Q2 2021 Alnylam Pharmaceuticals Inc Earnings Call

Okay.

Operator: Ladies and gentlemen, thank you for standing by, and welcome to the Alnylam Pharmaceuticals Q2 2021 earnings call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you need to press star 1 on your telephone. If you require any further assistance, please press star then 0.

Ladies and gentlemen, thank you for standing by and blocks of the out now and Pharmaceuticals Q2.2021 earnings call. At this time all participants are in a listen only mode. After the speaker's presentation there'll be a question and answer session to ask the question during the session of need the press star 1 on your telephone if you require any further assistance. Please press Star then zero I would now like to turn the call over to your host Kristy.

Christine Regan Lindenboom: Good morning, I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are John Merganori, Chief Executive Officer, Tolga Tanguler, Chief Commercial Officer, Akshay Vaishnaw, President of R&D, Jeff Poulton, Chief Financial Officer, and Yvonne Greenstreet, President and Chief Operating Officer. For those of you participating via conference call, the accompanying slides can be accessed by going to the events section of the Investors page of our website, investors.alnylam.com event. During today's call, as outlined in slide 2, John will provide some introductory remarks and provide general context. Tolga will provide an update on our global commercial progress, and Akshay will review recent clinical and preclinical updates.

Linda and boom may begin.

Good morning, and Christine many of them senior Vice President of Investor Relations and corporate communications and all 9 of them with me today on the part of our John Merkin Murray Chief Executive Officer until the Taylor Chief Commercial Officer actually base now has and the RMB.

Yeah, Okay, and Chief Financial Officer, and Yvonne Greenstreet, President and Chief operating Officer.

For those of you participating via conference call of the accompanying slides can be accessed by going to the events section of the investors page of our web site investors Dot on island of Dotcom Flash event.

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

Total will provide an update on our global commercial progress Akshay will review recent clinical and preclinical updates.

Christine Regan Lindenboom: Jeff will review our financials, and Yvonne will provide a brief summary of upcoming milestones before opening the call to your questions. I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor Provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent quarterly report on file with the SEC.

Jeff will review, our financials and the bar will provide a brief summary of upcoming milestones before opening the call to your questions.

I would like to remind you that the call will contain remarks concerning on the island's future expectations plans and prospects, which constitute forward looking statements for the purposes of the safe Harbor provision under the private Securities Litigation Reform Act of 1095.

Actual results may differ materially from those indicated by these forward looking statements as a result of various important factors, including those discussed and our most recent quarterly report on file with the SEC and.

Christine Regan Lindenboom: In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'd like to turn the call over to John.

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

We specifically disclaim any obligations to update such statements with that I'd like to turn the call over to John John.

John Merganori: Thanks Christine, and thank you everyone for joining the call today. In the second quarter and recent period, we made tremendous progress bringing RNAi therapeutics to patients around the world through our commercial, medical, and R&D efforts while delivering solid financial performance. To start, our teams delivered steady, ongoing commercial execution and continued revenue growth, including 12% quarterly growth for Ampatro, strengthening of Giblari performance, and a continued impressive uptake for Oxlumo. In our pipeline efforts, highlights include excellent progress building our ATTR amyloidosis franchise. We have completed enrollment in the Apollo B Phase III study of T-Seran and expect to complete enrollment in the Helios B Phase III study of T-Seran within the next two weeks.

Thanks, Christine and thank you everyone for joining the call today and the second quarter and recent period, we made tremendous progress, bringing <unk> therapeutics to patients around the world with our commercial medical and R&D efforts, while delivering solid financial performance.

The start our teams delivered steady on bill and commercial execution and continued revenue growth, including <unk>.

<unk> percent quarterly growth from Petro and strengthening of give Laurie performance and the continued impressive uptake for <unk>.

And our pipeline efforts highlights include excellent progress building, our <unk> amyloidosis franchise, we completed enrollment of the Apollo B phase III study of the TCR and and expect to complete enrollment of the Helios B phase III study of the tree Saran within the next 2 weeks significantly ahead of schedule.

John Merganori: Significantly ahead of schedule, and already with more than 600 patients enrolled, we also submitted our Butreceran NDA based on the Helios-A results in patients with HATTR amyloidosis with polyneuropathy, and the FDA accepted our submission, assigning a BDUFA date in April of 2022. Furthermore, we initiated a biannual dosing study of Lutriceran, and we introduced a new preclinical program, ALN-TTR-SCO4, which we believe could enable an annual dosing regimen. We also advanced programs in our earlier stage clinical pipeline, including new positive interim data from the phase one study of Zalvisiran, our investigational RNAi therapeutic for hypertension, which is now advanced into the CARDIA phase two program

And already with more than 600 patients and the world.

We also submitted our <unk> NDA based on the Helios, a results and patients with <unk> amyloidosis with Polyneuropathy and the FDA accepted our submission of signings of the <unk> date in April of 2022.

Furthermore, we initiated a biannual dosing study of <unk> and we introduced the new preclinical program al and Ctr and seal for which we believe could enable and annual dosing regimen and we.

We also advanced programs and our earlier stage clinical pipeline, including new positive interim data from the phase 1 study of <unk>, our investigational <unk> therapeutic for hypertension, which has now advanced into the cardiac phase II program.

John Merganori: We believe all of these achievements represent meaningful progress toward our Alnylam P to the 5th by 25 goal, a bold vision for Alnylam with transformative medicines in both rare and common diseases for patients around the world, and a robust and high-yielding pipeline of first and or best-in-class product candidates from our organic product entry. All this while delivering exceptional financial performance. So with that, let me now turn the call over to Tolga for a review of our commercial results. Tolga. Thanks, John.

We believe all of these achievements represent meaningful progress toward our myeloma Pete of the fifth by 'twenty 5 goals.

The old data for all dialogue with transformative medicines, and both rare and common diseases for patients around the world.

And a robust and high yielding pipeline of first <unk> best in class product candidates from our organic product engine.

All of this while delivering exceptional financial performance so with that let me now turn the call over to told US for a review of our commercial results toga.

Thanks, John and good morning, everyone. We're very pleased with our second quarter performance.

Tolga Tanguler: And good morning, everyone. We're very pleased with our second quarter performance. For Ompatra, we achieved $114 million in global net product revenues, representing approximately 12% quarter-on-quarter growth compared with the first quarter. Additionally, we ended the quarter with over 1,725 patients on commercial treatment. In the U.S., we continue to see strength on many fronts, including 12% growth in demand and notable growth in new prescribers. We have also seen encouraging signs of the healthcare system reopening.

4 O and Petro, we achieved $114 million and global net product revenues, representing approximately 12% quarter on quarter growth compared with the first quarter.

We ended the quarter with over 17.125 patients on commercial treatment.

And the U S. We continue to see strength on many fronts Inc.

Including 12% growth and demand and notable growth and new prescribers.

We have also seen encouraging signs of the health care system reopening for.

Tolga Tanguler: For example, in the second quarter, we received more starter forms for Ompatro in the U.S. than we have since early 2019. We're also seeing an uptick in face-to-face interactions between our field team and healthcare professionals, which is an indicator that the healthcare system is continuing to open up. Furthermore, speed to patient diagnosis is continuing to improve with ongoing growth in the use of PYP scans, which is often the start of the patient journey toward a polyneuropathy diagnosis.

For example, and the second quarter, we received more start forms from petrol and the U S debt we have since early 2019.

We're also seeing an uptick and face to face interactions between our field team and how can it professionals, which is an indicator that the health care system is continuing to open up.

Further.

Speech of patient diagnosis is continuing to improve with ongoing growth and the use of Typ scans, which is also and to start off the patient journey toward of Polyneuropathy diagnosis.

Tolga Tanguler: Patient compliance also remains high and stable at pre-COVID levels, and we continue to observe a trend in concomitant use of Ompetra to treat the polyneuropathy of HATTR amnidosis, along with the use of a TTR stabilizer to treat the cardiomyopathy of this disease in mixed phenotype patients with regard to the rest of the world. Market access has now been achieved in over 30 countries worldwide. In Q2, we saw significant 17% quarter-on-quarter growth in our rest of world markets, with particular strength in Europe and Canada. We're also observing a good balance of first-line use and switches from stabilizers in these markets.

Patient compliance also remains high and stable at pre Covid levels.

And we continue to observe of threat and concomitant use of force Petro to treat the polyneuropathy of <unk>, how many doses along with the use of our ctr stabilizer to treat the cardiomyopathy of this disease and mixed phenotype patients.

With regard to the rest of the world.

The market access has now been achieved and over 30 countries worldwide. In Q2, we saw significant 17% quarter on quarter growth and our rest of world markets with particular strength in Europe and Canada. We're also observing a good balance of first line use and switches from stabilizers in the.

Markets.

Tolga Tanguler: Moving to Givlari, we achieved $31 million in global net product revenues in the second quarter, representing approximately 24% quarter-on-quarter growth compared with Q1. And as of June 30th, we had over 270 patients worldwide on commercial therapy. This quarter, we saw significant growth driven by net new patient ads. This was an improvement relative to the first quarter, in which the performance was softer than anticipated, likely due to reduced patient flow through the U.S. healthcare system caused by COVID.

Moving to give Laurie, we achieved $31 million and global net product revenues and the second quarter.

<unk>, approximately 24% quarter on quarter growth compared with Q1 and as of June 30th we obtained over 270 patients worldwide on the commercial therapy.

This quarter, we saw significant growth driven by net new patient adds.

This was an improvement relative to the first quarter and which the performance was softer than anticipated likely due to reduce patient flow through the U S health care system caused by Covid.

Tolga Tanguler: We're also seeing continued expansion of the prescriber base, including new riders, particularly from community centers, in addition to Porphyria Centers of Excellence. In the U.S., we continue to make strong progress toward establishing VBAs, with over 10 finalized to date with commercial payers. We also have confirmed access for over 98% of covered U.S. lives with no significant headwinds.

We're also seeing continued expansion of the prescriber base, including new riders, particularly from community of sensors. In addition to porphyria centers of excellence.

In the U S. We continue to make strong progress toward establishing beat the as we go over 10 and finalized to date with commercial payers and we.

And also have come from excess for over 98% of covered the U S lives with no significant headwinds.

Tolga Tanguler: We continue to make great progress with market access efforts for Givlari across the Simia region with a recent launch in Italy, ongoing launch in Germany, temporary authorization for use or ATU supply in France, as well as name patient sales in other countries. In addition, we were pleased to recently receive approval for GiveLary in Japan for the treatment of AHP in adults as well as adolescents aged 12 and older, with a launch expected in September.

We continue to make great progress with market access efforts towards the lari across the CBA region with the recent launch and Italy ongoing launch and Germany temporary authorization for use or HEU supply and France is 1 of those named patient sales and other countries.

In addition, we were pleased to recently received the approval of you of Lori and Japan for the treatment of HP and adults as well as the dollar since age 12 and older with the launch expected in September.

Tolga Tanguler: Moving to Oxnumo, we're seeing continued demand strength in the drug's second full quarter of launch. We achieved $16 million in global net product revenues in the second quarter and attained approximately 100 patients on commercial Oxnumo treatment in the US and EU as of June 30th.

Moving talks of the mall, we're seeing continued demand strength and the drug second full quarter of launch we achieved $60 million and global net product revenues in the second quarter and.

And attain the approximately 100 patients on commercial Oaks, the wood treatment and the U S and EU as of June 30th.

Tolga Tanguler: As we're still early in the launch, Oxlumab performance is also being modestly benefitted by the dynamics of a loading dose. Our market access efforts are progressing very well, with no access headwinds and confirmed medical policy inclusions for over 80% of covered U.S. lives and 7 VBAs finalized to date with commercial payers. Geographic expression of Oxluma is moving along nicely, with recent approval in Brazil and launch underway in Germany and ATU supply in France, supported by early transitions from our expanded access program.

