Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals conference call to discuss nine-month results from the HELIOS-A phase III study. There will be a question-and-answer session to follow. Please be advised that this call is being taped at the company's request. I will now advise to send the call over to the company.
Good afternoon. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are John Maraganore, Chief Executive Officer, Akshay Vaishnaw, President of R&D, and Yvonne Greenstreet, President and Chief Operating Officer. Also on the line and available for Q&A are Tolga Tanguler, Chief Commercial Officer, Pushkal Garg, Chief Medical Officer, and Rena Denoncourt, Vice President, TTR Franchise Lead. 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, alnylam.com/events. During today's call, as outlined in slide two, John will provide some introductory remarks, Akshay will discuss the HELIOS-A study and nine-month results in more detail, Yvonne will give an update on next steps with vutrisiran, and we will then open the call for your questions.
I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor Provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those in our most recent annual and quarterly reports 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 obligation to update such statements. With that, I'd like to turn the call over to John. John?
Thanks, Christine, and thank you all for joining us. Earlier today, we presented full nine-month results from our HELIOS-A phase III study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis. These results were presented at the American Academy of Neurology conference. Akshay will go through the results in just a minute, but let me start by saying we are thrilled with these nine-month results in patients with hereditary ATTR amyloidosis with polyneuropathy. Given these data and considering that vutrisiran is administered as a once-quarterly subcutaneous injection, we believe that vutrisiran will be a very welcome treatment option for patients with hATTR amyloidosis with polyneuropathy if approved by regulatory authorities. These positive phase HELIOS-A data lay the foundation for the planned expansion of our ATTR franchise into what we believe could represent a multi-billion dollar opportunity for Alnylam over time.
If approved, we expect the launch of vutrisiran based on the current study results will drive significant growth of our hATTR amyloidosis polyneuropathy opportunity. In addition, we plan to soon start studying a biannual sub-Q dosing regimen for vutrisiran, potentially enabling the introduction of an even more convenient treatment option for patients. Then, we expect that the ongoing clinical studies with both vutrisiran and patisiran in cardiomyopathy, if positive, will open up a broader ATTR amyloidosis opportunity for Alnylam. This includes the APOLLO-B phase III study of patisiran, which is expected to complete enrollment in early 2021 and read out top-line data in mid-2022, followed by the HELIOS-B phase III study of vutrisiran, which is actively enrolling throughout 2021. Notably, vutrisiran is now the fifth RNAi therapeutic program developed at Alnylam to report positive phase III results, all in a span of just over three years.
This is a real, truly remarkable accomplishment, one we are proud of and one we believe underscores the power of an organic, reproducible, and modular platform, as well as an R&D strategy anchored on human genetics. As we've discussed before, these elements combine to create an overall probability of clinical success for our programs that greatly exceeds historical industry norms. In addition, this study highlights our deep understanding of the science and pharmacology of RNAi therapeutics, allowing us to successfully predict target knockdown, thereby accelerating development as well. In the instance of vutrisiran, we were able to progress from a relatively small phase I study in healthy volunteers directly to a pivotal trial in patients with only 3.5 years from first in human to pivotal trial readout, an exceptional achievement in our view.
We also announced today that we have filed our NDA with the FDA, bringing vutrisiran one step closer to potentially becoming another program in the Alnylam portfolio to reach the market. We anticipate a PDUFA date in early 2022, and if approved, vutrisiran would meaningfully increase the number of revenue-generating Alnylam assets, all of which are in a growth phase for the foreseeable future. We believe this profile of organic growth and organic generation of commercial products is nearly unprecedented in biotech history. The positive HELIOS-A results in vutrisiran's NDA filing also move us further along our path toward achieving our Alnylam P 5x25 goals.
Alnylam P5x25 is aimed at bringing transformative medicines for rare and prevalent diseases to patients around the world while advancing a robust and high-yielding pipeline of first and/or best-in-class clinical programs from our organic product engine and delivering exceptional financial performance along the way. Now, before turning it over to Akshay, I would like to take a moment to acknowledge the many people across the globe who participated in HELIOS-A and made this important medical advance possible. It should not go unmentioned that a significant portion of these study results were generated during the COVID-19 pandemic, where our entire development organization, and especially our clinical operations team, our CRO partners, and study site staff successfully enabled continuity and integrity of the study. Of course, we are particularly indebted to and inspired by all the patients participating in HELIOS-A and other vutrisiran studies.
Without their participation, we could never have generated the evidence needed to seek approval for vutrisiran and, if approved, bring an impactful treatment option forward to the entire ATTR community. With that, I'll now turn it over to Akshay to review the results in more detail. Akshay, take it away.
Thanks, John, and welcome, everybody. We're indeed thrilled with these results from our HELIOS-A phase III study. I'll now review the program and the results with you in more detail. As most of you are aware, hereditary ATTR amyloidosis is a multisystem orphan disease caused by mutations in the transthyretin or TTR gene that leads to aggregation of misfolded TTR monomers into amyloid fibrils. Amyloid deposition in nerves, heart, gut, and kidney causes tissue damage. This multisystem disease manifests as polyneuropathy due to the amyloid deposition in nerves or cardiomyopathy due to deposition in the heart, although most patients exhibit a mixed phenotype, which can also include GI and renal involvement. As indicated by the name, the polyneuropathy involves all classes of nerves, leading to disabling sensory, motor, and autonomic symptoms. Regardless of the clinical presentation, hATTR amyloidosis is a progressive, debilitating disease that is often fatal.
