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Alnylam Pharmaceuticals Inc (ALNY) Q2 2019 Earnings Call Transcript

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Alnylam Pharmaceuticals Inc (NASDAQ: ALNY)
Q2 2019 Earnings Call
Aug 6, 2019, 8:00 a.m. ET

Contents:

  • Prepared Remarks
  • Questions and Answers
  • Call Participants

Prepared Remarks:

Operator

Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals Conference Call to discuss Second Quarter 2019 financial results. 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. Please go ahead.

Christine Regan Lindenboom -- Vice President of Investor Relations and Corporate Communications

Good morning. I'm Christine Lindenboom, Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are John Maraganore, Chief Executive Officer; Barry Greene, President; Akshay Vaishnaw, President of R&D Manmeet Soni, Chief Financial Officer; and Yvonne Greenstreet, Chief Operating Officer and Jeff Poulton, who will assume the role of Chief Financial Officer effective July the 13. For those of you participating via conference call, the slides that are available via webcast can also be accessed by going to the Investor page of our website, www.alnylam.com.

During today's call as outlined in Slide 2, John will provide some introductory remarks and provide general context. Barry will provide an update on our commercial and medical affairs progress. Akshay will review recent clinical updates. Manmeet will review our financial. Jeff will comment on some of his perspectives and priorities as our new incoming CFO and Yvonne will provide a brief summary of upcoming milestones before opening the call to your questions.

I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by those forward-looking statements as a result of various important factors, including those discussed in our most recent quarterly update on file with the SEC. In addition, any forward-looking statements represent our views only as of the date of this recording and it should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements.

And with that, I'd turn the call over to John.

John Maraganore -- Chief Executive Officer

Thanks, Christine, and thank you everyone for joining the call this morning. In the second quarter of 2019, we continued strong execution across both our commercial and R&D objectives. Barry will get into the details on our commercial and medical affairs progress, but at a high level, as we approach the one-year anniversary of the ONPATTRO launch and approval, we continue to be very pleased with the ONPATTRO uptake, with over 500 patients on commercial drug at the end of the second quarter. Importantly, we continue to see opportunity for a steady and continued revenue growth in the quarters and years to come, driven by new patient finding, global expansion, and near to mid-term evidence generation activities.

Moreover, advancement of Phase III development activities for patisiran and vutrisiran into the entirety of hereditary and wild-type ATTR amyloidosis is expected to expand our opportunity significantly. And of course, our revenue growth is not just about our ATTR program alone since we have a broader portfolio of late-stage assets including a program in registration.

We also made excellent progress against our R&D goals. Akshay will cover this in more detail, but with positive givosiran Phase III results and completed regulatory submissions, we believe we're poised for approvals in the US and Europe and launches of our second product early next year assuming positive regulatory reviews. Just yesterday, we announced that the FDA has granted givosiran, a priority review with a February 4 PDUFA date and no need for an AdCom. In addition, we're now positioned for two additional Phase III program readouts by the end of the year starting with inclisiran, our PCSK9 program license to the Medicines Company which will read out in the next few weeks, and then the lumasiran, our wholly owned primary hyperoxaluria RNAi therapeutic program and to enable longer-term growth in a capital-efficient manner, we completed our largest ever partnership with Regeneron to build an industry-leading pipeline of innovative medicines focused on ocular and CNS diseases where we see significant opportunities for RNAi therapeutics.

Furthermore with the substantial funding from our Regeneron alliance, we believe our balance sheet has the strength to support a multiyear horizon for business execution. Based on all our commercial and R&D progress and near-term prospects, we couldn't be more excited about Alnylam today, and we believe that we have a clear line of sight toward our Alnylam 2020 goal of being a global multiproduct top tier biopharma company with a deep clinical pipeline for both for continued growth and a robust product engine to fuel future innovation, a profile rarely if frankly ever achieved in biotech.

All this sets up an incredibly important period in the Alnylam story. On one hand, we believe that our modular, reproducible and very importantly organic platform for innovative medicines is hard to match, where for many reasons we believe our return on investment exceeds industry norms. And now having achieved a landmark approval of the first ever RNAi therapeutic and having built a global and leverageable commercial capability to generate revenue growth, we have greater confidence than ever in our ability to deliver on the commercial promise of RNAi. At the same time, we know that some of our stakeholders are eager to hear how revenue growth and continued investment in our innovative pipeline will support the path to a self-sustainable and attractive financial profile for Alnylam in the coming years. For these reasons, I'm very excited to have Jeff Poulton, our incoming CFO, join our team to help us navigate through this important transition, growing Alnylam for the future.

Jeff will make some comments later in the call. I would also like to thank Manmeet Soni for everything he has contributed to for our company and the foundation that we've built together to support our Alnylam 2020 aspirations.

Now before I turn the call over to Barry, I would like to mention that we are planning to hold an R&D Day in New York City on the morning of Friday, November 22, where we will plan to recap our latest progress in advancing our pipeline of RNAi therapeutics. We very much hope that you'll be able to join us in person or on the webcast.

