Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals Conference Call to discuss results from the ILLUMINATE-A phase 3 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 we have made available via webcast can also be accessed by going to the investors' page of our website, www.alnylam.com. Now, turning to our call, as outlined in slide two, John will provide some opening remarks. Akshay will discuss the ILLUMINATE- A study results in more detail. Barry will walk us through next steps with 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 other 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 now would 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 3 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 six, 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 sum, 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 3 study for an investigational RNAi therapeutic across four distinct programs: the 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 3 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 3rd, 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 E.U. 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 3 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 multi-product 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 the Illuminate 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 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. Lieske in more detail. Primary hyperoxaluria Type 1, or PH1, is an ultra-rare autosomal recessive disease caused by a genetic defect in 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 and rates of 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, though 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 six 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, cardiomy opathy, pathological bone fractures, and in some cases, death. Most 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 three to four liters of water per day, crystallization inhibitors, and for a select population of patients with a specific genotype, pyridoxine, otherwise known as vitamin B6. Fortunately, 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 3 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 enrolled 39 patients across 16 study sites in eight countries around the world.
To be included, patients had to be at least six 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 per minute, corrected for body surface area. Patients were randomized 2:1 to receive lumasiran or placebo, with lumasiran. A 3 mg/kg dose administered once monthly for three months, followed by quarterly doses thereafter. The primary endpoint for the study was the % change from baseline in 24-hour urinary oxalate excretion averaged across months three to six 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 in slide 11.
The overall mean age at study entry was 18.1 years, with a range of six to 60 years old. The majority of patients, 56%, were between the ages six 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 had nephrocalcinosis compared to 92% of the placebo patients. Patients were enrolled across Europe and North America and the 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, being equal to 1.7 x 10 to the - 14. The reduction in urinary oxalate was rapid, reaching nadir by two 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 pre-specified subgroup analysis for the primary endpoint, lumasiran demonstrated a consistent treatment effect relative to placebo across all subgroups, including baseline kidney function and pyridoxine use, showing favorable effects on lumasiran irrespective of age, gender, ethnicity, eGFR, and prior history of symptomatic renal stones. We are 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 six tested secondary endpoints. Importantly, at month six, 84% of patients randomized to lumasiran achieved urinary oxalate levels at or below 1.5x the upper limit of normal, being equal to 8.3x 10 to the - 7, representing a near-normalization of urinary oxalate. Moreover, 52% of lumasiran treated patients achieved urinary oxalate levels within the normal range, being equal to 0.01. 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 the lower limit of quantification, with patients on lumasiran experiencing plasma oxalate reduction of 39.8% vs 0.3% for patients on placebo, being equal to 2.9x 10 to the - 8.
As expected, given the six-month duration of the primary analysis period, there were no notable changes in eGFR levels. With regard to pre-specified exploratory endpoints, three of 22 evaluable lumasiran patients demonstrated early signs of unilateral or bilateral improvement in nephrocalcinosis at six months, including one patient in the lumasiran arm demonstrating a two-grade improvement in one kidney and a one-grade improvement in the other kidney. In contrast, no improvement in nephrocalcinosis was reported for the 12 evaluable placebo patients, with one experiencing unilateral one-grade worsening. These effects of nephrocalcinosis are encouraging, and it would 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.
Unsurprisingly, 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 two 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 13. The bottom line here is that we're encouraged by the safety and tolerability demonstrated by lumasiran. There were no deaths and no severe or serious adverse events reported. Adverse events or AEs were reported in 84.6% of lumasiran patients and 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 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 six and remained 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 six-month double-blind primary analysis period, and all eligible patients transitioned 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 six, including infants, and our ILLUMINATE- C Phase 2 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 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 3rd, 2020. Assuming regulatory approvals, we expect to launch lumasiran in the United States in late 2020 and in the E.U. 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 3,000-5,000 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 60% remaining undiagnosed. Patient diagnosis can often occur later in the course of disease. In adult patients, for example, there's a median delay of approximately six years between the 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 healthcare 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 lifelong immunosuppression exceeds $1 million.
Thus, there is an urgent, unmet need for alternative 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 and soluble 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 its severity.
Now, given the epidemiology of the disease, lack of approved therapies, and Alnylam's approach toward disease education and disease awareness, we view the market opportunity to be in excess of $500 million, representing the potential for new and significant revenue sources 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 to an accurate diagnosis. An important goal of the campaign 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 an ex-screen 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 that end, we're working to ensure tools exist to speed diagnosis. We've implemented Alnylam Act for 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 among 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 developing partnerships with the Oxalosis and 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 its community.
Assuming positive regulatory outcomes, we'll be leveraging our global commercial capabilities for launching 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 has now shown its excellence in integration 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.