And as we are still early and the launch Auxilium of performance is also being modestly benefited by the dynamics of a loading dose.

Our marketing market access efforts are progressing very well with no access headwinds and confirm medical policy conclusions for over 80% of covered U S lives.

And 7 BVA and finalize the day date with commercial payers.

Geographic expansion of box relay is moving along nicely with the recent approval in Brazil, and launch underway in Germany, and <unk> supply and France supported by early transitions from our expanded access program.

Tolga Tanguler: We're very pleased to see broad utilization of Oxfamo at this early stage of launch, including across age groups. In conclusion, we believe we had a great second quarter of 2021 as we continue to make steady and continued growth across our wholly owned commercial portfolio, driven by the focus and hard work of our teams, improved patient flow through the healthcare system, improved disease awareness, and new patient findings. In the case of Givlar and Oxlumo, we also experienced growth partially fueled by new market expansion due to reimbursement and regulatory decisions. With that said, I will now turn it over to Akshay to review our recent R&D and pipeline program. Akshay

We're very pleased to see broad utilization of folks Shlomo, it's just around the stage of launch including across age groups.

In conclusion, we believe we had a great second quarter of 2021 is the continued to make steady and continued growth across our wholly owned commercial portfolio driven by the focus and hard work of our teams.

The improved patient flows through the health care system, Inc.

True disease awareness and new patient finding.

In the case of <unk>, we also experienced growth, partially fueled by new market expansion due to reimbursement and regulatory decisions.

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

Sure.

Akshay K. Vaishnaw: Thanks, Tolga, and good morning, everyone. I'll start with our efforts in ATTR amyloidosis, where we're advancing two clinical stage product candidates, patisserin and vutriserin. Arsalan Patra is currently approved in multiple markets around the world to treat the polyneuropathy associated with hereditary ATTR amyloidosis. We're committed to expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild-type at-term amyloidosis patients. To this end, we're conducting the Apollo B Phase 3 study.

Thanks, Paul and good morning, everyone I'll start with our assets and ATT amyloidosis, where we are advancing 2 clinical stage product candidates <unk> and <unk>.

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

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

To this and we are conducting the Apollo B phase III study.

Akshay K. Vaishnaw: During the second quarter, we completed enrollment in Apollo B and expect to report top-line results in mid-2022. We're also advancing vitriceran and investigational therapy, which is delivered by a quarterly subcutaneous injection and is also in development for AT-termoidosis. Here, we're conducting two phase three studies. The first is Helios-A, evaluating Butrysran in HAT-termoidosis patients with polyn

During the second quarter, we completed enrollment in the Apollo B and expect to report top line results in mid 2022.

We're also advancing of interest ran and investigational therapy, which is delivered by quarterly subcutaneous injection and he's also and development for <unk> amyloidosis.

Here, we are conducting 2 phase III studies.

The first is Helios, a and evaluating Boutris, Ryan and Asia and T terminally doses patients with Polyneuropathy.

Akshay K. Vaishnaw: At the AIM conference in April, we presented our positive nine-month Helios A results. Based on those results, we submitted our NDA to the FDA, which was accepted and signed on April 14, 2022. Patient dosing continues in Helios A, and we look forward to reporting top-line results from the 18-month endpoint in late 2021, which will also further characterize Rutrisran's impact on the expiratory cardiac endpoint. We plan to make additional regulatory submissions, including in the EU, in late 2021 based on the Helios A results.

At the AAN conference in April we presented a poster of 9 months Helios a result.

Based on these results, we submitted our NDA and to the FDA, which was accepted and find the Paducah date of April 14.2022.

Patient dosing continues and Helios, a and we look forward to reporting topline results from the 18 month endpoint and late 2021, which will also further characterize <unk> impact from the exploratory cardiac endpoints.

We plan to make additional regulatory submissions, including and the U.

In the late 2021 period based on the Helios a results.

Akshay K. Vaishnaw: The other Phase 3 Butreserin study is Helios B, which is our ongoing Phase 3 Cardiac Outcomes Study with Butreserin, Inheritry, and Wild-Type ATGY Amyloidosis with Cardiomyopathy. We're excited to have announced this morning that, due to high interest amongst physicians and patients, we now expect complete enrollment within the next two weeks, well ahead of schedule, and with more than EDS-B has a 30-month endpoint of all-cause mortality and CVFN, and we can now expect the full results in early 2024.

Yeah of the phase III vitreous or in the studies Helios B, which is our ongoing phase III cardiac outcome study with the vitreous strength in hereditary and wild type <unk> amyloidosis with cardiomyopathy.

We're excited to have announced this morning, the due to high interest amongst physicians and patients. We now expect to complete enrollment within the next 2 weeks well ahead of schedule and with more than 600 patients randomized to date.

<unk> has a 30 month endpoint of of all cause mortality and CV events.

And we can now expect before results in early 2024.

Akshay K. Vaishnaw: The study design includes the potential for an interim analysis and will consider the following results from Apollo B in alignment with regulatory authority. Lastly, for Vutrisran, we're very excited about the potential opportunity for biannual dosing regimens, which could further differentiate Vutrisran from other products and provide yet another dosing regimen option for patients. We're now generating the clinical data to potentially advance this additional 50 milligram biannual dosing schedule for ritriceride. Specifically, we've revised the open-label extension period of the Helios A study to now include a randomized treatment extension where patients from the Helios A study will be randomized to receive Botriceram at a dose of either 25 milligrams every three months or 50 milligrams

The study design includes the potential for an interim analysis and we'll consider this volume results from Apollo B and alignment with regulatory authorities.

And lastly from interest ran and we're very excited about the potential opportunity for biannual dosing regimen, which could further differentiate of interest earned from other products and provide yet another dosing regimen option for patients.

And we're now generating the clinical data to potentially advance additional 50 milligram biannual dosing schedule for which is around.

Specifically, we have revised the open label extension period of the Helios a study to now include the randomized treatment extension where patients from the Helios a study will be randomized to receive the interest ran out of those would be the 25 milligrams every 3 months or 50 milligrams by annually.

Akshay K. Vaishnaw: These data, intended to demonstrate the safety and efficacy of the 50 milligram biannual regimen, are expected in 2022. Thus, beyond Patisran and Vutrisran, we have a new addition to the ATTR amyloidosis franchise we're building. Specifically, using our iCarrier platform, we've generated a new TTR-targeting siRNA, LNTTR-SEO4, that we believe could support an annual dosing regimen of greater than 90% TTR-NOC. We intend to share more detail on the iCarrier platform and our preclinical work at an upcoming scientific meeting in mid-2021.

These data intended to demonstrate the safety and efficacy of the 50 milligram find new regimens are expected in 2022.

Beyond <unk> and <unk>, we are of New addition to the <unk> amyloidosis franchise, we're building specifically using icaria platform, we've generated of new TTL targeting ESI and RNA <unk> 4 that we believe could support and annual dosing regimen.

To the 90% of <unk> knockdown.

We intend to share more detail and the carrier platform and our preclinical work and at upcoming scientific meeting in mid 'twenty 'twenty 1.

Akshay K. Vaishnaw: Let's now move on to Lamastran, our RNAi therapeutic recently approved in the EU and US as the first treatment for primary hyperoxylurea type 1, or PH1. We were very pleased to announce positive top-line results from Illumina AC just last week. As a reminder, ILLUMINATE-C is a single-arm, multinational Phase III study designed to evaluate the efficacy and safety of lumatran in PH1 patients of all ages with severe renal impairment, including patients on dialysis.

Let's now move onto the master and our RNA therapeutic recently approved and the EU and U S. As the first treatment for primary Hyperoxaluria type 1 or <unk>.

1.

We were very pleased to announced positive topline results from illuminate C. Just last week.

As a reminder, illuminate C is the singular multinational phase III study designed to evaluate the efficacy and safety of and the mass brands and ph 1 patients of all ages with severe renal impairment, including patients on dialysis.

Akshay K. Vaishnaw: A total of 21 patients were enrolled in the study, and Lumasaran was found to achieve substantial reductions in plasma oxalate relative to baseline, both in patients who are not yet on dialysis and patients who are hemodialysis dependent. Elevated plasma oxalate can result in systemic oxalosis, with severe clinical consequences impacting the heart, bones, eyes, skin, and other organs. Moreover, Maserat demonstrated an encouraging safety and tolerability profile with no deaths or drug-related SAEs. The most common AEs were ISRs, all of which were Myles.

The total of 21 patients were enrolled and the study and the mass revenue was found to achieve substantial reductions in plasma oxalate relative to baseline.

And patients will not yet on dialysis and patients so hemodialysis dependent.

Elevated plasma oxalate and resulted in systemic oxalosis and severe clinical consequences impacting the heart bones on the skin and other organs.

Moreover, the master and demonstrated and encouraging safety and Tolerability profile with no debt or drug related aes.

The most culminate the ISR and all of which were mild.

Akshay K. Vaishnaw: There were two discontinuations from treatment during the extension period due to adverse events, but neither was drug related. We now intend to submit supplemental regulatory filings with the FDA and the EMA in late 2021 with the goal of strengthening the label supporting Oxluma. As we have noted previously, we're also excited about the potential for Lumasaran for patients with recurrent renal stones, and later this year, we plan to start a Phase II trial to evaluate that potential.

The 2 discontinuation from treatment during the extension period due to aes, but neither was drug related.

We now intend to submit the supplemental regulatory filings with the FDA and EMA in late 2021 with the goal of strengthening the label supporting all of <unk>.

As we have noted previously we're also excited about the potential from the master and for patients with recurrent renal stones and later this year, we plan to start the phase II trial to evaluate that potential.

Akshay K. Vaishnaw: As you know, we have two additional late-stage programs that are in development with partners. These include LEC-VO or Inquisiran, partnered with Novartis, which was approved last year in the EU for the treatment of adults with hypercholesterolemia or mixed dyslipidemia. LECVIO marks the first RNAi therapeutic approved for a prevalent condition. Recently, Novartis resubmitted its NDA for Lectio in response to a complete response letter it received from the FDA due to the inability of FDA inspectors to visit a third-party manufacturing facility in Europe due to COVID. Importantly, the FDA has not raised any concerns related to the efficacy or safety of Inclisiraz.

As you know we of 2 additional late stage programs that are in development with partners and this includes let COVID-19 or <unk> partnered with Novartis, which was approved last year in the EU from the treatment of adults with hypercholesterolemia or mixed dyslipidemia.

Net via remarks, but first RNA therapeutic approved for a prevalent condition.

Recently, and Novartis resubmitted, the NDA for like for Ya and response to the complete response letter received from the FDA due to the inability of FDA inspectors to visit of third party manufacturing facility in Europe due to Covid.

Importantly, the FDA has not raised any concerns related to the efficacy or safety of Inc. Lisa.

Akshay K. Vaishnaw: Novartis announced that the FDA has accepted the resubmission and has signed a PDUFA date of January 1, 2022. Our late-stage programs also include Fitusiran in development for haemophilia A or B with or without inhibitors, partnered with Sanofi, who is leading development of Fitusiran in the ATLAS Phase III program. Sanofi announced substantial progress with FITUSRAN and now expects to share data from initial pivotal trials as early as the beginning of next year, with a potential regulatory submission later in 2022.

And the vast amounts of the FDA has accepted the resubmission and assigned a <unk> date of January 1.2022.

Our late stage programs and also includes the Tucson and development team for the a or b with or without inhibitors partnered with Sanofi.

