Alnylam Pharmaceuticals Inc

NASDAQ:ALNY

Earnings Call Transcript 2021-Q2

[Operator]

Ladies and gentlemen, thank you for standing by. And welcome to the Alnylam Pharmaceuticals Q2 2021 Earnings Conference Call. At this time, all participants are in listen-only mode. After the speakers' presentation, there will be a question-and-answer session. [Operator Instructions]

I'd now like to turn the call over to your, Christine Lindenboom. You may begin.

[Christine Lindenboom, Investor Relations]

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 Maraganore, 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 investor.alnylam.com/events. During today's call, as outlined in slide two, John will provide some introductory remarks and general context; Tolga will provide an update on our global commercial progress; Akshay will review recent clinical and preclinical updates; Jeff will review our financials; and Yvonne will provide a brief summary of upcoming milestones before opening the call to your questions.

I'd 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 annual report on file with the SEC.

In addition any forward-looking statements represent our views only as of 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. John?

[John Maraganore, Chief Executive Officer]

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 with 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 ONPATTRO strengthening of GIVLAARI performance and the continued impressive uptake for OXLUMO. On our pipeline efforts, highlights include excellent progress building our ATTR Amyloidosis franchise. We completed enrollment in the APOLLO -B Phase 3 study of Patisiran and expect to complete enrollment in the HELIOS-B, Phase study of Patisiran within the next two weeks, significantly ahead of schedule, and already with more than 600 patients enrolled.

We also submitted our Vutrisiran NDA based on the HELIOS-A results in patients with hATTR amyloidosis with polyneuropathy and the FDA accepted our submission assigning the PDUFA date in April of 2022. Furthermore, we initiated a biannual dosing study Vutrisiran and we introduced a new preclinical program ALN-TTRsc04 for 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 1 study of zilebesiran, our investigational RNAi therapeutics for hypertension, which is now advanced into the KARDIA Phase 2 program. We believe all of these achievements represent meaningful progress toward our Alnylam P5x25 goals, 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 engine. 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?

[Tolga Tanguler, Chief Commercial Officer]

Thanks John, and good morning, everyone. We're very pleased with our second quarter performance. For, ONPATTRO, we achieve $114 million in global net product revenues, representing approximately 12% quarter-on-quarter growth compared with the first quarter. We ended the quarter with over 1,725 patients on commercial treatments. In the US, 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. For example, in the second quarter, we received more stock forms for ONPATTRO in the US 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. Further, speed to patient diagnosis is continuing to improve with ongoing growth in the use of QRT scans, which is often the start of the patient journey toward a polyneuropathy diagnosis. Patient compliance also remains high and stable at pre COVID levels. And we continue to observe a trend and concomitant use of ONPATTRO to treat the polyneuropathy of hATTR amyloidosis, along with the use of hATTR stabilizer to treat the cardiomyopathy of this disease in mixed genotype 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.

Moving to GIVLAARI, 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 30, we attained 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 reduce patient flow through the US healthcare system caused by COVID. We're also seeing continued expansion of the prescriber base, including new writers, particularly from community centers, in addition to porphyria centers of excellence. In the US, we continue to make strong progress toward establishing VBS with over 10 finalized to date with commercial payers. We also have confirmed access for over 98% of covered US lives with no significant headwinds. We continue to make great progress with market access efforts for GIVLAARI across EMEA 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 of GIVLAARI in Japan for the treatment of AHP In adults, as well as adolescents age 12 and older with a launch expected in September.

Moving to OXLUMO, we're seeing continued demand strength in the drugs second full quarter of launch. We achieved $16 million in global net product revenues in the second quarter, and attained approximately 100 patients or commercial OXLUMO treatment in the US and EU as of June 30. As we're still early in the launch, OXLUMO performance is also being modestly benefited by the dynamics of learning those. Our market access efforts are progressing very well with no access headwinds and confirm medical policy inclusions for over 80% of covered US lives. And seven VBAs finalized to date with commercial payers. Geographic expression of OXLUMO is moving along nicely with their recent approval in Brazil, and launch underway in Germany and ATU supplying France, supported by early transitions from our expanded access program.

