Ladies and gentlemen, thank you for standing by. Welcome to Alnylam Pharmaceuticals' conference call to discuss approval of OXLUMO. 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'd now like to turn the call over to the company. Please go ahead.
Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are John Maraganore, our Chief Executive Officer; Akshay Vaishnaw, our President of R&D; and Andy Orth, our Senior Vice President, Head of U.S. Business. Also joining us and available for Q&A are Yvonne Greenstreet, our President and Chief Operating 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 investor page of our website, www.alnylam.com. Intro to our call, as outlined in slide two, John will provide some introductory remarks and offer context around approval of OXLUMO, the trade name for lumasiran. Akshay will review the label and the data that supported the approval of OXLUMO, and Andy will discuss our commercial plans for OXLUMO before opening 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 important factors, including those in our most recent annual report, quarterly report, and 8-K current reports on file with SEC.
In addition, any forward-looking statements represent our views only of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I will now turn the call over to John. John?
Thanks, Christine, and thanks to all of you for joining the call today. Last night, the FDA approved OXLUMO for the treatment of primary hyperoxaluria type 1, or PH1, to lower urinary oxalate levels in pediatric and adult patients. This is a tremendous milestone for patients, families, and the community affected by this life-threatening condition for which there were previously no approved therapeutic options. On this holiday week, the FDA approval for OXLUMO is such a wonderful gift for Thanksgiving for the PH1 community.
Until now, the only intervention that could alleviate the profound oxalate burden in these patients was a dual liver kidney transplant. OXLUMO has now become the first-ever targeted treatment approved by both the FDA and the EMA to reduce oxalate overproduction and address the underlying pathophysiology of PH1 in patients of all ages. In addition, OXLUMO is now the first-ever RNAi medicine approved for use in both adult and pediatric patients, including infants, a significant platform milestone that we believe further underscores the broad potential of Alnylam's RNAi medicines.
For Alnylam, OXLUMO is our third commercial product to receive regulatory approval in just over two years. With this approval, we have now achieved our Alnylam 2020 goal that we set in early 2015, where we committed to having three approved medicines by the end of 2020. With another approval expected by year end for Inclisiran, our investigational RNAi therapeutic in development for the treatment of hypercholesterolemia in partnership with Novartis, we are well on track to actually exceed our original Alnylam 2020 goals. Of course, as you know, regulatory approval is just the first step in making OXLUMO available to patients.
As Andy Orth will elaborate further, we are in the midst of proactive discussions with payers in the U.S. to help ensure that patients who may benefit from OXLUMO will have access to it. This approach continues to leverage our innovative value-based agreements, or VBAs, and is consistent with our patient access philosophy and the access track record we've achieved for our two previously launched commercial products, ONPATTRO and GIVLAARI. With regard to our global launch plans, we will leverage much of the commercial infrastructure that's already been built for ONPATTRO and GIVLAARI.
With the European Commission granting marketing authorization for OXLUMO just days ago, we look forward to making OXLUMO available to patients in Europe as well and are also working on plans to bring OXLUMO to patients in other parts of the world, including a recent filing for OXLUMO in Brazil. Now, there's a lot more coming from Alnylam. By the end of the year, we expect regulatory decisions in the U.S. and Europe for Inclisiran to be commercialized by Novartis. Then, in early 2021, we expect a top-line readout from the HELIOS-A phase 3 study of vutrisiran in hereditary ATTR amyloidosis in patients with polyneuropathy.
This is a critical step in expanding Alnylam's TTR franchise. We're also excited to provide you with an update on our broader pipeline during our virtual R&D day event next month. In closing, I'd like to take a moment here to express our sincere gratitude to patients impacted by PH1, caregivers and families, clinical investigators, and study staff who have participated and continue to participate in the Illuminate clinical trials.
I'd also like to acknowledge the broader PH1 community, notably the Oxalosis and Hyperoxaluria Foundation, the OHF, and research consortia who work tirelessly on behalf of patients. Our Illuminate program would not have been possible without all of you. Additionally, I'd like to acknowledge the FDA for recognizing the immense need for treatments in PH1 and for the agency's urgency in expediting the review of this file during an unprecedented public health crisis, no less, just ahead of our PDUFA date in order to bring OXLUMO to patients as rapidly as possible.
Finally, I'd like to also recognize my Alnylam colleagues, past and present, whose passion, dedication, and unwavering commitment, especially during the pandemic, no less, have made this medicine a reality for patients. So with that, I'll turn the call over to Akshay to review the label and the data that supported it. Akshay.
Thanks, John, and hello, everyone. I certainly echo John's sentiments regarding the sense of pride and gratitude among all of us here at Alnylam for having the privilege to be able to bring this innovative therapy to patients, including young children suffering from PH1, as well as their families and healthcare teams. And to be able to bring our third medicine to market in just over two years is especially gratifying. Now, to remind you, PH1 is an ultra-rare autosomal recessive disease caused by a genetic defect in the liver enzyme alanine-glyoxylate aminotransferase , or AGT, which results in hepatic overproduction of an insoluble metabolite turned oxalate.
