next question comes from Palmitas with Stiefel.

Yes, yes very helpful. Thank you.

Our next question comes from <unk> Richter with Goldman Sachs.

Good morning, Thanks for taking my question can you help us understand what the impact of Covid in the Ukraine are on the cardio one study on the ladder what proportion of the study is based in the Ukraine and then just curious also on the lowered revenue guidance are you comfortable with the FX assumptions for the forward here.

Two great questions.

Clearly the cardio study is incredibly important to us and we're focused on enrolling thesis.

Expeditiously as we can obviously the Ukraine situation is devastating.

From a geopolitical and human perspective, but has had an impact.

Roland then copy of one but perhaps for Scott you can address that and also some of the approaches but lets say king to try and ensure enrollment into the study sure. Thanks have a good subject for the revenue guidance question and thanks, Amit for your question. So.

Look.

We've got these two studies that we've kicked off as we said four for south Eastern which is a very exciting program for us.

We think can actually transform the landscape for hypertension cardio one as a monotherapy study started the Midland last year, and then cardio <unk> study looking at combination therapy that started towards the end of last year.

As it is pretty common in diseases like in hypertension, and other common diseases. We do have we did envision a geographic footprint for the study that was heavily reliant on eastern European countries for Carty, one specifically Ukraine that was the first study in the first country that was up and running.

And we were expecting there was a lot of investigator interest in this study.

In the Ukraine.

Unfortunately.

Because of our global the global events, that's been severely impacted so we while we were enrolling that she had to stop curtail all our activities in the Ukraine.

Including.

Interacting with investigators being able to continue dosing patients et cetera, and I've had to put those activities on hold there was also a headwind with Cowen.

With regard to this sort of a prevalent condition.

That we were also facing so what we've done is we've actually expanded the geographic footprint of this study, we're bringing additional countries online additional sites online.

As an important mitigation measure.

And then the second thing is.

That we've had the opportunity to go back and look at our protocol and look for areas, where we can actually just facilitate enrollment by streamlining certain activities, reducing any burdens that may have been included in the protocol as originally conceived and streamline that.

And we think thats going to help as well so that's what's led to that change.

Two was not formally in the Ukraine, but it wasn't it has been there are sites in eastern European countries that may have some FX impact as well or feel some impact and so we're also really employing similar measures they're broadening the footprint.

And to have amended the protocol to sort of streamline some of the procedures in the study as well so that's the story there.

Just remind everybody that we expect to complete enrollment of cardio one in early 2023 with the top line data expected mid 2023 and for cardiac to complete enrolment at around year end 2022, so the data will be forthcoming.

Energy cost.

Looking forward to so Jeff I think a question for you in terms of how we source a bounce.

Yeah, let.

Let me give you a little bit.

Details solving so.

Our guidance slide updated guidance slide we did footnote at the bottom.

The FX rates are that we've included in the updated guidance, which were as of April 18th and we also provided what we included in our original guidance on January 31. So you can see the strengthening of the dollar there.

Just to.

Make sure it's clear the exposure that we've got two ex U S revenue.

Based on our Q1 revenues, 49% of our revenues were in the U S. Dollar in Q1, 38% were in Europe . So primarily in the Euro and 13% were in R. O W markets, primarily Japan. So those are the yen and the euro are our two biggest exposures.

Yeah.

If you use the revised rates that we have compared to what we used in the original guidance thats about a $20 million headwind relative to the original guidance that we gave him. The dollar is actually further strengthened since April 18th bound in terms of the sensitivity to that.

Just as a rough estimate sort of from this point going forward each 1% strengthening of the dollar against.

Ex U S currency is about a $3 million headwind for us. So the guidance range that we gave hopefully would accommodate additional.

Additional movements in FX, but we're not obviously, we're not in the business of predicting which why the FX rates are going to move.

Okay.

Our next question comes from Paul Matteis with Stifel.

Great. Thanks, so much for taking my question.

Salveen Richter: Great, thanks so much for taking my question. On Vutrisiran, I just wanted to clarify two things. One, I don't know how much detail you go into, but you know, given the proximity of this, this amendment to the PDUFA, you know, how deep were you in labeling discussions? And I guess how confident are you that all other aspects of the review were, were kind of largely resolved and more of the check the box phase?

<unk> I just wanted to clarify two things.

One I don't know how much detail you can go into but given the proximity of this amendment to the <unk>.

