Alnylam Pharmaceuticals, Inc. (ALNY) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals conference call to discuss results from the ILLUMINATE-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 would now like to turn the call over to the company.

Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are John Maraganore, our Chief Executive Officer; Akshay Vaishnaw, our President of R&D; and Barry Greene, our President. Also joining us and available for Q&A are Yvonne Greenstreet, our Chief Operating Officer; Pushkal Garg, our Chief Medical Officer; and Pritesh Gandhi, General Manager of the Lumasiran Program. For those of you participating via conference call, the slides will be made available via webcast and also be accessed by going to the Investors page of our website, www.alnylam.com. Now turning to our call. As outlined in Slide 2, John will provide some opening remarks, Akshay will discuss the ILLUMINATE-A study results in more detail, Barry will walk us through next steps of the program and the market opportunity, and we will then open the call for your questions. Before we begin, 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 factors, including those discussed in our most recent annual report, quarterly report and 8-K current 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 now like to turn the call over to John.

Thanks, Christine, and thanks to all of you for joining the call this morning, especially on a Sunday. I hope you're all continuing to stay safe and healthy. And for all peaceful protesters for the Black Lives Matter cause, we stand with you. Now earlier this morning, we were very pleased to present the full set of results from the ILLUMINATE-A Phase III study of lumasiran, an investigational RNAi therapeutic in development for the treatment of primary hyperoxaluria type 1 or PH1. Akshay will provide an overview of the study results shortly but at a high level, lumasiran achieved substantial reduction of urinary oxalate relative to placebo at month 6, the primary endpoint of the study, and the majority of patients achieved a normal or near normalization of urinary oxalate levels, which is the key secondary endpoint. Lumasiran also demonstrated an encouraging safety and tolerability profile in some. We believe these results are exciting news for patients with PH1 and their caregivers and physicians since currently there are no approved pharmacological therapies for this devastating disease. The ILLUMINATE-A study now represents the sixth positive Phase III study for an investigational RNAi therapeutic across 4 distinct programs: patisiran, givosiran, inclisiran and now lumasiran. And we believe it further underscores the transformational potential of this modality as a whole new class of medicines. Indeed, in all of these studies, RNAi therapeutics demonstrated robust treatment effects and generally encouraging safety. It's very exciting to see this emerging profile for RNAi therapeutics as a whole new frontier of medicine with the potential for high impact for patients. These newly reported positive Phase III results also underscore the high probability of success that we've achieved at Alnylam, which really reflects the power of a reproducible and modular platform combined with the impact of human genetics. As you know, we have now completed our lumasiran regulatory filings with the FDA and the EMA and just recently the FDA granted us priority review status with a PDUFA date of December 3, 2020. The FDA also communicated that it has no intention of holding an advisory committee meeting at this time. With regard to our MAA filing with the EMA, our application has been validated and lumasiran received an accelerated assessment designation. Assuming favorable regulatory reviews, this positions Alnylam to potentially bring lumasiran to the U.S. market by the end of 2020 and to the EU market shortly thereafter, which would mark the arrival of the third RNAi therapeutic to the market and with inclisiran, the fourth. Importantly, the positive lumasiran Phase III results paved the way for us to meet and likely exceed our Alnylam 2020 vision and goals, which were first announced in 2015, while building a multiproduct global commercial company with a deep clinical pipeline to drive future growth, and a robust and organic product engine to fuel sustainable innovation and patient impact. Without a doubt, this is a profile that is rarely achieved in biotech and one that is now more tangible than ever for Alnylam and its shareholders. Finally, I'd like to take this opportunity to express our profound gratitude to the patients who participated in and who continue to participate in our ILLUMINATE trials, their loved ones, caregivers and advocates. We believe the ILLUMINATE-A results provide new hope that we can make a positive impact on patients -- for patients with this devastating disease. Finally, we would also like to thank investigators and study staff worldwide whose dedication and insights have been instrumental to the success of the ILLUMINATE-A study. With that, I'll now turn it over to Akshay to review the results in more detail. Akshay?