ATTR amyloidosis has a common pathogenic mechanism related to wild-type or mutant TTR production and deposition in a range of tissues. It's a single disease caused by TTR that results in a spectrum of clinical manifestations. Alnylam's RNAi therapeutics reduce the production of the disease-causing TTR protein in the liver, thereby reducing continued amyloid deposition, thus halting or improving the manifestations of disease. This concept was first demonstrated with ONPATTRO, or patisiran, and has now been further supported by the vutrisiran data I'll review shortly. ONPATTRO and vutrisiran are the two complementary products that comprise our ATTR amyloidosis franchise. ONPATTRO, the first RNAi therapeutic ever approved, is administered every three weeks by IV infusion and is currently approved in over 30 countries for the treatment of the polyneuropathy of hATTR amyloidosis in adults.
Vutrisiran, the focus of today's call, is an investigational RNAi therapeutic that utilizes the same RNAi mechanism as ONPATTRO. It is administered as a quarterly subcutaneous injection via prefilled syringe. Vutrisiran utilizes our enhanced stabilization chemistry, or ESC, GalNAc conjugate delivery technology. Let me turn specifically to the HELIOS-A study and begin by reviewing the study design. This design was aligned with both the FDA and EMA. HELIOS-A is a randomized, open-label study in patients with hATTR amyloidosis with polyneuropathy. The study enrolled 164 patients who were randomized three-to-one to receive vutrisiran at a dose of 25 milligrams administered subcutaneously once every three months, or patisiran administered intravenously once every three weeks at a dose of 0.3 mg per kg.
This study had an innovative design where the efficacy results in the vutrisiran-treated patients at nine months were compared to an external historical control group, specifically the placebo arm from the APOLLO trial of patisiran in a similar patient population. The small patisiran arm was included in HELIOS-A as a reference comparator, but not for formal statistical comparison. The primary endpoint is the change from baseline in the modified neuropathy impairment score, or mNIS+7. This is a 304-point score where 0 indicates absence of disease and 304 points corresponds to the end-stage disease. The mNIS+7 score assesses sensory, motor, and autonomic function. In addition, we included two secondary endpoints at month nine, encompassing clinically meaningful readouts to further assess the impact of vutrisiran on disease symptoms.
The secondary endpoints were the Norfolk Quality of Life-Diabetic Neuropathy Questionnaire, which is a validated instrument to measure the quality of life, and the 10-Meter Walk Test, which assesses gait speed. At the nine-month time point, we also included a few exploratory endpoints, including NT-proBNP, a well-known biomarker of cardiac stress, to evaluate potential effects of vutrisiran on the cardiomyopathy. We expect to announce top-line results for the 18-month endpoints later this year. Let me now turn to the baseline demographics on slide 14. The patient population enrolled in HELIOS-A included a wide range of disease severity and was representative of the global population with this disease, with patients enrolled from 57 sites in 22 countries. Baseline characteristics were generally well-balanced between the vutrisiran and patisiran reference arms in HELIOS-A and the placebo arm from APOLLO, and the populations were clinically comparable.
Furthermore, just as we did with APOLLO, we predefined a cardiac subpopulation as those patients with thickened heart wall and without a history of hypertension or aortic valve disease. This cohort provides an enriched population in which to examine cardiac effects. Turning to slide 15, knockdown of serum TTR levels in the vutrisiran group as of once-quarterly sub-Q injection was rapid and sustained over a nine-month period and similar to that observed in the patisiran reference arm. Clearly, a comparable level of TTR knockdown was achieved with a quarterly 25 milligram sub-Q dose regimen, just as we predicted by our clinical pharmacology modeling. Specifically, vutrisiran achieved a mean steady-state serum TTR reduction from baseline of 83%. We're also very pleased to see the low interpatient variability in TTR knockdown effect over the time period observed. Let's now turn to the clinical efficacy results reporting the study.
I'll start with the results from the primary endpoint, namely the change in mNIS+7 from baseline at nine months. As shown here on slide 16, vutrisiran resulted in a 17-point mean treatment benefit relative to the external placebo group at nine months. This effect was highly significant, with a p-value of 3.54 times 10 to the minus 12, indicating the robustness of the treatment effect. Of note, the mean difference at nine months for patisiran versus placebo in the APOLLO study was 16 points, a truly remarkable concordance. In contrast to the control group that demonstrated rapid and marked worsening in neuropathy, the mean change in mNIS+7 relative to baseline for vutrisiran-treated patients was a negative value, indicating an improvement in the overall score on average.
Improvements were seen across all components of the mNIS+7 score and also across all pre-specified groups, such as age, sex, race, geography, and prior TTR stabilizer use. Let's now turn to the key secondary endpoint in HELIOS-A, which was the change in the Norfolk Quality of Life score at nine months relative to baseline. Vutrisiran-treated patients demonstrated a mean improvement in quality of life relative to the APOLLO placebo arm. Specifically, vutrisiran treatment resulted in a negative 3.3 mean change, again indicating that patients on average experienced improvement as compared to a 12.9-point mean increase or worsening reported for the APOLLO placebo group, resulting in a 16.2-point mean treatment benefit. This result was a highly significant one with a p-value of 5.43 x 10 to the - 9. Improvements were also observed across all domains in the Norfolk QOL questionnaire and all pre-specified patient subgroups.