How deep are you in labeling discussions and I guess, how confident are you that all other aspects of the review, where we're kind of largely resolved in more of a check the box space and then just second on <unk> can you just clarify is this going to be at 100% in office dose product.

And are you are you comfortable that from a market opportunity perspective, there isn't some meaningful subpopulation of patients that really my preferred the independents at home dosing. Thanks, so much.

Okay. So I think first question Scott I think is for you.

<unk>.

How confident are we in.

Achieving.

Approval.

The need to do to date.

Given the approximate pizza.

The amendment, yes.

Thanks for your question, Paul I think look I think what I'll say is again this amendment was solely prompted.

By this inspection issue at the secondary packaging and labeling facility.

We feel all other activities with regard to the review of the <unk>.

The agency was conducting we're on track and we felt good about it I can't comment specifically about the label.

I think we feel everything else is really going well and on track.

And this is really solely about this one issue that needed to be.

As I've discussed.

Salveen Richter: And then just second on Vutrisiran, can you just clarify, is this going to be an 100% in office dose product? And are you, are you comfortable that from a market opportunity perspective, there isn't some meaningful subpopulation of patients that really might prefer the independence of home dosing? Thanks so much.

Thanks, Pascal and talk of perhaps you can take the second question.

With respect to whether that's a market opportunity combination with respect them do things.

Hi, Paul.

So this study was obviously designed with physician administered routing. Therefore, we are eligible for part B.

In the U S.

Through the omicron.

And Covid, we actually were able to build a pretty substantial.

Site of care and in home.

Injection capabilities. Therefore, we believe these capabilities will be nicely applied to quarterly dosing and subsequently six monthly dosing and given the severity of these patients. We still believe these patients are being monitored by the physician in and quarterly or biannual.

Checkups of these patients are actually very much pedal to the regiment that the doctors would like to see so in either way, we have the right capabilities that we'd be able to accommodate what the patient needs are.

Pushkal Garg: Okay, so I think first question, Pushkal, I think is for you. You know, how confident are we in, Achieving approval by the need-to-do for date, given the proximity to putting in the amendment. Yeah, thanks for your question, Paul. I think, look, I think what I will say is, again, this amendment was solely prompted by this inspection issue at the secondary packaging and labeling facility. All, you know, we feel all other activities with regard to the review that the agency was conducting were on track, and we felt good about it. I can't comment specifically about the label.

Okay. So the hope dosing just to clarify it would be a health care provider visiting the patient is that right.

That's exactly right.

Right now at the moment until you actually serve about.

We serve about 20% of our patients through home infusion.

Makes sense. Thank you.

Our next question comes from Matthew Harrison with Morgan Stanley .

Great. Good morning, Thanks very much.

I guess, just one quick follow up can you.

There seems to be where I've gotten a lot of questions on on on on the filing here and just to make sure. It was this a voluntary action by you or was it suggested by the FDA. If you could just clarify that I think that would help a lot of people in them.

My.

The key question is just can you talk a little bit about what youre doing in CNS more in depth and in particular.

Sort of where youre starting in terms of dosing how long you think it might take before we see them clear knockdown and what you see or maybe the key safety risks to watch out for.

Yes, so maybe.

Pushkal Garg: But, you know, I think we feel everything else is really going well and on track. And this is really solely about this one issue that needed to be, as I've discussed. Thanks, Pushkal.

The first question with respect to the filing yes.

Yes. It was a voluntary action that will be decided in close consultation with the FDA. So I think that's another effect because that gives us confidence in actually achieving and approval by the Paducah date, maybe Pascal you could take the question on <unk>.

N S opportunity, where we are with <unk>.

Tolga Tanguler: And Tolga, perhaps you could take the second question with respect to whether there's a market opportunity for subpopulation with respect to home dosing. Yeah. Yeah. Hi, Paul.

Absolutely so as we announced today were very excited that we've kicked off this program we filed the Cta at the end of last year.

With <unk>, which is our first CNS directed RNA therapeutics.

And we've kicked off the initial study in patients with early onset Alzheimer's disease, we're going directly into patients with this.

This therapeutic.

First with some single doses and ultimately with multiple doses in the context of the study.

And it's a very interesting upstream targets that we think has applications for the broadly Alzheimer's disease.

As well as for the other indications <unk> amyloid Angiopathy, which is a devastating disease that results in St. Paul hemorrhage.