Thanks, John, and welcome, everybody. As you'd expect, we're thrilled about these data, especially for what they could mean to patients with PH1 and their caregivers. Let me begin with an overview of the disease and its pathophysiology and then review the results that were presented today by Dr. [ Klauss ] in more detail. Primary hyperoxaluria type 1 or PH1 is an ultra-rare autosomal recessive disease caused by genetic defect of the liver enzyme, alanine-glyoxylate aminotransferase or AGT, resulting in hepatic overproduction of an insoluble metabolite called oxalate. Many patients present in childhood including infancy, but onset can occur at any stage in life with significant variability in clinical manifestations in later disease progression. Patients typically present with recurrent kidney stones and experience deposition of calcium oxalate in the renal parenchyma, referred to as nephrocalcinosis. This results in progressive and irreparable damage to the kidneys, ultimately leading to end-stage renal disease, or ESRD, but the rate of progression to ESRD can be unpredictable. Fortunately, a significant proportion of patients are not diagnosed until ESRD. Once the kidneys have failed, intensive dialysis is the only means to remove the excess oxalate from the body. But even with an intensive regimen of up to 6 days a week, dialysis is inadequate in removing all of the oxalate that the liver continues to produce. This leads to systemic oxalosis with oxalate depositing and accumulating in extra renal tissues, including the eyes, heart, bones and joints, resulting in vision impairment, cardiomyopathy, pathological bone fractures and in some cases death. Thus patients with the advanced disease require a dual or sequential liver-kidney transplant to remove the metabolic defect in the liver and to replace the terminally damaged kidneys. Complications of ESRD and transplantation are associated with high morbidity and mortality with transplant recipients having to live with lifelong immunosuppression and the possibility of needing new organs in the future. Current management options in patients with intact kidney function include hyperhydration with patients including young children, having to consume 3 to 4 liters of water per day, crystallization inhibitors and for a select population of patients with a specific genotype, pyridoxine, otherwise known as vitamin B6. Unfortunately, these strategies do not address the underlying pathophysiology of PH1 and are very often inadequate at overcoming oxalate overproduction. Lumasiran is an investigational RNAi therapeutic that is designed to silence the hydroxyacid oxidase 1 or HAO1 mRNA in the liver. HAO1 encodes glycolate oxidase, or GO, a liver enzyme upstream of AGT. AGT is either deficient or defective and is responsible for oxalate overproduction in individuals affected by PH1. Thus by inhibiting glycolate oxidase synthesis in the liver, lumasiran lowers production of hepatic oxalate, the key toxic metabolite responsible for the clinical manifestations of PH1. As a reminder, lumasiran utilizes our enhanced stabilization chemistry, or ESC, GalNAc-conjugate delivery technology, which enables subcutaneous administration. Lumasiran is now the third ESC-GalNAc-conjugate to yield positive Phase III results, further validating Alnylam's GalNAc delivery platform. Let's now turn to today's news based on an oral presentation given earlier today at the virtual ERA-EDTA Nephrology Congress. ILLUMINATE-A was a global randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of lumasiran in adults and children with PH1. The largest interventional study addressing PH1 to date, enrolling 39 patients across 16 study sites in 8 countries around the world. To be included, patients have to be at least 6 years of age and have relatively preserved renal function with an estimated glomerular filtration rate, or eGFR, of greater than or equal to 30 ml/min corrected for body surface area. Patients are randomized 2:1 to receive lumasiran or placebo with lumasiran at 3 mg/kg administered once monthly for 3 months, followed by quarterly doses thereafter. The primary endpoint for the study was the percentage change from baseline in 24-hour urinary oxalate excretion averaged across month 3 to 6 in patients treated with lumasiran as compared to placebo. Key secondary endpoints included the proportion of patients achieving a normalization or near normalization of urinary oxalate, eGFR and other measures of urinary and plasma oxalate. Exploratory endpoints include nephrocalcinosis and renal stone events. Baseline characteristics are shown on Slide 11. The overall mean age of study entry is 18.1 years with a range of 6 to 60 years old. The majority of patients, 56%, were between the ages 6 to 18. A similar proportion of patients were on pyridoxine or vitamin B6 therapy in each study arm. Almost 85% of the patients had experienced kidney stones in their lifetime with close to 39% having experienced stones in the 12 months prior to study entry. It's worth noting that a higher proportion of patients randomized to the lumasiran arm had reported a history of symptomatic renal stone events at study entry as compared to patients on placebo. With respect to nephrocalcinosis at study entry, 71% of lumasiran treated patients have nephrocalcinosis compared to 92% of the placebo patients. Patients were enrolled across Europe and North America and Middle East. I'll now turn to the efficacy results. In the ILLUMINATE-A study, lumasiran met the primary efficacy endpoint. Specifically, lumasiran treatment in PH1 patients resulted in a 65.4% mean reduction in urinary oxalate relative to baseline with a mean treatment difference of 53.5% relative to placebo, PV equal to 1.7 x 10 to the minus 14. The reduction in urinary oxalate was rapid, reaching nadir by 2 months after the initial dose and was sustained throughout the duration of the study. The effects of lumasiran toward the primary endpoint were highly robust. Specifically, in a prespecified subgroup analysis of the primary endpoint, lumasiran demonstrated a consistent treatment effect relative to placebo across all subgroups, including baseline kidney function and pyridoxine use, showing a favorable effect of lumasiran irrespective of age, gender, ethnicity, eGFR and prior history of symptomatic renal stones. We're very encouraged to see this consistent treatment effect in a relatively small study of 39 patients. Now turning to the secondary endpoints, lumasiran met all 6 tested secondary endpoints. Importantly, at month 6, 84% of patients who randomized lumasiran achieved urinary oxalate levels at or below 1.5x the upper limit of normal, PV 8.3 x 10 to the minus 7, representing a near normalization of urinary oxalate. Moreover, 52% of lumasiran-treated patients achieved urinary oxalate levels within the normal range, P is equal to 0.001. In contrast, none of the patients on the placebo arm achieved normal or near-normal levels of oxalate. Regarding some other secondary endpoints, lumasiran also led to a rapid and sustained reduction in plasma oxalate levels in patients whose baseline plasma oxalate was at or above 1.5x lower limit of quantification, with patients on lumasiran experiencing plasma oxalate reduction of 39.8% versus 0.3% for patients on placebo, P is equal to 2.9 x 10 to the minus 8. As expected, given the 6-month duration of the primary analysis period, there were no notable changes in eGFR levels. With regard to prespecified exploratory endpoints, 3 of 22 evaluable lumasiran patients demonstrated early signs of unilateral or bilateral improvements in nephrocalcinosis at 6 months, including 1 patient in the lumasiran arm demonstrating a 2-grade improvement in 1 kidney and a 1-grade improvement in the other kidney. In contrast, no improvement in nephrocalcinosis was reported for the 12 evaluable placebo patients with 1 experiencing unilateral 1 grade worsening. These effects on nephrocalcinosis are encouraging. And it will be of interest to see if we observe similar effects in the other ILLUMINATE studies and potentially further improvements with prolonged dosing in the ILLUMINATE open-label extension studies. And surprisingly, given that longer term follow-up is likely needed to demonstrate an impact on kidney stones, there was no significant difference between renal stone events in the 2 treatment arms, even though a higher proportion of patients on lumasiran had a history of renal stones at baseline. Let's now turn to safety, as shown on Slide 16. The bottom line here is that we're encouraged by the safety and tolerability demonstrated by lumasiran. There were no deaths, no severe or serious adverse events reported. Adverse events, or AEs, reported -- were reported in 84.6% of lumasiran patients and 69% -- 69.2% of placebo patients. This difference was driven predominantly by injection site reactions, or ISRs, which were reported in 34.6% of lumasiran-treated patients and no placebo-treated patients. All the ISRs were mild in severity, transient and did not result in treatment interruption or discontinuation. Most common ISR-related symptoms were erythema, pain, pruritus or discomfort at the injection site. Beyond ISRs, all AEs were mild to moderate in severity. AEs reported in greater than or equal to 10% of patients in either group were headache, rhinitis and upper respiratory tract infection. One patient in the lumasiran arm discontinued treatment due to an AE of fatigue and disturbance in attention. The patients completed study assessment through month 6 and remains in safety follow up. No clinically relevant changes were observed in laboratory parameters, including liver function tests, vital signs and electrocardiograms related to the lumasiran. 38 of 39 patients enrolled in the study completed the 6-month double-blind primary analysis period, and all eligible patients transition to the 54-month extension phase of the study to receive open-label lumasiran. In summary, results from ILLUMINATE-A signal hope to patients and families who we believe may substantially benefit from lumasiran in the future, assuming approval. In the meantime, lumasiran is currently also being evaluated in our ILLUMINATE-B pediatric trial in children under the age of 6, including infants. And our ILLUMINATE-C Phase III study in patients of all ages with advanced disease, including patients on dialysis. The single-arm open-label studies are ongoing and are designed to enable broad utility of lumasiran across the full spectrum of patient age and severity of the disease. Consistent with our previous guidance, we remain on track to report top line results from ILLUMINATE-B in mid-2020 and ILLUMINATE-C in 2021. And with that, I'll now turn the call over to Barry. Barry?