On the graph on the right, we see the results of another secondary endpoint, the 10-Meter Walk Test, which measures gait speed. Gait speed is an important and clinically meaningful measure of patient function and is often referred to as the functional vital sign. In contrast to the placebo group that demonstrated worsening in gait speed at month nine, the vutrisiran-treated patients remained stable. This result was also highly significant with a p-value of 3.1 x 10 to the - 5. Of note, we also evaluated some exploratory endpoints relative to polyneuropathy, including the Rasch-built Overall Disability Scale, or R-ODS, a patient-reported outcome measure of activities of daily living and disability, and modified body mass index, or mBMI, which assesses nutritional status. Both of these exploratory endpoints demonstrated improvements compared with the external placebo group.
To further understand the vutrisiran treatment effect, we conducted binary analyses to evaluate the proportion of patients who showed improvement in neuropathy impairment and QOL relative to baseline. As you can see on this slide, the majority of patients, specifically 50.4%, showed improvement in neuropathy relative to baseline by nine months. Additionally, the majority of vutrisiran-treated patients, in this case 53.4%, showed improvement in Norfolk QOL relative to baseline. These analyses provide evidence that, like patisiran, vutrisiran not only halts neuropathy progression but achieves reversal of neurological impairment and its clinical sequelae in the majority of patients. On this slide, we present a side-by-side post-hoc comparison of the results at nine months with vutrisiran in HELIOS-A and with patisiran in APOLLO.
On the primary and two secondary endpoints, vutrisiran demonstrated treatment effects that are highly consistent with those seen with patisiran in APOLLO, consistent with the similar levels of TTR knockdown I shared with you earlier. Notably, the effects of vutrisiran on the mNIS+7 primary endpoint are virtually identical to those seen for patisiran in APOLLO, with a minus 2.2 and minus 2 least square mean difference from baseline, respectively. Similarly, the cross-study comparison showed similar effects on Norfolk QOL and gait speed measures with overlapping 95% confidence intervals. Also, while not a formal comparison, I want to note that the efficacy observed with patisiran in the small reference arm in HELIOS-A was generally similar to that seen in the oriGenal APOLLO trial, which speaks to the robustness of the study design and execution and patisiran's consistent efficacy profile.
Please note that the efficacy data shown for the HELIOS-A patisiran reference arm are mean changes as specified in our statistical analysis plan and not least-squares mean changes. In addition, at nine months, we analyzed the exploratory endpoint of NT-proBNP, which is a marker of cardiac stress. On this endpoint, higher values indicate a greater level of cardiac stress. In both the overall study population shown on the left and in the cardiac subpopulation shown on the right, vutrisiran treatment led to statistically significant results on this endpoint as well. Specifically, while the external placebo group showed an average increase or worsening in NT-proBNP levels over nine months, levels in the vutrisiran group remained stable. We're very pleased with this result as it supports further evaluation of vutrisiran effects on cardiomyopathy manifestations of disease, which we're studying in the HELIOS-B trial.
Now let's turn to the top-line safety results. vutrisiran demonstrated an encouraging safety and tolerability profile. There were two study discontinuations, 1.6%, due to adverse events that both led to death in the vutrisiran arm by month nine, neither of which were considered related to study drug. One death was due to COVID-19, and one was due to an iliac artery occlusion during a hospitalization for pneumonia in a patient with pre-existing congestive cardiac failure. There were two serious adverse events or SAEs deemed related to vutrisiran by the study investigator, consisting of dyslipidemia and an E. coli urinary tract infection. Treatment-emergent adverse events occurring in 10% or more of the patients receiving vutrisiran included diarrhea, pain in extremity, fall, and urinary tract infections. These events are common in the disease itself and occurred at a similar or lower rate than observed in the external placebo comparator group.
Injection site reactions were reported in five vutrisiran patients, 4.1%, and all were mild and transient. There were no clinically significant changes in liver function tests, hematology, or renal function related to vutrisiran. We look forward to reporting top-line results for the 18-month analysis in late 2021, which will permit longer-term evaluation of a number of important neuropathy-focused endpoints such as mNIS+7, Norfolk Quality of Life, and others. In addition, we'll look at a number of exploratory endpoints at 18 months intended to further characterize vutrisiran's potential impact on cardiac manifestations of the disease, including biomarkers of cardiac stress like NT-proBNP, echocardiographic parameters such as the left ventricular wall thickness and longitudinal strain, and cardiac amyloid burden through the use of Technetium scans. In summary, we're very pleased with the nine-month results from HELIOS-A.
Vutrisiran met the primary and secondary endpoints at nine months with statistically significant improvements in neuropathy impairment, quality of life, and gait speed. The majority of patients showed improvements in neuropathy impairment and quality of life compared with baseline. As expected, vutrisiran effects on the primary and secondary endpoints were similar to those observed in the patisiran arm of the APOLLO study. vutrisiran also demonstrated improvement in the exploratory cardiac endpoint NT-proBNP compared with the external placebo group, providing initial evidence suggesting that vutrisiran treatment may potentially result in the improvement of cardiac manifestations of disease. Finally, vutrisiran demonstrated an acceptable safety profile and a favorable benefit-risk profile. Patients in HELIOS-A continue to be treated, and the efficacy and safety of vutrisiran will be further investigated through an 18-month treatment period and an extension period of HELIOS-A.
In closing, let me also thank the patients, patient families, investigators, study staff, and collaborators for their participation in the HELIOS-A phase III study. We simply could not have achieved this remarkable milestone without the hard work and dedication of countless people, not least our Alnylam colleagues. With that, let me now turn the call over to Yvonne. Yvonne.