So both of those are part of the development plan.

Tolga Tanguler: So this study was obviously designed with physician-administered routing. Therefore, we are eligible for Part B in the U.S. Through the Omicron and COVID, we actually were able to build a pretty substantial site of care and home injection capabilities. Therefore, we believe these capabilities will be nicely applied to quarterly dosing and subsequently six-monthly dosing. And given the severity of these patients, we still believe these patients are being monitored by the physician. And quarterly or biannual checkups of these patients are actually very much a peril to the regimen that the doctors would like to see.

Tolga Tanguler: So in either way, we have the right capabilities that we'll be able to accommodate what the patient needs are. Okay, so the home dosing, just to clarify, would be via a health care provider visiting the patient, is that right? That's exactly right.

Initial study as I said goes into patients as the population that we think.

Is a tremendous unmet need.

And lacks a lot of other confounding comorbidities et cetera should allow for a clean background for us to assess the safety and tolerability and knocked down.

Of this of this first CNS therapeutics, so we'll be looking closely in the single ascending dose cohorts for.

For safety and Tolerability, and then an important biomarkers that will be looking at particularly.

Soluble <unk> alpha and beta in the CSF and Thats going to help us understand knocked down.

There are also imaging modalities that are incorporated into the study other biomarkers that will be looking at in the context of the study to follow patients.

And look at look for pharmacologic activity, but the main thing we'll be looking at will be soluble AVP alpha and beta CSF.

In terms of the exact timeframe, but where we are.

We're actively conducting this study at multiple sites and.

And as we've said assuming enrollment goes as predicted we expect to be able to report out some proof of concept data at the end of the year.

And just to add.

One of the reasons why we're.

So excited about this program is obviously the huge unmet medical need in patients with.

Outside of the <unk> III <unk> amyloid angiopathy, but if we're successful.

With these indications that re dos and law.

Opportunity to be able to bring the power of our online platform to many many other CNS diseases, where it's you know.

Huge medical need so we're very focused on ensuring progress with this program and efforts in delivering.

Supports data asset.

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

Tolga Tanguler: And right now at the moment, we actually serve about we serve about 20% of our patients through home infusion. Thank you. Our next question comes from Matthew Harrison with Morgan Stanley. Great. Good morning.

Good morning, Thanks for taking the question.

Just two quick follow ups to Paul's question can you can you comment on whether you guys.

Started labeling discussions before that which was around.

Could you quickly and also.

Has there been any indication that the new fill and finish plant.

Requires.

Actions.

At this point Oscar I guess.

Had a chance yet.

The additional CMC package Citibank.

I think there's a few questions for you first call.

With respect to enable discussions and.

And indications around the potential for an inspection, yes. So ritu its first of all I think.

Matthew Harrison: Thanks very much. I guess just one quick follow up, can you, There seems to be, or I've gotten a lot of questions on the filing here, and just to make sure, was this a voluntary action by you, or was it suggested by the FDA, if you could just clarify that, I think that would help a lot of people, and then my sort of key question is just, can you talk a little bit about what you're doing in CNF more in depth, and in particular, sort of where you're starting in terms of dosing, how long you think it might take before we see some clear knockdown, and what you see are some maybe of the key safety risks to watch out for.

Yes, I mean, what I can say is that we've had of late cycle meeting we.

Label discussions et cetera is an ongoing process that happens in parallel with the regulatory review of the application. So all of those activities were underway.

Matthew Harrison: Thanks. Yes, so maybe if it's the first question with respect to the filing, yes, it was a voluntary action that we decided in close consultation with the FDA. So I think that's another factor that gives us confidence in actually achieving an approval by the PDUFA date. Maybe Pushkal, you could take the question on the CNS opportunity where we are with ONATP. Absolutely.

And as I said.

This was really all about this.

This.

This the unrelated inspection that happened at this packaging and labeling facility in.

Actually I think.

What I would say is that it's a complement to our teams in the discussions that we're actually able to.

With agility.

Put in an amendment quickly for the second facility.

And actually mitigate this risk quite substantially so I think thats.

A testament to your second question, which is somewhat related to that the facility that we amended two is one that we actually have experienced it's a facility that we already use for on Petro we use it forgive Laurie we're actually up.

<unk> could be using it for ox pneumo.

And it's been in fact inspected by FDA and EMA in 2020 in 2021.