We're very pleased to see broad utilization of OXLUMO 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 flows through the healthcare system, improved disease awareness and new patient finding. In the case of GIVLAARI and OXLUMO, 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. Akshay?

[Akshay Vaishnaw, President of Research and Development]

Thanks Tolga, and good morning, everyone. I'll start with our efforts in ATTR amyloidosis, where we're advancing two clinical stage product candidates, Patisiran and Vutrisiran. Also, ONPATTRO is currently approved in multiple markets around the world to treat the polyneuropathy associated with hereditary ATTR amyloidosis. We're committed to expanding the products labeled for the treatment of cardiomyopathy in both hereditary and wild-type ATTR amyloidosis patients. To this end, we're conducting the APOLLO-B Phase 3 study. During the second quarter we completed enrollment in APOLLO-B and expect to report top line results in mid 2022. We are also advancing Vutrisiran and investigational therapy, which is delivered by a quarterly subcutaneous injection and is also in development for ATTR amyloidosis. Here, we're conducting two Phase 3 studies. The first is HELIOS-A evaluating Vutrisiran and hATTR amyloidosis patients with polyneuropathy. At the AAN conference in April, we presented our positive nine months HELIOS-A results. Based on those results, we submitted our NDA to the FDA, which was accepted and signed the PDUFA date of 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 Vutrisiran impact on the exploratory cardiac endpoints.

We plan to make additional regulatory submissions including in the EU in the late 2021 period based on the HELIOS-A results. The other Phase 3 Vutrisiran study is HELIOS-B, which is our ongoing Phase 3 cardiac outcomes study with Vutrisiran in hereditary and wild-type ATTR amyloidosis with cardiomyopathy. We're excited to have announced this morning but due to high interest amongst physicians and patients, we now expect to complete enrollment within the next two weeks well ahead of schedule. And with more than 600 patients randomized to date. HELIOS-BI has a 30 month endpoint of all cause mortality and CV events. And we can now expect the full results in early 2024. The study design includes the potential for an interim analysis and we'll consider these following results from APOLLO-B in alignment with regulatory authorities. Lastly, for Vutrisiran, we're very excited about the potential opportunity for biannual dosing regimen, which could further differentiate Vutrisiran from other products and provide yet another dosing regimen option for patients.

We're now generating the clinical data potentially advances this additional 50 milligram biannual dosing schedule for Vutrisiran. 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 Vutrisiran at a dose of either 25 milligrams every three months, or 50 milligrams biannually. These data intend to demonstrate the safety and efficacy of the 50 milligram biannual regiment are expected in 2022. Beyond Patisiran and Vutrisiran, we have a new addition to ATTR amyloidosis franchise we're building. Specifically, using our IKARIA Platform, we've generated a new TTR targeting siRNA ALN-TTRsc04 that we believe could support an annual dosing regimen greater than 90% TTR knocked out. We intend to share more detail on the IKARIA Platform and our preclinical work at an upcoming scientific meeting in mid-2021.

Let's now move on to Lumasiran, our RNAi therapeutic recently approved in the EU and US as the first treatment for primary hyperoxaluria Type 1 or PH1. We are very pleased to announce positive top line results from ILLUMINATE-C just last week. As a reminder, ILLUMINATE-C is a single arm multinational Phase 3 study designed to evaluate the efficacy and safety of Lumasiran in PH1 patients of all ages, with severe renal impairment, including patients on dialysis. A total of 21 patients were enrolled in the study and Lumasiran was found to achieve substantial reductions in plasma oxalate relative to baseline. Both inpatients will not yet on dialysis. And patients are haemodialysis dependent. Elevated plasma oxalate can result in systemic alkalosis with severe clinical consequences impacting the heart, bones, eyes, skin, and other organs. Moreover, Lumasiran demonstrated an encouraging safety and tolerability profile, with no deaths or drug related SAEs. The most common AES were ISRs, all of which were mild. There were two discontinuation -- some treatment during the extension period due to AEs but neither was drug related. We now intend to submit supplemental regulatory filings with the FDA and EMA in late 2021 with the goal of strengthening the label supporting OXLUMO.

