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spk11: Ladies and gentlemen, thank you for standing by and welcome to the Allen Island 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. I would now like to turn the call over to your host, Christine Lindenboom. You may begin.
spk07: Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at El Nilem. With me today on the phone are John Merganori, Chief Executive Officer, Tolga Tangular, Chief Commercial Officer, Akshay Vaishnal, President of R&D, Jeff Bolton, 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.alnyloves.com slash events. During today's call, as outlined in slide two, John will provide some introductory remarks and provide 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 would like to remind you that this call will contain remarks concerning Alnyloves' 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. 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?
spk13: 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 Ampatro, strengthening of Givlari performance, and a continued impressive uptake for Oxalumo. On our pipeline efforts, highlights include excellent progress building our ATTR Ameliodosis franchise. We completed enrollment in the Apollo B Phase 3 study of Petit Sarand. and expect to complete enrollment in the Helios B phase three study of Lutrisiran within the next two weeks. Significantly ahead of schedule and already with more than 600 patients enrolled. We also submitted our Lutrisiran 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 butresaran, and we introduced a new preclinical program, ALN-TTR-SC04, 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 I study of Zabiseran, our investigational RNAi therapeutic for hypertension, which is now advanced into the CARDIA Phase II program. We believe all of these achievements represent meaningful progress toward our Alnylam P to the fifth by 25 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.
spk10: Thanks, John, and good morning, everyone. We're very pleased with our second quarter performance. For Ompatro, we achieved $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 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. For example, in the second quarter, we received more start forms for OnPatro 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. Further, 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. Patient compliance also remains high and stable at pre-COVID levels. And we continue to observe a trend in concomitant use of Onpatro, to treat the polyneuropathy of HATTR amyloidosis, 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. 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 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 reduced patient flow through the U.S. healthcare system caused by COVID. 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 VDAs 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 continue to make great progress with market access efforts for GIVLARI across the CMEA region with a recent launch in Italy, ongoing launch in Germany, Temporary Authorization for Use, or ATU, supply in France, as well as named patient sales in other countries. In addition, we were pleased to recently receive approval of GIVLARI in Japan for the treatment of AHP in adults, as well as adolescents aged 12 and older, with a launch expected in September. Moving to Oxlumo, we're seeing continued demand strength in the drug's second full quarter of launch. We achieved $60 million in global net product revenues in the second quarter and attained approximately 100 patients on commercial Oxlumo treatment in the U.S. and EU as of June 30th. As we're still early in the launch, Oxlumo performance is also being modestly benefited 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 seven VBAs finalized to date with commercial payers. Geographic expansion of VoxLuma is moving along nicely with a recent approval in Brazil and launch underway in Germany and ATU supply in France supported by early transitions from our expanded access program. We're very pleased to see broad utilization of VoxLuma 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 Givlar 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?
spk12: Thanks, Tolga, and good morning, everyone. I'll start with our efforts in ATTR amyloidosis, where we're advancing two clinical stage product candidates, Patisran and Vufisran. Oslo and Patrae 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 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're also advancing butyriceran in investigational therapy, which is delivered by a quarterly subcutaneous injection, and is also in development for AT-terramyloidosis. Here, we're conducting two Phase III studies. The first is Helios A, evaluating butyriceran in HAT-terramyloidosis patients with polyneuropathy. At the AAN 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 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 Vutrisran's impact on the expiratory 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 III butrysperine study is Helios B, which is our ongoing Phase III cardiac outcome study with butrysperine, inheritory, and wild-type ATTR 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 600 patients randomized to date. EDIUS-B 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 this following results from Apollo-B and alignment with regulatory authorities. Lastly, for vitreous RAN, we're very excited about the potential opportunity for biannual dosing regimen, which could further differentiate vitreous RAN 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 vitriceran. 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 vitriceran at a dose of either 25 milligrams every three months or 50 milligrams biannually. These data, intended to demonstrate the safety and efficacy of the 50-milligram biannual regimen, are expected in 2022. 