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Alnylam Pharmaceuticals Inc
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Hello, thank you for standing by. And welcome to the Alnylam Pharmaceuticals Second Quarter 2022 Earnings Conference Call. At this time, all participants are in a listen-only mode. After the speaker presentation, there will be a question-and-answer session. [Operator Instructions] Please be advised that today’s conference may be recorded. [Operator Instructions]
I would now like to hand the conference over to the company. Please go ahead.
Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Akshay Vaishnaw, President; and Jeff Poulton, Chief Financial Officer.
For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, investors.alnylam.com/events.
During today’s call, as outlined on Slide 2, Yvonne will offer introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress. Akshay will review recent clinical and preclinical updates. And Jeff will review our financials and guidance, followed by a summary of our upcoming milestones before we open the call for your questions.
Please note we are in a quite period with regards to the upcoming APOLLO-B results and therefore will not be addressing any questions on that matter.
I would like to remind you that this call will contain remarks concerning Alnylam’s future expectations, plans and prospects which constitute forward-looking statements for the purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recently quarterly report on file with the SEC.
In addition, any forward-looking statements represent our views only of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements.
With that, I will now turn the call over to Yvonne. Yvonne?
Thanks, Christine. And thank you, everyone, for joining the call today. We are very pleased with our second quarter results and the progress we've made towards our near- and long-term goals. Commercially, we achieved 14% product sales growth compared with the first quarter as we continue to drive a steady increase in patients on therapy across our portfolio of marketed products, including ONPATTRO, GIVLAARI and OXLUMO. And we're excited to have expanded that portfolio with a recent U.S. approval and positive CHMP opinion for ONPATTRO for hATTR amyloidosis patients with polyneuropathy. And we are looking forward to executing on ONPATTRO’s launch and the potential for further global expansion.
Five RNAi therapeutics from our organic platform approved in under four years is truly remarkable. In addition to our growing commercial portfolio, we continue to make great strides with our RNAi therapeutic pipeline programs. This includes our progress in establishing our TTR franchise, where we are tracking towards plan and are on the cusp of seeing results from the APOLLO-B Phase 3 study of patisiran in patients with ATTR amyloidosis, with cardiomyopathy.
We've announced the day that we expect to share top line data within the next three weeks with full data to be released thereafter at the medical congress. In addition to these highly anticipated results, we also continue to make exciting progress across numerous other progress within our pipeline. We have and continue to innovate a part of what we believe to be one of the most productive, organic and self-sustainable platforms in biotech, which has the potential to deliver meaningful value creating therapies for rare and prevalent diseases in the years to come.
To that end, there are many recent and upcoming milestones that underscore the breadth and scope of our pipeline. The cemdisiran we reported positive top line Phase 2 results in patients with IgA nephropathy, a kidney disease with significant unmet medical need. We're now working with Regeneron, to finalize Phase 3 plans, and potentially initiate the program by the end of this year.
We were also excited to see positive data presented by Sanofi from the Phase 3 ATLAS-PPX study of fitusiran in patients with hemophilia, which met its primary endpoint and demonstrated that fitusiran prophylaxis, significantly reduce breathing episodes compared to prior factor bypassing agent prophylaxis.
Looking through to the end of this year, we expect to have updates across our pipeline, including the potential for top line results from early studies, of AI and HSV in NASH, AI and XVH in Gouache, and AI and ATP in early onset Alzheimer's disease. Our first CNS endeavor.
Sticking together, this all highlights our focus on these three key drivers for Alnylam’s growth of the next several years. First, is the potential near term expansion of our TCR franchise opportunity, where we aim to become a global leader in delivering impactful and highly differentiated medicine to patients. The second key growth driver is our expansion beyond rare diseases into prevalent diseases. And the third growth driver for the company comes from our sustainable innovation engine, comprised of new platform, enhancements opportunities to extrahepatic delivery, and our ability to find new genetically validated targets, which can drive further pipeline expansion to 2025 and beyond.
We believe all of this positions as well to deliver on our Alnylam P fifth by 25 goals, making Alnylam a top biotech company, developing and commercializing transformative medicines for rare and common diseases for patients around the world, driven by high yielding pipeline of first and/or best-in-class product candidates from our organic product engine, all while deliver exceptional financial results.
With that, let me now turn the call over to Tolga, to review our commercial performance. Toga?
Thanks Yvonne. And good morning, everyone. Q2 was a strong quarter for our commercial portfolio with 14% quarter-over-quarter growth as Yvonne highlighted. We're also excited about the FDA approval and launch of AMVUTTRA in June. And we are encouraged by early promising size of [indiscernible]. I have more detail to share on that shortly.
As anticipated, we are also experiencing improved market conditions following COVID impacting Q1, as we saw increased promotional activities, improve the patient flows, healthy demand, and improved patient compliance across our portfolio.
I'll now provide details on the performance of each of our products. We continue to see growth for ONPATTRO achieving $153 million in global net product revenues in the second quarter, representing a 12% increase compared with the first quarter and 35% growth compared with Q2 2021. At the end of Q2, over 2,400 patients were on commercial ONPATTRO treatment worldwide, up from over 2200 patients at the end of the first quarter, representing steady 9% quarterly patient growth.