Thanks, Akshay. Good morning, everyone. We are, of course, thrilled with these results and the opportunity to help PH1 patients, and we look forward to working closely with the FDA through the regulatory review process, working toward the PDUFA date of December 3, 2020. Assuming regulatory approvals, we expect to launch lumasiran in the United States in late 2020 and the EU shortly thereafter. Now with regard to market opportunity for lumasiran. As you know, PH1 is an ultra-rare orphan disease with a prevalence of approximately 3,000 to 5,000 patients in the U.S. and Europe. As we have in other programs, we're now sharpening our pencils on the prevalence of patients with active and diagnosed disease where lumasiran could be a treatment option, and we will report our findings in the near future. In clinical practice, as you've heard, PH1 has a low index of suspicion with many patients, we believe as many as 50%, remaining undiagnosed. Patient diagnosis can often occur later in the course of disease. In adult patients, for example, there is a median delay of approximately 6 years between onset of clinical manifestations and diagnosis, with up to 65% of patients receiving their diagnosis only after reaching end-stage kidney disease, highlighting the tremendous disease burden, suffering and associated economic toll on the health care systems. With progression of disease and as the kidneys begin to fail, intensive dialysis is a bridge to dual liver-kidney transplant. And the average cost of transplantation and accompanying life-long immunosuppression exceeds $1 million. Thus, there is an urgent unmet need for an alternate treatment options that adequately reduce oxalate production at its source, preserve kidney function and have the potential to change the course of this devastating disease. Based on the data from ILLUMINATE-A, we believe that lumasiran has the potential to be a first-in-class, best-in-class medicine that substantially curbs the production of oxalate, insoluble toxic metabolite, responsible for the clinical manifestations of PH1 and has the potential to have a favorable impact on kidney function and disease progression. With our comprehensive clinical development strategy, we hope to make lumasiran available to all patients across the spectrum of PH1 disease, age of onset and severity. Now given the epidemiology of the disease, lack of approved therapies and Alnylam's approach to disease education -- disease awareness, we view the market opportunity to be in excess of $500 million, representing the potential for new and significant revenue source to Alnylam and, of course, providing benefit to many PH1 patients. As we prepare for the potential commercial launch of our third wholly owned RNAi therapeutic, we're working on a number of initiatives to enhance disease education and awareness, leading to earlier diagnosis and improved diagnosis rates, focusing on disease education for both pediatric and adult urologists and nephrologists. On that front, we're continuing to leverage our HCP facing disease awareness campaign referred to as Behind The Stone. The campaign urges physicians to look beyond acute stone events and provides tools and resources, including aboutph1.com, a disease education website that details the red flags of the disease, highlights its unpredictable rate of progression and navigates the path for an active diagnosis. An important goal of the care team is to increase suspicion of PH1 in any pediatric patient who presents with even a single kidney stone and any adult patient with recurrent stone events and to include PH1 as part of the differential diagnosis. This should then prompt genetic screening to help confirm or rule out PH1. The campaign also emphasizes the importance of early intervention in disease management, given the devastating consequences of progressive renal function decline. To this -- to that end, we're working to ensure tools exist to speed diagnosis. We've implemented Alnylam act as third-party genetic testing and counseling service in the U.S. and Canada. For the patient community, we recently launched a disease state awareness website called takeonph1.com. The site provides helpful information about the mechanism of disease and its progressive nature, educates on the role of genetic testing, particularly amongst siblings and highlights the importance of consistent disease management as a means to slow decline in kidney function. The site now also houses educational resources such as award-winning PH1 of a Kind video animation series designed for children living with PH1 and their caregivers and developed in partnership with the Oxalosis & Hyperoxaluria Foundation, or OHF. With many patients diagnosed in early childhood, this video series fills a significant gap in educational content for young patients and their families and continues to demonstrate Alnylam's commitment to the needs of this community. Assuming positive regulatory outcomes, we'll be leveraging our global commercial capabilities to launch lumasiran, including commercial infrastructure we put in place for ONPATTRO and GIVLAARI. We believe our planned strategies for HCPs, patients and payers will support a successful launch. Along with our track record in R&D, Alnylam is now showing its excellence in innovation and commercialization of novel disease-modifying medicines. We'll apply these capabilities to the [ exciting ] potential launch of lumasiran later this year. In closing, I'd also like to thank the patients' caregivers, patient advocates and study investigators and staff that continue to work extraordinarily hard for the PH1 community, particularly in these unprecedented times. I'll now turn the call back to Christine to coordinate Q&A. Christine?