Leading development of <unk> and the Atlas Phase III program.

<unk> announced substantial progress with the Tucson, and now expects to share data from initial pivotal trials as early as beginning of the banks here with the potential regulatory submission later in 2022.

Akshay K. Vaishnaw: Now, in addition to our late-stage clinical programs, we believe we've also been making great progress with our early and mid-stage programs. One of the exciting parts of our story now is the potential expansion of RNAi therapeutics beyond rare diseases into prevalent disease opportunities. We believe now is the time to address many unmet needs in common disease settings such as hypertension, NASH, gout, and diabetes, amongst others, and we believe the pharmacological properties of RNAi therapeutics provide the foundation for success. Our program for hypertension is a great example.

Now in addition to of late stage clinical programs. We believe we have also been making great progress without early and mid stage programs 1.

The exciting part of our story now is the potential expansion of RNA therapeutics beyond red lease into prevalent disease opportunities.

Believe now is the time to address many unmet needs and common disease settings, such as hypertension, Nash gout diabetes amongst others and we believe the pharmacological properties of RNA Therapeutics provides the foundation for success.

Our program for hypertension is a great example, so best around formerly known as <unk> and ADT and our investigational <unk> therapeutic targeting the genetically validated target and <unk> for the treatment of hypertension.

Akshay K. Vaishnaw: So Bessaran, formerly known as LNA-GT, is our investigational RNAi therapeutic targeting the genetically validated target angiotensinogen for the treatment of hypertension. In the second quarter, we reported interim results from a Phase 1 study, in which patients treated with single doses of Zilpersiran at 100mg or higher doses experienced durable reductions in serum agt of more than 90% throughout a week Reductions in 24-hour systolic blood pressure of greater than 10 mmHg were observed at week 8 after single doses of 100 mg or higher, which is antihypertensively active, and persisted through week 12. In the highest dose group, a greater than 15 millimeters mercury reduction in blood pressure was observed.

And the second quarter, we reported interim results from the phase 1 study in which patients treated with the single dose of the bets around at 100 milligrams of higher doses of experienced durable reductions in serum AZT of more than 19% throughout 2 of weeks.

Reductions in 24 hour systolic blood pressure of greater than 10 millimeters of Mercury of observed at week 8 of the single doses of 100 milligrams of higher.

And as antihypertensive effect at the assisted through week 12.

And the highest dose group greater than 15 millimeters of Mercury reduction of blood pressure was observed.

Akshay K. Vaishnaw: We believe these durable pharmacologic effects may support tonic control of blood pressure with a once quarterly and potentially biannual dosing regimen. In the studies, the best round has been generally well tolerated, with an encouraging safety profile observed to date. The Phase I study has two parts that are designed to assess the tolerability of Zylbeth saran during potential augmented pharmacology induced either by a slow salt diet or by co-administration of the conventional Ras inhibitor, Urbicilatase.

We believe these durable pharmacologic effects may support tonic control of blood pressure.

And with a once quarterly and potentially biannual dosing regimen.

And the studies of the best round has been generally well tolerated with and encouraging safety profile observed to date.

The phase 1 study has 2 parts the designed to assess the tolerability of the best of 100 and potential augment of pharmacology inducing EBIT.

The low salt diet or by co administration of the conventional Ras inhibitor of the Santa.

These cohorts of completed dosing with data Readouts expected later this year.

We also recently initiated and our cardio phase II program was the best around.

Akshay K. Vaishnaw: These cohorts have completed dosing, with data readout expected later this year. We have also recently initiated our Cardio Phase 2 program with Zulbasar Abbas. The first of the two studies, CARDIA-1, is designed to evaluate the efficacy and safety of the best rounds of monotherapy in patients with mild to moderate hypertension. In late 2021, we plan on initiating Cardio II, which is designed to evaluate the efficacy and safety of Zilbesaran as an adult treatment in patients with uncontrolled hypertension whilst receiving treatment with standard of care.

The first of the 2 studies of cardio 1 is designed to evaluate the efficacy and safety of the the best friends of the monotherapy in patients with mild to moderate hypertension.

The study is currently enrolling patients in late 2021 and plan on and initiating cardio too which is designed to evaluate the efficacy and safety of the best ran as an add on therapy and patients with uncontrolled hypertension, whilst receiving treatment with standard of care.

Moving on and we're also advancing <unk> and HST and collaboration with our partner Regeneron for the treatment of Nash with.

We believe the R&M mediated knockdown of HST 17, visa team will pheno copied the genetic loss of function findings, reducing hepatic inflammation injury and fibrosis and Nash patients.

Enrollment and dosing continues and the phase 1 study of <unk> and HST, which has now transitioned to dosing and part B with Nash patients.

Akshay K. Vaishnaw: Moving on, we're also advancing LNHSD in collaboration with our partner Regeneron for the treatment of NASH. We believe that RNA-my mediator knockdown of HSD17B13 will phenocopy the genetic loss of function findings reducing hepatic inflammation, injury, and fibrosis in NASH patients. Enrollment and dosing continue in the Phase 1 study of ALN-HSD, which has now transitioned Let's turn briefly to our ALN HPVO2 program, also known as VIIR 2218, in partnership with VIIR.

Let's turn briefly to our <unk> 2 program also known as via 2218 and partnership with fear.

And the annual meeting in June via presented results from a phase II study of <unk> and HBV or 2 showing a positive safety profile and reduction of hepatitis b surface antigen.

When combined with Pegylated interferon Alpha of 12 weeks of more rapid and substantial hepatitis b surface antigen decline was observed and the co administration cohort compared to HBV O 2 alone.

As a reminder.

The <unk> retained the free opt and Ryan to co develop and co commercialize HBO to or to receive milestones and royalties, we considered to be quite attractive.

Akshay K. Vaishnaw: At the EASL meeting in June, VIIR presented results from a Phase II study of LNHPbO2, showing a positive safety profile and reduction of hepatitis B surface action. When combined with peculated interferon alpha for 12 weeks, a more rapid and substantial hepatitis B surfactant antigen decline was observed in the co-administration cohort compared to HPV02 alone.

We also we have also made great progress with our preclinical program and the next the H in development for the treatment of GAAP and.

Plan to file a Cta for this program in late 2021 the.

The significant unmet need from.

For the new treatments to address the current gas tax of very painful and debilitating condition and our scientists pioneered RNA therapeutics from this condition with broad intellectual property protection.

Akshay K. Vaishnaw: As a reminder, Alnylam has retained a free opt-in right to co-develop and co-commercialize HPVO2, or to receive milestones and royalties we consider to be quite attractive. We have also made great progress with our preclinical program, LNxDH, in development for the treatment of gout, and plan to file a CTA for this program in late 2021. Akshay Desai, Weinong Guo, Alnylam Pharmaceuticals Inc. We also continue to make great progress on our many preclinical RNAi therapeutic opportunities beyond the liver. Notably, we continue to advance our CNS and ocular efforts with Regeneron. This includes our ALNAPP program in development for the treatment of autosomal dominant Alzheimer's disease and cerebral amyloid angiopathy.

We also continued to make great progress on our many preclinical and RNA therapeutic option interest beyond the liver.

Notably, we continued to advance our CNS and ocular assets with Regeneron.

Includes our <unk> program in development for the treatment of and the 4 autosomal dominant Alzheimer's disease and cerebral amyloid angiopathy.

We now plan to file a cta for <unk> and ABP late 2021, representing a small shift and our timeline.

Finally, and our press release this morning, we announced our decision to discontinue our islands, the cough or LNC of V program in development for the treatment of COVID-19.

This was a portfolio of decision based on the availability of highly effective vaccines and alternative treatment options for COVID-19.

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

Thanks, Akshay and good morning, everyone I am pleased to be presenting all of the items Q2, 2021 financial results, which reflect another strong quarter of operational excellence across the business.

Turning to our results first from Petro, we generated $113.8 million and net revenue for the quarter, representing 12% growth from the first quarter of 2021, 71% growth compared with Q2.2020.

Jeff Poulton: We now plan to file a CTA for LNAPP in late 2021, representing a small shift in our timeline. Finally, in our press release this morning, we announced our decision to discontinue our LNCOV or LNCOV-based program in development for the treatment of COVID-19. This was a portfolio decision based on the availability of highly effective vaccines and alternative treatment options for COVID-19. With that said, let me now turn it over to Jeff to review our financial results. Jeff.

This marks the fourth consecutive quarter of double digit quarter on quarter growth following 1 quarter of flat and growth that we experienced during the onset of the pandemic and Q2 of last year.

U S. Non petro sales increased 6% versus Q1, 2021 and were primarily impacted by the following and.

Jeff Poulton: Thanks, Akshay. Good morning, everyone. I'm pleased to be presenting Alnylam's Q2 2021 financial results, which reflect another strong quarter of operational excellence across the business. Turning to our results first for Onpatro, we generated $113.8 million in net revenue for the quarter, representing 12% growth from the first quarter of 2021 and 71% growth compared with Q2 2020. This marks the fourth consecutive quarter of double-digit quarterly-on-quarter growth following one quarter of flattened growth that we experienced during the onset of the pandemic in Q2 of last year.

The approximate 12% increase and demand representing an acceleration from the 4% demand growth delivered in Q1 with the increase driven by the addition of new patients on therapy and continuation of greater than 90% patient treatment compliance.

The main growth was offset by a higher level of gross to net deductions and less inventory stocking and the quarter compared with Q1.2021.

And our international markets on Patrick performance remains very strong with growth of 17% versus Q1, and 2021, 79% versus Q2, 2020, primarily driven by increased patient demand broadly across our markets in Europe and Canada.

Sales from our international markets comprised 54% of our global total and Q2, clearly, reflecting the benefit of our global commercial footprint.

Jeff Poulton: U.S. Nompatra sales increased 6% versus Q1 2021 and were primarily impacted by the following. An approximate 12% increase in demand, representing an acceleration from the 4% demand growth delivered in Q1, with the increase driven by the addition of new patients on therapy and continuation of greater than 90% patient treatment compliance. Demand growth was offset by a higher level of gross to net deduction and less inventory stocking in the quarter compared with Q1 2021.

Turning to our results for good Laurie we generated $30.6 million and net revenue in Q2, representing 24% growth compared to the first quarter of 2021, driven by ongoing launches and the U S and Europe.

<unk> results and the U S and particular improved during the quarter where quarter.

Quarter on quarter growth of 26% compared to 6% quarter on quarter growth and Q1.

We benefited from improved patient flow through the U S health care system.

Jeff Poulton: In our international markets, Onpatria performance remained very strong with growth of 17% versus Q1 2021 and 79% versus Q2 2020, primarily driven by increased patient demand broadly across our markets in Europe and Canada. Sales from our international markets comprised 54% of our global total in Q2, clearly reflecting the benefit of our global commercial footprint.

Without the <unk>, we had an excellent second full quarter of sales generally generating $16.3 million and net revenue and the quarter up from $9.1 million and Q1 with growth contributions from both U S and rest of world markets.

Turning now to the summary of our full P&L results for the quarter.

Total combined product sales and the second quarter were $168 million, representing 107% growth versus Q2.2020.

Net revenue from collaborations for the quarter was $59.4 million the significant increase from Q2 last year, primarily due to revenue recognized from our regeneron collaboration.

Jeff Poulton: Turning to our results for Giblari, we generated $30.6 million in net revenue in Q2, representing 24% growth compared to the first quarter of 2021, driven by ongoing launches in the U.S. and Europe. Reported results in the U.S., in particular, improved during the quarter, with quarter-on-quarter growth of 26% compared to 6% quarter-on-quarter growth in Q1, as we benefited from improved patient flow through the With Axolumo, we had an excellent second full quarter of sales, generating $16.3 million in net revenue in the quarter, up from $9.1 million in Q1, with growth contributions from both U.S. and rest of the world markets.