In the U.S. sales of ONPATTRO increased 14% versus the first quarter, and were primarily impacted by an increase in patients on therapy and improved patient compliance following Q1, which was negatively impacted by COVID.
In our international markets ONPATTRO Q2 product sales increased 10% versus Q1 2022, primarily due to an increase in patients on therapy and the timely orders in distributor and partner markets.
Important to note our global results continue to be challenged by foreign exchange headwinds with ONPATTRO year-over-year reported growth of 35% being held back seven percentage points by the strengthening U.S. dollar.
As you are aware, we received U.S. approval for AMVUTTRA at the end of the second quarter. And we're very pleased with the initial launch so far as our teams continue to execute in line with our clients. We received 133 start forms from launch through July 22 keeping demand generation on track with approximately one third of start forms generated from patients new to Alnylam, and two thirds from switches from ONPATTRO. Over 20% of those start forms came from new prescribers, which we believe is an encouraging early sign of potential market growth. We hit the ground running, reaching over 61,000 key stakeholders within 48 hours of launch serving as a catalyst for field engagement.
We have also been engaging with health systems and the formulary processes has been started in over 60% of the priority deliver networks.
Further from an access standpoint, our teams have been engaged and feedback has been posted to date. In fact, there is one national policy published with a large national payer covering 24 million lives.
The first AMVUTTRA patient has also been treated and we're looking for continuing this rollout and updating you further on our Q3 call.
Moving to our ultra-rare disease franchise, first with GIVLAARI, we achieve $45 million in global net product revenues in the second quarter, representing a 28% increase compared with Q1 2022 and 47% growth versus Q2 2021. At the end of Q2, over 420 patients were on commercial GIVLAARI treatment worldwide, up from over 400 at the end of the first quarter, representing a 5% quarterly patient growth.
In the U.S. sales of GIVLAARI increased 25% versus the first quarter. And we're primarily a result of the following: a healthy demand growth of 12% driven by an increase in patients on therapy and improved patient compliance following a soft Q1, primarily impacted by COVID. Inventory stocking dynamics, which favorably impacted reported growth by 8%, and a degrees in gross net deductions in the quarter, which favorably impacted reported growth by approximately 5%.
In our international markets, GIVLAARI delivered 34% growth compared with the first quarter with the growth primarily driven by new patient adds, including a strong launch in the UK and favorability in growth net deductions. Finally, global GIVLAARI year-over-year reported growth of 47% was also held back by six percentage points due to our favorable foreign exchange rates.
Moving now to our second ultra-rare disease product OXLUMO. We achieved $15 million in global net product revenues in the second quarter, representing a 2% increase compared with the first quarter. At the end of Q2, over 200 patients were on commercial OXLUMO treatment worldwide, up from over 160 at the end of the first quarter, representing 25% quarterly patient growth.
In the us sales of OXLUMO increased 32% versus the first quarter and were primarily impacted by an increase in patient demand as well as inventory stock dynamics and a decrease in growth to net deductions during the quarter. In our international business, despite an increase in patients on therapy during the quarter, Q2 OXLUMO sales decreased by 15% compared with Q1, primarily due to an increase in gross to net deductions during the quarter and the timing of orders in our distributor and partner markets.
On a year-over-year basis, global OXLUMO sales decrease 9% despite an approximately doubling of patients on therapy. The decrease was primarily due to a higher proportion of patients on the monthly loading dose portion of their treatments as well as lower net pricing in our international markets in Q2 2022. Additionally, as with ONPATTRO and GIVLAARI changes in foreign exchange rates also negatively impacted OXLUMO Q2 2022 results with reported year-over-year growth of minus 9% held back by 5 percentage points due to the strengthening U.S. dollar.
In conclusion, we are pleased with the growth in revenues and patient demand, achieving Q2 and look forward to our Q3 results, which will include the first full quarter of AMVUTTRA's launch.
With that I will now turn it over to Akshay to review our recent IND and pipeline progress. Akshay?
Thanks Tolga and good morning, everyone.
I'll start with our efforts in AT amyloidosis doses where we are advancing two clinical stage product candidates: Patisiran and Vutrisiran. While Patisiran are on ONPATTRO currently approved in multiple markets around the world to treat polyneuropathy associated with hereditary AT amyloidosis doses. We are committed to expanding the product's label for the treatment of cardiomyopathy in both hereditary and wild-type AT amyloidosis patients. Excuse me, to this end we're conducting the APOLLO-B Phase 3 study and as announced this morning, we expect to report top line results within the next three weeks.
We're also advancing Vutrisiran, which is delivered by quarterly subcutaneous injection and was recently approved in the U.S. under the brand name AMVUTTRA to treat the polyneuropathy of hATTR amyloidosis in addition to receiving the positive CHMP opinion in the EU. Here to we are committed to expanding the label for the treatment of cardiomyopathy in hereditary and wild‑type patients. Vutrisiran is also in development for Stargardt Disease. HELIOS-A evaluating Vutrisiran in hATTR amyloidosis patients with polyneuropathy formed the basis by regulatory submissions and recent U.S. approved AMVUTTRA.