While the initial onset of disease is typically in childhood, including infancy, patients can present with symptoms at any stage in life, and there's significant variability in clinical manifestations and rates of disease progression, even among siblings. PH1 poses a tremendous physical, emotional, and economic burden on patients and families impacted by the disease. We heard this loud and clear at the FDA patient voice meeting in early October. For most, PH1 is an inexorably progressive disease, with patients often suffering from extreme pain due to recurrent episodes of kidney stones and grappling with the prospect of the inevitable deterioration of their kidney function.
The unpredictable rate of disease progression adds the angst of not knowing when the next acute stone event will occur or when it may be time to go on dialysis or have to go on a transplant waiting list. With regard to symptoms, while kidney stones are the most frequent, first symptom of PH1 and recur throughout life, most patients also experience deposition of calcium oxalate in the renal parenchyma, referred to as nephrocalcinosis or calcification of the kidney.
This results in progressive and irreparable damage to the kidneys and an accompanying decline in renal function, ultimately leading to end-stage renal disease or ESKD. However, the rate to ESKD, as I mentioned, can be entirely unpredictable, and unfortunately, a significant proportion of patients present with kidney failure. Once kidney function has been fully compromised, dialysis is the only means to remove the excess oxalate from the body, but even with an intensive regimen of several hours a day and upwards of six sessions 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, joints, resulting in vision impairment, cardiomyopathy, and pathological bone fractures, and in some cases, even death. Do patients with advanced disease generally require a dual or sequential liver kidney transplant to resolve the metabolic defect in the liver and to replace terminally damaged kidneys? Complications of ESKD and transplantation are associated with high morbidity and mortality, with transplant recipients having to live with lifelong immunosuppression and monitoring and the possibility of needing new organs in the future.
Until today, mainstay management options in patients with intact kidney function included 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. Unfortunately, these strategies largely aim to reduce the risk of stones and are generally inadequate at curtailing oxalate overproduction. Let's now turn to the pivotal Illuminate A phase 3 study that formed the basis of yesterday's FDA approval.
Illuminate A was a global randomized two-to-one drug-to-placebo double-blind placebo-controlled trial evaluating the safety and efficacy of OXLUMO in adults and children with PH1. It is the largest interventional study addressing PH1 to date, enrolling 39 patients across 16 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 GFR, of greater than or equal to 30 mL per minute corrected for body surface area.
The primary endpoint for the study was the percentage change from baseline in 24-hour urine oxalate excretion averaged across month three to six treated with OXLUMO as compared to placebo. In Illuminate A, treatment with OXLUMO resulted in 53% mean reduction in urine oxalate levels relative to placebo. In addition, all tested secondary endpoints achieved statistically significant positive results, including 52% of PH1 patients achieving urine oxalate levels at or below the upper limit of normal and 84% reaching at or below 1.5 times the upper limit of normal, compared with no patients achieving this endpoint in the placebo group.
With regard to safety, in the Illuminate A study, there were no serious or severe adverse events, and the most common adverse event related to OXLUMO was injection site reaction or ISRs reported in 38% of patients. ISRs occurred at various time points during the study period, including erythema, pain, pruritus, and swelling. The ISR-related symptoms were generally mild and resolved within one day of the injection and did not lead to discontinuation of the treatment. The agency also took into consideration results from the Illuminate B pediatric study.
Illuminate B was an open-label, single-arm trial evaluating the safety and efficacy of OXLUMO in PH1 patients under the age of six, including infants with preserved renal function with a GFR above 45. In the Illuminate B primary analysis, OXLUMO demonstrated a 72% mean reduction in spot urine oxalate-to-creatinine ratio from baseline to month six, averaged from month three to six. The primary endpoint of the study, which was the primary endpoint of the study. In terms of safety, there were no serious or severe adverse events related to the study drug, and the overall safety and tolerability profile of OXLUMO was consistent with that observed in the Illuminate A pivotal study.
Let's move on to the OXLUMO label and review some of the prescribing information. OXLUMO has been approved for the treatment of primary hyperoxaluria type 1 to lower urine oxalate levels in pediatric and adult patients. We're pleased that OXLUMO has been approved without an age restriction, representing a broad initial label. The drug is administered by a healthcare professional via subcutaneous injection once monthly for three months and thereafter as a convenient once-quarterly dose regimen. The dose is dependent on body weight, and for patients who weigh less than 10 kilograms, dosing remains monthly until they reach a weight of 10 kilograms.