As we have noted previously, we're also excited about the potential for Lumasiran for patients with recurrent renal stones. And later this year we plan to start a Phase 2 trial to evaluate that potential. As we have two additional late stage programs that are in development with partners. This includes Leqvio or inclisiran partnered with Novartis, which was approved last year in the EU for the treatment of adults with hypercholesterolemia or mixed dyslipidemia. Leqvio marks the first RNAi therapeutic approved for a prevalent condition. Recently Novartis resubmitted its NDA for Leqvio 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 inclisiran. Novartis announced that the FDA has accepted the resubmission and assigned a Padua date of January 1, 2022.

Our late stage programs also include Fitusiran in hemophilia A or B with or without inhibitors, partnered with Sanofi, who is leading development of Fitusiran in the ATLAS Phase 3 program. Sanofi announced substantial progress with Fitusiran and now expects to share data from initial pivotal trials as early as beginning of next year, with a potential regulatory submission later in 2022. 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 Disease into prevalent disease opportunities. We believe now is the time to address many unmet needs in common disease settings such as hypertension, Nash, gout, 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. So Belcesiran, formally known as ALN-HTT now investigational RNAi therapeutic is targeting the genetically validated target angiotensinogen for the treatment of hypertension.

In the second quarter, we reported interim results from the Phase 1 study in which patients treated with single doses of Belcesiran at 100 milligrams or higher doses experienced durable reductions in serum AGT of more than 90% throughout two weeks. Reductions in 24 hour systolic blood pressure greater than 10 millimeters mercury observed at week eight after single doses of 100 milligrams or higher if antihypertensive effect is persisted through week 12. In the highest dose group greater than 15 millimeters of mercury reduction in blood pressure was observed. 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 of Belcesiran has been generally well tolerated, with an encouraging safety profile observed today. The Phase 1 study has two parts designed to assess the tolerability of Belcesiran during potential augmented pharmacology inducing either by low salt diet or by co-administration of the conventional RAAS inhibitor of [Indiscernible]. These cohorts have completed dosing with data readout expected later this year.

We also recently initiated our cardio Phase 2 program with Zilebesiran. The first of the two studies is KARDIA-1 designed to evaluate the efficacy and safety of Zilebesiran in monotherapy in patients with mild to moderate hypertension. This study is currently enrolling patients. In late 2021, we plan on initiating KARDIA-2 which is designed to evaluate the efficacy and safety of Zilebesiran as an add-on therapy in patients with uncontrolled hypertension while receiving treatment with standard of care.

Moving on, we're also advancing ALN-HSD n collaboration with our partner Regeneron for the treatment of Nash. We believe that RNAi mediated knockdown of HSD17B13 will mimic genetic loss of function findings reducing hepatic inflammation, injury and fibrosis in Nash patient. Enrollment and dosing continues in the Phase 1 study of ALN-HSD, which has now transitioned to dosing in Part B with Nash patients.

Let's turn briefly to our ALN-HBV02 program, also known as VIR-2218, in partnership with Vir. At the EASL meeting in June Vir presented results from a Phase 2 study of ALN-HBV02 showing a positive safety profile and reduction of hepatitis B surface antigen. When combined with pegylated interferon alpha for 12 weeks, a more rapid and substantial Hepatitis B surface antigen decline was observed in the co-administration cohort compared to HBVO2 alone, as a reminder, Alnylam intend to free opt in right to co develop and co commercialize HBVO2 or to receive milestones and royalties we considered to be quite attractive.

We also made great progress with our preclinical program ALN-XDH in development for the treatment of gout and plan to file a CTA for this program in late 2021. The significant unmet need for new treatments to address recurrent gout attacks are very painful and debilitating condition. And our scientists pioneered RNAi therapeutics for this condition with broad intellectual property protection. 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 ALN-APP program in development for the treatment for autosomal dominant Alzheimer's disease and cerebral amyloid angiopathy. We now plan to file a CTA for ALN-APP in late 2021 representing a small shift in our timeline.

Finally, in our press release this morning, we announced our decision to discontinue our ALN-COV program in development for the treatment of COVID-19. This is a portfolio 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?