In April 2021 we presented positive results from the study at the AAN meeting, which shows the study met its primary and secondary endpoints at nine months. We continued to report results from the study and recently presented new 18-month results from exploratory cardiac endpoints at the ESC HF meeting. These findings show that in a variety of pre-defined – show that in a pre-defined cardiac sub-population of hATTR amyloidosis patients with polyneuropathy, treatment with Vutrisiran was associated with improvements in exploratory cardiac endpoints relative to external placebo, including levels of NT-proBNP and a trend towards improvement in echocardiographic parameters. These findings in the cardiac subpopulation were consistent with the previously reported results in the mITT population.
Additionally, in a planned cohort of patients from the mITT population, Vutrisiran treatment reduced cardiac uptake of technetium on scintigraphy imaging relative to baseline in the majority of accessible patients, including those with paradigm equal to two at baseline, suggesting that patients with the highest degrees of cardiac amyloid burden may recognize benefit from RNAi therapeutics. Vutrisiran also continue to demonstrate an encouraging safety and tolerability profile.
As mentioned this is just the start for Vutrisiran as is also being evaluated in the HELIOS-B Phase 3 study for the treatment of patients with AT amyloidosis with cardiomyopathy including both hereditary and wild-type AT amyloidosis. HELIOS-B which is fully enrolled has a 30-month endpoint of all-cause mortality in CV events with many patients followed up to 36 months and we expect the full results in early 2024. The study design includes the potential for an interim analysis, and we will consider this following results from APOLLO-B and engagement with regulatory authorities.
In addition to our late stage clinical programs, we believe we've also been making great progress without early and mid-stage programs. Notable highlight in the second quarter was our announcement of positive top line results from our Phase 2 study of Cemdisiran an investigational RNAi therapeutic targeting the C5 component of the complement pathway and is in development in collaboration with Regeneron for the treatment of IgA nephropathy or IgAN. In this study at week-32 treatment with Cemdisiran resulted in a 37% mean reduction from baseline in the 24-hour urine protein-to-creatinine ratio relative to placebo. This was the primary endpoint of the study and an important prognostic marker of disease progression.
The results of secondary endpoints were also consistent with the therapeutic benefit of Cemdisiran in IgAN. There were no significant drug related safety signals, and we believe these collective efficacy and safety data support continued clinical development of Cemdisiran monotherapy in patients with IgAN. We now look forward to gaining a line with Regeneron to finalize plans for Phase 3 and hope to initiate a program by the end of this year, pending regulatory agency feedback.
Moving on a key growth driver for Alnylam in the years come will be our organic product engine driving sustainable innovation. The second quarter features a new highlight in this regard. In Nature Biotechnology we published data from preclinical research on the delivery of lipophilic siRNA conjugates extrahepatic tissues including the CNS. These data provides early evidence of a potential role for 2'-O-hexadecy C16 conjugate siRNA in treating diseases of the CNS eye and lung with further exploring the potential for lipid conjugates to help achieve delivery to other organs.
In another publication in Nature Communications this time we published research findings identifying mutations in the INHBE gene associated with protection against abdominal obesity and metabolic syndrome, a condition impacting more than 20% of adults to avoid. Finding support the potential of INHBE which was previously referred to as Gen X to be evaluated as a novel therapeutic treatment of the treatment of Cardio-Metabolic Diseases, since INHBE loss of function improves waist-to-hip ratio and is associated with an improved lipid profile. With plan to pursue a development candidate for INHBE and its gene product actively leveraging out IKARIA platform. As you can appreciate, we have an incredibly broad and innovative platform that continues to advance and these are just a few recent highlights. We look forward to updating you on a number of these programs in the coming months.
With that let me now turn the call over to Jeff to review our financials and upcoming milestones. Jeff?
Thanks Akshay, and good morning everyone. I'm pleased to be presenting a summary of Alnylam's Q2 2022 financial results and an update to our full year guidance.
Starting with a summary of our P&L results for Q2 2022. Total product revenues for the quarter were $214 million or 33% growth versus Q2 2021. It's also worth noting that year-over-year growth in combined product revenues was held back by approximately 7% due to the foreign exchange impact of a strengthening U.S. dollar, which reached a 20-year high recently. And given that approximately 50% of our product revenues are generated via sales of international markets.
Net revenue from collaborations for the second quarter was approximately $9 million representing an 85% decrease compared with Q2 2021, primarily due to a reduction in revenue from our Regeneron collaboration, which is subject to quarter-to-quarter variability dependent on a variety of factors including the level of work completed during the quarter, which is reimbursed by Regeneron.
We do expect an increase in collaboration revenue and royalties in the second half of the year, primarily driven by increased activity across our Regeneron programs, as well as from an increased associated with Leqvio royalties and sales milestones as Novartis's U.S. launch progresses. Our non-GAAP R&D expenses increased 15% in the second quarter compared to the same period in 2021 primarily due to increased spend on early development activities and increased headcount to support the growth of our pipeline.
Our non-GAAP SG&A expenses increased 19% in the second quarter compared to the same period in 2021, primarily due to increased headcount and other expenses to support the growth of our commercial portfolio. Our non-GAAP operating loss for Q2 2022 was $161 million representing a $47 million higher loss compared with Q2 2021, which was primarily impacted by the reduction in collaboration revenue during the quarter.