So with that, I'll now turn the call over to Barry to review our commercial and medical affairs progress in more detail. Barry?

Barry Greene -- President

Thanks, John and good morning everyone. I'll begin by reviewing ONPATTROs commercial performance in the second quarter. We achieved $38.2 million in global ONPATTRO net product revenues in the second quarter. As in the first two-and-a-half quarters of launch, the majority of revenues stem from US sales and we're now pleased for the first time to provide more color on the geographic split with $10 million in the EU and $28.2 million coming from the United States. As of June 30, over 500 patients worldwide were receiving commercial ONPATTRO treatment. We're quite pleased with the overall growth and continued global demand this quarter even with increasing product options from recent market entrants and the availability of investigational drugs through expanded access programs, investigational clinical trials.

As a reminder, there have been three sources of patients in our launch to date. Patients from our expanded access program or EAP, patients who are known to sites and new de novo patients; in the first couple of quarters of launch, we effectively captured the first two sources and we are now very much into the de novo patient pool, particularly in the United States. Now when we include patients in clinical trials in our global EAP that number increases to greater than 750 patients worldwide who're now being treated with patisiran. We believe that we're on track to have approximately a 1,000 patients on ONPATTRO across commercial, clinical studies and our expanded access program by the year end 2019, a very exciting milestone in our overall efforts.

Let me now turn to the US market dynamics. On the physician front, we're seeing continued growth in both the number of new prescribers as well as repeat prescribers. In fact, over 50% of the prescriptions received in second quarter came from new prescribers. We believe new prescribers will continue to increase as healthcare provider disease awareness grows, fueled by multiple players engaged in disease state awareness and education. Regarding the mix of prescribers, we continue to see about 50% of the US start forms come from cardiologists, which we believe indicates strong recognition of the mixed phenotype and the awareness of polyneuropathy in this population. Additionally, we're seeing greater numbers of new prescriber specialties like primary care and hematology as disease awareness increases outside of the expert centers. Positive experience from patients and healthcare providers with ONPATTRO also continues to be a highlight, and of course, is a key predictor for future use. [Phonetic] Speech [Phonetic] therapy also continues to improve and overall persistence and adherence are very strong today. Regarding US market access as reported by external coverage reports, we're very pleased that we now have confirmed access to ONPATTRO if prescribed for more than 98% of US lives across commercial Medicare, Medicaid and other government payer categories.

We continue to effectively partner with US payers and have avoided the payer headwinds reported in this space and often reported with orphan disease launches. We're proud of this result in a very complex US market access environment and believe it reflects constructive, collaborative, and productive approach, including the use of value based agreements or VBAs we've adopted with the payer community.

Now turning to the EU and more broadly our, Canada, Europe, Middle East and Africa or CEMEA region, we're very pleased with ONPATTROs performance in the region. As we noted earlier, we achieved $10 million EU net product revenues during the second quarter. Some notable achievements during the quarter include favorable and competitively differentiating technology assessments in Germany, France and Italy. A highlight of the period was achieved in pricing agreements with NICE in England and with pricing authorities in Scotland. We also received marketing authorization approval in Canada where ONPATTRO is now available for commercial use. Through direct reimbursement, named-patient sales, or reimbursed expanded access, we're now selling ONPATTRO in over 10 countries in the CEMEA region. Given the timing of pricing and reimbursement discussions in CEMEA, we expect continued market access base growth in a number of commercial ONPATTRO patients for the rest of 2019 and into 2020, in addition to growth coming from patient finding and utilization were patients may experience inadequate response for other products with disease progression and tolerability.

Turning to our commercial progress outside the United States and CEMEA, we recently received marketing authorization approval for ONPATTRO in Japan. We're preparing for a launch in Japan and also advancing our plans to submit for regulatory approval in Brazil while exploring non-patient sales in Latin America countries. Given the presence of endemic disease and the favorable reimbursement environment, we expect Japan after the US to be our second largest country in revenues and patients on drug exiting 2020. As more countries around the world come online, we expect this to be an additional driver of future growth. Our team also remains committed to addressing the challenge of raising disease awareness and improving diagnosis in hATTR amyloidosis. Improved medical education and diagnosis will help patients reach treatment options faster. The data are clear that when patients receive treatment earlier in the disease course it improves their overall prognosis. Now regarding patient diagnosis as we've highlighted previously, our Alnylam Act program available in the US and Canada is a third party genetic screening initiative aimed at facilitating diagnosis of patients suspected of having hATTR amyloidosis.