[Jeff Poulton, Chief Financial Officer]

Thanks Akshay, and 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 ONPATTRO, 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 quarter-on-quarter growth following one quarter of flattened growth that we experienced during the onset of the pandemic in Q2 of last year. US ONPATTRO sales increased 6% versus Q1 2021. And we're primarily impacted by the following. An approximate 12% increase in demand, representing 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 deductions and less inventory stocking in the quarter compared with Q1, 2021. In our international markets, ONPATTRO performance remains 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 comprise 54% of our global total in Q2, clearly reflecting the benefit of our global commercial footprint.

Turning to our results for GIVLAARI; 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 US and Europe. Reported results in the US in particular improve 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 US healthcare system. With OXLUMO, we had an excellent second full quarter of sales, generating $16.3 million in net revenue in a quarter up from $9.1 million in Q1 with growth contributions from both US and rest of world markets.

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 last year, primarily due to revenue recognized from our Regeneron collaboration. We recognize $0.3 million in royalty revenues during the quarter, representing our initial recognition of royalties earned on Novartis as sales of Leqvio. Gross margin on total revenues was 82.4% for the quarter, a slight improvement from prior year. Our combined non-GAAP R&D and SG&A expenses for the quarter increased 19% versus Q2 2020. Key drivers of the increased continue to be additional R&D investment in advancing our late stage pipeline programs and increased SG&A investment to support our free commercial brands, including the launch of OXLUMO. 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 2020, driven by strong top line growth and more moderate growth in operating expenses. Q2 also represents the sixth consecutive quarter that we've delivered an improvement in our non-GAAP operating loss. And we believe this clearly signals the path we are 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 and 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 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 million to $660 million to $640 million to $665 million, 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, Yvonne?

[Yvonne Greenstreet, President and Chief Operating Officer]

Thanks Jeff, and hello, everyone. Let me start by reviewing an exciting partnership we announced with PeptiDream, 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 conjugates to create multiple opportunities to deliver RNAi therapeutics to tissues outside the liver. The collaboration has the potential to have multiple training opportunities by targeting disease causing mRNA strong scripts and a wide variety of tissue types.

Let me now turn to a review of remaining goals to 2021. ONPATTRO within our TTR programs, we plan to present 18 month top line results from HELIOS-A Phase 3 study with Vutrisiran. We also plan additional regulatory submissions for Vutrisiran in the EU, Japan and Brazil in late 2021. Based on the excellent progress and enrollment, we also plan to complete enrollment in HELIOS-B in the coming weeks as we announced today. With Zilebesiran as Akshay 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 KARDIA-2 Phase 2 combination study later this year as well.

For Lumasiran, we plan to initiate a Phase 2 study for renal stone events in late 2021. We believe this Phase 2 study represents meaningful Lifecycle Management of OXLUMO with a 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 ALN-HSD, we expect to report initial Phase 2 results of healthy volunteers from the Phase 1 study.

Turning to cemdisiran for complement mediated diseases, our partner Regeneron plans to initiate a Phase 3 study of cemdisiran and pozelimab combination in myasthenia gravis. In addition to multiple Phase 2 studies in PNH. We believe the combination of cemdisiran and pozelimab represents an attractive therapeutic strategy for complements mediated diseases. We're very excited to file our first CNS CTA for ALN-APP now expected in late 2021 in development for the treatment of autism or dominant Alzheimer disease, and cerebral amyloid angiopathy. This sets us up for potential initial PSC data in 2022. And given the exciting preclinical progress, we plan to advance ALN-XDH in development for the treatment of gout toward a CTA filing in late 2021.

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

[Christine Lindenboom, Investor Relations]

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

[Operator]

[Operator Instructions]

Our first question comes from Gena Wang with Barclays.

[GenaWang]

Thank you for taking my question and also congrats on the very strong quarter. So I have a one big picture question, Alnylam has been very successful as a standalone company with 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 to grow into top five Biotech Company as your goal?

[JohnMaraganore]

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 P5x25, 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 year period, by execution with our organic product engine and our capabilities to achieve sustainable innovation. So it's certainly our plan to continue on that path. But of course, 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 P5x25 goals and our abilities to execute continuously on that sustainable source of innovation. So that's how we're focused, Gena.

[Operator]

Our next question comes from Alethia Young with Cantor Fitzgerald.