We have a lot of reasons to have confidence in sort of regulatory standing of that particular facility.

Always up to the FDA with an amendment to make their own determination as to whether inspections necessary and obviously, we defer to their judgment.

Pushkal Garg: So as we announced today, we're very excited that we've kicked off this program. We filed the CTA at the end of last year with ONATP, which is our first CNS-directed RNAi therapeutic. And we've kicked off the initial study in patients with early onset Alzheimer's disease. We're going directly into patients with this therapeutic, first with some single doses and ultimately with multiple doses in the context of the study. And it is a very, you know, interesting upstream target that we think has applications for broadly Alzheimer's disease, as well as for another indication, cerebral amyloid angiopathy, which is a devastating disease that results in cerebral hemorrhage.

But what we do feel quite confident in the facility that we've supplemented our amended two in our application.

The quality of what's done in that facility. So.

Hopefully that answers your question.

Pushkal Garg: So both of those are part of the development plan. The initial study, as I said, goes into EOAD patients as a population that we think has a tremendous unmet need, lacks a lot of other confounding comorbidities, etc. So it should allow for a clean background for us to assess the safety and tolerability and knockdown, you know, of this first CNS therapeutic. So we'll be looking closely in the single ascending dose cohorts for safety and tolerability, and then important biomarkers that we'll be looking at, particularly soluble APP alpha and beta in the CSF. That's going to help us understand knockdown.

Got it and if I can squeak in one very quick follow up.

Pushkal Garg: You know, there are also imaging modalities that are incorporated into the study, other biomarkers that we'll be looking at in the context of the study to follow patients and look at for pharmacologic activity. But the main thing we'll be looking at will be soluble APP alpha and beta in the CSF. In terms of the exact timeframe, but we're, you know, we're actively conducting the study at multiple sites. And as we've said, you know, assuming enrollment goes as predicted, we expect to be able to report out some proof of concept data at the end of the year. And just to add, you know, one of the reasons why we're so excited about this program is obviously there's huge unmet medical needs in patients with, you know, Alzheimer's, as well as cerebral amyloid angiopathy.

Jeff and pulled out you mentioned January February compliance.

Headwinds COVID-19 headwinds.

You guys have previously talked about despite sort of definitely worse points in the pandemic was there something unique to the January February Omar Khan wave that hit on Petro versus the prior years.

So I think to talk about the question for you I mean, some more color on because it impacts absolutely with respect going Patrick I mean look each variant humbles us we always learn new things about how the health system impacts we have actually anticipated and I think <unk> shared some of our insights early.

Particularly with the HP patient when it comes to give Laurie.

With on Petro.

Given the elderly patient population and given the health care system, how the health care system reacted across the world, We certainly had seen that.

Some skip dosing, but it has nicely recovered in March so, we're rather comfortable where we're.

The direction is going.

Yes, that's great programming, we're optimistic going forward with that.

I think this.

Can a virus has shown the potential to surprise us on multiple occasions.

Understood.

Sure.

Thanks.

Next question.

Our next question comes from Johanna Mod with Bank of America.

Pushkal Garg: But if we're successful with these indications, it really does unlock the opportunity to be able to bring the power of our RNAi platform to many, many other CNS diseases where, as you know, there are huge medical needs. So we're very focused on ensuring progress with this program and delivering support data at Columbia. Our next question comes from Ritu Baral with Cowan. Good morning, thanks for taking the question. Just a quick follow-up to Paul's question.

Hi, good morning, Thanks for taking my question.

Ritu Baral: Can you comment on whether you guys had started labeling discussions before the VUTRESA ran, the DUFA delay, and also has there been any indication that the new fill-and-finish plant requires an inspection at this point after, I guess, the FDA has had a chance to review the additional CMC package submitted? I think those are two questions for you, Pushkal, you know, with respect to label discussions and any indications around the potential for an inspection. Yeah, so Ritu, it's Pushkal.

Just another point of clarification on your revised guidance so.

It does include the tree assuming that it gets approved and how are you thinking about.

The early days of the launch.

Really trade Pn and.

Specifically, it's interaction with untapped trial do you expect.

<unk> be part of the early launch metrics there or are you assuming a different patient population will start on <unk>.

On <unk>, if you could give us some color on that that rate.

And then secondly on it does have some data to soon as well for <unk> and then just wondering how you think that could potentially change the competitive dynamic in the marketplace with another entrant. Thank you.