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, ALM-TTR-SCO4, that we believe could support an annual dosing regimen with greater than 90% TTR knockdown. We intend to share more detail on the iCarrier platform and our preclinical work at an upcoming scientific meeting in mid-2021. Let's now move on to Lumasran, our RNAi therapeutic recently approved in the EU and US as the first treatment for primary hyperoxaluria type 1, or PH1. We were very pleased to announce positive top line results from Illuminati just last week. As a reminder, Illuminate-C is a single-arm, multinational, Phase III study designed to evaluate the efficacy and safety of Lumacerin 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 Lumacerin 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, the Maserin 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 discontinuations from 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 oxaluma. As we have noted previously, we're also excited about the potential for Lumaceran for patients with recurrent renal stones. And later this year, we plan to start a phase two trial to evaluate that potential. As you know, we have two additional late-stage programs that are in development with partners. This includes LEC-VO or Inclisiran, partnered with Novartis, which was approved last year in the EU for the treatment of adults with hypercholesterolemia or mixed dyslipidemia. LEC-VO marks the first RNAi therapeutic approved for a prevalent condition. Recently, Novartis resubmitted its NDA for LEC-VO 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 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 FITUSERAN in the Atlas Phase III program. Sanofi announced substantial progress with FITUSERAN 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 have 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. Zilbesaran, formerly known as LNAGT, 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 the phase one study in which patients treated with single doses of Zilbesaran at 100 milligrams or higher doses experienced durable reductions in serum AGT of more than 90% throughout 12 weeks. Reductions in 24-hour systolic blood pressure of greater than 10 millimeters mercury were observed at week 8 after single doses of 100 milligrams or higher. This antihypertensive effect 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, Zilbesaran has been generally well tolerated with an encouraging safety profile observed to date. The phase one study has two parts that are designed to assess the tolerability of Zilbesaran during potential augmented pharmacology inducing either by a slow salt diet or by co-administration of the conventional RAS inhibitor, erbisartan. These cohorts have completed dosing with data readout expected later this year. We also recently initiated our Cardio Phase 2 program with Zilbesseran. The first of the two studies, Cardio 1, is designed to evaluate the efficacy and safety of Zilbesseran as a monotherapy in patients with mild to moderate hypertension. This study is currently enrolling patients. In late 2021, we plan on initiating Cardio 2, which is designed to evaluate the efficacy and safety of Zilbesseran as an add-on therapy in patients with uncontrolled hypertension whilst receiving treatment with standard of care. Moving on, we're also advancing ALN-HSD in collaboration with our partner, Regeneron, for the treatment of NASH. We believe that RNA-mediated knockdown of HSD17B13 will phenocopy the genetic loss-of-function findings reducing hepatic inflammation, injury, and fibrosis in NASH patients. Enrollment and dosing continues in the Phase I study of ALN-HSD, which has now transitioned to dosing in Part B with NASH patients. Let's turn briefly to our ALN-HBVO2 program, also known as VIIR-2218, in partnership with VIIR. At the EASL meeting in June, VIIR presented results from a Phase II study of ALN-HBVO2 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 has retained a free opt-in right to co-develop and co-commercialize HBVO2 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. The significant unmet need for new treatments to address recurrent gout attacks are a 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 ALNAPP program in development for the treatment for autosomal dominant Alzheimer's disease and cerebral amyloid angiopathy. We now plan to file a CTA for Airline 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 Airline COV or Airline COV 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, let me now turn it over to Jeff to review our financial results. Jeff?
spk14: Thanks, Akshay. Good morning, everyone. I'm pleased to be presenting Al Nilem's Q2 2021 financial results, which reflect another strong quarter of operational excellence across the business. Turning to our results first for Enpatro, 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. U.S. on PATRO 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 deductions and less inventory stocking in the quarter compared with Q1 2021. In our international markets, on-patch 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 comprised 54% of our global total in Q2, clearly reflecting the benefit of our global commercial footprint. 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 U.S. healthcare system. With Oxalumo, we had an excellent second full quarter of sales, generally 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 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 percent 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 recognized $0.3 million in royalty revenues during the quarter, representing our initial recognition of royalties earned on Novartis' sales of Lectio. Gross margin on total revenues was 82.4 percent for the quarter, a slight improvement from prior year. Our combined non-GAAP R&D and SG&A expenses for the quarter increased 19 percent versus Q2 2020. Key drivers of the increase continue to be additional R&D investment in advancing our late-stage pipeline programs and increased SG&A investment to support our three commercial brands, including the launch of UxLumo. 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'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. 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. 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?