[AlethiaYoung]

Hey, guys, thanks for taking my question. You guys crushed at this quarter. I guess I wanted -- it's another kind of big picture. But just wanting to talk a little bit about as you started to do bigger programs like in hypertension, even ones beyond as you build up your business? Like, how do you kind of think about the balancing act of 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 flavor wouldn't you go out alone? Or do you think that these are opportunities for potential partnership thing?

[JohnMaraganore]

Yes, well, first of all, thanks, Alethia 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 cemdisiran really points to the ability to reimagine the treatment of hypertension, a leading cause of cardiovascular morbidity and mortality around the world. 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's really no reason why we aren't 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'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. 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 Yvonne, to comment a little bit more about our sort of going forward views. But Jeff, do you want to talk first on the financials, and then upon a little bit about our perspectives on growth in the prevalent disease markets?

[JeffPoulton]

Yes, I think I agree with everything you said, John, and one of the metrics P5x25 goals is getting to profitability across the period and we're committed to doing that. I think the one other comments that I would make as it relates to cemdisiran is from a commercial standpoint, our hope is that we'll be able to leverage infrastructure that hopefully we will have built by then from a perspective of supporting an expansion of the TTR franchise for successful in the APOLLO-B and HELIOS-B studies to get into a larger sort of cardiomyopathy footprint. So that's one factor as well.

[JohnMaraganore]

And Yvonne, do you want to comment a little bit more strategically going forward? How we think through this?

[YvonneGreenstreet]

No, I think actually, both of you have covered this well. We believe we're a unique company. And we have every intention of building a top five bar tech. And we have every intention of progressing all of our opportunities, obviously, in a thoughtful fashion.

[JohnMaraganore]

Is that answered your questions, Alethia?

[Operator]

Our next question comes from Maury Raycroft with Jefferies.

[MauryRaycroft]

Hi, good morning, everyone. Congrats on the quarter. And thanks for taking my question. I was wondering if you can talk about the parallels between zilebesiran and inclisiran. And then investors should be thinking about? And is there anything additional, you could say about the KARDIA-2 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 timeline look like for both KARDIA-1 and 2?

[JohnMaraganore]

Fantastic. Let me start my comments. And then maybe Akshay, you can chime in here on some more of the specifics on the KARDIA program, and the dosing regimen. For starters, I mean, look, we're very, again, very excited about zilebesiran and its potential to reimagine the treatment of hypertension. And you are very right, Maury, to point to the analogy with inclisiran, because both siRNA are designed to address very prevalent -- both very prevalent diseases, one is in hypercholesterolemia with inclisiran the other hypertension with zilebesiran. And both, of course, enable a very infrequent dose regimen to control these leading causes of CV morbidity, mortality in both cases, right with HDL and LDL, I'd say from a development program standpoint was attractive, strategically about both efforts is that the biomarker or the clinical marker that we're measuring in our Phase 2 studies and our Phase 2 studies, in the cases, zilebesiran blood pressure. And in the case of inclisiran LDL cholesterol, those are the exact same endpoints that will be used in our Phase 3 trials, in support of an approval. And so it is attractive that we have completely de-risked the primary endpoint of what will ultimately be a Phase 3 with zilebesiran. And that's a very analogous situation to what we have with inclisiran in the setting of hypercholesterolemia, so very attractive profile. And, of course we're very, very encouraged by the safety profile that we saw with inclisiran and 1000s of patients that we're studying. And we're obviously aiming to achieve similar results with zilebesiran, as we do further studies with that agent. So at a high strategic level, that is -- those are some of the reasons why there are a lot of analogies between inclisiran and zilebesiran.

So with that, Akshay, maybe you can talk a little bit about more of the KARDIA program, some of the timelines there, as well as some of the dosing approaches through three months or six months like. So Akshay, take it away.