As a reminder to those dialed in, we ask that you limit yourself to one question each and then get back in the queue for any additional questions.
Thank you. Ladies and gentlemen, ladies and gentlemen, to ask a question today, please signal by pressing star one on your telephone. Please ensure that the mute function on your telephone is switched off to allow your signal to reach our equipment. Again, to ask a question today, please signal by pressing star one on your telephone. We will pause for just a moment to allow everyone an opportunity to signal for questions. Thank you. We'll take our first question today from Gena Wang from Barclays. Please go ahead.
Thank you for taking my questions, and congratulations on the great data. So the first question is, thank you. It's a great data.
The first question is regarding the one discontinuation due to AE. Just wondering, would that need to be drug-related? And the second question is that ILLUMINATE- B, since your top-line data will be mid-2020 and the PDUFA date will be in December, will FDA be looking at ILLUMINATE- B data before making the decision? And is it possible the label could extend it to patients younger than six years old?
Yeah. 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 ILLUMIN ATE- population for the approval. Akshay, do you want to comment on the first question?
Yeah. I believe the patient's AE wasn't being related, but Pushkal will probably be closer to those details. I'll let him comment. I'd 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?
Yeah. Happy to. Hi, Gena. So the one patient that discontinued was someone who had some AEs with fatigue and disturbance in attention. They discontinued pretty early, and it was considered unrelated to study drug.
Thank you.
Thank you, Gena.
Thank you.
We'll go to our next question now from Paul Matteis from Stifel. Please go ahead.
Great. Thanks so much. And let me add my congrats as well. Thank you. Two questions. One, just given. I guess you've talked about this and you've 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 one 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? Thanks so much.
Yeah. So, Paul, 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, pre-specified exploratory endpoint, and obviously a very interesting result, even within the six months of treatment. Akshay, do you want to handle the question on eGFR as well?
Yeah. 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 timeframes that this study's done in six months are really not long enough to evaluate outcomes like eGFR. And that's why it wasn't a primary or a first secondary. Of course, it's something of interest that will follow over time and hope to see benefits in.
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 urine oxalate, hopefully. I think we're encouraged by the exploratory endpoint nephrocalcinosis because that suggests that three patients in the lumasiran arm showed some degree of improvement in nephrocalcinosis. It was an exploratory endpoint, and one deteriorating in the placebo arm that we're at the beginnings of seeing the translation of oxalate changes to concrete benefit in the organ itself, in the kidney. So obviously, long-term studies will be important for GFR, for this nephrocalcinosis data that look very encouraging, and other clinical outcomes.
Yeah. Barry, you want to answer the second question?
Yeah, absolutely, Paul. I just emphasize what 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 six years and over. Hard to know, Paul, exactly how many patients we'll accrue to the study. As you know, we open EAP in centers, but most of the patients, we believe, over a period of time, we're actually going to 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 two 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.
Great. It makes the context on the clinical side.
Yeah. Thanks, Paul.
Thank you. We will now go to our next question from Alethia Young from Cantor Fitzgerald.
Hey, guys. Thanks for taking my question and congrats on the data. I'm glad to hear you guys as well. Thank you. Yeah. 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 why it kind of takes, I think, in that case, you mentioned six 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?
Thanks. Yeah. 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. Good morning. 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. In this particular patient population, as you can imagine, there are two, 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 two.
It is more protracted in the adult patient population, where that patient journey could be up to five to seven years. And a lot of it, of course, is just because of their 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, 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 urine oxalate, which is a widely available test, a well-known test, and doing the genetic analysis.
Absolutely, Akshay. Good.
Thanks, Paul. Did that answer your question, Alethia?
Yes. Thank you.
Thank you.
Thank you.
We'll go to our next question now from Maury Raycroft from Jefferies. Please go ahead.
Hi. Good morning, everyone. And congrats on the data update today. Thanks. I was wondering—no problem. I was wondering for the three patients that you showed 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?
Yeah. Those are great questions. Maybe Pushkal, can you answer those questions?
Yeah. Absolutely. So Maury, as you know, we were—and as Alicia noted, 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, etc.
So we're going to continue to follow these patients over time and see how the data materialize. 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 three patients.
I would just add - 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 one that showed worsening in the placebo arm, will now get the benefits of drug. So we'll monitor nephrocalcinosis across the entire cohort as a function of time going forward. Akshay, did you want to answer the - ?
Yeah. But that's an independent evaluation, as you just described.
And there's another independent evaluation that 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.
Yeah. That's a good point.
Got it. Thank you very much.
T hanks, Laurie.
Thank you. We will now go to our next question today from Anupam Rama from JP Morgan.
Hey, guys. Congrats on the dinner, and thanks so much for taking the question. Just a quick one from you, Barry. 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?