Okay. Thank you can you can answer the first question around the interplay with respect to victory and on Patrick how are we thinking about the early days of the launch right.

Pushkal Garg: I think, yes, I mean, what I can say is that, you know, we've had a late cycle meeting, we, you know, label discussions, etc. is an ongoing process that happens in parallel with the regulatory review of the application. And all those activities were underway. And as I said, you know, this is really all about this, this unrelated inspection that happened at this packaging and labeling facility. And, you know, I actually, I think we, what I would say is that it's a compliment to our teams and the discussions that we're actually able to, you know, with agility, put in an amendment quickly for this second facility, and actually mitigate this risk quite substantially.

Pushkal Garg: So I think that's, you know, a testament to your second question, which is somewhat related to that. The facility that we've amended to is one that we actually have experience with. It's a facility that we already use for PONPATRO, we use it for GiveLary, we were actually planning to be using it for OxLumo.

Pushkal Garg: And it's been in fact, inspected by FDA and EMA in 2020 and 2021. So we have a lot of reasons to have confidence in sort of regulatory standing of that particular facility. It's always up to the FDA with an amendment to make their own determination as to whether inspections necessary and obviously we defer to their judgment.

Pushkal Garg: But what we do feel is quite confident in the facility that we've supplemented or amended to in our application, and the quality of what's done in that facility. So hopefully that answers your question. Got it.

Tolga Tanguler: And if I can squeak in one very quick follow up, Jeff and Tolga, you mentioned January, February compliance had headwinds, COVID headwinds. It's not something that you guys have previously talked about, despite, you know, sort of definitely worst points in the pandemic. Was there something unique to the January, February Omicron wave that that hit on Patro versus the prior year?

<unk> I think if you we should kind of maybe take a quick step back and look at the numbers that.

We're discussing here I think from both from virtually opportunity as well as any new competitive entrants.

Dynamic.

We're still looking at.

2000, 20000 to 30000 patients PR and mixed genotype patients and being the market leader. We're now as we announced this quarter. We moved from 525 in Q1, 'twenty, one 'twenty 200 patients.

In Q.

Past quarter, so we're adding.

Steady increase of patients.

For the treatment of this devastating condition.

And which we will certainly help us I believe to bring in some net.

<unk>, especially those patients that are diagnosed early in their treatment, we start seeing that dynamic already we don't Petro.

We also have certainly anticipate an acceleration of switches.

From the existing therapies that they may have been progressing or may not have found the best treatment regimen, which we certainly provides that.

That opportunity.

And we do anticipate number of home Petro patients.

That might be interested in this new treatment regiment.

They may prefer it.

Not guiding right now about the net and switch numbers, but we do overall anticipate.

Growth.

To accelerate.

Tolga Tanguler: I think, Tolga, that's a question for you. I mean, some more color on the COVID impacts. Absolutely. Particularly with respect to Onpatro. I mean, look, each variant humbles us.

No that's a great answer.

Tolga Tanguler: So we always learn new things about how the health system impacts. We have actually anticipated and I think shared some of our insights early on, particularly with the AHP patient when it comes to Givlari. With Onpatro, given the elderly patient population and given the health care system, how the health care system reacted across the world, we certainly had seen that. Some skipped dosing, but it has nicely recovered in March.

Tolga Tanguler: So we're rather comfortable where the direction is going. Yeah, that's great. So I mean, we're optimistic with you going forward. But as Tolga said, I think this, you know, virus has shown the potential to surprise us on multiple occasions, but you know, we're cautious. Thanks. Thanks.

Maybe just to add that we really are still in the early stages.

Building the TCR franchise.

We're currently addressing the needs of 2003 hundred patients.

With Patrick but there are another 30 or 40 patients.

Who.

<unk>.

Addressable.

Im Patrick so still lots of growth to come again and the second question. So I think that's also a few how youre thinking about.

And the new entrants into the market, particularly.

Yes.

Specifically with the Pn category, we see an accelerated.

Growth and also in diagnosis and I think more share of voice increase share of voice I think is going to certainly help that that pattern.

If you think of <unk> profile, a subcutaneous injection every every quarter. It's certainly we believe is it will remain an attractive and we will continue to help us.

To be the market leader, but I think again, we shouldnt think of this category as a zero sum game.

We believe more entrants like in the MS category will probably help.

Further expansion of the category given what you've already indicated that there are still a lot of undiagnosed.