Thanks, Barry. Operator, we will now open the call for questions. [Operator Instructions]

[Operator Instructions] We'll take our first question today from Gena Wang from Barclays.

Congratulation on the great data. So the first question is -- it's a great data. So the first question is regarding the 1 discontinuation due to AE. Just wondering was that deemed to be drug related? And the second question is ILLUMINATE-B, since your top line data will be mid '20 and the PDUFA day will be in December, will FDA be looking at ILLUMINATE-B data before making the decision? And is it possible the label could be extended to patients younger than 6 years old?

Yes. Let me have Akshay answer the first question and also Pushkal Garg is on the phone. He may join in as well. But on the second question, Gena, the plan is to have top line results in mid-2020 for ILLUMINATE-B. And we're focused on the ILLUMINATE-A study for regulatory purposes. Obviously, any data that we have available to us is submitted as part of the NDA and the review process. But our focus is on the ILLUMINATE-A population for the approval. Akshay, do you want to comment on the first question?

Yes. I believe the patient's -- the AE wasn't deemed related. But Pushkal will probably be closer to those details. I'll let him comment. I'll reiterate what John said that the approval is focused on ILLUMINATE-A, but we, of course, always submit all available data as we're obliged to do so, including any ILLUMINATE-B data. But Pushkal, you want to comment?

Yes, happy to. Gena, so the 1 patient that discontinued was someone who had some AEs of fatigue and disturbance in attention. They discontinued pretty early, and it was considered unrelated to study drug.

We'll go to our next question now from Paul Matteis from Stifel.

Great. And let me add my congrats as well. Two quick questions. One, on -- just given, I guess, you've talked about this and you presented some great natural history data at your R&D Day. Given the clear-cut association between oxalate levels and outcomes, I guess, are you surprised in this study that you didn't really see an effect on eGFR or any other exploratory clinical endpoints? And then just 1 question for Barry. Are you planning on having an EAP ahead of launch? And what's your kind of expectation for patients on therapy when you launch lumasiran?

Yes. So Paul, let me -- I'm going to have Akshay answer your first question. But let me just start by correcting you, if I may, that we did see an impact on nephrocalcinosis in the study, which was an exploratory -- prespecified exploratory endpoint and, obviously, a very interesting result, even within the 6 months of treatment. Akshay, do you want to handle the question on GFR as well?

Yes, I mean, Paul, in the first instance, I think the objective would be to prevent any further decline in renal function. And we seem to see no decline in renal function of significance over time in either group. And so the time frames that this study is done in 6 months is really not long enough to evaluate outcomes like eGFR. And that's why it wasn't a primary or a secondary. Of course, it's something of interest that we'll follow over time and hope to see benefits in. And the long-term goal would be, if lumasiran is approved, that diagnosis is earlier, patients don't get into a situation where they have impaired renal function and so we can prevent that ever happening by reducing urinary oxalate, hopefully. And I think we're encouraged by the exploratory endpoint nephrocalcinosis because that suggests with 3 patients in the lumasiran arm showing some degree of improvement in nephrocalcinosis, it was an exploratory endpoint, and 1 deteriorating in the placebo arm that we're at the beginnings of seeing translation of the urinary oxalate changes to concrete benefit in the organ itself in the kidney. And so obviously, long-term studies will be important for GFR, for this nephrocalcinosis data that looked very encouraging and other clinical outcomes.