I also want to briefly mention that the safety and efficacy of OXLUMO continue to be evaluated in the ongoing Illuminate C phase 3 clinical trial in PH1 patients of all ages with more severe renal impairment, including patients on dialysis. Together, the Illuminate studies comprise a comprehensive clinical development program intended to demonstrate the safety and efficacy of OXLUMO across the full spectrum of patients diagnosed with PH1.
We remain on track to report results from the Illuminate C study in 2021, and assuming positive results, plan to file a supplemental NDA, including those findings, to help inform treating physicians. With that, I will now turn the call over to Andy. Andy?
Thank you, Akshay, and hello, everyone. I'm thrilled to be here to discuss Alnylam's third product launch in just over two years, OXLUMO. We intend to leverage the learnings and infrastructure we've built for the commercial launches of ONPATTRO and GIVLAARI to help us successfully commercialize OXLUMO. We believe OXLUMO has the potential to be a very meaningful treatment option for patients with PH1. Let's begin with the overall market opportunity in terms of estimated prevalence of PH1 and the addressable population.
Given the heterogeneity in the clinical presentation of this disease, ranging from asymptomatic patients to those who present with systemic oxalosis and ESKD and the significant delays in diagnosis, getting to an exact patient number is a challenge, as with any ultra-rare disease. Nevertheless, we estimate the total genetic prevalence of PH1 to be in the range of four individuals per million in the U.S. and Europe, with up to 2,100 patients who may have a confirmed PH1 diagnosis. We believe a segment of that population, constituting approximately 1,000 to 1,700 patients in the U.S. and EU, would include patients who are diagnosed but not transplanted and are thus eligible to receive OXLUMO.
We expect the initial commercial uptake to be primarily among diagnosed pediatric patients where there is more urgency to treat and expect robust penetration in the remaining untransplanted patients with active and diagnosed disease over time. In addition, we see further growth opportunity with improved disease awareness and increases in diagnosis rates, and as we expand the commercialization of OXLUMO to territories beyond the United States and Europe.
We believe this is a commercially attractive ultra-rare orphan disease opportunity with over $500 million in global peak revenue potential that we expect to be achieved with steady and continued growth over time. Now, let's discuss pricing. Consistent with Alnylam's patient access philosophy, we price our therapies based on the value delivered to patients and the ability to continuously innovate for the benefit of patients. Our overarching access philosophy is grounded in helping patients, delivering value, and being proactive.
It includes a commitment to refrain from increasing the price of our medicines by more than the annual Consumer Price Index for Urban Consumers , a measure of inflation, unless there is new innovation delivering value to patients. It also includes a commitment to proactive engagement with payers to identify innovative approaches for access, such as value-based agreements or VBAs. We're very proud that across our two currently marketed products, we've now executed approximately 30 VBAs. We aim to demonstrate the value of our medicines objectively and transparently and to be a market leader in this regard. Let's now turn to the specifics of OXLUMO.
In the U.S., the average price for OXLUMO before mandatory discounts to government programs is estimated to be about $490,000 per patient per year. This is based on patient need demonstrated in the Illuminate A and Illuminate B clinical trials. In a real-world setting, since OXLUMO is indicated for both pediatric and adult patients, actual costs will vary relative to patient use and weight. We believe the average effective net price for OXLUMO will be about $380,000 when taking into account expected discounts to government insurers and programs such as Medicaid. Patient affordability is a key focus for us.
Similar to the patient experience with ONPATTRO and GIVLAARI, we expect commercially insured patients in the U.S. will pay little to nothing in out-of-pocket costs for OXLUMO if they enroll in our copay assistance program. Exact costs may vary based upon patients' individual insurance coverage. We will also offer support for uninsured patients who may be eligible to receive OXLUMO at no charge if they meet certain eligibility criteria. In addition, we've been working closely with the payer community on VBAs that include a new component called a patient need adjustment, or PNA, to ensure seamless access to therapy for patients and budget predictability for payers.
Since OXLUMO is indicated for both pediatric and adult patients and is dosed according to body weight, individual need for patients taking OXLUMO will vary and may change over time. To address uncertainty with regard to cost predictability, a participating payer will qualify for a PNA rebate if the average number of vials utilized by a plan member exceeds an established threshold. To further address budget predictability for payers, Alnylam is also making available for OXLUMO its prevalence-based adjustment, or PBA component, which was first introduced last year for Alnylam's second approved therapy, GIVLAARI.
There are often uncertainties in diagnosis rates and disease prevalence estimates in ultra-rare, poorly diagnosed orphan diseases, making it challenging for payers to predict the number of patients who will be covered within their plans. This PBA feature triggers a rebate to participating payers if the number of diagnosed patients they cover exceeds current epidemiological estimates for PH1. When determining the price of OXLUMO, we prioritized patient access and delivering value to payers and physicians. Five factors also influenced OXLUMO's price, including the following.