spk09: 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 Peptidrine will discover and develop peptide siRNA conjugates to create multiple opportunities to deliver RNA 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. 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 HELIUS-A phase three study with Butrisaran. We also plan additional regulatory submissions for Butrisaran in the EU, Japan, and Brazil in late 2021. Based on the excellent progress in enrollment, we also plan to complete enrollment in HELIUS-B in the coming weeks as we announced today. With Saldíceran, as actually mentioned, we plan to present additional data from the phase one study later this year, hopefully at the American Heart Meeting in November, pending abstract acceptance, and plan to initiate the CARDIA2 phase two combination study later this year as well. For Lumathiran, we plan to initiate a phase two study for renal stone events in late 2021. We believe this phase two study represents meaningful life cycle management of oxalumines 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 ALN-HSD, we expect to report initial safety results in healthy volunteers from the phase one study. Turning to Semdesiran for complement-mediated diseases, our partner Regeneron plans to initiate a phase three study of semdisarand and pizelimab combination in myasthenia gravis, in addition to multiple phase two studies in PNH. We believe the combination of semdisarand and pizelimab represents an attractive therapeutic strategy to complement mediated diseases. We're very excited to file our first CNS CTA for AI and APP, now expected in late 2021. in development for the treatment of autosomal dominant Alzheimer's disease and cerebral amyloid angiopathy. This sets us up for potential initial POC data in 2022. And given the exciting preclinical progress, we plan to advance ARN-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,
spk07: 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.
spk11: Ladies and gentlemen, if you have a question or a comment at this time, please press the star then the one key on your touchtone telephone. If your question has been answered or you wish to move yourself in the queue, please press the pound key. Our first question comes from Gina Wang of Barclays.
spk03: Thank you for taking my question and also congrats on the very strong quarter. So I have a one big picture question. Onala 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?
spk13: Hi, Gina. 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 5th 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-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 P to the 5th by 25 goals and our abilities to execute continuously on that sustainable source of innovation. So that's how we're focused, Gina.
spk03: Thank you.
spk11: Thank you. Our next question comes from Alicia Young with Cantor Fitzgerald.
spk06: Hey, guys. Thanks for taking my question. You guys crushed it this quarter. I guess I wanted to – it's another kind of big picture, but just wanted to talk a little bit about as you started to do bigger programs like in hypertension and even ones beyond as you build up 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?
spk13: 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 Delbisiran 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 is 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. 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, Yvonne, a little bit about our perspectives on growth in the prevalent disease markets?
spk14: Yeah, I think I agree with everything you said, John, and one of the metrics in our P to the 5th by 25 goals is getting to profitability across the period, and we're committed to doing that. I think the one other comment that I would make as it relates to Zabvisaran is, from a commercial standpoint, our hope is that we'll be able to leverage Zabvisaran uh infrastructure that hopefully we will have built by then from a you know 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 as well and yvonne do you want to comment a little bit more strategically going forward how we think of this
spk09: No, I think actually both of you have covered this well. You know, we believe we're a unique company. And, you know, we have every intention of building a top five biotech. And we have every intention of progressing all of our opportunities, obviously, in a thoughtful fashion.
spk13: Thank you, Yvonne. Awesome.
spk09: Thank you very much.
spk13: Does that answer your question, Alethea? Yeah.
spk06: Yeah, it was great. Thank you, guys.
spk11: Great. Thank you. Our next question comes from Joseph Stringer with Needham & Company.
spk13: Joseph Stringer Hi, Joseph. I can't hear you. Are you on mute?
spk11: Joseph Stringer Joseph, your line is open. You can ask your question.
spk13: Joseph Stringer Maybe we should go to the next question.
spk11: Joseph Stringer Okay. Our next question comes from Maury Raycraft with Jefferies.
spk16: 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 Zalbicerin and Incliserin that investors should be thinking about, and is there anything additional you could say about the CARDIA-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 timelines could look like for both CARDIA-1 and 2. Fantastic.
spk13: 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 Salvi-Saran and its potential to reimagine the treatment of hypertension. And you're very right, Maury, to point to the analogy with Eccles-Saran, because, you to address both very prevalent diseases. One is in hypercholesterolemia with Inclisiran, the other in hypertension with Saubisiran. And both, of course, enable a very infrequent dose regimen to control these 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 I studies and our Phase II studies in the cases of obese around blood pressure and in the case of increased around LDL cholesterol, those are the exact same endpoints that will be used in our Phase III 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 three study with Zalvisaran. And that's a very analogous situation to what we had with Inclisaran in the setting of hypercholesterolemia. So a very attractive profile. And of course, we're very, very encouraged by the safety profile that we saw with Inclisaran in thousands of patients that were studied. And we're obviously aiming to achieve a similar result with Zalvisaran. 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 Inclisiran and Zolbisiran. So with that, Akshay, maybe you can talk a little bit about more of 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.