We recognized <unk> 3 million and royalty revenues during the quarter, representing our initial recognition of royalties earned on Novartis of sales of <unk>.

Gross margin on total revenues was 82, 4% for the quarter of slight improvement from prior year.

The combined non-GAAP R&D and SG&A expenses for the quarter increased 19% versus Q2.2020 heat.

Key drivers of the increased continue to be additional R&D investment and advancing our late stage pipeline programs and increased SG&A investments to support our free commercial brands, including the launch of <unk>.

Jeff Poulton: Turning now to a summary of our full P&L results for the quarter. Total combined product sales in the second quarter were $160.8 million, representing 107% growth versus Q2 2020. Net revenue from collaborations for the quarter was $59.4 million, a significant increase from Q2 of last year, primarily due to revenue recognized from our Regeneron collaboration. We recognized $0.3 million in royalty revenues during the quarter, representing our initial recognition of royalties earned on Novartis' sales of Lectvio. Gross margin on total revenues was 82.4% for the quarter, a slight improvement from the prior year.

Also recall that last year and Q2 operating expenses were at the lowest quarterly level in 2020 and were impacted by the onset of the pandemic.

Our non-GAAP operating loss for the quarter decreased by approximately $51 million versus the same period, and 2020, driven by strong topline growth and more moderate growth and operating expenses.

Q2 also represents the sixth consecutive quarter that we've delivered and improvement in our non-GAAP operating loss and.

And we believe this clearly signals and the path we're on towards profitability.

Cash cash equivalents in marketable securities were $1.9 billion as of June 30 of 2021 compared to $1.87 billion as of December 30 of 2020 with the increase primarily due to the second drawdown of our credit facility with Blackstone, which occurred during Q2 and cash received from the.

Jeff Poulton: Combined non-GAAP R&D and SG&A expenses for the quarter increased 19% versus Q2 2020. Key drivers of the increase continue to be additional R&D investment in advancing our late stage pipeline program and increased SG&A investment to support our three commercial brands, including the launch of OxyLuna. Also recall that last year in Q2, operating expenses were at the lowest quarterly level in 2020 and were impacted by the onset of the pandemic. Our non-GAAP operating loss for the quarter decreased by approximately $51 million versus the same period in 2019, driven by strong top-line growth and more moderate growth in operating expenses.

The exercise of employee equity awards and purchases of shares under our employee stock purchase plan offset by cash used in our operations to support overall growth.

Lastly, turning to our financial guidance, we believe our results for the second quarter continued to demonstrate successful commercial execution.

As a result of the strength of our first half 2021 results. We are increasing our full year 2021, combined net product revenue guidance from $610 million to $660 million to $640 to $665 million.

Jeff Poulton: Q2 also represents the sixth consecutive quarter that we've delivered an improvement in our non-GAAP operating income, and we believe this clearly signals the path we're on towards profitability. Cash, cash equivalents, and marketable securities were $1.9 billion as of June 30, 2021, compared to $1.87 billion as of December 30, 2020, with the increase primarily due to the second drawdown of our credit facility with Blackstone, which occurred during Q2, and cash received from the exercise of employee equity awards and purchases of shares under our employee stock purchase plan, offset by cash used in our operations to support overall growth.

Representing a 3% increase from the midpoint of the prior range to the midpoint of the new range.

Our guidance for net revenue from collaborations and royalties and for combined non-GAAP R&D and SG&A expenses remain unchanged with that I'll now turn the call over to Yvonne to review our upcoming milestones the van.

John.

Thanks, Jeff and Hello, everyone.

Let me start by review and exciting partnership we announced with Patchy Dream.

The dream is an industry leader and the discovery and optimization of peptide like guidance against the wide variety of the sepsis true. This collaboration we and perhaps the dream will discover and develop peptides.

Jeff Poulton: Lastly, turning to our financial guidance, we believe our results for the second quarter continue to demonstrate successful commercial execution. As a result of the strength of our first half 2021 results, we are increasing our full year 2021 combined net product revenue guidance from $610 to $660 million to $640 to $665 million, representing a 3% increase from the midpoint of the prior range to the midpoint of the new range. Guidance for Net Revenue from Collaborations in Royalty, and combined non-GAAP R&D and SG&A expenses remain unchanged. With that, I'll now turn the call over to Yvonne to review our upcoming milestones. Yvonne?

And a conjugate to create multiple opportunities to deliver and high therapeutics the tissues outside the liver.

The collaboration has the potential to yield multiple treatment opportunities by targeting disease, causing and RNA transcripts and a wide variety of tissue types.

Let me know tons of review of remaining goals for 2021, the <unk> within our TCR programs. We plan to percent 18 months topline results from the Helios a phase III study with the tree surround.

We also plan additional regulatory submissions with the chiefs are and in the EU, Japan, and Brazil and late 2021.

Based on the excellent progress and enrollment we also plan to complete enrollment and <unk> in the coming weeks has to be announced today.

Yvonne L. Greenstreet: Thanks, Jeff, and hello, everyone. Let me start by reviewing an exciting partnership we announced with Peptidry. Peptidream is an industry leader in the discovery and optimization of peptide ligands against a wide variety of receptors. Through this collaboration, we and Peptidream will discover and develop peptide siRNA containers, which creates multiple opportunities to deliver RNI therapeutics to tissues outside the liver. The collaboration has the potential to yield multiple treatment opportunities by targeting disease-causing mRNA transcripts in a wide variety of tissue types.

Without the surround and actually mentioned we plan to present additional data from the phase..1 study later this year hopefully at the American Heart meeting in November pending abstract acceptance and plan to initiate the cardiac phase II combination study later this year as well.

So the Max ran and we plan to initiate the phase II studies of renal stood and events in late 2021, we.

We believe this phase II study represents meaningful lifecycle management of Oxy, and then with the potential to significantly expand the overall opportunity.

Yvonne L. Greenstreet: Let me now turn to a review of remaining goals for 2021. For starters, within our TTR programs, we plan to present 18-month top-line results from the HeVS-A Phase 3 study with Guthrie Stringer. We also plan additional regulatory activities for Patrice Ryan and the EU, Japan, and Brazil in late 2021.

We also plan to submit supplemental regulatory applications and both the U S and EU based on the illuminate C results.

With <unk> and HFC, we expect to report initial safety results of healthy volunteers from the phase 1 study.

Turning to SMT surround the complement mediated diseases, a ton of regeneron and plans to initiate a phase III study of SMT surround and present, the map combination and myasthenia Gravis and addition to multiple phase II studies and Pn H.

Yvonne L. Greenstreet: Based on the excellent progress in enrollment, we also plan to complete enrollment in Helios B in the coming weeks, as we announced today. With Zalbisaran, as Akshay mentioned, we plan to present additional data from the Phase I study later this year, hopefully at the American Heart Meeting in November, pending abstract acceptance. We plan to initiate the Cardia II Phase II Combination Study later this year as well. For Lumasharan, we plan to initiate a Phase II study for renal stone events in late 2021.

We believe the combination of SMT strength and does that the <unk> represents an attractive therapeutic strategy to complement mediated diseases.

We're very excited to file our first CNS Cta for AI and AEP now expected in late 2021 and development for the treatment of autosomal dominant outside of this disease.

Yvonne L. Greenstreet: We believe this Phase 2 study represents meaningful life-cycle management of oxalumone with the potential to significantly expand the overall opportunity. We also plan to submit supplemental regulatory applications in both the US and EU based on the Illuminate C results. With ALNHSC, we expect to report initial safety results in healthy volunteers from the Phase 1 study. Planning to Semdiceran for complement-mediated diseases, our partner Regeneron plans to initiate a Phase III study of Semdiceran and Pazilumab combination in Myasthenia gravis, in addition to multiple Phase II studies in PNH. We believe the combination of Sanvisaran and Pozolimab represents an attractive therapeutic strategy to complement mediated diseases.

And cerebral amyloid angiopathy.

This sets us up the potential initial POC data in 2022.

And given the exciting preclinical programs, we plan to advance and ex the H in development for the treatment of gout toward of CCA, finding and late 2021 net.

And we now turn it back to Christine to coordinate our Q&A session Christine.

Thank you Yvonne operator, we will now open the call for question the style.

And I'd like to ask of the limit yourself to 1 question and allow the backlog that you have.

And there's no question.

Ladies and gentlemen, the feel of a question of our Combi and at this time. Please press Star then the 1 key on your Touchtone telephone. If your question has been answered or you wish to move yourself from the queue. Please press the pound key.

Yvonne L. Greenstreet: We're very excited to file our first ENS CTA for AI and APP, now expected in late 2021, in development for the treatment of autosomal-dominant Alzheimer's, called Cerebral Amyloid Anxiety. This sets us up for potential initial POC data in 2022. And given the exciting preclinical progress, we plan to advance ALMxCH in development for the treatment of gout toward a CTA filing in late 2021. I will now turn it back to Christine to coordinate our Q&A session. Christine

Question comes from Gena Wang of Barclays.

Thank you for taking my question and also congrats on the very strong quarter.

So I have the 1 big picture question.

All of us being very successful as a Standalone company.

Stablish platform.

Prove the drugs and also of numerous high quality pipeline assets. So just wondering going forward are you willing to be under a bigger umbrella or do you want to continue being a standalone company and to grow and to top 5 biotech companies.

John.

Hi, Hi, Gena.

Thank you first of all for your comments on the quarter.

Christine Regan Lindenboom: Thank you, Yvonne. Operator, we will now open the call for 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.

And thank you for your comments on what we've been able to achieve as a company and.

And I think it's fair to say that debt. We believed that we have a path forward as the company to build significant value.

Operator: Ladies and gentlemen, if you have a question or a comment at this time, please press the star and then the 1 key on your touchtone telephone. If your question has been answered or you wish to move yourself from the queue, please press the pound key. Our first question comes from Gena Wang of Barclays.

It's very evident of the piece of the pit by 'twenty 5.5 year goals and plans that we outlined earlier this year as to how we believe that we can build a top 5 biotech company in market cap over the next 5 year period by execution with our organic product engine and our capabilities to achieve sustainable innovation.

Gena Wang: Thank you for taking my question and also congratulations on a very strong quarter. So I have one big picture question. Alnylam has been very successful as a standalone company with an established platform, several approved drugs, and also numerous high-quality pipeline assets. So just wondering, going forward, are you willing to be under a bigger umbrella or do you want to continue being a standalone company and grow into the top five biotech companies as your goal?

So it is certainly our plan to continue on that path, but of course, we have of fiduciary duty to shareholders and obviously, we'll always consider that component of how we have an obligation to our shareholders, but our plans right now we're very focused on our piece of the fit by 'twenty 5 goals and our abilities to.

Execute.

<unk> on debt sustainable source of innovation. So that's how we're focused right now.

John Merganori: Hi Gena. Thank you, first of all, for your comments on the quarter. And thank you for your comments on what we've been able to achieve as a company. And I think it's fair to say that we believe that we have a path forward as a company to build significant value. It's very evident in the P to the fifth by 25 five-year goals and plans that we outlined earlier this year as to how we believe that we can build a top five biotech company in market cap over the next five years by execution with our organic product engine and our capabilities to achieve sustainable innovation.

Thank you.

Thank you.

Our next question comes from Alicia Young with Cantor Fitzgerald.

Hey, guys. Thanks for taking my questions guys cost of this quarter.