First, we considered the debilitating and life-threatening nature of this inherited disease. Second, we considered the high burden of the current standard of care, which involves intensive management of kidney stone episodes, with patients often having to endure extreme pain, undergo hospitalization and surgical intervention, and, once the disease progresses, a grueling dialysis regimen. The third factor we considered is the ultra-rare nature of this condition, with an estimated 1,000-1,700 patients in the U.S. and Europe who may be diagnosed and have not yet received a transplant.
Additionally, OXLUMO is the first approved therapy to treat PH1 by substantially reducing urinary oxalate, the toxic metabolite responsible for the severe clinical manifestations of this disease. Finally, our enhanced VBA framework that incorporates innovations such as PNAs and PBAs that support access and give participating payers greater short-term and long-term budget predictability, thus reducing insurance barriers for adults and children with PH1 who are prescribed OXLUMO. Regarding timing for availability of OXLUMO, FDA approval came just ahead of our PDUFA date of December 3rd.
Nevertheless, we expect to have OXLUMO available for shipment to healthcare providers in the U.S. by the end of the year. Beginning right now, healthcare providers can initiate the process for getting a patient on OXLUMO therapy by completing and submitting a start form through Alnylam Assist, our U.S. patient services program, which I'll touch on shortly. All key elements to support OXLUMO launch are in place.
We have pivoted to digital-first in the current environment, and our OXLUMO educational and planned promotional efforts have been optimized for use in both digital and in-person engagements. We have launched a number of educational websites specifically tailored to our patient, caregiver, and HCP audiences. We're especially proud of our award-winning PH1 One-of-a-Kind children's video animation series, a terrific educational resource that we co-developed with the Oxalosis and Hyperoxaluria Foundation for pediatric patients and their caregivers.
Our core field-based roles are trained, in place, and ready for launch. We will interact with our customers and the PH1 community using multiple engagement models and are having success educating on PH1 to further raise disease awareness and improve diagnosis. We have also been collaborating with patient advocacy groups such as the OHF, as well as other patient groups focusing on kidney health, who have very important capabilities and intimate knowledge of the needs of the patient community, and we plan to continue these collaborative efforts.
Additionally, we continue to offer Alnylam Act, a third-party genetic testing initiative sponsored by Alnylam aimed at facilitating diagnosis of patients suspected of having PH1. We are also extending our in-house patient services capability, Alnylam Assist, to cover OXLUMO. Alnylam Assist is a comprehensive patient services program that offers support to patients throughout treatment and has consistently earned excellent patient satisfaction ratings for our ONPATTRO and GIVLAARI patients. The final piece is our continued proactive engagement with payers, as I mentioned earlier.
We recognize that our efforts in advancing OXLUMO to market will only be successful if patients who may benefit from this new medicine have access to it. 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. I'll now turn the call back to Christine to coordinate Q&A. Christine?
Thanks, Andy. 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 into the queue for any additional questions.
Thank you, Christine. So if you would like to ask a question, please press star one on your telephone keypad. If you're using a speakerphone, just make sure that your mute function is turned off to allow your signal to reach our equipment. Again, that is star one to ask a question. We'll take our first question from David Lebowitz from Morgan Stanley. Please go ahead. Your line is open.
Thank you very much for taking my question. Congratulations on the approval. When you look forward to the launch, what is the typical diagnosis age of patients at this point in time, and what would you say is the ideal diagnosis age given the nature of lumasiran, and how do you, I guess, intend to push the diagnosis age down going forward?
Yeah. First of all, thank you, David. And that's a great question. Obviously, and I'm going to hand it over to Andy, but obviously, as it is important for health that patients get treated as soon as possible. We know that as oxalate deposits in the kidney, as kidney stones are formed, there's damage. Some of it can be irreversible that ultimately needs to be reckoned with. And so getting to patients as quickly as possible is a major priority from the standpoint of optimal therapy. Andy, do you want to answer David's questions?
Yeah, sure. Thanks for the question, David. In the beginning here, as we launch, the most obvious are going to be the young patients, David, who shouldn't be forming stones in any way, shape, or form. They tend to be the easiest to diagnose as they get sent to centers or to specialists. As we continue to increase disease awareness across nephrologists, both adult and pediatrics, and urologists, we're going to see that age actually increase to folks who are forming these stones a little later in their life. So hopefully, that answers your question.
Thanks for taking my question.
Thanks, David.
Moving on to our next question comes from Maury Raycroft from Jefferies. Please go ahead. Your line is open.
Hi. Good morning, everyone, and congrats on the update. Question is just how many patients from your current clinical trials do you expect to convert to commercial drug, and can you talk about timing expectations around this?
Yeah. Great. Thanks, Maury. I'll turn it over to Akshay in a second, but just remind you, Maury, that patients in the clinical studies go on to an open-label extension study for a period of time, and that's an important way to collect safety data. Akshay, do you want to talk about the specifics of when patients come off the open-label study?