Finally, at the end of the quarter with cash, cash equivalence and marketable securities of $2.1 billion compared to $2.4 billion at the end of 2021. We continue to believe our current cash balance is sufficient bridges to a self-sustainable financial profile.
Now I'd like to turn to our full year 2022 financial guidance. Following the strength of our operating results in Q2, we are reiterating the financial guidance we provided on our Q1 results call in April. Starting with net product revenues we anticipate combined net product revenues for our four commercialized products will be between $870 million and $930 million. However, given the continued strengthen of the U.S. dollar since we issued our guidance in April, and the fact that approximately 50% of our global product sales are generated in the international markets, we are currently trending towards the lower half of our $870 million to $930 million guidance range. Our guidance for net revenue from collaborations and royalties is a ranged between $175 million and $225 million, and our guidance for combined non-GAAP R&D and SG&A expenses is a ranged between $1,390 million and $1,450 million.
Let me now turn from financials and discuss some key goals and upcoming milestones on deck through the end of 2022. We'll continue executing on our global commercialization of ONPATTRO, GIVLAARI and OXLUMO as well as the launch of AMVUTTRA. Next our TTR franchise will have important updates with Patisiran's top line results from the APOLLO Phase 3 study are expected in the next three weeks. With Vutrisiran we plan to report results on a biannual dose regimen and initiate a Phase 3 study in Stargardt Disease both in late 2022.
Lastly, we plan to file an IND and initiate a Phase 1 study for ALN-TTRsc04 in healthy volunteers by the end of the year. In our mid-stage portfolio we are looking forward to milestones that include completion of enrollment in the Phase 2 study of Lumasiran in patients with recurrent renal stones by year-end. Completion of enrollment in our Phase 2 KARDIA-2 study of Zilebesiran at or around year-end, and results from the Phase 2 study of ALN-HBV02 in combination with monoclonal antibody VIR-3434, which are partners that we expect to report later this year.
Wrapping up, we have a few early stage readouts coming as well. These include top line results from Part B of the Phase 1 study of ALN-HSD in patients with NASH expected in mid-2022. Preliminary top line results from the Phase 1 study of ALN-APP in patients with early onset Alzheimer's disease expected in late 2022 and preliminary top line results from the Phase 1 study of ALN-XDH in patients with gout also expected for late 2022.
Let me now turn it back to Christine to coordinate our Q&A session. Christine?
Thank you, Jeff.
Operator, we will now open the call for questions. To those dialed in we'd like to ask you to limit yourself to one question each and then get back in the queue if you have any additional questions. Also, as a reminder we are in a quiet period with regard to our APOLLO-B study and will not be responding to questions on that topic.
Thank you. [Operator Instructions] Our first question comes from Paul Matteis with Stifel. You may proceed.
Hey good morning. Thanks much for taking my question. Just on Vutrisiran, just a two-part question the commercial dynamics, I guess one, can you talk about the initial prescribing for patients new to [indiscernible] and how much of that is coming from cardiologists? And then just curious on the economics of in-office dosing for Patisiran and how does that compare for a physician versus ONPATTRO as an infusion? Thank you.
Thanks Paul for that question. I just like to start off by saying that we really are delighted to have [indiscernible] with AMVUTTRA and it's great to have additional ONPATTRO for patients here and its target that on the call, the initial sign but also very, very encouraging.
Tolga, I'd like to hand over this question to you. So it's around the commercial dynamics with respect to the initial launch, how much in cardiology and then any commentary on the economics with respect to ONPATTRO compared to fitusiran from a physician perspective? Thanks Tolga.
Absolutely. Hi Paul. This is really exciting time. We launched the product and reporting the information that's available to us within the five weeks. In that five weeks we were able to receive over 130 start forms and of those one-third of those were actually naive patients. They are new to Alnylam and that's actually a very good robust number, it's early for us and these are only start forms. Patients need to go through the system and make sure that they actually get the product in, but as an early sign one-third as new naive patient dynamic is very encouraging.
In terms of the economics, essentially the product is Part B therefore it is still a buy-and-bill and those patients that are going to be looking at a very similar dynamics as we see in ONPATTRO. What we're also excited about is frankly 20% of our prescribers in this very short period are new prescribers of TTR, new prescribers of ONPATTRO. So that's also very exciting dynamic that I'd like to underline.
Thanks, Tolga. And thanks Paul. Next question, please.
Thank you. [Operator Instructions] Our next question comes from David Lebowitz with Citi. You may proceed.
Thank you very much for taking my question. First on Vutrisiran, this is not with respect to any details on the data. I just want to, as far as presentation, I know historically in the past for top line releases, you've put out key values. I just want to confirm that we would likely see P-values certainly on the primary endpoint, but also the secondary end points as well. And one little add-on here as far as pricing goes, can you at least give us perspective on what type of shift we might see once cardiomyopathy gets added to the label?
Great. David thanks for that question. I think the first one Akshay is for you.
Yes. Just clarifying Dave that you said Vutrisiran, but I suspect you met the Patisiran with respect to the APOLLO-B results, am I correct?
Indeed, of course.