I guess I wanted to like it's another kind of big picture, but just wanted to talk a little bit about as you start to do bigger programs like and hypertension and even once beyond as you build out your business like how do you kind of think about the balancing act of making that investment and kind of the commitment the profitability because I mean some of these programs are pretty big opportunities. So I know I just wanted to get a flavor of when you go out of the alone or do you think.

These are opportunities for potential partnerships.

John Merganori: So it's certainly our plan to continue on that path. But, of course, you know, we have a fiduciary duty to shareholders. And, obviously, we'll always consider that component of how we have an obligation to our shareholders. But our plans right now are very focused on our P to the fifth by 25 goals and our abilities to execute continuously on that sustainable source of innovation.

Yeah, well first of all thanks, Alicia for the for the comments from the quarter. We're really pleased with the results, obviously and Thats the real credit to our our overall organization for delivery as they did.

We're very excited about the opportunities for <unk> therapeutics and more prevalent diseases I think of the data with Dolby surround.

Really points to the ability to re imagine the treatment of hypertension, a leading cause of cardiovascular morbidity and mortality around the world. So I mean, how and how can you and not get excited about transformational medicines that can.

John Merganori: So that's how we're focused, Gena. Thank you. Thank you. Our next question comes from Alifea Young with Cancerfish Geralds.

That can make a fundamental impact on <unk>.

Alifea Young: Hey guys, thanks for taking my question. You guys crushed it this quarter.

A major issue of public health.

Alifea Young: I guess, I wanted, it's another kind of big picture, but just wanted to talk a little bit about as you start to do bigger programs, like in hypertension, and even ones beyond as you build out your business, like, how do you kind of think about the balancing act of, you know, making that investment and kind of the commitment to profitability, because I mean, some of these programs are pretty big opportunities. So I know, I just wanted to kind of get a flavor. Would you go at it alone, or do you think that these are opportunities for potential partnership things? Yeah,

Globally with the potential obviously over time to help many many people. So we're very excited about that direction. There is really no reason why we arent able to advance these assets on our own.

We have a great team, we have a proven track record of execution on the R&D side and there is simply no reason why we have any need for capabilities or even funding from third party partners, but obviously, we also want to make sure that we navigate our path toward a sustainable and ultimately profitable.

And of responsible manner. So we are very thoughtful about how we balance our opex investments along with the the growth of our revenues toward of toward the.

John Merganori: Yeah. Well, first of all, thanks, Alicia, for the comments on the quarter. We're really pleased with the results, obviously, and it's a real credit to our overall organization for delivering as they did. Look, we're very excited about the opportunities for RNAi therapeutics in more prevalent diseases. I think the data with Delfisiran really points to the ability to reimagine the treatment of hypertension, a leading cause of cardiovascular morbidity and mortality around the world.

Sustainable financially sustainable self sustainable profile and so that is a core part of our strategy. Let me with those intros, Let me first start with Jeff and then transfer over to of on the comment a little bit more about are sort of going forward views, but Jeff do you want to talk first of all of the financials and then the bond of little bit about our prospectus.

John Merganori: So, I mean, how can you not get excited about transformational medicines that can make a fundamental impact on a major issue of public health globally with the potential, obviously, over time, to help many, many people? So we're very excited about that direction. There is really no reason why we shouldn't be able to advance these assets on our own. We have a great team.

On growth and the prevalent disease markets.

Yes.

I think I agree with everything he said, John and 1 of the metrics and our piece of the fifth by 'twenty 5 goals as getting to profitability across the periods and we're committed to doing that I think the 1 other comment that I would make as it relates to sort of be saran.

And is from a commercial standpoint, our hope is that we'll be able to leverage.

John Merganori: We have a proven track record of execution on the R&D side, and there's simply no reason why we have any need for capabilities or even funding from third-party partners. But obviously, we also want to make sure that we navigate our path toward a sustainable and ultimately profitable business in a responsible manner. So we are very thoughtful about how we balance our OpEx investments along with the growth in our revenues toward a sustainable, financially sustainable, self-sustainable profile.

The infrastructure that hopefully we will have built by them from a perspective of supporting the expansion of the TCR franchise.

And we're successful and the Apollo B Helios B studies to get into a larger sort of cardiomyopathy footprint.

1 factor as well.

And of volume do you want to comment a little bit more strategically going forward, how we think of it.

No I think actually both of you have covered this wow.

We believe we're a unique company.

And we have every intention of building a top 5 bonczek.

John Merganori: And so that is a core part of our strategy. Let me, with those introductions, first start with Jeff and then transfer over to Yvonne to comment a little bit more about our sort of going forward views. But Jeff, do you want to talk first about the financials and then Yvonne a little bit about our perspectives on growth in the prevalent disease market? Yeah, I think I agree with everything you said, John.

And we have every intention of progressing and all of our opportunities obviously in a thoughtful and and thoughtful fashion.

Thank you of awesome. Thank you and answer your question of Lithia GAAP Yeah. It was great. Thank you guys.

Great. Thank you.

Our next question comes from Joseph Stringer with Needham <unk> Company.

John Merganori: And one of the metrics in our P to the fifth by 25 goals is getting to profitability across the period. And we're committed to doing that. I think that the one other comment that I would make as it relates to Zabi Saran is, from a commercial standpoint, our hope is that we'll be able to leverage the infrastructure that, hopefully, we will have built by then from a perspective of supporting an expansion of the TTR franchise if we're successful in the Apollo B and Helios B studies to get into a larger sort of cardiomyopathy footprint. So that's one factor And Yvonne, do you want to comment a little bit more strategically on how we think of this going forward?

Hi, Josef I can't hear you are you on mute.

And Joseph Your line is open and you can ask your question.

Maybe we should go to the next question Okay.

Our next question comes from Maury Raycroft of Jefferies.

Good morning, everyone and congrats on the quarter and thanks for taking my question.

I was wondering if you can.

I was wondering if you can talk about the parallels between <unk> and and closer and that investors should be thinking about and is there anything additional you can say about the cardio to design, including whether it's going to be dosing every 3 months of 6 months and lastly, if you can provide any perspective into what timeline school of like for both cardio 1 and 2.

Fantastic.

Let me start my comments and then maybe Akshay you can you can.

Chime in here on some more of the specifics on the Carty of program and the dosing regimen.

Jeff Poulton: No, I think actually...

Akshay Desai: Akshay Desai, Weinong Guo, Alnylam Pharmaceuticals Inc.

For starters I mean look we're very again very excited about all of the surround and its potential to re imagine the treatment of hypertension, and you're and you're very right Morey to point to the analogy with increase of rent because.

Akshay Desai: and we have every intention of progressing all of our opportunities, obviously in a thoughtful fashion. Thank you, Yvonne. Awesome, thank you very much. Does that answer your question, Alethia? Yeah. Yeah, it was great.

Both.

Rnas are designed to address very credible very prevalent diseases, 1 is and hypercholesterolemia with the increase around the other and hypertension with Dolby surround and both of course enable a very infrequent dose regimen to control these leading.

Yvonne L. Greenstreet: Yeah, it was great. Thank you, guys. Great, thank you.

Joseph Robert Stringer: Our next question comes from Joseph Stringer with Medium & Company. Hi Joseph, I can't hear you, are you on mute? Again, Joe, if your line is open, you can ask your question. Maybe we should go to the next one.

Causes of morbidity and mortality, both and both cases, right with HDL and LDL and I'd say from a development programs cash flow, which track the strategically about both both efforts is that the biomarker or the clinical marker that we're measuring and our phase 1 studies and our phase II studies of the cases all of the surround blood pressure.

Operator: Q&A: Our next question comes from Maury Raycroft with Jeff. Hi, good morning, everyone. Congratulations on the quarter.

Maury Raycroft: And thanks for taking my question. I was wondering if you could talk about the parallels between Zalbicerin and Inclisirin that investors should be thinking about and is there anything additional you could say about the Cardio II design, including whether it's going to be dosing every three months or six months and, lastly, if you can provide any perspective into what timelines could look like for both Cardio I and II.

And of the case of of increased rent LDL cholesterol and those of the exact same endpoints that will be used in our phase III trials in support of and approval and so it is attractive that we have completely de risked the primary endpoint of what will ultimately be of phase III study.

Thats all of the surround and Thats, a very analogous situation to what we had with the police surround and the setting of hypercholesterolemia, so very attractive.

Maury Raycroft: Let me start my comments and then maybe, Akshay, you can chime in here on some more of the specifics on the CARDIA program and the dosing regimen. You know, for starters, I mean, look, we're very, again, very excited about Salve Ceran and its potential to reimagine the treatment of hypertension. And you're very right, Maury, to point to the analogy with Incliseran because, you know, both SRNAs are designed to address both very prevalent diseases.

The profile and of course, we're very very encouraged by the safety profile that we saw with within <unk> and thousands of patients that were studied and we're obviously aiming to achieve.

And similar results with Dolby surround as we do further studies with that with that agent.

At the highest strategic level that is those those are some of the reasons why theres a lot of analogies between increase rent and Dolby surround so with that Akshay, maybe you can talk a little bit of a bit more of the cardiac program. Some of the timelines there as well as some of the dosing approaches Q3 months of your CUSIP lovely.

Maury Raycroft: One is in hypercholesterolemia with Incliseran, and the other in hypertension with Salve Ceran. And both, of course, enable a very infrequent dose regimen to control these, you know, leading causes of CV, morbidity, and mortality, in both cases, right, with HDL and LDL. I'd say from a development program standpoint, what's attractive strategically about both efforts is that the biomarker or the clinical marker that we're measuring in our phase one studies and our phase two studies, in the cases of Salve Ceran blood pressure and in the case of Incliseran LDL cholesterol, those are the exact same endpoints that will be used in our phase three trials in support of an approval.

Akshay take it away.

Yes, Thanks John.

So.

As all of this round, we will execute 2 phase III studies cardio 1 is.

He is looking at resolve this around and.

As a monotherapy in patients with multiple hundred hypertension.

About just shy of 400 patients 275, or so and that study or the.

The docs randomized controlled study.

And that will be called blip that studies up and running that we complemented by cardio too which will kick off.

Maury Raycroft: And so it is attractive that we have completely derisked the primary endpoint of what will ultimately be a phase three study with Salve Ceran. And that's a very analogous situation to what we had with Incliseran in the setting of hypercholesterolemia. So, a very attractive profile.

In the months to come later this year.

And there we will evaluate and cardio to the combination of subtleties around with other antihypertensive medications and of course that will include Ras inhibitors calcium channel blockers diuretics and of more details to come.

Study will be larger.

About 650 patients or so.

John Merganori: And of course, you know, we're very, very encouraged by the safety profile that we saw with Incliseran and thousands of patients that were studied. And we're obviously aiming to achieve a similar result with Salve Ceran as we do further studies with that agent. So at a high strategic level, those are some of the reasons why there's a lot of analogies between Incliseran and Salve Ceran. So with that, Akshay, maybe you could talk a little bit more about the CARDIA program, some of the timelines there, as well as some of the dosing approaches, Q3 monthly or Q6 monthly. So Akshay, take it away.

We're not guiding right now through the exact.

The completion date of both studies and then just getting going as well as I said.

And more details to come later in the year as recruitment ramps up but this is hypertension. So we're anticipating enrollment will go relatively quickly.

And so we're looking forward to and exciting outcome building on the very promising data from the phase 1 the <unk>.

John has already commented on.

With the reference to dose and regimen and there'll be a spectrum of doses evaluated again and more details to follow.

But I can reiterate that we'll be looking at both 3 and 6 monthly dosing regimens and these studies.