[AkshayVaishnaw]

Yes, thanks, John. So, Maury, zilebesiran we will execute two Phase 2 studies, KARDIA-1 is looking at zilebesiran as mono therapy in patients with mild to moderate hypertension. About just shy of 400 patients here in 75 or so in that study, orthodox randomized control study. And that'll be -- that study is up and running that we complemented by KARDIA-2 which will kick off in the months to come later this year. And then we'll evaluate in KARDIA-2, the combination of zilebesiran with other antihypertensive medications and of course, that will include Ras inhibitors, calcium channel blockers, diuretics, and more details to come. That study will be larger, about 650 patients also 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 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 an exciting outcome building on the very promising data from the Phase 1 that John has already commented on. With reference to dose and regimen there'll 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 monthly dosing regimens in these studies. And 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 the development in Phase 3. So I hope that's helpful, Maury.

[Operator]

Our next question comes from Salveen Richter with Goldman Sachs.

[SalveenRichter]

Good morning, thanks for taking my question. Given your agreement with PeptiDream, could you just talk about extrahepatic targets that you're or tissues that you're looking to target beyond CNS?

[JohnMaraganore]

Yes, 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. 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?

[AkshayVaishnaw]

Yes, so, Salveen, of course, we're interested in a range of organs with several reasons; one is that RNAi as a pharmacologic activity can be conducted in any tissue in any cell in the body. So we can take a siRNA to any cell type, and expect to see targets knocked down, and we can say that with confidence. And if you combine that with the possibility that they're genetically validated, and ontologically, validated targets in many, many different tissues, we've got broader ambitions with PeptiDream beyond the liver. So of course, we already in the CNS ANI that we have several options there in terms of the kinds of conjugates we've built. I'm sure we can add to those with PeptiDream 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 RNAi. And we believe that by the end of the decade, we'll see RNAi in many, many different tissues beyond the liver, and approved programs associated with that.

[Operator]

Our next question comes from Paul Matteis with Stifel.

[PaulMatteis]

Great, thanks so much. I was wondering if you could give any comments on the expansion of the exec chair role and if there's any sort of back story to that or any relationship to the prior ONPATTRO 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.

[JohnMaraganore]

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 Bonny in an expanded role, he's 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, 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've done. Mike is an extremely experienced commercial leader. I have worked with Mike in for many, many years. I know him, obviously extremely 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 could 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 question?

[AkshayVaishnaw]

Yes, Paul. I think it's clear to everybody the primary endpoint 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 Patisiran in the ATTR [Indiscernible] populations. So we're looking forward to that result in the middle of next year, the studies fully enrolled, of course. And that's exciting. Now vis-à-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 the study is blinded, and so forth, to comment on the exact nature of those data and what we'll see, we hope to see a trend, but that's something we'll have to wait for next year.

[JohnMaraganore]

Is that answered your questions?

[Operator]

Next question comes from Ritu Baral with Cowen.

[RituBaral]

Hi, guys, thanks for taking the question. 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 breakeven question. And then a very quick follow up for Tolga 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 be impact be there? Thanks.

[JohnMaraganore]

Okay. That's great. Let me start with the IAA. Then will, Akshay you may want to comment on the IAA after that, and then we'll go to Tolga on your question for delta variant and perspectives on Q3, we obviously aren't going to foreshadow Q3, but we can give you some sense from our -- at least our view. So regarding the interim analysis, Ritu, what we designed HELIOS-B, we included the end -- and with 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 in the study to basically understand how and what type of interim analysis we might do, we continue to believe that an interim analysis could be useful in the study. But obviously, we have the beautiful benefit of the APOLLO-B readout that will occur sometime this time next year, that will give us line of sight on mortality and see the events that are happening in that study, and the wisdom and any trends that we might see and the wisdom of doing an earlier interim analysis with HELIOS-B as it relates to that study. Now, it's extremely good that we also have tilted it on the enrollment of HELIOS-B, as it relates to the study and the fact that the ultimate ending date of that study is now been accelerated significantly. So obviously, all 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 side of things?

[AkshayVaishnaw]

No, I think you covered it, John.

[JohnMaraganore]

Okay, terrific. And so let's now go to Tolga to comment a little bit on his perspectives on Q3 as it relates to the Delta variant. Tolga?