Yes. And Barry, you want to answer the second question?

Yes, absolutely, Paul. Just to emphasize, as John said, I think we're really delighted by the nephrocalcinosis results so early in the clinical study. Yes, in terms of EAP, the EAP is up and running in the United States and several European countries for patients 6 years and over. Hard to know, Paul, exactly how many patients will accrue to the study. As you know, we opened EAP in centers, but most of the patients, we believe, over a period of time, we'll actually find out in the community given the significant underdiagnosis. So time will tell how many patients we'll have. But clearly, we'll follow the game plan as we have for our first 2 drugs, where those on EAP will convert to commercial drug. And then just to note, since it's probably out there, the patients that roll over to the open-label extension study will stay on clinical study, and those patients will not be commercial patients for some period of time.

We will now go to our next question from Alethia Young from Cantor.

Congrats on the data. I'm glad to hear you guys are well. I wanted to talk a little bit about why the diagnosis potentially is sometimes so long? Just maybe give us a little bit more color on like why it kind of takes, like, I think, in that case you mentioned 6 years, to get a diagnosis? Is it just kind of hard to discern by doctors? Or is it just not looked for? Or are there tests that need to be done?

Yes. Well, maybe I can ask Pritesh Gandhi, who's our General Manager for the program, to comment on that since he's got the closest relationship with the program overall. Pritesh?

Thanks, John. Thanks, Alethia. It's a very interesting question with respect to diagnosis. As with most rare diseases, diagnosis is generally delayed from initial symptoms to definitive diagnosis. And in this particular patient population, as you can imagine, there are 2, in essence, segments. There's the pediatric segment and then there's the adult segment. From the pediatric perspective, the patient journey is much shorter from symptom onset to definitive diagnosis, and that diagnosis can be made within months to a year or 2. It is more protracted in the adult patient population, where that patient journey could be up to 5 to 7 years. And a lot of it, of course, is just because of rare disease and that we just really need to educate around this particular condition so that PH1 can be part of the differential diagnosis.

And maybe, Pritesh, I would just add to that. And I'm sure you agree, that like -- as you said, like other rare diseases, education, availability of therapies always increases the speed to diagnosis, and likelihood of diagnosis. So we hope that this helps the field and patients get diagnosed earlier. And of course, diagnosis is relatively straightforward by means of collecting urinary oxalate, which is a widely available test, a well-known test, and doing the genetic analysis.

Absolutely, Akshay.

Thanks, both. Does that answer your question, Alethia?

Yes.

We'll go to our next question now from Maury Raycroft from Jefferies.

Congrats on the data update today. I was wondering -- no problem. I was wondering for the 3 patients that you've shown improvement in nephrocalcinosis, was there anything different in these patients at baseline? I guess were they earlier stage supporting rationale for treating sooner than later? And based on what you know, do you project some additional patients will improve on nephrocalcinosis with longer term treatment?

Yes. Those are great questions. Maybe Pushkal, can you answer those questions?

Yes. Absolutely. So Maury, as you know, we were really excited to see at this early time point some trends towards improvement in nephrocalcinosis. We've looked preliminarily, and these patients don't look particularly different than the others in the study in terms of their oxalate lowering, et cetera. So we're going to continue to follow these patients over time and see how the data materializes. As you've heard, there's about 70% or so of patients who had nephrocalcinosis at baseline. So there's an opportunity for us to continue to follow this over time. But nothing unique about these 3 patients.

I would just add and maybe Akshay was going to as well. But obviously, the benefit of this study is that all the patients will now transition to active drug treatment. And so the additional placebo patients, including that 1 that showed a worsening in the placebo arm, will now get the benefits of drugs. So we'll monitor nephrocalcinosis across the entire cohort as a function of time going forward. Akshay, did you want to add something?

Yes. But that's an independent evaluation, as you just described, and there's another independent evaluation that in ILLUMINATE-B, we're also looking carefully there as well at the nephrocalcinosis. So there'll be multiple opportunities to study outcomes in this key aspect of the disease.

We will now go to our next question today from Anupam Rama from JPMorgan.

Congrats on the data. Just a quick one for me, Barry. I don't -- sorry if I missed it, but how are you thinking about the sales force sort of size and scope for lumasiran, if there's any potential expansion that's needed with the potential approval later this year and launch early next year?

Yes, absolutely. Barry, you want to answer that?

Yes, Anupam, thanks. So as I mentioned on the conference call, we've built significant commercial capabilities globally, and we'll leverage those capabilities, things like call centers, things like our access people. We will be adding a small number of nephrology, urology focused folks in a highly leveraged way and then use the tools we've built to virtually get out into the community. So we will add a couple of customer-facing roles, mostly on the sales side, but leverage the rest of our infrastructure.

We'll go to our next question now from Ritu Baral from Cowen.