John Merganori: Yeah, thanks, John. So, Maury, Zalbisaran will conduct two phase two studies. Cardio One is looking at Zalbisaran as a monotherapy in patients with multi-moderate hypertension. About just shy of 400 patients, 375 or so in that study, an orthodox randomized control study. That study is up and running, and it will be complemented by Cardio Two, which will kick off in the months to come later this year. And there, we'll evaluate in Cardio Two the combination of Zalbisaran with other antihypertensive medications, and of course, that will include RAS inhibitors, calcium channel blockers, and diuretics.

And so we'll have a comprehensive look at the pharmacology of the drugs and put us in the good position to select the right dose.

And sort of further development of the phase III. So I hope that's helpful.

Very helpful. Thanks for taking my questions.

Thanks Laurie.

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

Good morning, Thanks for taking my question just given your agreement with Pepsi Dream could you just talk about extra hepatic targets that you're.

Our tissues that youre looking to target beyond CNS.

Yeah. Thanks Alvin.

Let me, let me start and then I'll hand, it over to Akshay to talk a little bit further we're obviously very excited about the agreement that we formed last week with packet Dream as Ivan said in her remarks, but the dream is really.

Akshay K. Vaishnaw: We have more details to come. That study will be larger. About 650 patients or so. You know, we're not guiding right now as to the exact completion date of both studies. They're just getting going, as I said, and more details will come later in the year as recruitment ramps up. But you know, this is hypertension, so we're anticipating enrollment will go relatively quickly. And so we're looking forward to an exciting outcome building on the very promising data from phase one that John has already commented on.

Really a leading company and peptide.

<unk>.

Design and and.

Synthesis, and obviously working with them as part of our continued investment in extra hepatic delivery, where we've already been very successful and CNS and ocular. So we're very excited about that so akshay do you want to talk a little bit about how we look at the future of extra hepatic delivery and.

Akshay K. Vaishnaw: With reference to dose and regimen, you know, there will be a spectrum of doses evaluated. Again, more details to follow. But I can reiterate that we'll be looking at both three and six months' dosing regimens in these studies, so we'll have a comprehensive look at the pharmacology of the drugs and put us in a good position to select the right dose and regimen for further development in phase three. So I hope that's helpful. Very helpful indeed. Thanks for taking my question. Thanks, Maury. Our next question comes from Salveen Richter of Goldman Sachs.

And tissues of interest.

Yes.

And then of course, we're interested in in a range of organs for several reasons 1 is the of.

And I.

As of Pharmacologic.

Activity can be conducted and any tissue and and you sell and the body. So we can take and that's RNA to any cell type.

And I expect to see target and locked down and we can say that with confidence.

And if you combine that with the possibility that some of the genetically validated and pharmacologically validated targets and many many different tissues, we've got broader ambitions with pep to dream beyond the liver. So of course, we already in the CNS and eye.

Salveen Richter: Good morning, thanks for taking my question. Just given your agreement with PeptiDream, could you just talk about extrahepatic targets that you're looking to target beyond the CNS? Yeah, thanks Salveen.

John Merganori: Yeah, thanks, Salveen. Let me start, and then I'll hand it over to Akshay to talk a little bit further. We're obviously very excited about the agreement that we formed last week with Peptidream. As Yvonne said in her remarks, Peptidream is really a leading company in peptide design and synthesis. And obviously, working with them is part of our continued investment in extrahepatic delivery, where we've already been very successful in CNS and Ocular.

And the.

We have several options there in terms of the kind of the conjugate is we've built and shall.

We can add to those with Pep to dream, and then there'll be new tissues, you'll be hearing about.

From us.

But you can remain confident that this collaboration is being conducted to really maintain and extend our leadership position of RNA.

And we believe.

By the end of the decade, both the RNA and many many different tissues beyond the liver and the.

John Merganori: So we're very excited about that. So Akshay, do you want to talk a little bit about how we look at the future of extrahepatic delivery and tissues of interest? Yeah, first of all, you know, of course, we're interested in a range of organs, but for several reasons. One is that RNAi, as a pharmacologic activity, can be conducted in any tissue or cell in the body. So we can take an sRNA to any cell type and expect to see target knockdown. And we can say that with confidence.

Approved programs associated with.

Thank you.

Thanks Sylvain.

Our next question comes from Paul Matteis of Stifel.

Great. Thanks, so much.

Was wondering if you could give any comments on the expansion of the exact share all and if theres any sort of baxter or any of that or any relationship to the prior and.

Petro and.

Investigation that was announced earlier this year and in terms of marketing and then just 1 question on Apollo B.

What do you assume for the number of events and that study in terms of mortality and hospitalization and do you think that Theres a chance to show at least some sort of convincing numerical difference versus placebo. Thanks. So much.

Akshay K. Vaishnaw: And if you combine that with the possibility that there are genetically validated and pharmacologically validated targets in many, many different tissues, we've got broader ambitions with peptidrome beyond the liver. So, of course, we're already in the CNSNI. We have several options there in terms of the kinds of conjugates we've built. I'm sure we can add to those with peptides. And then there'll be new tissues you'll be hearing about from us. But you can remain confident that, you know, this collaboration has been conducted to really maintain and extend our leadership position in RNAi, and we believe that, you know, by the end of the decade, we'll see RNAi in many, many different tissues beyond the liver, and approved programs associated with that. Thank you. Thanks, Salveen. Our next question comes from Paul Matteis on Stieglitz.

Well I'll take the first part call and then Akshay you should obviously address the Apollo B thing.

So, yes, we announced this morning the.

The appointment of Mike Bonnie and an expanded role he has obviously been our chairman but.

We've now expanded his role as the executive chair of the company and this is really to help us continue and further strengthen our overall ethics and compliance function within the company and area that we're extremely committed to.

Having having a high quality best in class type of.

And of organization and its integration within the business. So that's what we've done Michael and extremely experienced commercial leader.

Paul Matteis: Great, thanks so much. I was wondering if you could give any comments on the expansion of the exec chair.

Paul Matteis: and if there's any sort of backstory to that or any relationship to the prior on the Patro investigation that was announced earlier this year in terms of marketing and then just one question on Apollo B, what do you assume for the number of events in that study in terms of mortality and hospitalization, and do you think that there's a chance to show at least some sort of convincing numerical difference versus placebo? Thanks so much.

I've worked with Mike and for many many years.

No.

Obviously extremely well and so we welcome him in this new governance role in a way that really is aimed to help us continue to be the best company, we can possibly be across every dimension of what we do and Mike brings a lot of experience to that side of it. So akshay do you want to handle the Apollo b.

<unk>.

John Merganori: Well, I'll take the first part, Paul, and then Akshay, you should obviously address the Apollo B thing. So yes, we announced this morning the appointment of Mike Bonney in an expanded role. He's obviously been our chairman, but we've now expanded his role as the executive chairman of the company. And this is really to help us continue and further strengthen our overall ethics and compliance function within the company, an area that we're extremely committed to having a high quality, best-in-class type of organization and its integration within the business. So that's what we did.

Yes, Paul.

I think.

It's clear to everybody and the primary endpoint 6 minute walk distance and Thats, how we powered the study from the beginning it's the most efficient way to show potentially the benefit of <unk>.

The surround the.

<unk> kind of modestly population and so we're looking forward to that result of the middle of next year. The studies fully enrolled of course.

And that's exciting and vis vis the specifics of mortality and hospitalization study wasn't powered around that.

And we look forward to seeing those data it's hard to tell right now of course because of the study is blinded and so forth.

John Merganori: Mike is an extremely experienced commercial leader. I have worked with him for many, many years, and I obviously know him very well. And so we welcome him in this new governance role in a way that really is just aimed to help us continue to be the best company we can possibly be across every dimension of what we do. And Mike brings a lot of experience to that side of it.

The comment on the exact nature of those.

The data and what we will see we hope to see a trend, but that's something we'll have to wait for next year.

Fair enough and does that answer your question, yes, Thanks, Matt absolutely. Thanks.

Our next question comes from Rich, who borrow with Cowen.

Hi, guys. Thanks for taking the question.

Akshay K. Vaishnaw: So Akshay, do you want to handle the Apollo B question? Yeah, Paul, I think it's clear to everybody, the primary endpoint is the six-minute walk distance, and that's how we powered the study. From the beginning, it's the most efficient way to show potentially the benefit of patisserin in the ATTR cardiomyopathy population. So we're looking forward to that result in the middle of next year when the study is fully enrolled, of course. And that's exciting.

Given the given the rapid.

Timelines for Helios, B, especially relative to Apollo b versus initial expectations.

John what are your.

Current thoughts on a potential interim.

Continue to be a point of.

Akshay K. Vaishnaw: Now, vis-a-vis the specifics of mortality and hospitalization, the study wasn't powered around that. And, you know, we look forward to seeing those data. But it's hard to tell right now, of course, because the study was blinded and so forth, to comment on the exact nature of those. [inaudible] Fair enough. Does that answer your questions? Yeah, thanks. Our next question comes from Ritu Baral of

Client conversations and also of the safety from.

And to the whole.

Breakeven.

Breakeven question and then a very quick follow up for tender and Jeff.

Q2 was great but.

Currently since we can't have nice things.

The Delta area and is going to be hitting Q3, what are you seeing so far and what might be impacting the bar.

Okay. That's great. Let me, let me start with the IAA that we'll Akshay you may want to comment on the IAA. After that and then we'll go to the toga on your question for Delta variant and.

Ritu Baral: Hi guys, thanks for taking the question.

Ritu Baral: Given the rapid timelines for Helios B, especially relative to Apollo B versus initial expectations, John, what are your, I guess, current thoughts on a potential interim? It's continued to be a point of client conversations and also, obviously, feeds into the whole break-even question. And then a very quick follow-up for Tenga and Jeff. Q2 was great, but apparently, since we can't have nice things, the Delta variant is going to be hitting Q3. What are you seeing so far and what might the impact be there? Thanks. Okay.

Perspectives on Q3, we obviously arent going to foreshadow Q3, but we can give you some.

<unk>.

From a from a or at least our view so regarding regarding the interim analysis with 2 what do we designed Helios B we included the and.

The alignment of both the FDA and the EMA. We included the ability to do an interim analysis that was not at that time specified.

Because we wanted to have more time and the study to basically understand how and what type of interim analysis, we might do we continue to believe that and interim analysis could be useful and the study, but obviously, we have the beautiful benefit of the Apollo B readout that will occur.

John Merganori: Okay, that's great. Let me start with the IA, then we'll, Akshay, you may want to comment on the IA after that, and then we'll go to Tolga on your question about the Delta variant and, you know, perspectives on Q3. We obviously aren't going to foreshadow Q3, but we can give you some sense of what we think from at least our view. So regarding the interim analysis, Ritu, when we designed Helios B, we included the ability to do an interim analysis that was not at that time specified, and the next slide is a summary of the study that we did in 2016. We wanted to have more time in the study to understand what type of analysis we might do.

So this time next year that will give us line of sight on.

Mortality and CV events that are happening and that study and the wisdom and any trends that we might see and the wisdom of doing the earlier interim analysis and Helios b.

As it relates to that study now it's extremely good debt. We also have.

Killed it on the enrollment of Helios B as of the as it relates to the study and the fact that.

The ultimate and and.

The date of that study has now been accelerated significantly. So obviously all of these things will factor into our decision, but that decision, which includes regulatory alignment of course won't be really happening until next year akshay anything to add to the IAA.

John Merganori: We continue to believe that an earlier interim analysis as it relates to that study would be extremely good. It is extremely good that we have killed enrollment as it relates to the study and the fact that the ultimate ending data has been accelerated significantly. That decision will not be happening until next year.

The side of things nothing you've kept the John.