[TolgaTanguler]

Yes, absolutely. Thank you for that question. Look, I mean, we obviously as an organization learned a lot and build a lot of capabilities that includes alternative sites of care, home care when it's possible, and how we have been able to continue to engage with physicians and other important customers, that will stay with us, regardless of where the Delta Varian is going. So we clearly were able to take advantage of healthcare systems opening up. And that has obviously been reflected on our ability to reform and communicate with our key stakeholders. In the near term, we don't anticipate a significant impact given the success of the vaccine. But obviously, like everyone else, we are observing and continue 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.

[JohnMaraganore]

No, I think you nailed it. I would just say obviously, we're to -- our confidence is partially driven -- as partially reflected in our new guidance range, which we - up to $640 million to $665 million this morning. So obviously, we wouldn't have done that if we felt -- if felt confident around our ability to continue to perform for the rest of the year. And I think that's speaks for itself.

[Operator]

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

[TazeenAhmad]

Good morning. Thanks for taking my questions. So, mine is going to also be on ATTR. Can you give us some color about why you think the enrollment rate of HELIOS-B is much faster than you might have been 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 from the profile that's been enrolled in APOLLO-B? And I guess I'm trying to get a little bit of color on whether or not we can make any read through assessments based on what you show for APOLLO-B as read through to HELIOS-B? Thank you.

[JohnMaraganore]

Yes, those are great questions, Tazeen. I am going to just pass them both over to Akshay. Akshay, why don't you handle them?

[AkshayVaishnaw]

Yes, so the enrollment in HELIOS-B 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 hATTR amyloidosis with polyneuropathy and is of great interest in Cardiomyopathy space, as you know the data from the original APOLLO study would suggest that in Cardiomyopathy in hATTR patients, there are these important effects on biomarkers post hoc analysis showing mortality and hospitalization. So all of these bode well. And I think a very promising in terms of the hope for both Patisiran and vutrisiran in the various studies, including HELIOS-B Vutrisiran. So I think that's helped a lot. There's great interest. Of course, the Vutrisiran is once every three months subcutaneously. And we're also investigated once every six months. So that's a very exciting value proposition for patients. It's convenient, and an effective way we hope to treat the disease, I'm sure that's an attractive fact that we've heard that from folks. And that's especially important in these COVID times to see patients as much. And then finally, we have enormous experience in the TTR space in terms of working with investigators working with patients and working globally, at triple digit number of sites that we now know, through 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 with patient population, 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. I think we anticipate seeing more wild-type patients in both studies, and they'll have a substantial burden of disease in terms of [Indiscernible] section one, two in some patients with class three diseases. So, I think the APOLLO readout and as John emphasized on earlier question for regarding the interim analysis for HELIOS-B is an important readout, will give us the great insight that will then leverage to make decisions around the IAA for HELIOS-B.

[TazeenAhmad]

Okay, Akshay thanks for that. Maybe just the follow up, Akshay, sometimes when studies enrolled faster than expected and 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.

[AkshayVaishnaw]

Yes, 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 that 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 we've been paying a lot of attention to the studies of patients coming into APOLLO-B and HELIOS-B studies, inclusion and exclusion criteria that the 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. 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 Vutrisiran as a drug as opposed to something awry in the study. So we're feeling good.

[JohnMaraganore]

Yes, I'm going to be less -- there's should be zero concern about that, Tazeen.

[Operator]

Our next question comes from Mani Foroohar with SVB Leerink.

[ManiForoohar]

Hey, guys. Thanks for taking my question. First, let's start with the PeptiDream collaboration. We've seen some early but interesting data with other autologous approaches, using an antibody targeting approach, specifically in skeletal muscle. Do you want to give us a little bit of sense of how you think about that data versus the unique advantages of PeptiDream approach, and sort of the scope of extrahepatic targets on a specific tissue types that you think the PeptiDream collaboration are especially well suited for. And then secondarily more sort of a more commercial question. Presuming that we continue to see reasonable vaccine protection against the Delta variant with booster doses received from Bayer from Pfizer, and J&J? Where are we in terms of how many innings in are we in terms of the recovery in clinical volumes? And is there additional tailwind to be had there commercially on growth acceleration across the existing pipeline? I'm sorry, cost of the existing commercial platform?

[JohnMaraganore]

Could you, Mani, could you repeat the second part of your question again? COVID impact and yes --

[ManiForoohar]

Yes, how much, presuming that we don't have a return to lockdown sort of bear that dynamic. How much runway is there as the rebound in clinical volumes, and how much of a tailwind remains?