Yeah. So as with any rare disease, there's an expectation to continue patients onto open-label extension studies because clearly, the number of patients that have been studied is not as large as in prevalent diseases. So they'll continue for a number of years and will accumulate safety information, which will be important for the further understanding of the drug. I've forgotten the precise number of years. Pritesh, you might want to drop in on that.
Yeah. Thanks, Akshay, and thanks for the question, Maury. So as both Akshay and Jon had mentioned, we do have open-label extension studies. Our patients do get followed up in our open-label extension studies for a total of five years. So once the patients have received clinical supply and clinical trial of the open-label extension study for five years, that is when they will convert to commercial supply.
Got it. Understood. Thanks for taking my questions.
Great. Thanks, Maury.
We'll now take it from Alethia Young from Cantor Fitzgerald. Please go ahead. Your line is open.
Hello, Alethia.
Can you hear me? Can you hear me?
Now we can. Yeah. You might have been unmuted. Yeah.
Hey, congrats on your third one, and there's many more to come. But I wanted to ask about if there's any kind of potential founder effect or what might be your best markets around the world in kind of pockets for this PH1 thing?
Yeah. Thanks, Alethia. Akshay, do you want to handle that?
Yeah. So Alethia, in contrast to some other genetic diseases, there is no enormous founder effect in the sense of a particular mutation being concentrated in a geographic area or country. One thing that does occur, and this is seen with other autosomal recessive disorders, is there tends to be a slightly higher incidence in areas where there's consanguinity. And so those parts of the world where there may be high rates of consanguinity are associated with higher rates of this disease. But generally speaking, the mutations that result in this disease have been seen all over the world.
Thank you, Akshay.
Great. Thank you.
Thanks, Alethia.
We'll now take it from Joel Beatty. Please go ahead. From Joel Beatty, please go ahead. Your line is open.
Hi. Congrats on the approval. Could you characterize the number of patients in the expanded access program and any other patients that may be waiting to get onto drug in the near term?
Yeah. Thanks, Joel. And thanks for your congrats at the beginning. Appreciate that. Well, we don't give out specifics on that for reasons, including competitive reasons. But we do have a very active global expanded access program in countries where we can make OXLUMO available for physicians to provide it to their patients. We don't give the numbers, but it's a significant double-digit number around the world.
And we look forward to converting patients onto active drug when PDUFA occurs. I mean, obviously, in some European countries, they won't be able to get onto commercial drug for 12-18 months until we get pricing and reimbursement. But that does represent a pool of patients that will be available in the future for commercial drug on top of patients that will come onto commercial product without having gone through the expanded access program. I don't know. Akshay, anything to add on that from your perspective?
No. No, you covered it, John.
Yeah. Great. Thank you.
Thank you.
We'll now take it from Gena Wang from Barclays. Please go ahead. Your line is open.
Thank you for taking my questions. I also wanted to add my congrats as well on the early approval and the broad label.
Thank you.
Sure. So the question is for the value-based agreement, the patient need adjustment, just wondering if the threshold is four patients per million, and is that the same across different programs and similar for patient need adjustment? I'm not sure if you can share the numbers for the threshold over which. But if not, can you give a little bit of direction on at what stage, or if we're using adult patients, that will trigger that threshold? And lastly, quickly on the WAC price and the net price, is that the minimum price beyond the initial loading dose?
Yeah. Thanks for that, Gena. And thanks for your congratulatory note. Before I hand it over to Andy, let me just say that obviously, the value-based agreement framework that we've engineered for OXLUMO is something we're very proud of. We've been able to develop this in consultation with some members of the payer community. And we think it really helps address budget certainty for the payer community. And I expect it to be very well received by the payer community.
And when we do these value-based agreements, of course, we also put them in place with certain commitments from the payers in turn to reimburse the product per the label, to not put in place any step edits and so forth. So it really is a give-and-take arrangement that has been very successful in our other two brands. So with that as context, Andy, do you want to answer her specific questions?
Sure. Sure. So with the VBAs, Gena, we engage in the dialogue with the payer, and it's highly data-driven. Some of the data is clearly ours, right, from the clinical trial nature, how much product are the individual patients consuming at various sizes and at various times, etc., as well as epidemiological data we find out in the academic research. So we bring that to the table and go back and forth with the payer. So there are differing numbers between different diseases, clearly, on that front. And each one is a bit bespoke, but we don't release the specific numbers. And then to the question you also ended with, the prices we did cite are indeed maintenance dosing, right, ongoing at that point in time. And was there one more question you had in the middle, Gena? I can't remember.
The vials, the threshold of the vials.
The threshold, yeah. And that's something we're not releasing at this point in time. Yep.
Okay. Thank you.
Okay.
Thank you.
We'll now take our next question from Ritu Baral from Cowen. Please go ahead. Your line is open.