Okay terrific and so let's now go to the toga the comments a little bit on his perspectives on Q3 as it relates to the Delta variant toga.

Akshay K. Vaishnaw: Akshay, anything to add to the IA side of things? Okay, terrific. And so now we go to Tolga to comment a little bit on his perspectives on Q3 as it relates to the Delta variant. Okay, Tolga?

Absolutely.

Thank you for that question look I mean, we obviously as an organization and learned a lot and build a lot of capabilities that includes all of them.

Tolga Tanguler: Yeah, absolutely. Thank you for that question. Look, I mean, we obviously as an organization learned a lot and built a lot of capabilities that include alternative types of care, home care when it's possible, and how we've been able to continue to engage with physicians and other important customers. And that will stay with us regardless of where the Delta variant is going. So we clearly were able to take advantage of the healthcare systems opening up, and that has obviously been reflected in our ability to inform and communicate with our key stakeholders. In the near term, we don't anticipate a significant impact given the success of the vaccine.

The terms of sites of care homecare, when it's possible and how we been able to continue to engage.

With physicians and other important customers of debt.

And will stay with us regardless of where the delta of the area and is growing and so we clearly were able to take advantage of the health care system opening up.

And that has obviously been reflected on our ability to to inform and communicate of.

With our with our key stakeholders.

In the near term.

We don't anticipate of significant impact given the success of the.

The vaccine, but but obviously like everyone else.

Tolga Tanguler: But obviously, like everyone else, we are observing and continuing to build our capabilities and the learnings that we've had since 2020. John, I don't know if you have anything else to add to that. No, I think you nailed it. I would just say, obviously, Ritu, our confidence is partially driven as partially reflected in our new guidance range, which we moved up to 640 to 665 this morning. So obviously, we wouldn't have done that if we didn't feel confident about our ability to continue to perform for the rest of the year.

We are observing and and continue to build our capabilities and the learnings that we've had.

2020, John.

John I don't know if you have anything else to add to that.

No I think you nailed it I would just say obviously with 2 our confidence is partially driven partially reflected in our and our new guidance range, which we.

Of $2.640 to $2.65 of this morning.

So obviously, we wouldn't have done that if we felt good and feel confident around our ability to continue to perform for the rest of the year and I think that speaks for itself.

Great. Thanks.

John Merganori: And I think that speaks for itself. Great, thanks. Great. Thanks, Ritu. Our next question comes from Tazeen Ahmad with Banks of America.

Great. Thanks Ritu.

Our next question comes from Tony and I met with Bank of America.

Yeah.

Hi, good morning, Thanks for taking my call good morning.

So minus go and tell from being an ETR.

Tazeen Ahmad: Hi, good morning. Thanks for taking my question. Good morning.

Tazeen Ahmad: So, mine is going to also be on ATTR. Can you give us some color?

Some color about.

Why do you think the enrollment rate of Helios B.

Tazeen Ahmad: , and the enrollment rate for Helios B is much faster than you might have anticipated initially. And then, can you give us any idea of the profile of the patients that are being enrolled in Helios B? Are they in any way really different?

And is is.

And as much faster than you might've been in the anticipated initially.

And then can you give us any idea of the profile of the patients that are being enrolled and Helios B R. A day and in any way really difference from the profile, that's been enrolled and Apollo B and I guess I'm trying to get.

Tazeen Ahmad: from the profile that's been enrolled in Apollo B. And I guess I'm trying to, you know, get.

And yet get a little bit of color on whether or not and we can make any any read through is that net based on let you share for for Apollo B and as Richard the Helios B. Thank you.

Tazeen Ahmad: get get in a little bit of color on whether or not we

Tazeen Ahmad: Any read-through assessments based on what you showed for Apollo B as read-through to Helios?

Tazeen Ahmad: Helios Be. Thank you.

Akshay K. Vaishnaw: Yeah, those are great questions, Tazeen. I'm going to just pass them both over to Akshay. Akshay, why don't you handle them?

Yeah, those are great question and <unk>.

And then of just past the both over to Akshay Akshay, what a true ahead of them.

Yes, so the enrolment of the Helios B is going extremely well and I think from.

Akshay K. Vaishnaw: Yeah, so the enrollment at Heliospy has gone extremely well. And I think a few of the major factors are, We obviously have a validated platform. We get excellent TTR knockdown. TTR knockdown is a proven approach in HA-TTR amyloidosis with peripheral neuropathy, and it's of great interest in the cardiomyopathy space, as you know.

Few of the major factors.

We obviously have of.

Validate the platform, we get excellent and TTM and knock down <unk> is a proven.

<unk> in <unk> amyloidosis, with peripheral neuropathy, and it's of great interest.

And the cardiomyopathy space as you know.

Akshay K. Vaishnaw: The data from the original Apollo study would suggest that in the cardiomyopathies in HATTR patients, there are these important effects on biomarkers, post hoc analysis showed in mortality and hospitalization. So all of these bode well and are very promising in terms of the hope for both patisserin and rutricerin in the various studies including Helios Beef and Ritrus Ranch. So I think that that's helped a lot. There's been great interest. Of course, Futrisran is given once every three months subcutaneously, and we're also investigating once every six months.

The data from the original Apollo study would suggest that in the cardiomyopathy seen Asia detailed patients there.

These important effects on Biomarkers post hoc analysis showed them.

Mortality and hospitalization so all of these bode well and.

Income very promising in terms of the hope for both the <unk> and <unk>.

In the in the in the various studies, including Helios B interest run.

I think thats helped a lot there's great interest of course, the interest around as once every 3 months subcutaneously and will also investigate and once every 6 months. So that's a very exciting value proposition of the patients is convenient.

Akshay K. Vaishnaw: So that's a very exciting value proposition for patients. It's a convenient and an effective way, we hope, to treat the disease. So I'm sure that's an attractive factor.

And then the effective way, we hope to treat the disease and I'm sure. That's an attractive factor we've heard that from the folks.

Akshay K. Vaishnaw: We've heard that from folks. And that's especially important in these COVID times, you know, so you don't have to see patients as much.

And that's especially important and these COVID-19 times.

And so you have to see patients so as much.

And then finally, we have enormous experience and the TTM space in terms of working with investigators working with patients and where.

Akshay K. Vaishnaw: And then, you know, finally, we have enormous experience in the TTR space in terms of working with investigators, working with patients, and working globally at triple-digit numbers of sites that we now know through our work. And so that's been very effectively leveraged by our clinical development team and clinical operations team. So those are some of the factors, and we look forward to the results in due course. Now your other question related to similarities in the patient population, you know, at a high level, I would say Yes, indeed. They are largely similar, and they are basically patients with ATTR cardiomyopathy, which could be hereditary or wild-type.

And globally.

And the triple digit number of size, but we now know.

Through the work and so.

That's been very effect can be leveraged by the clinical development team and clinical operations teams. So those of some of the factors.

And we look forward to.

2 the results in due course.

And now your other question related to similar to the patient population and at a high level I would say, yes. Indeed, they are they are largely similar and they are basically patients with <unk> cardiomyopathy, which could be her tree or wild type I think we anticipate seeing more.

Akshay K. Vaishnaw: I think we anticipate seeing more, you know, wild-type patients in the in both studies, and you know they'll have a substantial burden of disease in terms of association 1, 2, and some patients with class 3 disease. So I think the Apollo readout, and as John emphasized in an earlier question regarding the interim analysis for Helios B, is an important readout and will give us great insight that we will then leverage to make decisions around the IA for Helios B.

Wild type patients.

And the in the and.

And by the studies and.

They will have a substantial burden of disease and 2.

Compensation and <unk>, 2 and some patients.

The class III disease.

So I think the of polo readout and as John emphasize on the earlier question for regarding the interim analysis for Helios, B ease and important readout.

Give us the great insight.

And we'll then leverage to make decisions around the IAA for Helios B.

Akshay K. Vaishnaw: Okay, Akshay, thanks for that. Maybe just to follow up, Akshay, sometimes when studies enroll faster than expected, investors can get a little concerned about whether or not the quality of the patients being enrolled is ideal. Now, obviously, you can only give a limited amount of information on this question, but is that a concern at all for you? Thank you.

Okay, Thanks, and Im sure.

Maybe just a follow up akshay.

And when when the studies enroll faster than expected and investors can get a little kind of sir and get that whether or not the quality of the patients being enrolled.

And is.

As ideal now obviously you can only get.

The limited amount of information on this question, but is that of concern at all from you. Thank.

Akshay K. Vaishnaw: Yeah, I mean, we monitor the quality of our studies, obviously, very, very carefully, just for the reasons that you say. I think we've established a good track record. We have three approved drugs; we've executed numerous phases one, two, and three studies now. And so we're confident that the quality control systems we have in place when we do clinical trials are adequate. And you can rest assured that we've been paying a lot of attention to these studies, patients coming into Apollo B and Helios B studies, inclusion and exclusion criteria, patient management through the studies. And, of course, we do a lot of work ourselves and in collaboration with our CROs. So there are numerous points of control.

Thank you.

Yes.

And we monitor the quality of our study is obviously very very carefully just for the reasons that you say I think we've established a good track record we have 3 approved drugs and we've executed numerous phases, 1.2 and 3 studies now.

And so we're confident that the the quality control systems, we have in place when we do clinical trials are adequate and you can rest assure that we've been paying a lot of attention to.

The studies patients coming into the Apollo B and the Helios B studies, the inclusion exclusion criteria of the patient management through the studies and of.

Of course, we do a lot of work ourselves and and collaboration with <unk>.

Numerous.

Points of control and.

So I think really the rapid enrollment is more reflection of the tremendous work by my colleagues and the attractiveness of the hypothesis and interest or and as of drug as opposed to.

Akshay K. Vaishnaw: And so I think, really, the rapid enrollment is more a reflection of the tremendous work by my colleagues and the attractiveness of the hypothesis and nutrition as a drug, as opposed to, you know, something going awry in the study. So we're feeling good. Yeah, I'm going to be less British. I'm going to be less British.

Something awry and the study.

So we're feeling good.

And it would be less spread it and would it be I'm going to be less British theres, there should be zero concern about that.

Okay. Thank you. Thank you.

John Merganori: There should be zero concern about that. Thank you. Our next question comes from Manny Fruhar with SBB Larynx. Thanks for taking the question. First, let's start with the Peptidream collaboration. We've seen some early but interesting data with other oligo approaches using an antibody targeting approach, specifically in skeletal muscle. And then secondarily, sort of a more commercial question, presuming that we continue to see reasonable vaccine protection against the Delta variant with booster doses as we've seen from data from Pfizer and J&J, where are we in terms of how many innings in terms of the recovery and clinical volumes? And is there additional tailwind to be had commercially on growth acceleration across the existing commercial platform? Could you, Manny, could you repeat the second part of your question again? COVID, COVID impact, and yeah.

Our next question comes from Manny for hard with SBB Leerink.

Hey, guys. Thanks for taking the question.

First let's start with the pet the dream of collaboration and we've seen some early but interesting data with other all of your approaches.

Using an antibody targeting approach.

Specifically and skeletal muscle of do you want to give us a little bit of kind of how are you.

Think about that that data versus the unique advantage of the perhaps of the demob Jim approach.

And sort of the scope of extra hepatic.

Targets on the specific test that you think of the country and collaboration and especially well suited for.

And then secondarily sort of all of our commercial questions.

Resuming that we continue to see reasonable reasonable of actually protection and I guess, the Delta Varian with booster doses of received from there from Pfizer and J&J.

Where are we in terms of how many innings and are we in terms of the recovery and clinical volumes and and is there additional tailwind to be had there commercially on the growth acceleration across the existing pipeline I'm, sorry cost of the existing commercial platform.