Untreated patients.

Thanks.

Thanks, Chris.

Our next question comes from Gena Wang with Barclays.

Christine Lindenboom: Thank you. Next question. Our next question comes from Kazin Amon with Bank of America. Hi, good morning.

Thank you for taking my questions I have two.

Kazin Amon: Thanks for taking my question. Just another point of clarification on your revised guidance. So it doesn't include VUTRI, assuming that it gets approved, but how are you thinking about the early days of the launch for VUTRI and PN and specifically its interaction with ONPATRO? Do you expect, Cannibalization to be part of the early launch metrics there, or are you assuming a different patient population will start on Boutry versus who's already on Patron? If you could give some color on that, that'd be great.

<unk> clarification question kind of lung hypothetical question so.

Hello.

Do you see data on a blinded basis.

And then for overlapping sites.

The same Seattle.

Versus the <unk>.

Steady and full Hypersthenic questions just stay in the unfortunate event.

Apollo B missed a six minute walk test endpoint, what kind of a secondary endpoint data and we're convinced you Helios b outcome data will be positive.

But I think three.

Three questions.

To use that.

Sure.

Tolga Tanguler: And then secondly, Ionis does have some data due soon as well for ATTR. And I'm just wondering how you think that could potentially change the competitive dynamic in the marketplace with another entrant. Thank you. Okay, I think you can you can answer both the first question around the interplay with respect to Vutri and Onpatro. How are we thinking about the early days of the launch?

Yes.

Tolga Tanguler: Right. So Kazin, I think if you we should kind of maybe take a quick step back and look at the numbers that we're discussing here, I think, from both from Vutri opportunity, as well as any new competitive entrant dynamic, we're still looking at, you know, 20,000 to 30,000 patients, PN and mixed genotype patients and, and being the market leader, we're now as we announced this quarter, we moved from 1525 in Q1 21 to 2200 patients in Q this this past quarter.

Absolutely hygiene.

Tolga Tanguler: So we're adding a steady increase of patients for, you know, the treatment of this devastating condition. And Vutri will certainly help us, I believe, to bring in some net naive patients, especially those patients that are diagnosed early in their treatment, we start seeing that dynamic already with Onpatro. We also certainly anticipate an acceleration of switches from the existing therapies that they may have been progressing or may not have found, you know, the best treatment regimen. Vutri certainly provides that, that opportunity.

Tolga Tanguler: And, and we do anticipate number of Onpatro patients that might be interested in this new treatment regimen that they may prefer it. We're not guiding right now about the net and switch numbers, but we do overall anticipate growth to to to to accelerate. Yeah, that's a great answer, Tolga.

So look on a couple of these blinded data. So as every sponsor does running a blinded clinical trial, we have folks in our clinical team data management et cetera, who are responsible for looking at blinded data over the course of the study that is really to ensure that the study is being conducted properly to make sure. The proper patients are being enrolled.

Yvonne Greenstreet: And maybe just to add that we really are still in the early stages of, you know, building the TTR franchise. You know, we're currently addressing the needs of 2200 patients with Onpatro, but there are another, you know, 30 or 40,000 patients there, who, you know, are addressable by Onpatro. So there's still lots of growth to come here.

Tolga Tanguler: The second question, Tolga, I think it's also for you, how are you thinking about, you know, new entrants from into the market, particularly from Ionis? Yeah, I mean, specifically with the PN category, we see an accelerated growth and also in diagnosis. And I think more share of voice, increased share of voice, I think is going to certainly help that pattern. If you think of Vutri's profile of subcutaneous injection every quarter, it certainly, we believe, will remain an attractive and will continue to help us be the market leader.

Tolga Tanguler: But I think, again, we shouldn't think of this category as a zero-sum game. I believe more entrants, like in the MS category, will probably help further expansion of the category, given what Yvonne indicated, that there are still a lot of undiagnosed and untreated patients. Thanks.

They meet enrollment criteria to look at outlined data points someone has a two meter walk at $6 6 million or 2000 meters to query the site and see if there was a data entry error for instance to see if there's patterns where sites are not conducting following procedures properly. So that's all part of whats happening. So there are people who are looking at blinded data over there.

Of course the study it is all blinded.

And and so that's just part of the norms of the house studies done and conducted to ensure that when we finally lock the database that we have a clean data set that allows for interpretable data.