Yes. And you are right we'll present top line results in the form of the PR with P-values as we test the primary and secondaries in a hierarchical order. So that's as much [indiscernible] present time.
Thanks Akshay. And maybe Tolga, you could take the second question, respect to pricing and any shift as we hopefully enter the Cardiomyopathy?
Look we're excited about the possibility of serving Cardiomyopathy patents, but as you could appreciate it's a little too soon for us to share any information because it's a little too soon, but we'll obviously update appropriately when we make those decisions.
Alright. Thanks David. Next question, please.
Thank you. Our next question comes from Salveen Richter with Goldman Sachs. You may proceed.
Good morning. Thanks for taking my question. Could you just speak to the dynamics with regard to switching and combination that's playing out between your TTR franchise and Pfizer’s tafamidis? Thank you.
I think Tolga that that question is straight over to you.
Yes. I mean, switching wise obviously in the U.S. we're indicated for polyneuropathy and the tafamidis indicated for cardiomyopathy, therefore we don't – we do not see any switching dynamics. In terms of common use we see similar rates that we've seen in the past. It's about anywhere between 15% to 20%. What we see, what we're excited about switching dynamics is in ex-U.S. particularly in Europe and Japan where both of those products are available in polyneuropathy we've seen a significant source of our business is really built by the switches. Obviously we continue to add new naive patients both in Europe and Japan, but early on we've seen a good, strong dynamic which alludes to us that the physicians believe that there is actually – probably more opportunity to use ONPATTRO as a silencer in the earlier part of the disease to get adequate treatment.
Thanks Tolga. Next question.
Thank you. Our next question comes from Ritu Baral with Cowen. You may proceed.
Good morning guys. Thanks for taking the question. I was hoping for just to follow up to Paul and Salveen's just a little more detail on the new patients. Tolga, you mentioned the prescribers, but are you seeing less severe patients? Is – are you seeing more mixed phenotype patients? And does this sort of bolus imply that there's some there's sort of warehoused patients to work through as we look at the new patient question for AMVUTTRA?
Yes. It's a great question. Thank you. If I indicated before, it's little too soon for us to really give a lot of specific dynamics. It's an area where we're obviously closely monitoring. What we're encouraged about is the early side indicate that we do see some – a little younger patients, but again it's difficult to generalize at this point. We're only five weeks into the launch. What we're again excited about is the fact that we are seeing a broad range of patients quickly getting either switched or not even being treated. Part of it, I'm sure is going to be a little bit of the warehousing, but it's important to highlight that in Q1 we had a great strong robust ONPATTRO growth. With what we originally thought was probably the patients, the physicians will be waiting and warehousing some of those patients for AMVUTTRA that didn't exactly happen. But I'm certain that part of the uptake that we see in the first five weeks might be contributed to that warehousing dynamic.
Yes. Thanks Tolga. It really does look at the introduction of AMVUTTRA is helping us, will help us grow the overall TCR franchise going forward which I think is very encouraging.
Thanks, Ritu. Next question.
Thank you. Our next question comes from Tazeen Ahmad with Bank of America. You may proceed.
Hi. Good morning. Thank you for taking my question. Mine's on HELIOS-B, so you've reiterated your confidence that the early 2024 target for data readout is something that you feel confident about. I'm just wondering is there at all a scenario in which you would opt to extend the observation period though to allow for a higher chance of seeing a significant improvement in mortality benefit.
Maybe I'll stop by retracing our confidence in an early 2024 data readout from HELIOS-B and Akshay any perspective on how we might think about that study going forward.
Yes. We've revisited the study designs and thoroughly assessed how robust is the study? Is it structured and powered in a way to help us meet the primary endpoint of the factory endpoint and we are comfortable with the study design. And so the study designs unaltered the only thing we'll consider is the interim analysis, of course in due course. And the other thing I would say by the way is that, as you, patients come in over a long period in the study in a large study like that, so many of them will have gone to 36 months and that provides additional coverage in terms of the robustness of the study. So we're comfortable and we'd reiterate later early 2024 and looking forward to positive results.
Thanks, Akshay. Next question please.
Thank you. Our next question comes from Joseph Stringer with Needham. You may proceed.
Hi, thank you for taking our question. Our question was for AMVUTTRA. I know its early days but how do you anticipate the time from start form to getting patient on drug? How do you think this compares relative to your experience with ONPATTRO? Thank you.
Yes. That's a great question and clearly with AMVUTTRA being our second product in the TTR franchise, we're really building on what's a very robust commercial operation that we have under Tolga's leadership. Tolga perhaps you could talk a little bit about that [indiscernible] speaking?
Thanks Yvonne. Obviously we're very well positioned to be able to maximize the opportunity for AMVUTTRA given our experiences with ONPATTRO and AMVUTTRA's really attractive profiles being subcutaneous injectable every months. In regards to – in regards to the – how the timing is going to work is look, I mean, at the end of the day we do have the right capabilities, right patient services, benefit verification, and so forth already in place within this category. And what we've so far done is working very closely with not only with major national and regional payers, but also with integrated delivery networks and other health providers to make sure that formularies are in place.