spk12: Yeah, thanks, John. Maury Zarbisaran will execute two phase two studies. Cardio 1 is looking at Zarbisaran as a monotherapy in patients with multi-modal hypertension. About just shy of 400 patients, 375 or so in that study, orthodox randomized control study. And that study's up and running. That will be complemented by Cardio 2, which will kick off in the months to come later this year. And there we'll evaluate in cardiac tube the combination of xylopisarab with other antihypertensive medications. And of course that will include RAS inhibitors, calcium channel blockers, diuretics. There are more details to come. That study will be larger, about 650 patients or so. You know, we're not guiding right now to do 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, 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 the Phase 1 that John has already commented on. With reference to dose and regimen, you know, 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 further development in phase three. So I hope that's helpful, Maury.
spk16: Very helpful.
spk11: Thanks for taking my questions. Thanks, Maury. Our next question comes from Salveen Richter with Goldman Sachs.
spk00: Good morning. Thanks for taking my question. Just given your agreement with PeptiDream, could you just talk about extrahepatic targets or tissues that you're looking to target beyond CNS?
spk13: 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 oculars. 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?
spk12: Yeah. So, Solveig, of course, we're interested in a range of organs for 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 an sRNA to any cell type and expect to see target knockdown, and we can say that with confidence. 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 peptidrine beyond the liver. So, of course, we're already in the CNS and I. We have several options there in terms of the kinds of conjugates we've built. I'm sure we can add to those with peptidrine, 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.
spk00: Thank you.
spk11: Thanks, Sylvain. Our next question comes from Paul Matias with Stiefel.
spk15: 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 backstory to that or any relationship to the prior on 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.
spk13: 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 chair of the company. And this is really to help us continue and further strengthen our 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 for many, many years, 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?
spk12: Yeah, Paul, you know, I think – Clear to everybody, the primary endpoint is 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 paticeran in the ATTR cardiomyopathy population. So we're looking forward to that result in the middle of next year. The study is fully enrolled, of course. And that's exciting. Now, vis-à-vis the specifics of mortality and hospitalization, the study wasn't powered around that. And, you know, 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.
spk15: Fair enough.
spk13: Does that answer your questions?
spk11: Yeah, thanks, Matt.
spk13: Absolutely.
spk15: Thanks.
spk11: Our next question comes from Ritu Bara with Cowan.
spk04: 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 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.
spk13: Okay. That's great. Let me start with the IA question. then we'll, Akshay, you may want to comment on the IA after that, and then we'll go to Toga on your question for Delta variant and, you know, perspectives on Q3. We obviously aren't going to foreshadow Q3, but we can give you some sense from at least our view. So regarding the interim analysis, Ritu, when we designed Helios B, we included the, 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 you know, mortality and CB 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 in Helios B as it relates to that study. Now, it's extremely good that we also have, you know, killed it on the enrollment of Helios B as it relates to the study and the fact that, you know, the ultimate ending date of that study has 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 IA side of things? No, I think you covered it, John. 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? Yeah, absolutely.
spk10: Thank you for that question. Look, I mean, we obviously as an organization learned a lot and built a lot of capabilities that includes alternative sites of care, home care when it's possible, and how we've been able to continue to engage with physicians and other important customers. That will stay with us regardless of where the Delta variant is going. So we clearly were able to take advantage of the healthcare system opening up And that has obviously been reflected on 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 vaccines. 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.
spk13: No, I think you nailed it. I would just say, obviously, Ritu, our confidence is partially reflected in our new guidance range, which we upped to 640 to 665 this morning. So, obviously, we wouldn't have done that if we didn't feel confident around our ability to continue to perform for the rest of the year. And I think that speaks for itself.
spk04: Great. Thanks.
spk13: Great. Thanks, Ritu.
spk11: Our next question comes from Tazina Med with Bank of America.
spk05: Hi. Good morning. Thanks for taking my question.
spk11: Good morning.
spk05: 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 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.
spk13: Yeah, those are great questions, Tuzin. I'm going to just pass them both over to Akshay. Akshay, why don't you handle them?