Yeah. Absolutely. Barry, do you want to answer that?
Yeah. No problem. 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 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.
Thank you, Barry. Thank you.
Thank you. We'll go to our next question now from Ritu Baral from Cowen. Please go ahead.
Good morning, everyone. Thanks for taking the question. First question, can you guys remind me if you have any phase four commitments ongoing, either on safety or any of the efficacy endpoints?
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 and the eGFR scores, which will hopefully be more mature at that point, be of more relevance as you discuss coverage?
Thanks. Yeah. Those are great questions. Akshay, do you want to comment on the first point, that phase four commitments, and Barry follow up on payers?
Sure. Yeah. So as far as the phase four commitments, it's too early for 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 from an efficacy viewpoint, it should support approval or full approval. The primary endpoint was agreed to with regulatory authorities in the U.S. and the E.U. And as far as safety is concerned, as most of us know and are aware, in rare diseases, 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 if, just as a routine matter, they continue to understand the 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, I'd be happy to 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 urine oxalate itself is directly related to time to progression to renal failure. So it's 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.
Yeah. Barry, do you want to follow up?
I just want to just have one quick question. Just one 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.
Clear comment.
Correct.
Correct. Yeah.
Absolutely. Barry, do you want?
Sorry. Thank you.
Yeah. Absolutely. Thank you, too. So just 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, and it takes a different approach in 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 we've launched Givlaari in the United States, and we've not hit payer headwinds. So 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 O npattro 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 on the payer front here as well. And again, we'll take that partnership approach, no t the battling approach, to work with payers.
Thanks, Barry.
Thank you. We will take our next question now from Luca Issi from RBC. Please go ahead.
Hi. Good morning, and thank you for taking my question. Luca Issi from RBC Capital. Congrats on the data. Great news for the company and, most importantly, the patients.
Do you want—is there a plan to pursue a fixed dose approach here instead of a weight-based approach given your competitors 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? Many of these patients are more likely to respond to vitamin B6. Thank you.
Yeah. Look, I think the second question would probably be best answered by Pushkal. But Barry, do you want to answer the first one first?
The fixed dose vs weight-based dose?
Well, 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.
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?
Yeah. Hi, Luca. It's a great question. As you 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, the physiology is also changing. Some of these patients are very young, three months, six months of age. And so the 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 patients.
Thanks, Pritesh. Yeah.
And your second question, Luca, again, was?
The B6 step group, John. I can.
Pushkal, do you want to handle that?
Yeah. Yeah. Let me start with just some of the data. And so I think to 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 know that whereas, and that, 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 a minority of patients actually fully respond to B6, probably on the order of about 5% based on available data. so while it's a very benign vitamin B6, the point is that patients still have the opportunity to benefit from oxalate lowering with lumasiran. and that's what we saw in the clinical study as well. About half 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.
I think that our expectation would be and hope would be that it'll 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 one more thing with respect to B6, and just to add to what Pushkal said, with respect to B6, a vast majority of the patients were not near normalized or normalized with 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 two therapy here.
Great. Thanks, Pritesh. Very helpful. Very helpful.
Thanks, Luca.
Thanks, Luca.
Thank you. We'll go to our next question now from Mani Foroohar from SVB Leerink. Please go ahead. Okay.
Thank you for taking my question.
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 to the patient population, i.e., with a smaller population than AHP for Givlaari and substantially smaller than ATTR for Onpattro, would that imply that perhaps a higher absolute price for lumasiran would make sense vs Givlaari? 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 ultrasound? Will we see renal ultrasounds in the patients who didn't have one at month six in the future?
Then as a third question, I'm comparing this data versus what we saw from the Phase 1/2 OLE in terms of absolute benefit reduction of oxalate at an absolute value in terms of percentage of patients using near normalization, normalization. There appears to be a bit of drop-off across all three. 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 serves while we have optically less impressive benefit, numerically speaking, here? Just if you can explain that, that would be really helpful.
Thank you. Yeah. Mani, those are great questions. I'm going to just handle the first one so that we can be more efficient on the other two. Obviously, we're excited about the value proposition that lumasiran brings for patients.
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. 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. Lumasiran will certainly fit into that mold for how we think about it. This is an ultra-rare orphan disease, and certainly, that'll be a factor that reflects on how we think about the value proposition as well. 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 two 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 1/2 OLE and comparing those data to the Phase 3. My thinking is that, first of all, we have to be very careful comparing across trials, right? Things can be very different between trials, and said that there's that general issue of the baseline demographics, disease severity, nature of population, etc. Second, is the sample sizes, very different sample sizes. This would be deemed a more definitive readout. And we often also want to be careful about the kinds of assays used when the key endpoint is a biochemical assay like this. And the preliminary Phase 1/2 data were enzymatic assays. This is a robust LC-MS/MS assay, which we've agreed to with regulators.