Given the fact that we actually also set the price despite its very attractive profile its parity with ONPATTRO, we have not so far seen any significant headwind. Nevertheless like any new product it does take time for the healthcare system to absorb and make sure the PNT committees and so forth are in place to get the product approved. We're very pleased with the early signs of what we've so far done and how the healthcare systems are reacting, but I'm sure we're going to see some delays early on and eventually get to a place where I think it's going to be at parity with ONPATTRO or even maybe a little faster approval dynamic, but it's a little too soon for us to share where we are right now with that.
Thanks, Tolga. I think good progress thus far and we're very pleased. So next question, please.
Thank you. Our next question comes from Maury Raycroft with Jefferies. You may proceed.
Hi good morning and thanks for taking my questions. I was going to ask a question on Givosiran for hypertension. Just wondering if you can elaborate on steps you've taken to streamline the protocol to speed up enrollment and what the status is on that?
Yes. Just to everybody it’s a reminder, we unfortunately experienced and delays with our KARDIA-1 study with zilebesiran primarily due to the fact that we selected sites in the Ukraine and obviously with the ongoing war those sites were unable to move forward. We've expanded our site footprint in a very fee progress upfront. We also took the opportunity to just refine the protocol to make it an easier study to execute the [indiscernible]. I don't know, Akshay, do you want to add any?
No, I think you covered it Yvonne. The only other thing more specifically on the streamlining is we may inevitably more in these protocols, one tries to capture as much scientific information as one can. But given the needs of the program we're able to remove some of the assessments, don't take anything away from the core issue downtown hypertensive effects and safety, and so – and yet maintain two large robust protocols, which will be easier to approve one in monotherapy and one in combination therapy. So between the site expansion and these things, the profiles we are optimistic about readouts next year.
Great. And just to add that we're expecting to complete enrollment in KARDIA-2 at the end of this year.
That's right.
So we're looking forward to that. Thank you. Next question, please.
Thank you. Our next question comes from Luca Issi with RBC Capital. You may proceed.
Great. Thanks so much for taking my question. Congrats on the quarter. Maybe one on TTR polyneuropathy, how are you thinking about a competitive landscape here? Obviously Ionis have reported successful Phase 3 and it seem very confident they can compete commercially given the AstraZeneca global footprint. I know we don't have the full data at this point, but how are you thinking about implications of that launch for your franchise? Thanks so much.
Thanks. Yes, look I think that was primary question about, how we believe that we're going to compete in the TTR PN space, particularly with potential new competitors coming on stream with AstraZeneca.
Yes. Thank you, Yvonne. Look, first of all we are always excited to bring new mode of medication, different alternative treatments to patients because there's a lot of wood to chop when it comes to TTR PN prevalence and what the patients that are currently being treated. We anticipate the prevalence numbers around 25,000 to 30,000 patients worldwide and we are a very small fraction of that that we've been able to deliver. So what we've seen in similar categories, a good expansion of diagnosis and treatment rates going on. In regards to where we are, look at the end of the day we have been able to actually establish ourselves in the last four years as the major driver including in Europe and Japan against tafamidis that's also been promoted by an important company.
One of the important, I think, drivers of our growth is going be obviously the making AMVUTTRA available worldwide. And we are well positioned to do that. We have Europe and Japan and geographic footprint and available in over 50 markets through other partners and distributors. Given the fact that we're going to be a year ahead already off set competition and plus again a very attractive profile that AMVUTTRA offers for the patients with the subcutaneous injectable over three months, and soon with six months if those trials work.
We really like our chats in terms of how we're well positioned to be able to make this product available and continue to be a leader – as a portfolio leader. But again, I just want to reiterate, having said that there are going to be products available and that's good for patients, and we're excited about that.
Thanks. So Akshay, do you want to say anything about [indiscernible] effective profile?
Yes, no, I'll just add to what Tolga said which was makes a lot of sense, but in terms of the data themselves, I think, we've got a very comprehensive data associated with vutrisiran around AMVUTTRA in hATTR and of course the primary showing improvement in neuropathy which is exciting. And in terms of the other end points for the secondary, but not just those exploratory cardiac endpoint, the impact on the heart and [indiscernible] the respiratory endpoints, but still notable, particularly with the new observation of the reducing technician scan uptake. And that that's very exciting for patients and physicians.
And so, along with the convenience Q3, and then hopefully soon Q6 monthly dosing, this is a very differentiated product in the market that Tolga explained. We've been leaders in and ultimately I will add that love patients need good options in this space will want to see the full data package associated with frontiersin [ph] recalling that the first time round with inotersen and there were some safety issues of note including renal effects, injection site reactions, platelet effects. And I'm sure they, and everybody is keen to know that the safety is good.
So let's see, but I think we're off to a great start with AMVUTTRA.
Thanks for the opportunity.
Sure, very helpful. Thank you. Next question, please.
Thank you. Our next question goes from Gary Nachman with BMO. You may proceed.
Okay, great. So back to AMVUTTRA and the start forums and the two third switches from ONPATTRO, what's the profile of initial patients that are switching from ONPATTRO? Are you getting a sense if it's more patient or physician driven? Do they stay on ONPATTRO up until they get AMVUTTRA if that takes some time? And how do you expect that split between new and switches to shift over the next couple of quarters? Thank you.
Tolga I think that we have lots of interest than the AMVUTTRA early demand.