Thanks, Akshay, and hello, everybody. I too am thrilled to be at this stage in vutrisiran's journey. As mentioned in our press release today, we have now filed our NDA for vutrisiran with the FDA, bringing us one exciting step closer to making this transformative medicine available to patients. And if approved, we expect to launch vutrisiran in early 2022. In addition, and as we've previously guided, we plan to soon begin study of a biannual dosing regimen for vutrisiran, which could further differentiate vutrisiran's already strong profile.
Based on the positive data from HELIOS-A, we believe that vutrisiran, if approved, will present an exciting commercial opportunity with an attractive treatment option for patients with hATTR amyloidosis with polyneuropathy around the world. For its initial market opportunity, we believe that vutrisiran could address unmet needs for the 20,000-30,000 hATTR amyloidosis patients with polyneuropathy, including those with the so-called mixed phenotype. As a once-quarterly subcutaneous injection, we expect to see strong uptake, and as John touched on, we believe that vutrisiran, based on HELIOS-A alone, has the potential to expand our Alnylam's overall share of the hATTR amyloidosis polyneuropathy market in multiple ways. First, we expect broad patient access and the potential for earlier treatment with vutrisiran.
With a once-quarterly and, in the future, possibly biannual treatment regimen, we anticipate increased use by healthcare professionals who treat patients with hATTR amyloidosis with a mixed phenotype, as a convenient subcutaneous route of administration may be particularly desirable to this physician group. We also imagine we'll get more switching and an expanded prescriber base with the ease of a sub-Q injection delivery route. And importantly, vutrisiran, if approved, would provide greater patient choice among treatment options. In short, we believe the promising efficacy and encouraging safety for vutrisiran demonstrated in HELIOS-A will make this medicine a very attractive option for patients and their healthcare professionals following approval. In summary, we're extremely excited by the prospect of bringing vutrisiran to the market if approved and believe that it will make a meaningful difference in our overall ATTR franchise.
And in closing, I'd also like to thank the patients, caregivers, patient advocacy groups, and study investigators and staff that continue to work extraordinarily hard for the ATTR community. With that, I will now turn the call back to Christine to coordinate the Q&A. Christine?
Thanks, Yvonne. Operator, we will now open the call for questions. As a reminder to those dialed in, we would like you to limit yourself to one question each and then get back in the queue for any additional questions.
Ladies and gentlemen, to ask a question, you will need to press the star and the one key on your touch-tone cell phone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question coming from the line of Gena Wang with Barclays. Gena, your line is open.
Thank you for taking my question.
First, I wanted to congratulate on the great data. I just have one maybe clarifying question regarding the baseline NIS score. When I look at the slide 14, it says baseline is 57 for placebo APOLLO and HELIOS-A is a 43, 43. But when we look at the slide 16, in the footnote, it says different numbers, a 60.6 and a 74.6 for placebo. When we look at APOLLO data, the placebo arm score should be 57, patisiran arm should be 60.5. Just wanted to know what the numbers there, did we miss anything there? And just one quick question regarding the two SAEs deemed related to vutrisiran, if you can make a little bit more comments on dyslipidemia and the UTI.
First of all, Gena, thanks for the congratulatory comment.
The difference in the baseline characteristics that you refer to versus the plot on slide 16, one is NIS and the other is the mNIS+7, which is a slightly different score. They're related. The NIS is a component of the mNIS+7, but the mNIS+7 has other components. Akshay, you should comment if you'd like further on that. And then Akshay, maybe you can comment on the safety question.
Sure. So your explanation is correct, John. And so for any given mNIS score in a patient, the mNIS+7 score will always be higher. So you're simply looking at a little bit apple to the oranges, Gena, in that the table in slide 14 is the NIS score, and the footnote you refer to in 16 is referring to mNIS+7 scores, which are higher, respectively, both for vutrisiran and patisiran. So that accounts for that difference, and that's how one reconciles it.
Vis-à-vis the two SAEs deemed related by the investigators for vutrisiran, dyslipidemia and UTI, we have no explanation for why the dyslipidemia was classified as related or indeed a serious adverse event. The patient continued in the study, continued to receive drug, did fine. We have no preclinical or clinical evidence of lipid derangements in association with vutrisiran and indeed with RNAi therapeutics. We have the example of inclisiran, which is now approved in Europe as Leqvio, as in fact a treatment for elevated levels of LDL cholesterol. So I really don't know why the investigator chose to classify that. Of course, in this age group, there are many individuals that will have elevated lipid levels, and that may get picked up during a study. And of course, it's up to the investigator to classify the event, and that's what's occurred here.
But it does not cause any concern to us in particular. And as far as the UTI is concerned, UTIs are common actually in patients with hATTR amyloidosis because of autonomic dysfunction in the bladder and urinary tract. And so it's not at all surprising to document UTI. And in the APOLLO study, going back to that prior study, the UTIs were greater in the placebo group versus patisiran. Here, we don't have a true placebo comparison that was concurrent. And to document one UTI is not at all surprising. And there's no systematic signal otherwise here to worry about. So neither of those two SAEs are of any particular concern on balance. I hope that's helpful.
Great. Thank you.
Thanks, Gena.
Now, next question coming from the line of Ritu Baral with Cowen.
Good afternoon, guys. Thanks for taking the question.