Good morning, guys. Thanks for taking the question. I wanted to ask about the patients that are sort of left on the table with the current label. You mentioned the non-transplanted patients are about 1,000-1,700 per slide 14. But how should we think about those patients with impaired renal function that have not yet been transplanted and would be covered by the Illuminate C sNDA? And then just comparatively, very quickly, can you talk about how important patient identification and Alnylam Act and ASSIST are for OXLUMO versus ONPATTRO and GIVLAARI?
Okay. That's a great question. Why don't we have the first question answered by Pritesh, and then Andy, you can answer the second question. Go ahead, Pritesh.
Thanks, John. And thanks for the question. In terms of the non-transplanted patients, right, so we're talking really about the patients here that are diagnosed in terms of the numbers that Andy provided, right? We also understand that about 50% of the patients are not diagnosed currently. And we will be working, of course, with clinicians and engaging clinicians in disease awareness efforts, including Alnylam Act, to try and discover patients and identify patients so that we can accelerate the time to diagnosis.
In terms of the impaired renal function, I mean, as we have seen with the label, we don't have data right now in patients with an estimated glomerular filtration rate less than 30 milliliters per minute, including dialysis patients. And those patients are being studied in the Illuminate C study. And we will see those data in 2021, and then we'll make a decision.
And then, Andy, do you want to answer the second question on patient finding and how will it look versus ONPATTRO and GIVLAARI?
Sure. Sure. Thanks, Ritu, for the question. So clearly, patient finding here is going to be critical. And it's something we've become very skilled at through the launches of ONPATTRO and GIVLAARI. And we'll use all the same tools, techniques, and technologies we've had such great success with in both of those. On Alnylam Act specifically, clearly a little bit different here with the autosomal recessive population. But we are having success using this as a confirmatory tool out there when we do identify these patients with their healthcare providers.
Got it. So no good idea right now on that Illuminate C population yet. We'll understand more later.
Exactly. Yeah. I think that's to Pritesh's answer, I think that's the safe thing to say right now.
Fair enough. Thanks for taking the questions.
Thanks for it too.
We'll now take our next one from Anupam Rama from JP Morgan. Please go ahead. You're open.
Hi, guys. This is Tessa on the call this morning for Anupam. Congratulations from us as well on the approval. So just one from us. You also recently got approval for OXLUMO in Europe. What are some of the similarities and differences worth noting between the US and EU in terms of market dynamics in PH1? Thanks so much.
Yeah. Thanks. Thanks. And Tessa, we appreciate the congratulatory comments. Pritesh, do you want to talk a little bit about the U.S. versus Europe dynamics a little bit?
Yeah. Sure. Thanks for the question. Really appreciate it. And thanks for the congratulations note as well. It's very different in the U.S. versus the E.U. as we have expected, right? I mean, in the E.U., specifically in countries like France, there are already centers of excellence that are existing. And patients do go to those centers of excellence, and the diagnosis happens in those centers of excellence. In the U.S., in contrast, there are relatively few centers of excellence, and it is a little bit fragmented as expected. And we do anticipate that there will be patients in the centers of excellence in the U.S., but also that we will be able to find patients in the community as we have seen with our other rare diseases as well.
So with our disease state efforts, disease awareness efforts, we will be able to find additional patients in the community in the U.S.
Andy, anything else from your perspective on this question?
No. Just similar to you already mentioned it, John, right? The U.S. will be out in front with immediate reimbursement and patient finding and developing the market there. And then the reimbursement trends we're going to see throughout Europe and ex-U.S. will be much more similar to GIVLAARI.
Great. Tessa, does that answer your question?
Absolutely. Thanks so much.
Thank you.
We'll now take it from Paul Matteis from Stifel. Please go ahead. Your line is open.
Great. Thanks very much. And congrats again on the approval. One clarification and one question on your commentary surrounding the market opportunity. Just to clarify, is the Illuminate C population excluded from the current label? Just from our read, it looks like the drug is actually broadly indicated. So maybe you could just clarify that. And then separate, on your $500 million market opportunity guidance, what assumptions go into that? If we look at the currently diagnosed population at the midpoint, and just based on your net price, you can get there. Of course, no drug gets 100% penetration. And there will be competition in this market too from Dicerna likely. So how are you kind of thinking about what needs to play out in order to reach your goal? Thanks.
All right. Terrific. Well, Pritesh, you can answer the second question. But let me start on the first one and just say the indication I mean, the label speaks for itself. The indication statement is broad, and we're pleased by that. In the label, it is stated that a severe renal impairment population has not been studied. So that is what is in the label. But I think it speaks for itself. I don't know, Akshay, anything else you'd like to add to that point?
No. And it's a very heterogeneous disease. And part of the objective in Illuminate C is not just to study patients with very severe renal impairment and on dialysis, but also patients' extrarenal manifestations. And there will be patients who have extrarenal manifestations as in Illuminate C but do not have GFRs below 30. I'm sure that will occur in some patients. And they would be eligible per the current label. So we'll see how it goes. But this is really, I think, a very helpful label to the patient and provider community. And I think we can help a lot of patients.