And so those activities are underway as it's done at every clinical trial thats done by every sponsor.

In terms of overlapping sites, we don't actually have the exact count, but we probably estimate the 20% to 25% of sites may be overlapping I'd remind you that doesn't a reflect necessarily the number of patients that are overlapping between the two different studies.

And three.

Where we do our study it's all under the context of our protocol with the CRO that we work with.

And our protocol has cleared trial procedures training procedures oversight et cetera that is all specific.

<unk> Apollo B I can't comment on the cross that bridge bio used I actually don't know.

And.

And then I think your third question was would you called hypothetical what I'll say is we will be looking at the totality of data coming out of this study.

As you know the primary endpoint is around six minute walk test, but we'll be looking at <unk>, which is an important secondary endpoint will be looking at BNP will be looking at echocardiographic parameters and importantly, we will be looking although it's a short study.

At 12 months, we will be looking at.

Event rates with regard to mortality and importantly hospitalization.

And be looking at the totality of those data to understand what we're seeing in terms of the impact of silencing in this patient population and that will help us interpret the data within Apollo B, but also.

Help us think about the impact in this disease overall as it relates to Helios b, so hopefully that answers your questions.

Did that answer your question.

Yes.

Regarding the secondary endpoint.

Okay.

Any particular.

The separation will be lucky.

The group's confidence.

It will be positive.

Hi, Gena.

It's really it's impossible to answer that question I think we'll be looking at the totality of the data.

<unk>.

To really make that assessment, so theres no theres no single data point there'll be looking at there is no single number that we'd be looking at yeah. Thanks, I think we've got time for one more question.

Our last question comes from <unk> Rama with Jpmorgan.

Hey, guys. Thanks, so much for taking the question maybe I had a follow up on <unk> question, but I just wanted to confirm that you will have some of that mortality CV hospitalizations in the topline results versus waiting for.

A full presentation at a medical conference or something like that and specifically what your expectations on those two metrics would be at a 12 month look thanks so much.

Yeah.

So on a pump.

Those are pre specified secondary endpoints, it's been our practice to when we report top line results to speak to P values.

With regard to.

Primary and secondary endpoints, you can expect that to be providing the topline, but additional color and detail of course will come at a medical conference subsequently.

And I'm, sorry, I think I missed the second part of your question.

Like what would be your expectations at a 12 month look on CV hospitalizations and mortality.

Yeah. So what I would say is the study was not powered for those endpoints at all.

They are being captured but theyre not powered endpoints.

As you can imagine 12 months is a relatively short time.

Necessarily see effects on those.

I'll remind you that <unk> it took <unk>.

Nine months to start to see a hospitalization separation and roughly 12 to 18 months to see a mortality separation.

Yes.

That said, our post hoc data from Apollo.

Showed potentially a much earlier separation on those events some of the data that's been published in.

Circulation a few years ago.

So there is some potential.

We've seen on other parameters.

<unk> of silencing potentially on echocardiographic parameters, technetium et cetera at earlier time points.

I think you are looking forward to seeing the results.

And seeing what that looks like so there is and Thats why we can capture these as important secondary endpoints to look at we are indeed.

Thank you everyone for joining us on this call greatly to the Doctor.

Christine Lindenboom: Thank you. Thank you. Thank you.

Gena Wang: Our next question comes from Gena Wang with Barclays. Thank you for taking my questions. I have two clarification questions and one hypothetical question.

Pushkal Garg: So for Apollo B, do you see data on the blinded base? And then for overlapping sites, do you use the same CRO versus the Bridge Biles attribute study? And for hypothetic questions, you know, just say in an unfortunate event, Apollo B missed a six-minute walk test endpoint, what kind of a secondary endpoint data that will convince you Helios B outcome data will be possible? Pushkal, I think, you know, three questions for you there. Yeah, absolutely. Hi, Gena.

Pushkal Garg: So look, on a couple of these, blinded data. So as every sponsor does running a blind clinical trial, we have folks in our clinical team, data management, etc, who are responsible for looking at blinded data over the course of the study. That's really to ensure that the study is being conducted properly to make sure the proper patients are being enrolled and they meet enrollment criteria, to look at outlying data points, you know, someone has a two meter walk at six in six minutes or 2000 meters to query the site and see if there's a data entry error, for instance, to see if there's patterns where sites are not conducting following procedures properly. So that's all part of what's happening.