I wanted to drill in a little bit on the proBNP change on slide 20. And I guess, what are your expectations for what proBNP could show at the 18-month time point, and how might it compare to the tafamidis 80 milligram change in their publication? And they represented it a few different ways in the publication, including, I think, absolute as well as least squares mean. Can you sort of compare the magnitude of the changes and expected changes?
Of course. Thanks, Ritu. Akshay, do you want to handle that?
Yeah. I mean, it's hard to compare across studies, of course, Ritu. So comparing to tafamidis is difficult. Most of those patients, of course, had wild-type disease. Some had hATTR amyloidosis in the tafamidis study.
The general sense overall across all endpoints seen with tafamidis is that it slowed down the rate of deterioration in the endpoints they studied, both biomarkers and the clinical endpoints, rather than stabilizing or improving. That's my observation of their data. Now, concerning our data in the current study, BNP showed stabilization/some improvement, maybe. We hope to see that trend continue over 18 months, and maybe we'll see further improvement. That's kind of what we saw in APOLLO. In actual fact, with patisiran, the nine-month data between what we see here and patisiran looked very similar in APOLLO. So hopefully, we'll see continued stabilization and/or improvement at 18 months.
Got it. And also, just a quick follow-up. Can you give us any more detail on the biannual trial design and how the knockdown data that you showed on slide 15 might inform that trial design?
I can just jump in real quickly. What we've said, Ritu, is that we're going to start studying Q6 monthly dosing. And obviously, there are many efficient ways in which we can introduce a Q6 monthly study, including in the context of ongoing open-label studies that we have with patisiran. So in due course, very soon, we'll be talking more about that study and how we plan on generating the evidence for Q6 monthly. But clearly, we have obtained alignment with regulators on the path forward, and we're certainly committed to generating the data in an efficient manner across our portfolio. Akshay, anything to add to that from your standpoint?
No. I think you covered it well, John. Just harkening back to the NT-proBNP point, though, again, we should remember, Ritu, that patisiran is indicated for the polyneuropathy of hATTR amyloidosis.
And equally, that's the initial application here for vutrisiran with these HELIOS-A data. So while these cardiac data obviously are very interesting, and we hope they're going to be important in the ultimate evaluation of the drug across the full spectrum of diseases, we should recall that the initial indication is for hATTR with polyneuropathy.
Yeah.
Thanks for taking the question.
Now, next question coming from the line of Maury Raycroft with Jefferies.
Hi, everyone. Congrats on the update today, and thanks for taking my questions as well. I was just wondering for the percent TTR knockdown data, it seems like vutrisiran is knocking down a little bit deeper and with less variability than patisiran.
Just wondering if you can comment on that and if you think the difference could drive additional clinical benefit versus patisiran in longer-term data, and how could this impact the commercial dynamic between patisiran and ONPATTRO?
That's a great question, Maury. Akshay, do you want to comment on that? And I might jump in afterwards.
Yeah. I mean, net net, we're actually very excited about the TTR knockdown data here with patisiran. We had modeled those and predicted the effect we would get with patisiran 25 milligrams Q3 monthly prior to the initiation of this study. And what we see here is almost exactly what we had modeled, and it's almost exactly superimposing with what we saw with patisiran in the original APOLLO study. Now, the actual graphs you're looking at here are comparing vutrisiran to patisiran. The patisiran is a much smaller sample size.
And so I think there may be some minor differences, but basically, it's an overlapping result. And I think overall, our 25 Q3 monthly seems to give the patisiran effect very, very nicely. That's what I would say, John.
Yeah. I would just add it's a real triumph of our clinical pharmacology group that's able to so effectively predict this. So it is very pleasing. I wouldn't think there is less intersubject variability with patisiran. That's consistent with what we see with GalNAc conjugates in general. And it probably reflects really the differences between LNP-based delivery with patisiran and the GalNAc conjugate with vutrisiran. We do tend to see very remarkably consistent results with our GalNAc platform in general.
Got it. Very helpful. Thanks for taking my questions.
Thank you.
Now, next question coming from the line of Salveen Richter with Goldman Sachs. Your line is now open.
Hi.
Thank you so much for taking our question. This is Sonia on for Salveen. How should we think about the potential read-through of the cardiac endpoint of NT-proBNP to the APOLLO-B and potentially HELIOS-B studies?
Yeah. That's a great question. Let me start, and then maybe Akshay, you can comment. I mean, look, again, this was an evaluation of vutrisiran in patients with hATTR polyneuropathy, but we know that these patients do have underlying cardiac disease. And so that's why it's meaningful to look at potential impact on cardiac exploratory measures. But keep in mind, these are exploratory endpoints. Personally, I think that they are another set of data that are hypothesis-generating that are supportive and will, of course, be tested and evaluated in a randomized clinical study as they need to be with APOLLO-B and then HELIOS-B. Akshay, what do you think?
Yeah.
I mean, I think your comment about hypothesis-generating is important that we're excited about these results, and it's great that we can stabilize and hopefully improve this BNP level. But it's not the endpoint. The endpoint is, of course, six-minute walk distance for APOLLO-B and mortality and hospitalization in HELIOS-B. These are the true clinical endpoints that we hope to demonstrate benefit in. This result is just another pointer that things are going in the right direction with TTR reduction as a therapeutic strategy when the heart is involved. But much more work to do yet, and we hope that this all translates to positive clinical results in the cardiac studies, APOLLO-B and HELIOS-B.