Could you Manny could you repeat the.

The second part of your question again, the Covid Covid impact and yes.

Manny Fruhar: Yeah, it's how much the presuming that we don't have a that we don't have a that we don't have a return to lockdown sort of bear dynamic is, how

Yes, how much the presuming that we don't have that we don't have a.

And we don't have a return to lockdown and sort of Baird sort of dynamic.

Manny Fruhar: How much runway is there in the rebound and clinical volumes, and how much of a tailwind remains? Good. Okay. All right. So, Akshay, do you want to handle the peppy dream question, and then Tolga, maybe you can address Manny's question on tailwinds on that side? So go ahead, Akshay.

How much runway is there and the rebound and clinical volumes and how much of a tailwind remains.

Good Okay, alright, so so akshay do you want to handle the Pat the dream question and down.

And then told the maybe you can you can address manny's question on on the tailwind of that site. So go ahead I'm sorry.

Akshay K. Vaishnaw: Yeah. So Manny, you know, broadly speaking, you know, we ourselves have invented a number of delivery systems for RNAi therapeutics to deliver them to the nervous system and the eye. Of course, we've been very open with the lipid nanoparticle approach from Patra and then the GalNac conjugates for the liver. And then we have novel conjugates, which we haven't shared as many details about for the central nervous system in the eye. And so I'm confident that, you know, over the period of time, there'll be many, many approaches that we and others will come up with. As you said, others have published on antibody targeting the transferrin receptor for muscle.

Yes.

Broadly speaking.

We have sales of invented a number of delivery systems for RNA therapeutics.

To deliver in the.

The system and the eye.

And of course, we've been very open with the lipid nanoparticle approach from <unk> and then the gallon that conjugates for deliver and then we have novel conjugates, which we havent share theres. Many details both of the central nervous.

The system and the eye and so I'm confident the AUM.

The period of time that there'll be many many approaches that we and others will come up with as you said.

Of the published on the antibody targeting b of the.

Transferrin receptive of muscle.

Akshay K. Vaishnaw: You know, some of the advantages of peptide-based approaches, of course, are screening, specificity, ease of manufacture, and cogs. There are many, many advantages. I think we'll probably have a much more diverse library that we can tap into. In fact, we know we have a much more diverse library we can tap into with Peptidream. And so we'll be able to reach a vast array of receptors for the internalization of RS RNAs, and so it's really a very exciting collaboration.

Some of the advantages of peptide based approaches of course.

Screening.

The specificity.

He's of manufacture Cogs.

There are many many.

The advantage I think we will probably have a much more diverse library that we can.

In fact, we know we have a much more diverse library, we can talk with Pep Pep the dream.

And so.

We can we will be able to reach a vast array of of receptors for internalization of of Arris Rnas and so it's really very exciting collaboration.

Akshay K. Vaishnaw: We ourselves have some pilot data, they have pilot data, and so more details to come, but I think this really opens up an enormous number of possibilities for Alnylam. Tolga, do you want to handle the second question? Sure, absolutely.

Our sales have some pilot data they have pilot data.

And so more details to come but I think this really opens up an enormous number of possibilities fault zone.

Total debt do you want to handle the second question.

Sure absolutely I mean look obviously of having seen the the health care systems opening up and we've been able to.

Tolga Tanguler: I mean, look, obviously, having seen the healthcare systems opening up, we've been able to generate pretty healthy growth of 12% quarter over quarter. And due to that, we were able to increase our guidance for the full year. Now, looking at the future, obviously, you know, we're very pleased with the capabilities that we built, which help us a lot tremendously. If you look at our adherence rates, if you look at how we've been able to engage with our customers, those numbers have been relatively steady.

Generally the pretty healthy growth of 12% quarter over quarter.

And due to that we were able to increase our guidance for the full year net.

Now looking at the future obviously.

We're very pleased with the capabilities that we built which helps us a lot tremendously if you look at our accounts rates.

If you look at how we've been able to engage with our customers those numbers had been had been relatively steady.

Tolga Tanguler: The big remaining question is going to be, depending on our ability to find new patients, if the healthcare systems close down significantly, which we don't anticipate, obviously, that impacts some category growth. But what we've been able to achieve so far, the first half of the year and through 2020, I think should demonstrate that we've been able to navigate an environment where we're limited by the healthcare systems. The more it opens up, it will certainly help us to be able to continue to grow at that steady rate that we've been able to demonstrate. Yeah, I would just add, thanks, Tolga.

The big.

And the remaining question is gonna be depend.

And depending on how.

The ability to find new patients as it used to health.

Care systems closed down significantly, which we don't anticipate obviously that impacts.

Some of category growth, but what we've been able to achieve so far and.

The first half of the year and through 2020 I think should demonstrate that we've been able to navigate and an environment.

We're rather limited.

With the with the with the health care systems.

The more of it opens up it will certainly help us to be able to continue to grow at that stage of bank debt, we've been able to demonstrate.

Yeah, and I would just add thanks, toga and I would just add to your question that we know that there are still there's.

John Merganori: And I would just add, Benny, to your question that, you know, we know that there are still, there's still going to be more and more patients that come back into the healthcare system. I think we all know that people have stayed out because of concerns. And as time goes on, you know, we're going to see more coming back. So I think this is an opportunity for more headwinds for the more tailwinds rather for the future because of just returning to the healthcare system and normal, normal care. Cycles that are going to be important going forward.

And theres still going to be more and more patients that come back into the health care system. I think we all know it that people have stayed up.

Does of concerns and as time goes on.

And we're gonna see more coming back. So I think this is an opportunity for more headwinds for the more tailwind rather for the future.

Because of just return into the health care system and normal.

Normal care cycles that are going to be important going forward.

John Merganori: Great, let's take the question, guys.

Great. Thanks, taking the question guys.

Thank you.

Operator: Our last question comes from Luca Issi with RBC Capital.

Our last question comes from Luca <unk> with RBC capital.

Luca Issi: Oh fantastic, thanks for squeezing me in, and congrats on all the achievements.

Fantastic. Thanks for squeezing me in and congrats and all of the progress 2 quick 1 here. The first can you maybe talk a little bit more about the <unk> platform here I find it interesting and in your press release, you mentioned of the platform is both long acting and reversible. So wondering if you can offer any color on how youre planning to do both and.

Luca Issi: And then, congrats on all the progress. Two quick ones here.

Luca Issi: The first, can you maybe talk a little bit more about the ICARIA platform here? I find it interesting that in your press release, you mentioned that the platform is both long-acting and reversible, so I'm wondering if you can offer any color on how you're planning to do both. And then the second one on Fitusiran, obviously data in early 2022, but wondering if you can comment on the ultimate commercial opportunity for this product, given the evolving competitive landscape in both hemophilia A and hemophilia B.

The second 1 of the 2 Saran, obviously data and early 2022, but wondering if you can comment on the ultimate commercial opportunity for this product given the evolving competitive landscape and both hemophilia a and hemophilia b. Thank you.

Luca Issi: Thank you. Great. Thanks, Luca. Two great questions. Let me answer both, and then, Akshay, you can jump in if you have additional views. Look, we're very excited about the Icaria platform. Icaria, by the way, is an island in Greece that's one of these blue zone islands where people live for a long time. So we like Greek islands, and we like people who live for a long time

Great. Thanks, Luca 2 great questions. Let me, let me let me answer both and then Akshay you can jump in and if you have additional abuse look we're very excited about the icaria platform of carrier by the way from Ireland, and Greece, and that's 1 of these Blue Zone Islands, where people live from 1 time so.

And we like Greek Islands, and we like people living for a long time.

John Merganori: But the scientific foundation for this is going to be something that we present relatively soon, sometime in the fall at a scientific meeting. And I think what you're going to see is really continued evidence of almylam innovation and almylam ingenuity as it relates to RNA interference. So the reason it's both long acting and reversible is that it's RNAI. We're targeting RNA. We're not targeting DNA, which has got a lot of uncertainties and risks associated with it.

But the the.

And of the scientific foundation for this is going to be something that we present.

Relatively soon sometime in the fall at a scientific meeting and I think what Youre going to see is really continued evidence of El myeloma innovation and know myeloma genuity as it relates to RNA interference. So the reason that is both long acting and and reversible is its arent AI, we're targeting RNA, we're not targeting.

DNA, which has got a lot of uncertainties and risks associated with it and so by targeting RNA with with with our and AI platform and with some adjustments that we made to it we're able to achieve both both long acting and.

John Merganori: And so by targeting RNA with our RNAI platform and with some adjustments that we've made to it, we're able to achieve both long-acting and reversible effects, and I think importantly as well, Luca, a deeper level of knockdown.

And reversible and I think importantly, as well Luca of deeper level of knockdown. So it's really got many attributes that we think are exciting and.

John Merganori: So it's really got many attributes that we think are exciting, and TTRS-C04 will be the first program providing annual dosing, almost a vaccine for the treatment of HATTR and, more broadly, ATTR amyloidosis. So very, very exciting. Now, on Tatu Saran, that's our program on hemophilia. You know, what Sanofi has said is that they're planning to have a filing, a regulatory filing, in the second half of next year. They continue to be very excited about the program, as are we. And while the landscape in hemophilia certainly is evolving and has evolved with the introduction of hemlibra, it's fair to say that there are many aspects of Tatu Saran.

And <unk> will be the first program, providing annual dosing almost of vaccine for the treatment of of <unk>.

<unk> and <unk>.

Broadly ATT amyloidosis, so very very exciting now on the 2 surround and Thats our program in hemophilia.

And what canopy has said is that they are planning to have.

The filing a regulatory filing of the second half of next year.

And they continue to be very excited about the program.

And while the landscape and hemophilia certainly is evolving and has evolved with the introduction of Ham Libra, It's fair to say that there are many aspects of the ramp up.

File, including its effectiveness potential effectiveness and hemophilia B, where there is no subcutaneous treatment option today and that's the while smaller than hemophilia, a and it's still a very sizable market opportunity and some of the longer acting factors that were being developed for hemophilia b have not panned out of successfully namely and Dell beyond.

Akshay Desai: Akshay Desai, Weinong Guo, Alnylam Pharmaceuticals Inc. Akshay Desai, Weinong Guo, Alnylam Pharmaceuticals Inc., Excellent. Excellent. Thanks so much. All right. Thank you. So I think that was the last question.

From CSL. So there really is a very nice opportunity just in hemophilia B alone and then obviously the opportunity to compete and the hemophilia a market.

Against him Libre is something which therapy is quite keen on on doing as well.

And therapy is coming as well, but I think thats going to really be niche and the whole hemophilia segment at the end of the day, So akshay anything to add to those 2 comments I just made no you covered it John.

John Merganori: So let me thank everybody for joining us on this call. We're obviously really happy with our second quarter results and overall results for 2021. And we're really looking forward to the next six months of the year and what we can deliver from our science as well as our commercial execution. And we're very much on our way to our P to the fifth by 25. So, by all accounts, it's an exciting time for Alnylam.

Excellent excellent. Thanks, so much alright, thank you.

So.

I think that was the last question. So let me thank everybody for joining us on this call. We're obviously really happy with our second quarter results and and overall results from 2021, and we're really looking forward to the to the next 6 months of the year and what we can deliver from our science as well as our commercial execution and.

And we're very much on our way towards muted a bit by 25. So it's an exciting time for our myeloma by all accounts. Thank you and have a great day.

Operator: Thank you, and have a great day. Ladies and gentlemen, this does conclude today's presentation. You may now disconnect. Have a wonderful day.

Ladies and gentlemen, this does conclude today's presentation. You may now disconnect and have a wonderful day.