Hi, Gary. I mean, look at the end of the day, what we're really excited about is AMVUTTRA’s profile is giving us the ability and physicians the ability to be able to actually diagnosis and treat more patients. And what we've so far seen early signs is in terms of initiations it's both when it comes to switches, as well as naive patients. We have a good, robust patient services and our patients have been informed about the availability and some of those patients proactively reached out to their physicians.
What we've also seen is, as I indicated earlier, a good new, prescribers coming into the treatment of this condition and excited to be actually providing this medicine to those patients that probably were on the fence given that was an infusion with ONPATTRO earlier profile and AMVUTTRA tends to offer a very convenient option with great safety and efficacy data.
Therefore we do what we so far seen in 133 start forms is a good, broad range of both patient prescriber base, as well as patient demographics that ranges across younger as well as more traditional demographics.
Thanks. So, let's take the next question.
Thank you.
Thank you. Our next question line of Anupam Rama with J.P. Morgan. You may proceed.
Hey guys, thanks so much for taking the question. Maybe following on the last question on AMVUTTRA on switching dynamics, what does your market research suggest on the timeframe in which you would expect switching to kind of peak or where most patients that are going to switch have made the switch? I think that's what we're trying to understand, many of us. Thanks so much.
Hi, Anupam. That's a great question. And thank you for putting it forward very precisely. So I think Tolga, there is a specific question here around what our market research is setting up right about the time for sort of peak switching.
What we are really interested at this point is really to make sure that the overall category is growing. So our focus is actually right now is really to make sure that we are bringing as many as new patients as possible given this new option. The switch is what we believe is going to play out a little more organically and will obviously update the Street for about a year about the switch and net naive patients. What we expect that to organically happen is most patients will end up with AMVUTTRA given its profile.
However, we also know that in rare diseases, there are patients who are pleased with their existing treatment. Some of these patients never had any new treatment before AMVUTTRA sorry ONPATTRO was available. So we do expect some patients to remain on therapy. But in similar dynamics that we've seen is – similar dynamics that we've seen in other categories patients tend to gravitate towards a more better option, which we believe AMVUTTRA is.
But I also wanted to take the opportunity to remind everyone that we are going to be updating on the start form dynamics for two to three quarters.
Just one other comment. From a modeling perspective. It doesn't matter for ONPATTRO or AMVUTTRA the same price, same value per patient per year. So just a reminder on that point.
Great point.
Good. Okay. Let's take the – hit the next question.
Thank you. Our next question comes from Tong Wu with Barclays. You may proceed.
Hello, actually, can you hear me? [Indiscernible]
Yes, we can hear you.
Okay, good. This is Gena Wang from Barclays. Yes, so I have a question maybe follow-up the start form one to thirty-three start form. You said thirty four new to Alnylam just if you can give a little bit more clarity, what percentage of these are the switcher from tech savvy and versus truly naive patients?
And then quickly on HELIOS-B I just wanted to do some maintenance check, last time we discussed [indiscernible] dropping rate maintained at the low single digit, any change in the dropping rate?
Okay. Let's start with Tolga the AMVUTTRA question, and then back shape of the HELIOS-B question.
We really appreciate the excitement around the strong launch of AMVUTTRA, yet it’s only five week of data. So we wanted to make sure that we all recognize that the [indiscernible] data we're providing is as good as we possibly can at this point. Those 34 new patients are naïve to us.
And in terms of your own modeling one should also remember that the TEGSEDI remains a very small portion of the overall category. So we wouldn't necessarily index our naïve patients just only on switches from an alternative treatment.
Yes. Good opportunity to grow.
Exactly.
New patients coming into AMVUTTRA. So actually HELIOS-B has drop in rates.
Yes, thanks, Gena. I can reiterate the drop in rates remain well within expectations. And I think I've discussed before we obviously had put in a buffer in the sample size to account for tap drops. We are well within those estimates. So we're comfortable with the design Gena. Thank you.
Thanks, actually. That's great. Next question.
Thank you. Our next question comes from Eliana Merle with UBS, you may proceed.
Hey guys. Thanks for taking the question. I guess not an ATTR question, but on the pipeline for Lumasiran in recurrent renal stems, I guess maybe just with the Phase 2 finishing enrolling later this year and thinking about Phase 2 data next year. I mean, how should we think about what you are looking to see here it's obviously a much broader population. I guess what could we learn in terms of the relationship between oxalate reduction and reduction in stone formation and this broader population and your confidence in the biology there?
And then I guess thinking about sort of the regulatory pathway from there, like what a potential Phase 3 could look like? And any types of like patient segmentation in terms of accessing this much larger population?
Actually, I'm not sure if you called all of that.
Yes.
I think it's around the [indiscernible] study, what we're looking to see from Phase 2 data, how we're thinking about oxalate reduction and then I think plans for moving forward that study.
Yes. So thanks for the question. So the lumar recurrence stone formation study is ongoing is obviously a very large population globally numbering in the millions probably. And what we want to see is a reduction in urinary oxalate. Now in the pH1 population, of course, we saw very such reductions urinary oxalate, they have an enzymatic defect in the liver. And the targeting of GO1 leads to 70 plus percent reduction in urinary oxylate. This is a hypothesis we're testing. One of the interesting things is we may not need to achieve levels like that to see a reduction in stone events.