spk12: Yeah, so the enrollment in Heliospeed 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 peripheral neuropathy, and it's of great interest. In the cardiomyopathy space, as you know, 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 showing mortality and hospitalization. So all of these bode well and I think are very promising in terms of the hope for both Petisoran and Vutrisoran. in the various studies, including Helios B for butrycerin. So I think that's helped a lot. There's great interest. Of course, butrycerin is once every three months subcutaneously, and we're also investigating 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 factor. 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 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 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 of 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, you know, they'll have a substantial burden of disease in terms of immunocompromised patient one, two, and some patients with class three disease. So I think the Apollo readout, and as John emphasized on an earlier question regarding the interim analysis for Helios B, is an important readout and will give us the great insight that we'll then leverage to make decisions around the IA for Helios B.
spk05: 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, you know, 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.
spk12: 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 the studies of patients coming into Apollo B and Helios B studies, the inclusion-exclusion criteria, 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 a reflection of the tremendous work by my colleagues and the attractiveness of the hypothesis and vitreous saran as a drug as opposed to, you know, something awry in the study. So we're feeling good.
spk13: Yeah, I'm going to be less British. There should be zero concern about that. Okay.
spk05: Thank you.
spk11: Thank you. Our next question comes from Manny Fruhar with SBB Layering.
spk02: Hey, guys. Thanks for taking the question. First, let's start with the Peptidreme collaboration. We've seen some early but interesting data with other oligo approaches using an antibody targeting approach, specifically in skeletal muscle. Do you want to give us a little bit of a sense of how you Think about that data versus the unique advantage of the peptidema approach and sort of the scope of extrahepatic targets. Are there specific teacher types that you think the peptidema collaboration is especially well-suited for? 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 are we in terms of the recovery and clinical volumes? And is there additional tailwind to be had there commercially on growth acceleration across the existing pipeline? I'm sorry, across the existing commercial platform.
spk13: Manny, could you repeat the second part of your question again? COVID impact and, yeah.
spk02: Yeah, it's how much – presuming that we don't have a – that we don't have a return to lockdown sort of bear dynamic, how much runway is there in the rebound in clinical volumes and how much of a tailwind remains?
spk13: Good. Okay. All right. So, Akshay, do you want to handle the Pathy Dream question? Yeah. And then Tolga, maybe you can address Manny's question on tailwinds on that side. So go ahead, Akshay. Okay.
spk12: Yeah. So, Manny, you know, broadly speaking, you know, we ourselves have invented a number of delivery systems for RNA therapeutics to the liver, to the nervous system, and the eye. Of course, we've been very open with the lipid nanoparticle approach from PATRA and then the Galnak conjugates for the liver, and then we have novel conjugates, which we haven't shared as many details for, for the central nervous system and the eye. And so I'm confident that Over the period of time, there will 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. 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. In fact, we know we have a much more diverse library we can tap with Peptidreme. And so we'll be able to reach a vast array of receptors for internalization of RSRNAs. And so it's really a very exciting collaboration. 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 all nine.
spk13: Tolga, do you want to handle the second question?
spk10: 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 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 close 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 in an environment where they're limited with the healthcare systems. The more it opens up, it will certainly help us to be able to continue to grow at that state of rate that we've been able to demonstrate.
spk13: Yeah, and I would just add, thanks, Tolga, and I would just add, Benny, to your question that, you know, we know that there are still going to be more and more patients that come back into the healthcare system. I think we all know it, 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, you know, more headwinds or more tailwinds, rather, for the future because of just return into the healthcare system and normal care cycles that are going to be important going forward.
spk02: Great. Let's take the question, guys.
spk11: Thank you. Our last question comes from Luca Issi with RBC Capital.
spk01: Oh, fantastic. Thanks for squeezing me in, and congrats on all the progress. Two quick ones here. 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 Fetuceran, 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.
spk13: 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 product. 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 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 El Milo innovation and El Milo 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 our RNAi platform and 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 TTR-SCO4 will be the first program providing, you know, annual dosing, almost a vaccine for the treatment of HATTR and more broadly ATTR amyloidosis. So very, very exciting. Now on Pituceran, that's our program in 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 the Fetuceram profile, including its effectiveness, potential effectiveness in hemophilia B, where there is no subcutaneous treatment option today. And that's a, while 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 in Delveon 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. You know, gene therapy is coming as well, but I think that's going to really be niched in the whole hemophilia segment at the end of the day. So Akshay, anything to add to those two comments I just made? No, you covered it, John. Excellent, excellent. Thanks so much. All right, 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 PD to Fit by 25, so it's an exciting time for Al Milam by all accounts. Thank you and have a great day.
spk11: Ladies and gentlemen, this does conclude today's presentation. You may now disconnect and have a wonderful day.
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