First question. Can you guys remind me if you have any Phase IV commitments ongoing either on safety or any of the efficacy endpoints? And my follow-up, I'll just throw it out there now. How are you guys thinking about payer discussions with the data that you're going to have on hand? What's going to be most important to the payers? Is it the normalization of urinary oxalate? Will the nephrocalcinosis scores, the eGFR scores, which will hopefully be more mature at that point, be of more relevance as you discuss coverage?

Yes. Those are great questions. Akshay, do you want to comment on the first point on Phase IV commitments and Barry follow-up on payers?

Sure. Yes. So as far as the Phase IV commitments, Ritu, I think it would be imprudent of us to comment on that until the regulators have had an opportunity to complete their review of the file. A couple of things I would say, however, that this is a very comprehensive data set, I feel, we feel. And so it -- from an efficacy viewpoint, should support approval -- a full approval. The primary endpoint was agreed to with regulators both in the U.S. and EU. And as far as safety is concerned, as most of us know and aware, in rare disease, it's very common to get a post-approval commitment to continue to study safety in patients that have been on the program. And so it wouldn't be surprising. It's just as a routine matter to continue to understand safety of the drug in a larger population of patients. They ask us to look at that carefully for a longer period of time, as we've done for ONPATTRO and GIVLAARI. So that's what I would say to that. As far as the payer piece, Barry will comment on it. One thing I will say back to the comprehensive nature of the program is that we know from natural history data and again, this is all discussed with regulators and they support us in this, that urinary oxalate itself is directly related to time to progression to renal failure. So this is a very important outcome, we believe, for patients that we've demonstrated today. And with 84% of patients demonstrating normalization or near normalization, hopefully, those are many, many kidneys we can help and many patients and prevent many devastating complications that require dual liver-kidney transplant. So there's an evidently clinically important data set here today that we've discussed, but I'm sure Barry's got thoughts as well.

Yes. Barry, you want to follow up further?

Akshay, just 1 quick question -- just 1 quick clarification. So right now, you're proceeding with the assumption that this is going to be a full approval and not an accelerated approval, per your comment.

Correct, yes.

Absolutely. Barry, do you want to...

Absolutely. Thanks, Ritu. So just as a quick comment. In addition to the open-label extension study and any potential commitments, we will have a registry up and running and that will provide phenomenal data going forward to understand the disease even more. In terms of the payer front, as you know, every single payer in the United States takes a different approach and every country around the world has a very clear health technology assessment process. We've been pretty successful with ONPATTRO, and as you've heard, at least where we've launched GIVLAARI in the United States, we have not hit payer headwinds. So we will -- we'll do what we've done before. We'll proactively take a value-based agreement approach in the United States and countries around the world and partner with payers, assuming some level of risk on our side to ensure access. And as we've seen with ONPATTRO and GIVLAARI, we've worked with payers to ensure that patients fit the label and get a prescription, get drug. And I'm pretty sure given that these are sick kids, we'll be pretty successful in the payer front here as well. And again, we'll take that partnership approach, not the battling approach to work with payers.

Thanks, Barry.

We will take our next question now from Luca Issi from RBC.

Luca Issi from RBC Capital. Congrats on the data, great news for the company and most importantly patients. Two questions. One, is there a plan to pursue a fixed-dose approach here instead of a weight-based approach given that your competitor is doing so? And then the second question is, were there any patients in this trial with the G170R genotype? And if so, is it possible that the payers would require those patients to step through vitamin B6 before going to lumasiran, even if these patients are more likely to respond to vitamin B6?

Yes. Luca, I think the second question would probably be best answered by Pushkal. But Barry, you want to answer the first one first?

The fixed-dose versus weight-based dose?

Well, maybe -- let me -- maybe -- I'm sorry, Pritesh should answer that. I mean let me start by saying that, Luca, we think that the weight-adjusted dose approach here given the spectrum of weights and age in this population is the right approach to use. So we have no immediate plans to shift to a fixed dose. We don't think that, that's a substantial differentiator in a rare disease market like this. But Pritesh, do you want to add anything further to what I just said?

Yes. So Luca, it's a great question. As we know, this disease includes pediatric patients, right? And as we all know with pediatric patients, they do metabolize and clear drugs differently than adults. And on top of that, their physiology is also changing. Some of these patients are very young, 3 months, 6 months of age. And so their physiology is rapidly changing. And so with that, you're going to have to adjust the dose to account for the changing physiology and the changing weight and body surface area. So we would have to continue with a weight-based dosing regimen, especially for the pediatric patients. In terms of the adult patients, I think we will have to look at fixed dosing if we think it's appropriate for the adult patient.

Thanks, Pritesh. And your second question, Luca, again, was...

B6 step through, John. I can...

Pushkal, do you want to handle that?

Yes. Yes. Let me start with just some of the data. And so I think -- and put some context around it. So Luca, as you're referring to, there is this G170R mutation that some proportion of patients have that's associated with B6 responsiveness. I think it's important to note that whereas -- and that's obviously -- the prevalence of that depends somewhat on the epidemiology and geography. But if you say 30% or 40% of patients may have that mutation, it's important to note that not -- that a minority of patients actually fully respond to B6, probably on the order of about 5% based on available data. So it's -- while it's a very benign vitamin B6, the point is that patients still have opportunity to benefit from oxalate lowering with lumasiran. And that's what we saw in the clinical study as well, about half of the patients were on B6 in the study, about 45% of patients had the G170R genotype, but we saw benefits in terms of oxalate reduction across that full spectrum of patients irrespective of B6 use. So we're really encouraged that -- and we know that any degree of oxalate lowering is really important for these patients in terms of preserving renal function and progression of disease. So we're really encouraged by the data. And I think that our expectation would be and hope would be that it will be used pretty widely across the spectrum of patients to reduce oxalate. Barry, you may have more to add?