[JohnMaraganore]

Good, okay, all right. So, Akshay, do you want to handle the PeptiDream question? And then Tolga, Maybe you can address Mani's question on tailwinds on that side. So go ahead, Akshay.

[AkshayVaishnaw]

Yes, So, Mani, broadly speaking, we ourselves have invented a number of delivery systems for RNAi therapeutics to the liver to the nervous system in the eye. Of course, we've been very open with the lipid nanoparticles approach from -- and then the GalNAc conjugates for the liver. And then we have novel conjugates, which we hadn't shared as many details for the central nervous system in the eye. And so I'm confident that over the period of time that there'll be many, many approaches that we and others will come up with, as you said, published on antibody targeting via the transferrin receptor for muscle. Some of the advantages of peptide based approaches, of course, are screening, specificity, ease of manufacture cogs; there are many, many advantages. I think we'll probably have a much more diverse library that we can tap on. In fact, we know we have a much more diverse library we can tap with PeptiDream. And so we can, we'll be able to reach evolved array of receptors for internalization of our RNAi. And so it's really a very exciting collaboration. We ourselves have some pilot data, they have pilot data. And so more details become but I think this really opens up an enormous number of possibilities Alnylam.

[JohnMaraganore]

Tolga, do you want to handle the second question?

[TolgaTanguler]

Sure. Absolutely. I mean, look, obviously, having seen the healthcare systems opening up, we've been able to generate a 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 we're very pleased with the capabilities that we've built, which helps 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. The big remaining question is going to be depending on our ability to find new patients is if the healthcare systems closed down significantly, which we don't anticipate, obviously, that impacts some category growth but what we've been able to achieve so far, in the first half of the year and through 2020, I think should demonstrate that we've been able to navigate an environment where rather limited with the healthcare systems, the more it opens up, it will certainly help us to be able to continue to grow at that standard rate that we've been able to demonstrate.

[JohnMaraganore]

Yes, I would just add. Thanks, Tolga. And I would just add, Mani, to your question that 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 what that people have stayed off because of concerns. And as time goes on we're going to see more coming back. So I think this is an opportunity for more headwinds for the -- more tail winds rather for the future, because of just returning to the health care system and normal care cycles that are going to be important going forward.

[Operator]

Our last question comes from Luca Issi with RBC.

[LucaIssi]

Oh, fantastic. Thanks for squeezing me in and congrats on all the progress. Two quick one here. The first, can maybe talk a little bit more about the IKARIA Platform here. I find it interesting that in your press release, you mentioned that the platform is both long acting and reversible. So wondering if you can offer any color on how you're planning to do both. And then the second one of Patisiran, 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. Thank you.

[JohnMaraganore]

Great, thanks for the 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 IKARIA Platform. IKARIA, 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'd like people living for a long time. But the foundation, 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 Alnylam innovation and Alnylam ingenuity, as it relates to RNA interference. So the reason it's both long acting and reversible, is it's RNAi, 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 RNAi platform with some adjustments that we've made to it, we're able to achieve both long acting and reversible. And I think importantly, as well, Luca, a deeper level of knockdown. So it's really got many attributes that we think are exciting. And TTRsc04 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 Patisiran, that's our program in hemophilia, what Sanofi has said is that they're planning to have a filing, 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 the Patisiran profile including its effectiveness, potential effectiveness in Hemophilia B, where there is no subcutaneous treatment option today and that's a lot smaller than Hemophilia A, 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 as successfully namely Idelvion from CSL so there really is a very nice opportunity just in Hemophilia B alone, and then obviously the opportunity to compete in the Hemophilia A market against Hemlibra is something which Sanofi is quite keen on doing as well. Gene therapy is coming as well, but I think that's going to really be niche in the whole hemophilia segment at the end of the day. So Akshay, anything to add to those two comments I just made?

[AkshayVaishnaw]

No, you covered it, John.

[John Maraganore, Chief Executive Officer]

Excellent. 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 overall results in 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 P5x25. So it's an exciting time for Alnylam by all accounts. Thank you and have a great day.

[Operator]

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