And so you've got to be careful as you compare the two because of the slightly different sensitivities, etc., to assays. And finally, the overall baseline urine oxalate levels were higher, speaking to difficulties in comparing trials, were higher in this Phase 3 study than they were in the initial Phase 1/2 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 urine oxalate with 84% patients normalizing or near normalizing. This should translate to very, very significant clinical benefit based on prior relationship, the continuous relationship of oxalate reductions, which all patients in this study showed, by the way, and renal outcomes. So I'll stop there. And I don't know, Pushkal, if you've got anything to add to that.
Yeah.
I mean, I think, actually, I totally agree with everything you said. And I think, again, to reiterate, Mani, I mean, there's a great relationship. First of all, I think the data between the Phase 1/ 2 and the Phase 3 are quite similar overall. And I think, second of all, you see a greater 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 at this early time point, this cut was based on patients who had matched ultrasounds at baseline month six. 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. I think, as Akshay noted before, we're measuring this in ILLUMINATE- B as well. We'll look forward to those data later in the year.
Yeah. If I can follow up, Akshay mentioned the difference in assays. I'm looking at the presentation from this morning. I'm on slide 55, which you guys have in front of you, of the data from this morning, not this podcast, of course. It says in the bottom bullet that the data from the Phase 2 OLE was consistent between the two assays despite differences in the absolute values. Is the right way to think of that, while the assays are different, the degree of benefit shown by the Phase 2 OLE with both assays is the same?
And so any difference between the two 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 two studies, and they show a very significant degree of clinical benefit. So trying to parse significant 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 urine oxalate. The magnitude looks very similar.
And the overall scope of the drug to normalize or near normalize at 4%, 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.
That's helpful. And congrats again on another approval data set. I'll pass it to my colleagues to take a look with you.
Thank you, Meg.
Thank you. Navin Jacob from UBS has our next question today.
Hi, everyone. This is Navin Jacob. 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 the future treatment paradigm as that evolves.
My second one just has to do with how the different treatment journeys for pediatric vs adult, how that may translate to launch curves.
Okay. Pritesh, do you want to handle these questions?
Yeah. So with respect to the assay, right, for the Phase 2, we used a clinical assay that's used in most academic and community centers. For the Phase 3, of course, we have to use an assay that's met regulatory standards. And so we did that for the Phase 3 study. In terms of diagnosis, specifically, the assays are out there, and they're 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 genetic.
As it pertains to the second question, Jonathan, in terms of launch curve, I think one of the things that we are, of course, going to be focused in on is really getting this drug to patients that are already diagnosed. And 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 curve, in first, in terms of patients that have 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.
Great. Thank you.
Thank you. We have time for one more question from Leland Gershell from Oppenheimer. Please go ahead.
Hey. Good morning, guys.
Just adding my congratulations as well. A question for Akshay, I believe. I want to ask, as you think about the spectrum of disease progression from early to later stage, eventually to ESRD, and we think about how lumasiran could be helpful to these patients, would we expect any time-changing physiology or renal function that we could see more or less effect of the drug as patients get older? Or would it be the case that perhaps in the ILLUMINATE- B type population, we'd expect to see perhaps better results in the younger population? Perhaps we'd see more responsiveness, more effective benefit of the drug.
Thanks. Okay. Good question. Akshay, you want to handle that?
Yeah. Sure, so the fundamental lesion is hepatic overproduction of oxalate that deposits in the early stages of disease in the kidneys, causing stones, nephrocalcinosis, and renal decline.
As the disease progresses, patients end up with 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, high-grade heart block , 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. We would expect to see oxalate reductions both in early, mid, and late stages of the disease. 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, rapidly damage their kidneys but are suffering consequences in other organs. So we anxiously await the outcome of that study, obviously. But I think this is a very important hypothesis to attack this disease. ILLUMINATE- A looks like today are very encouraging, and we would expect to see oxalate reductions in ILLUMINATE- B and C.
And just following up on that, so 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 will look like that.
Yeah. 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 three- to six-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 have some observation of 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, etc. But that will just take more time. But I think the preliminary data from the exploratory endpoint on nephrocalcinosis certainly points in a good direction for these patients, which is great. That's fantastic.
T hanks very much for taking my questions, Pritesh.
All right. Thanks, Leland.
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 and a favorable regulatory review of the third RNAi therapeutic in the months ahead. So thanks, everybody, and stay safe and stay well. Bye-bye.
Thank you. That will conclude today's conference call. Thank you for your participation, ladies and gentlemen. You may now disconnect.