I think you covered it incredibly well.

If I could just add 1 more thing with respect to B6. And just to add to what Pushkal said, with respect to B6, a vast majority of the patients will not near normalize or normalize with vitamin B6. And what we've seen here with lumasiran in terms of 84% of the patients normalizing or near normalizing is just an amazing result that we have seen so far. So we do not anticipate step through therapy here.

We'll go to our next question now from Mani Foroohar from SVB Leerink.

A couple of quick ones. First, on commercial strategy. You guys have talked about aligning pricing with value as well as with the size of the opportunity in terms of patients given the impact on budgets in both single payers in Europe and elsewhere in the U.S. When we think about the potential pricing for this drug, should we think about it as proportional of the patient population, i.e., with smaller populations and AHP for givosiran and substantially smaller than TTR for ONPATTRO, would that imply that perhaps a higher absolute price for lumasiran will make sense versus givosiran? And then regarding the clinical data as shown, could you give us some clarity on the details of why nephrocalcinosis was only measured in the subpopulation of patients with renal ultrasounds, where we see renal ultrasounds in the patients who didn't have one at month 6 in the future. And then as the third question, I'm comparing this data versus what we saw from the Phase I/II OLE in terms of absolute benefit reduction of oxalate, and absolute value in terms of percentage of patients reaching near normalization, normalization. There appears to be a bit of drop-off across all 3. Is that just normal going from a single-arm study to a placebo-controlled study? Is there something we should look at in the baseline characteristics that shows why we have an optically less impressive benefit, numerically speaking here? Just if you can explain that, that will be really helpful.

Yes, Mani, those are great questions. I'm going to just handle the first one so that we can be more efficient on the other 2. Obviously, we're excited about the value proposition that lumasiran brings for patients. And we'll discuss the data package with payers and certainly make sure that we get alignment with payers as we have in the past with ONPATTRO and GIVLAARI. And by all accounts, we will be doing a value-based agreement approach. We've done that with ONPATTRO and GIVLAARI, and we've committed to doing that with all of our products. And lumasiran will certainly fit into that mold for how we think about it. This is an ultra-rare orphan disease. And certainly, that will be a factor that reflects on how we think about the value proposition as well. But at the end of the day, it's really too soon to comment today on that. We'll certainly do that when we get closer to approval or at the date of approval, we'll certainly be sharing our details on pricing at that time. So your other 2 questions, which were both very good. Let me hand them over to Akshay and Pushkal -- maybe, Akshay, you want to start?

I caught the one about the Phase I/II OLE and comparing those data to the Phase III. My thinking is that, first of all, we have to be very careful comparing across trials, right? So things can be very different between trials. And so there's that general issue of the baseline demographics, disease severity, nature of population, et cetera. Second thing is the sample sizes, very different sample sizes, this would be deemed a more definitive readout. And you often also want to be careful about the kind of assays used when the key endpoint is a biochemical assay like this and the preliminary Phase I/II data were an enzymatic assay. This is a robust LC-MS/MS assay, which we've agreed to with regulators. And so we -- you got to be careful as you compare the 2 because of a slightly different sensitivities, et cetera, of the 2 assays. And finally, the overall baseline urinary oxalate levels were higher, speaking to difficulties in comparing trials, they're higher in this Phase III study than they were in the initial Phase I/II OLE. And so these are all reasons why I think we have to be cautious. One thing we can't get away from is that we've seen a profound reduction in urinary oxalate today, 84% of patients normalizing or near normalizing. This should translate to very, very significant clinical benefit based on prior relationship -- the continuous relationship between urinary oxalate reductions which all patients in this study showed, by the way, and renal outcomes. So I'll stop there. I don't, Pushkal, if you've got anything to add to that.

Yes. I mean I think, Akshay, I totally agree with everything you said. And I think, again, to reiterate, Mani, I mean it's a graded relationship. First of all, I think the data between the Phase I/II and the Phase III are quite similar overall. And I think, second of all, you see graded relationship between urinary oxalate lowering and clinical outcomes. And as Akshay noted, we saw improvements in all patients. So really encouraging from that regard. I think your second question was around the number of patients with nephrocalcinosis data. And looking at this early time point, this cut was based on patients who had matched ultrasounds at baseline month 6. We're going to continue to follow that in this study. It's obviously an important predictor clinically of renal outcomes, nephrocalcinosis. So the data are encouraging that we've seen. We'll continue to follow it over the course of this study. And I think, as Akshay noted before, we're measuring this in ILLUMINATE-B as well. So we look forward to those data later in the year.

If I can follow-up. Akshay mentioned the difference in assays. I'm looking at the presentation from this morning on Slide 5, that you guys have in front of you, of the data from this morning, not this webcast, of course. And it says in the bottom bullet that the data from the Phase II OLE was consistent between the 2 assays despite the difference in the absolute values. So is the right way to think of that while the assays are different, the degree of benefits shown by the Phase II OLE with those 2 assays is the same, and so any difference between the 2 data sets should be ascribed to baseline characteristics. Is that the right way to interpret your comment, Akshay? Or am I missing something?