Great. Thank you.
Thanks, Sonia.
Now, next question coming from the line of Alethia Young with Cantor Fitzgerald.
Hey, guys. Thanks for taking my question. And man, congrats.
This is some great data.
Thank you.
Yeah. Definitely. I guess I want to talk a little bit more about ONPATTRO and patisiran in the real world. And do you think there's a scenario where patients who are kind of more severe might lean toward ONPATTRO and people who are slightly less severe? Or in light of thinking about these data, I just kind of want to kind of figure out where we might think about patients coming from kind of initially as this moves toward the finish line, thanks.
Yeah. It's a great question. Let me start, and then maybe Tolga and Yvonne could comment on this. I mean, look, ONPATTRO is really a wonderful medicine that's making a big difference for patients with hATTR polyneuropathy. Clearly, many patients are on therapy. Adherence rates are very high. They're doing very well.
If approved, we'll be able to bring forward vutrisiran as a quarterly sub-Q option. I suspect that some patients will welcome that. Some existing ONPATTRO patients will welcome that and want to switch. I think, obviously, we expect some of that. And we also expect new patients will view that as being the best option for their care. But it'd be too soon to speculate yet. Now, keep in mind, approvals are going to change or evolve in different countries, and reimbursement will evolve in different countries at different times. So you're going to have a bit of a patchwork, if you will, of what country has ONPATTRO on the market and approved and reimbursed. And so that is another dynamic here. Tolga, Yvonne, maybe we start with Yvonne and then Tolga. Yvonne, anything to add to that?
John, you've actually covered it very nicely.
I mean, I think we're very pleased with the performance of ONPATTRO. And as you say, we think that there are many patients who will wish to stay on ONPATTRO. I do think that if approved, vutrisiran is going to have a very compelling profile, just giving its once-quarterly regimen subcutaneous. And we may see physicians start to use treatment with vutrisiran earlier in patients. I think we may see more penetration in the mixed phenotype segment. I think we'll probably see some share that gets taken from Tegsedi, which is not so well tolerated. So I think what we're building here, John and Alethia, is actually a very robust franchise with both ONPATTRO and vutrisiran. Tolga, I don't know if you've got anything to add.
No.
Tolga, anything to add?
No.
I think you both covered it really well, and I do agree that the dynamic between EU and Japan, where we have a stabilizer and a silencer, the dynamic will be different for polyneuropathy, where in the U.S., we have the silencers, and obviously, the ONPATTRO is the market leader. In that respect, we do see a dynamic where the community physicians start diagnosing more and more patients with polyneuropathy, and perhaps they may be less eager to start the patients right now, given that our current regimen is every three weeks. We do anticipate perhaps those patients that are more likely to benefit from this disease, they may prefer it to on a quarterly regimen.
Thanks, Tolga. Alethia, does that answer your question?
Yeah. It was very helpful, and it will be interesting TBD. Thank you.
Good. Thank you.
Now, next question coming from the line of Debjit Chattopadhyay with Guggenheim Securities.
Hi. Good afternoon, guys. This is Robert calling in for Debjit. We have two quick questions here today. First is, how does the proBNP baseline compare between the APOLLO and HELIOS studies? And was there any change in ECV in either the patisiran or vutrisiran arms? Do you have any data on that? We'll plan on measuring that at 18 months.
Thanks. Could you repeat that second part of the question?
Yeah. Was there any change in ECV in either arm? And do you have that, or do you plan on measuring that at 18 months?
You mean ECV?
ECV, yeah.
Okay. All right. Akshay, do you want to answer those two questions? Akshay, did we lose you? Are you on mute?
Yep. I was on mute. Apologies.
The extracellular volume is a cardiac MRI measurement, and we, in fact, didn't use that. It's not commonly used in such large phase III studies, and so we won't have ECVs. We will have a variety of other cardiac endpoints at month 18, including further BNP data, echocardiography data on LV mass and LV strain, and, of course, the technetium scan data showing the amyloid in the heart, so that's what we'll have. As far as the absolute levels, I don't know if Pushkal, who's also on the call, remembers. We know that, or at least I remember the levels in APOLLO were about 700 pg/mL. I can't remember what they were here in the current study with vutrisiran. Do you know, Pushkal?
They were quite similar. I don't have the exact numbers, but they were actually in a very similar range and overlapping.
The other point I would just make is that the analysis that Akshay presented is an adjusted analysis, so it adjusts for baseline in the analysis. So what you're looking at is an apples-to-apples comparison in the data that he presented.
Yeah. And just because I'm looking closely at the slide, slide 20, Robert, in the footnote, you can see the baseline NT-proBNP was 772.8 in the vutrisiran cardiac subpopulation compared to 771.1 in the APOLLO placebo cardiac subpopulation. So pretty spot on to each other.
Awesome. Thanks. And congrats on the great data.
Thank you. Is there?
Our next question coming from the line of Paul Matteis with Stifel.
Great. Thanks so much. I had a couple of clarifying questions. One is to go back to what Gena was asking from the beginning. The Norfolk data here look really different than the ONPATTRO label.
I'm sure there's a good explanation, but maybe you can cover that, and then second, how do the vutrisiran data look compared to these 42 patients in the study who received patisiran? I'm assuming the FDA wanted that for some context, so any color there would be helpful, and if you don't mind, just one other quick comment. Remember, there were some discussions in the APOLLO study surrounding a delta in AV block rates between patisiran and placebo, and I think that's on the label. Can you just mention anything, whether or not you saw that in patisiran and whether or not you think that that was an artifact? Thanks so much.