And so let's look at the data as it comes out next year and see. And I say that because the important thing is once oxalate becomes saturating levels in the urine that's when stone formation occurs. So you may not need to take it all the way back down to normal, you might just need to get it out of that super saturation range by some relatively modest margin to prevent stone formation.
And so lots more work to do here, and we'll update you as we get data, but this is a very exciting opportunity with an approved drug that looks very safe to find the PH1 population. And that just reminds me of several safety will also be important seeing the RF population, but we're optimistic with what we've seen so far with Luma in PH1.
Thanks. Actually another program in our pipeline, which is orientates around patients with much more common seizure, I think, an exciting potential development for our Alnylam. Next question, please.
Thank you. Our next question comes from Myles Minter with William Blair. You may proceed.
Thanks for taking the question. Just on some around fitusiran and the [indiscernible] property data, can you just sort of discuss where you see like the complement inhibitor methodology sitting in the lines of therapy and I guess how it relates to the data that we've seen from the endothelin-1 receptor antagonist?
And I guess is that a key consideration for Regeneron? And how they would potentially design a pivotal study and the types of patients that you would enroll in that pivotal study? Thanks.
So quite a few questions there. I mean really just yes, I think start off by reiterating that we were really pleased with the Phase 2 results of fitusiran patient with [indiscernible] property, very common condition, 37% reduction in [indiscernible], I think this is great. And I think kind of it's another potential Phase 3 program for Alnylam. So we're very pleased to be working with our partners Regeneron moving forward the next steps.
Actually, I think there were enough questions in there, but I think much more specific around how we're thinking about that program.
Yes, we're very excited about the Phase 2 result with a 37% reduction in urinary proteinuria. Busy working with Regeneron right now, we take the lead in this program in the ICAN study design and we are sort of very busily looking forward to engaging regulatory authorities and hopefully kicking off the study by the year end. The specifics of where compliment or anti complement approaches sit, the interesting thing is the fundamental underlying pathology here are IGA immune complex is that [indiscernible] activate compliment that activated compliment then damages the glomerular basement membrane and proteinuria results.
An additional aspect of the disease, I don't think anyone really understands how this occur is hyperfiltration in the kidney and says blood flow dynamics change through glomerulus. So we have the opportunity here orthogonally to impact two key pathogenic factors. With anti-compliment approaches we can get at the fundamental underlying immunopathology and we've seen the preliminary results we've shared. So this will have a foundational role, I believe, in the future in what will end up being a polypharmacy situation where there will be anti-inflammatory approaches like anti-compliment cemdisiran would be a great fit for that. It could be a once a month, once every three months type injection.
And then in addition to that things that alter blood flow, so endothelin antagonist, ACE inhibitors, ACE inhibitors, et cetera. And so you will see drugs from both classes, the antihypertensive type drugs and anti-complement drugs being combined. And we'll see if steroids will also become part of the picture, but there is more work to do there, although they are rather general nonspecific agents and have [indiscernible] side effects.
And just to add up what these favorable results open up the potential for cemdisiran, if the needs of patients with other [indiscernible] seizures, so we're enthusiastically moving forward here.
Thank you for the question.
One more question. I think we have one more question before we close. Last question, please.
Thank you. Our last question comes from Olivia Brayer with Cantor. You may proceed.
Hey, good morning guys. Thanks for the question. I know you are in a quiet period with respect to APOLLO-B, but I wanted to ask if there are any monitoring requirements after patients reach that 12-month mark that are built in this study? And then I've got a follow-up on sequencing from mixed phenotype patients. Is there anything you can do to improve access for patients that could move on ONPATTRO or AMVUTTRA after [indiscernible]? Thank you.
So I just want to say, you pointed out we are in a quiet period, so we're not going to be taking any questions on APOLLO-B, but I didn't actually quite catch your second question. I think it was something to do with AMVUTTRA, but I didn't hear it properly. Could you repeat the question, the second part of the question?
Yes, sure. It's just about mixed phenotype patients, right. And whether there is anything you guys can do to improve payer access there for patients that could sequence onto ONPATTRO or AMVUTTRA after [indiscernible]?
You mean plug neuropathy and mixed phenotype patients?
Yes.
Yes, I mean, look, we certainly have the right capabilities to support those patients. The fact that we've been able to position this at parity pricing, so certainly we believe will help increase access. So far we haven't really had heard any headwinds around the access piece. But we are indicated for polyneuropathy and in the U.S. tafamidis is indicated for cardiomyopathy. So in terms of providing any brief strategy for access would not be something we would consider.
Like any of our new patients, we have great support of benefit verification and patient access support, which those patients would certainly be eligible if they go through our patient service program.
Thanks, Tolga.
Okay. So thank you everyone for joining us on this call. We're very happy with the progress that we've made in the second quarter and first half of 2022. We've delivered strong commercial results. We've advanced our diversified pipeline programs and development, and we've got a number of exciting catalysts on deck in the coming months.
So we look forward to updating you along the way while we continue to deliver on our near and long goals. Thanks everyone. And have a great day.
Goodbye.
Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.