I think the right way to interpret the comment, I would dare to say, is that if you did any statistical testing between these studies, you'd find that these data are entirely consistent between the 2 studies, and they show a very significant degree of clinical benefit. So trying to pass significances -- differences in data between small sample sizes like this in a rare disease is fraught with difficulty. And I think you've got to look at the overall consistency that every data set we've reported with this drug shows benefit in terms of reduction in urinary oxalate, the magnitude looks very similar. And the overall scope of the drug to normalize or near normalize 84%, I think bodes rather well for the drug. So trying to understand differences, I think is probably going to mislead us. And the conclusion for us here is that this seems to be a drug with great potential to be transformative in this disease.

Jonathan Lim from UBS has our next question today.

This is John on for Navin. I just wanted to start by following up with Mani's question about the assays. And I'm curious as to how these assays may be used in that -- in the treatment -- future treatment paradigm as that evolves? And my second one just has to do with how the different treatment journeys for pediatric versus adult, how that may translate to launch curves?

Okay. Pritesh, do you want to handle these questions?

Yes. So with respect to the assay, right, for the Phase II, we used a clinical assay that's used in most academic and in the community centers. For the Phase III, of course, we had to use an assay that met regulatory standards. And so we did that for the Phase III study. In terms of diagnosis, specifically, the assays are out there and they are available in terms of urinary oxalate measurement and we anticipate that making the diagnosis to the earlier conversation that we had is generally easy with biochemical analysis, stone analysis and genetics. As it pertains to the second question, Jonathan, in terms of launch curves, I think one of the things that we're, of course, going to be focused in on are really getting this drug to patients that are already diagnosed. The majority of those patients are going to be pediatric. And I think that the growth is going to come mostly from the adult patient population that needs to be diagnosed because of just how long it takes them to get diagnosed. So that's how we anticipate the launch curves, and first in terms of patients that were already diagnosed and then the growth is going to come from patients that need to be diagnosed.

Does that answer your question?

Yes, it's very helpful.

We have time for one more question from Leland Gershell from Oppenheimer.

Just adding my congratulations as well. A question for Akshay, I believe. I wanted to ask you now, as you think about the spectrum of patient progression from early to later stage, eventually to ESRD and we think about how lumasiran could be helpful to these patients, would we expect, based on changing physiology or renal brittleness, that we could see more or less effect of the drug as patients get older? Or would it be the case that perhaps, like in ILLUMINATE-B type population, we could expect to see perhaps better results in the younger population, perhaps you'd see more responsiveness, more effective benefit of the drug?

Okay. Good question. Akshay, you want to handle that?

Yes. Sure. So the fundamental lesion is hepatic overproduction of oxalate, that deposits in the early stages of disease in the kidney is causing stones, nephrocalcinosis and renal decline. And then as the disease progresses, patients end up in end-stage renal disease and calcium oxalate now starts depositing, in addition, in other areas of the body; the eye, the heart, the bone, causing ocular defects, cardiomyopathy, pathological bone fractures. That fundamental biochemical lesion does not change through the life of the patient or the natural history of the disease. That pathological basis is amenable to treatment with lumasiran throughout the course of disease. So we would expect to see oxalate reductions, both in early, mid and late stages of the disease. And even in later stages of the disease, we believe that reducing oxalate should be good for patients because we hope to stop deposition in these other organs outside the kidney and the devastating complications that you see there. And so ILLUMINATE-C is designed to evaluate that aspect by looking at patients on dialysis, who unfortunately, irreparably damage their kidneys, but are suffering consequences in other organs. So we actually await the outcome of that study, obviously. But I think this is a very important hypothesis to attack this disease. ILLUMINATE-A looks like they are very encouraging and we would expect to see oxalate reductions in ILLUMINATE-B and C.

And just following up on that. So would we expect to see perhaps an earlier change in the renal stones outcome in the older patients? Or it's just a matter of time that all patients will improve and it's hard to predict when we'll see perhaps an endpoint that might reflect that study?

Yes. I mean damage to kidneys and stone formation occurs over months and years actually, right? So we wouldn't expect to see, in any of these types of studies that we're conducting in a 3- to 6-month period, dramatic changes in renal function or renal stone formation. That's going to take a much longer period of time. But given that those events occur because of elevated oxalate levels, I think it's a sound hypothesis to test and observe these patients over longer periods of time. And as Barry said, there's going to be a registry as well. That'll be another great opportunity to look at patients over the long term and look at outcomes on stones, et cetera. But that will just take more time. But I think the preliminary data from the exploratory endpoint on nephrocalcinosis certainly point in a good direction for these patients, which is great.

And with that being our last question, let me go ahead and thank everyone for having joined us on the call today. We're obviously very excited about the data we presented today. This is terrific news for patients with PH1 and their families, their caregivers, their loved ones. So we're very happy about this, and we look forward to the approval [ to announce ] any favorable regulatory review of the third RNAi therapeutic in the months ahead. So thanks, everybody, and stay safe and stay well. Bye-bye.