Yeah, and then, Pritesh, do you want to comment a little on our guidance on market opportunity size?
Yeah. Yeah. And specifically, we also are on the competition piece here. So we are leaders in the space with respect to PH1. There is no approved therapy as we all know for this particular devastating disease. And that's when it has to be explicitly and specifically designed to target the PH1 pathway. And we know that this particular disease has got a lot more morbidity associated with it compared to the other primary hyperoxalurias. From the perspective of the competition with respect to lumasiran and OXLUMO, we have got very broad data, as you have indicated.
We have data both from Illuminate A and Illuminate B, which includes children and infants as young as four months of age. So we have very comprehensive data in both the pediatric patient population as well as the adult patient population. And the majority of the patients, when they are diagnosed, they are diagnosed before the age of 10. And so we have broad data from the perspective of the variety of different ages. And then lastly, also from a dosing perspective, the dose is going to be administered quarterly. And we feel that that is going to be an advantage here from a competitive perspective as well.
Yeah. And I would just conclude thanks, Pritesh. I would just conclude, Paul, obviously, we're going to make this as big of an opportunity as possible because we're going to help as many patients as we can. And we'll see how the market develops over time. But we do think it will be greater than $500 million at peak. And where it goes from there, we'll see.
Great. Thanks very much.
Thanks, Paul.
We'll take the next question from Mani Foroohar from SVB Leerink. Please, your line is open.
Hey, guys. Thanks for taking the question. Congrats again on third approval. I wanted to draw a little attention to around slide 17, you talk about the average annual WAC, net effective price. I want to drill down a little bit. Those numbers, what is the weight or age or how should we think about the typical patient or the average patient baked into that average WAC? And is it weight or age? And then secondly, should we think about that WAC as reflective and net price as reflective of the annual net price on a run rate basis for years after the first year? Or is that the net effective price we should model for patients in their first year, given that there is, looking at the label, a little bit of a loading dose dynamic consistent with the phase 3 trial? Thanks.
Yeah. Great questions, Mani. And Andy, do you want to answer that?
Yeah. Happy to. Thanks, Mani. So to your first question, the numbers we've shared here represent the average that we expect across those weight distributions, right? So that is what we expect to come onto drug here into the near future. And to your second question, that is the run rate number of a second full year going forward.
Great. So to clarify, when you say that's the run rate, that is the run rate for four quarterly doses. That's what you mean by that? Correct.
Correct.
Correct.
Awesome. Great. That's what I wanted to.
Mani, the other thing I'll add is, obviously, the doses do change based on age and weight, right? Which is important in terms of thinking about the distribution. That $490,000 number does represent the average.
Great. So the average would be sort of like a 40-kilogram, including some pediatric, or maybe like a 50-kilogram adult? Or how should I think about it?
We'll have to ask Andy. Andy, how do we calculate the average in that regard?
Yeah. So again, we took expected study data plus the expected population that we had out there, Mani. Depending if you want to build the model on that, you can use the dosing that you can see in the label that will get you to these numbers.
Great. Thanks, guys. That's really helpful.
Okay. Thanks, Mani.
We'll now take it from Ted Tenthoff from Piper Sandler. Please go ahead. Your line is open.
Mike, congratulations to you guys' incredible productivity during this period. My question has to do with the Dicerna deal. And I just wanted to remember what the payments were to them and really how this will work. So once you start selling, you pay them X%? Or how exactly does that deal work again? Thank you.
Yeah. Thanks, Ted. And thanks for your comments at the beginning. It's pretty amazing from the team's standpoint. Well, the way it works with Dicerna in terms of the cross-license that we put in place is that there are royalties that go both ways when products reach the market. And so they will start getting a single-digit royalty from Alnylam tiered sales as we launch this drug. And when and if, presumably, they launch their drug, we will receive royalties in return. So that's how it's structured.
Great. Thanks. Happy Thanksgiving, guys.
Yeah. You too, Ted.
We'll now move on to our next question. I will take it from Luca Issi. Please go ahead. Your line is open.
Oh, terrific. Thank you for taking my question. And fantastic news for these kids and families. So that's great. Just a quick question.
Yeah.
Just a quick question. The priority review voucher, just wondering if the plan there is to monetize the PRV or maybe use it for a separate drug at some point down the line. And then also, for PH2 and PH3, is there a vision maybe at some point down the line to go after these indications, maybe going after obviously separate target? Or do you think that that's just not worth it? Thank you.
Yeah. Thanks, Luca. Look, for patients with PH2 and PH3, there are other drugs that are in development that can address those patient populations. And the degree of disease burden and the number of patients is quite a bit less, both the burden and the number of patients. So from our standpoint, we're going to focus on PH1. Yvonne, do you want to comment on the priority review voucher?