Yeah. Thanks, Paul. Akshay, do you want to take those questions?
Yeah. There's a lot there. Let's go one at a time. I think I also might need Pushkal's help on some of the details.
As far as the Norfolk is concerned, I don't know what you're referring to, Paul, exactly, but what I can tell you is that as we look very carefully at these data and the APOLLO data, they look almost superimposable to us, up to including.
Hey, Akshay, do you mind if I clarify? On slide 19, the placebo-adjusted delta for patisiran and the Norfolk is bigger than APOLLO, but the absolute reduction in our drug is about four points less than patisiran.
Akshay, can I jump in on that one?
Yeah, please. Yeah. Because I suspect it's something they were still handling. Yeah.
So Paul, it's Pushkal. Just to clarify, right? So what happens, what numbers that you're seeing here are least squares mean differences. They basically are the output of a model that adjusts for the baseline value. It also adjusts for genotype.
So in APOLLO, that was done by just mixing the patients in the APOLLO study, APOLLO placebo, and APOLLO active, which was the patisiran patients. For the purposes of the HELIOS-A side, the model was built using the patisiran patients along with the APOLLO placebo patients. So when you put that in and you include the covariates that just adjust for the baseline, and there's some minor baseline differences, overlapping but minor differences, that's why you get those slightly different effect sizes or those values. But what I focus on is if you look at the vutrisiran minus placebo or patisiran minus placebo, those treatment effects are, in fact, identical. In fact, it's quite remarkable that they're as identical as they are, given two different drugs studied at two different points in time. So I think it's actually quite compelling. But that's why you're seeing those small differences.
It's just an artifact or it's a feature of the model and the way the analysis is done and adjusted.
Yeah. And please note that the confidence intervals are overlapping for those effects anyway, regardless.
And then the last point I would make on that, just to show the comparability, is if you look at the proportion that improved Norfolk QOL, it's almost identical between the studies. So yeah.
The data look great. I just wanted to clarify.
Can I just get clarification on two quick points? I've argued very, very similar, very overlapping between the two studies. And as Pushkal said, kind of remarkably so, actually. So anyway, sorry. Go on, Paul.
Yeah. I just wanted to clarify the AEs and whether or not you saw any AV block in vutrisiran in this study. I forget my other question, so maybe it wasn't that important.
But maybe just clarify that. Thank you.
Pushkal, you want to take that?
Yeah. Absolutely. So Paul, as you would expect in this kind of disease with a mixed phenotype, two-thirds of these patients had a history of pre-existing cardiac disease. We've gone through the data overall, and we feel there was no evidence of a cardiac signal from our review. Obviously, the regulators will also review the dataset, and we'll share all those data with them. But we feel very good about the overall cardiac signal coming out or cardiac safety in this study.
Okay. Thanks. And then Pushkal, I remember my other thing. Just on the patisiran arm in this study, the 42 patients, and how that looked compared to these patisiran results we saw today?
Yeah. You can see those actually. Akshay mentioned them in the presentation.
They're on slide, sorry, my vision now is dropping, on slide 19 at the bottom. And again, they're very much in the range of what we saw, both with patisiran in HELIOS-A and patisiran in APOLLO.
Oh, thank you. Sorry, I missed that. Appreciate it. Thanks so much.
Great. Thank you, Paul.
Our next question coming from the line of Anupam Rama with JP Morgan.
Hey, guys. This is Tessa for Anupam tonight. Thanks for taking our questions. Just one from us. You note that improvements across all domains of the Norfolk QOL-DN score were observed. As we recall, I think there are five subscale scores in the QOL-DN calculated to total 35 items. Do patients or physicians value changes in certain components versus others? And are there any specific subscales where patients are improving on average, or is it more broad across all five subscales? Thanks so much.
That's a great question. Let's go over to Pushkal on that. That's something you probably have the most knowledge of, Pushkal.
Yeah. It's a really important question. So you're right. The Norfolk Quality of Life measures patient-reported outcomes related to sensory deficits, motor deficits, and a number of other deficits. I think the one actually, I mean, so what we do see is we see consistent benefits of the drug across all of those domains. But I think what we are seeing is that one of the symptoms that patients respond to most quickly and has the biggest impact on them is their impact on autonomic function. So whether they get dizzy, etc., when they stand up, or other features. And so that's one that I think is quite prominent for patients because it's so troubling for them to have. But we do see consistent effects.
We've seen that with ONPATTRO, and we're similarly seeing that now in this study with vutrisiran in terms of these multiple domains and particularly the autonomic effects of TTR silencing on their symptoms.
Great. Thanks so much for taking our questions.
Thank you.
Our next question coming from the line of Mani Foroohar with SVB Leerink.
Hey, guys. Thanks for taking the question. And congratulations on meeting the high bars set by the previous ONPATTRO data in this dataset. I have more of a commercial question, given the data has been dissected to death previously. So you talked about the difference between sub-Q and IV. In the U.S., those are very different reimbursement channels, and even different for at-home sub-Q self-administered versus in-office administered.
Can you walk us through a little bit if there's any incremental build of commercial infrastructure around this launch and the TTR market? And more broadly, how to think about COGS plus royalty burden on a per-patient basis for a patient on vutrisiran versus a patient on patisiran as we think about potential margin impact at whatever price you guys label vutrisiran.