Pushkal Garg: So there are people who are looking at blinded data over the course of the study, it is all blinded. And, and so that's just part of the norms of how a study is done and conducted to ensure that when we finally lock the database, that we have a clean data set that allows for interpretable data. And so those activities are underway. As is done in every clinical trial that's done by every sponsor. In terms of overlapping sites, you know, we don't actually have the exact count, but we probably estimate that 20 to 25 percent of sites may be overlapping.

Steady staff as we continue to advance our commercial fishing.

Pushkal Garg: I'd remind you that doesn't, A, reflect necessarily the number of patients that are overlapping between the two different studies. And three, you know, where we do our study, it's all under the context of our protocol with the CROs that we work with. And our protocol has clear trial procedures, training procedures, oversight, et cetera, that is all specific to Apollo B. I can't comment on the CROs that Bridge Bio used. I actually don't know.

Pushkal Garg: So I think you're looking forward to seeing the results and seeing what that looks like. So there's, and that's why we've captured these as important secondary endpoints to look at. We are indeed. So, look, thank you, everyone, for joining us on this call. 2022 is off to a steady start as we continue to advance our international system. We think with all the exciting pipeline programs that we have in development, there are a lot of exciting and important upcoming milestones over the course of the year.

Pushkal Garg: And then I think your third question was what you called hypothetical. What I'll say is we'll be looking at the totality of data coming out of this study. As you know, the primary endpoint is around six-minute walk tests, but we'll be looking at KCCQ, which is an important secondary endpoint. We'll be looking at BNP.

Pushkal Garg: We'll be looking at echocardiographic parameters. And importantly, we'll be looking, although it's a short study of 12 months, we will be looking at event rates with regard to mortality and importantly, hospitalization, and be looking at the totality of those data to understand what we're seeing in terms of the impact of silencing in this patient population. And that will help us, A, interpret the data within Apollo B, but also help us think about the impact in this disease overall as it relates to Heliospeed.

Pushkal Garg: So hopefully that answers your questions. Thanks, Dr. Scott. Did that answer your question? Yes, like, you know, so regarding the second three, I'm like, Any particular separation you will be looking for that you think, Confident that he was... Gena, it's really it's impossible to answer that question.

We don't make financing pipeline.

Pushkal Garg: I think we'll be looking at the totality of the data, you know, to really make that assessment. So there's no there's no single data point that we're looking at. There's no single number I'll be looking at. Yeah, thanks. I think we've got time for one more question.

Anupam Rama: Our last question comes from Anupam Rama with J.P. Morgan. Hey guys, thanks so much for taking the question. Maybe I had a follow up on Gina's question, but I just wanted to confirm that you'll have some of that mortality, CV hospitalizations and the top line results versus waiting for, you know, a full presentation at a medical conference or something like that. And specifically what your expectations on those two metrics would be at a 12 month look. Thanks so much.

That we have in development.

Pushkal Garg: Yeah, so on a public we, Those are pre-specified secondary endpoints. It's been our practice to, when we report top line results, to speak to p-values with regard to, you know, primary and secondary endpoints. So you can expect that to be provided in the top line, but additional color and detail, of course, will come at a medical conference subsequently. And I'm sorry, I think I missed the second part of your question. Like, what would be your expectations at a 12-month look on CV hospitalizations and mortality? Oh, yeah.

Pushkal Garg: So, you know, what I would say is the study was not powered for those endpoints at all. So they are being captured, but they're not powered endpoints. And then, you know, we, as you can imagine, 12 months is a relatively short time to necessarily see effects on those. I'll remind you that tefamidus, it took nine months to start to see a hospitalization separation and roughly, you know, 12 to 18 months to see a mortality separation.

That all are exciting and important upcoming milestones over the course of the year. We look forward to updating you on this so thank you everybody for joining our call today and have a great day.

Pushkal Garg: You know, that said, our post hoc data from Apollo showed potentially a much earlier separation on those events, some of the data that's been published in circulation a few years ago. So, you know, there's some potential. And, you know, we've seen on other parameters, effects of silencing potentially on echocardiographic parameters, technetium, et cetera, at earlier time points.

Pushkal Garg: And we look forward to updating you on these. So thank you to everybody for joining our call today and have a great day. This concludes today's conference call. Thank you for participating. You may now disconnect. © BF-WATCH TV 2021, [music]

This concludes today's conference call.

You for participating.

You may now disconnect.

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