Yeah. Look, I think it's wonderful to receive the priority review voucher. It's a valuable thing to have either in terms of expediting programs in our pipeline. And as many of you know, it also has external value. But at this point in time, we're not commenting on exactly how we plan to use that voucher.
Great. Thanks.
Terrific. Thanks.
Thanks, Luca.
We'll now take it from Patrick Trucchio. Please go ahead. From H.C. Wainwright. His line is open.
Hi. Good morning. And congrats on the approval. So with the expectation that this is the third approval of many more to come, I'm wondering if you can discuss how the build-out of the commercial organization has progressed and what work remains to be done, and at what point we could see the benefits of scale from the build-out both in the U.S. and outside the U.S.
Yeah. That's a great question, Patrick. Look, we have built an amazing commercial organization globally really on the shoulders of ONPATTRO. And we've been leveraging that for GIVLAARI. And we will leverage that for lumasiran. So with that intro, Andy, do you want to comment further on that point?
Yeah. And specifically, when you look at the United States here, we are at scale. We are fully leveraging the infrastructure John mentioned that we put in place for ONPATTRO, leverage it obviously for GIVLAARI and now OXLUMO. And there's not only, right, I think, economic strength that comes out of that, but certainly execution strength of having done this a couple of times. And the global infrastructure that we've built will continue across Europe and then further into Asia here as these multiple products come in. So I think we're quickly reaching the scale you're talking about here.
That's helpful. Congrats again. Thank you.
Thank you, Patrick.
Moving on, we'll take it from Navin Jacob from UBS. Please go ahead. Your line is open.
Hi everyone. This is Jon for Navin. Wanted to give our congratulations on adding on to that. And we wanted to get a sense of the market opportunity in Brazil now that you filed. What is your data suggesting about the number of patients skewed towards younger versus older and weight classes? And then on a separate note, we're also curious to learn what measures you're taking to facilitate the launch in the COVID environment given the need for HCP administration. Thank you.
Yeah. No, those are two great questions. Pritesh, do you want to handle Brazil? And then we'll go to Andy for the sort of COVID-related launch.
Yeah. Absolutely. Thanks, John. Yeah. We anticipate the opportunity to be similar to the U.S. and the EU from an epidemiology perspective with looking at a genetic prevalence of about two per million. And now, of course, it all depends on where these patients are in Brazil and what kind of availability they have for transplantation. So considering that they may not be eligible for transplantation or they may actually not have organs available, those patients would potentially be eligible to receive OXLUMO as well. But in essence, we anticipate that we would see a prevalence of about two per million in Brazil.
Right. And Andy, do you want to handle the launch during the pandemic question?
Yeah. Happy to. And as we've seen with the other products in the portfolio here, we've gotten into a very strong space with interacting virtually with physicians and all other of our key stakeholders and have begun doing that with a field team already. And to note here, the team we've put in place to commercialize OXLUMO brings with them many, many decades of experience with these specific physician specialties. So their access to them in order to get these patients started on this important therapy as soon as possible is just great.
Yeah. And I would just add to that point how proud we've been during the course of the year globally on our commercial execution during the course of the pandemic. And I think our results on both ONPATTRO and GIVLAARI speak for themselves in that regard. And I expect nothing less from the team in terms of being able to execute on this important launch. Patients are waiting. And we know it, and they know it, and we're doing everything we can to help get this medicine to them even during this very difficult time.
That's very helpful. Thank you very much.
Thank you.
We'll take our final question for today. It comes from Zhiqiang Shu from Berenberg. Please go ahead. Line is open.
Good morning. Thanks for taking the question.
Good morning. Sure. Yeah.
I want to add my congrats as well. It's definitely a great achievement for the team.
Thank you.
So I want to ask about the difference between payer discussion in the U.S. and in Europe. I understand the payer and the VBA discussion framework is primarily in the U.S. How about the payer dynamic in Europe?
Yeah.
Thank you.
Yeah. Yeah. Great question. Do you want to handle that, Andy?
Sure. Sure. Happy to. And as we've talked about frequently here, we are proactively pursuing this value-based agenda globally with all payers. And in the United States, that includes our government payers as well as the commercial one. So we start there at all points in time. And as you mentioned, this is a little bit of a tougher road with some of the P&R activities that do go on throughout Europe. But we intend to kind of continue to push very hard on this and continue our leadership in this front globally.
Does that answer your question?
Yeah. Thank you very much.
Terrific.
At this very moment, I would like to turn the conference back to the company for any additional or closing remarks.
All right. Well, thanks everyone for joining us today. We really look forward to making OXLUMO available to PH1 patients, young and old, who are in need of treatment, and we're excited by the tremendous momentum that RNAi is achieving as a new class of medicines. I hope all of you have a wonderful Thanksgiving. And please stay safe over the holidays. Thanks so much.
That concludes today's call. Thank you for your participation. You may now disconnect.