Right. That's a great question, and I'm going to hand it over to Tolga. Let me just start, though, Mani, and say that we expect vutrisiran to be approved as an HCP-administered drug. So even though it's given subcutaneously, it would be given by an HCP, just like ONPATTRO is, which means that they both would be Part B, as in boy, drugs. Okay. So that's the first important correction to what you were saying. Tolga, do you want to answer Mani's question more completely?
Sure. No.
I think, first of all, it's a great question, and you obviously, John, covered the most important aspect of it. In regards to our commercialization efforts, I think actually our focus is more so in regards to the diagnosis and the treatment choice element, which obviously starts from making sure that at the systems level, these patients are as quickly as possible diagnosed and get their genetic testing so they can properly be treated. When it comes to our patient services, we already have established an excellent level of patient services, as you could see during the pandemic where we have excellent adherence rates. Therefore, that will essentially. We would be strengthening that function that is already well established. John, do you want me to go into the royalty burden, or?
Yeah. At a high level, you can. Yeah.
Yeah.
So I mean, at the end of the day, it is true that we will have a slightly higher royalty burden. Some of that will be essentially offset by the manufacturing and distribution improvements. But I think, again, we need to keep our eye on the ball, which is there's only about, worldwide speaking, less than 30% of patients are diagnosed, and a lot fewer of those patients are currently being treated. And I think that's where the opportunity is going to be. And certainly, if and when vutrisiran is approved for polyneuropathy, given the treatment regimen of once quarterly infrequent dosing without any safety monitoring is going to be a real, real benefit for the patients, and we're really excited about that.
That's great, Tolga. Mani, does that answer your question?
Great. That's perfect. Thanks, guys.
Thank you.
Our next question coming from the line of Patrick Trucchio with H.C. Wainwright.
Hi. Good afternoon, and congrats on the impressive data. Can you tell us what portion of the patients in HELIOS-A had prior stabilizer use and how that compared to baseline in APOLLO? And then secondly, do you have the NT-proBNP data broken down at baseline in nine months by patients naive to treatment versus those on stabilizer treatment? And was there a meaningful difference between the two groups?
That's great questions. Again, Pushkal, it might be best just to go right to you.
Yeah. Patrick, I don't have the exact number. I want to say probably about 30% or so had previously used a stabilizer. They were all washed out before they entered into the study. And sorry, your second question was, oh, did we break out the BNP by those two groups?
Is that what you're asking?
Yep.
Yeah. The numbers are small, so we didn't do a lot of subsetting around that, right? We've got relatively small numbers of patients. I think the point is that it was pretty consistent across both the ITT population and the cardiac subpopulation. So it sort of recapitulates what we did see with APOLLO as well. Does that answer your question, Patrick?
Yep. That's helpful. Thank you.
Great. Thank you.
And our last question coming from the line of Luca Issi here with RBC Capital Markets.
Oh, fantastic. Thanks so much for taking my question. Very impressive clinical execution, especially the context of COVID. So congrats on that. Maybe a quick one on what can you tell us about improvement in the 10-Meter Walk in the cardiac sub population versus the ITT population?
Just asking as obviously the primary point of HELIOS-B is six minutes walk. So again, wondering how we should think about the translatability of the 10-meter walk into the six minutes walk. And our second question, I think we saw last week in the 8-K, did you receive the subpoena from the DOJ on the marketing and promotion of ONPATTRO? So I'm wondering if you have any comments on that. Thanks so much.
Absolutely. Well, let me answer the second question first, and then maybe Akshay, you and Pushkal can answer the first one. Yes. Per the 8-K, we did receive a subpoena from the DOJ related to marketing practices on promotional practices on ONPATTRO. Obviously, we take something like that very seriously. We are going to absolutely work with whatever the government is looking for in terms of materials and provide them answers to that.
We do have experienced counsel that we are working with to help us on this matter, and we obviously always feel very strongly about the importance of ethics and compliance and integrity in everything that we do, but obviously, we'll work with the government to answer their questions. Then, Akshay, the technical question, please.
Yeah. I mean, again, Pushkal would have to say otherwise, but I'm not aware that we've broken down the 10-Meter Walk outcome at month nine by cardiac subpopulation. Pushkal, do you have any further comment on that?
Yeah. Actually, we did actually look at the various endpoints in that cardiac subpopulation, and in general, Luca, the results were quite consistent. Obviously, it's a smaller subset. It's a fraction of the overall population, but in general, the results were quite consistent.
And you'll recall that we saw that when we looked in the original APOLLO dataset that we saw the 10-Meter Walk test going similarly in that cardiac subpopulation as we saw in the overall population. So that's quite encouraging in terms of the impact on a functional outcome. Does that answer your question?
Does that answer your question, Luca?
Yeah. Yeah. No. Terrific. Super helpful, color. Appreciate the call, and thanks again.
Great. Thank you.
That's all the time we have for questions today. I will now turn the conference back over to the company for closing remarks.
Great. Well, listen, thanks everyone for joining us today. We couldn't be more excited about the prospect of making this new investigational medicine available to patients. We think it'll be a welcome option for patients with hATTR amyloidosis with polyneuropathy.
In the meantime, we look forward to sharing 18-month topline data from HELIOS-A later this year. That's our goal that we're aiming for. And we hope everybody has a great day otherwise. Thank you very much. Bye-bye now.
Ladies and gentlemen, that concludes our conference for today. Thank you for your participation. You may now disconnect.