As of July over 15,000 samples have been submitted and over a 1,000 patients with pathogenic mutations have been identified with a sustained hit rate of 6% to 8%. Since there are other sponsored genetic testing programs and HCPs also have reimbursed genetic tests, Alnylam Act represents only a portion of the genetic testing. We're also pleased now to partner with 23andMe to help customers for their consumer genetic service learn more about their genetic risk of the three most common TTR variance in the United States. In summary, with ONPATTRO achieving approval and access in more and more countries with improving diagnosis and patient finding and with continued evidence generating efforts highlighting the differentiated features of ONPATTRO, we're encouraged to see continuous and steady growth and we're confident in our future commercial potential even in an increasingly competitive environment. As I previously mentioned with more companies in the ATTR amyloidosis market, we believe overall awareness will continue to accelerate and we're enthusiastic about the benefits this will confer to patients. Moreover, as we look at the broader time horizon, we believe there are significant growth opportunities for our overall ATTR franchise, including through potential label expansion for ONPATTRO in both hereditary and wild-type ATTR amyloidosis patients with cardiomyopathy and also with the advancement of vutrisiran, our once quarterly subcu investigational RNAi therapeutic into potentially all segments of the ATTR amyloidosis market. We're very committed to being leaders in ATTR amyloidosis space and we believe our efforts position us well in the future.

Finally, let me briefly turn to givosiran which is now under active review by both US and European regulators. Assuming positive decisions by both agencies, we expect givosiran will launch in the US and CEMEA in early 2020. In the meantime, we're leveraging the capabilities built from ONPATTRO launch and commercialization and following the best practices developed country by country. Our team is focused on improving awareness and diagnosis of acute hepatic porphyria in the HCP and patient communities and laying the groundwork for a successful launch. As part of these overall efforts, we've launched our AIP physician and patient focused websites to give patients resources and education materials about their disease and to provide HCPs with content and tools to help them recognize the signs and symptoms of AHP and help them navigate through the appropriate tests to arrive at an accurate diagnosis.

Through Alnylam Act, we provide access to genetic testing at no charge for individuals in US or Canada who may carry a gene mutation known to be associated with AHP. While this program for AHP is in the early stage, we can report 479 tests submitted and 51 patients with AHP mutations as of July accounting for approximately 10% hit rate. There is a very clear unmet need and significant burden of disease in acute hepatic porphyria. Assuming positive regulatory reviews, we're very excited with the new treatment option we can bring to patients and the associated commercial opportunity for givosiran. We look forward to the possibility of delivering this medicine to AHP patients early next year. As we've said in the past, it's our belief that this would be attractive ultra-rare orphan disease opportunity with over $500 million in global peak revenue potential. As with ONPATTRO and other orphan drug launches in under-diagnosed populations, we expect givosiran to show consistent and steady pattern of revenue growth after launch.

With that, I'll now turn it over to Akshay to review our recent R&D and pipeline progress. Akshay?

Akshay Vaishnaw -- President, Research and Development

Thanks, Barry, and good morning everyone. In the interest of time, I'm going to limit my prepared remarks to our multiple Phase III clinical programs. We have a later opportunity to touch on our broader pipeline later in the year, at an R&D Day, as John mentioned earlier. Let me start with patisiran which is the unbranded name for ONPATTRO. At the Peripheral Nerve Society meeting in June, we presented new 12-month interim results from the ongoing global open label extension study of patisiran showing sustained improvement in neuropathy impairment and quality of life for patients out to [Phonetic] 13 [Phonetic] months of treatment.

These promising new results also showed the importance of treating patients as early as possible to minimize advancement of disease. The newly presented data also in our view showed what we believe to be a continued and favorable differentiation profile for patisiran including results in patients who experienced progression on tafamidis prior to initiating treatment with patisiran with the caveat of course that there would be no head-to-head studies comparing patisiran with other agents.

We now look forward to advancing the evaluation of patisiran in the APOLLO-B Phase III study aimed at expanding the ONPATTRO label to include cardiomyopathy in both [Phonetic] hereditary [Phonetic] and wild-type ATTR amyloidosis market. We are on track to start this study later this year, an impulse that we will seek regulatory support for an expanded label for patisiran in the '21 to '22 time frame.

As you know, we're also advancing vutrisiran which is delivered by quarterly subcutaneous injection and is also in development for ATTR amyloidosis. While we've been enrolling hATTR patients with polyneuropathy in the ongoing HELIOS-A Phase III study with vutrisiran, we are pleased to announce today that we have obtained regulatory alignment on the design of HELIOS-B. HELIOS-B will be a Phase III study of vutrisiran in inherited and wild-type ATTR amyloidosis patients with cardiomyopathy. Primary endpoint, we will evaluate vutrisiran's impact on cardiovascular hospitalizations and mortality. For competitive reasons, we will await providing further details until the study starts later this year. Successful HELIOS-B should allow vutrisiran to enter the very large wild-type ATTR amyloidosis market opportunity with clinical outcome data.

Let's move on to givosiran our investigational RNAi therapeutic in development for the treatment of acute hepatic porphyria. In April, we presented the complete positive results from the ENVISION Phase III study. Givosiran demonstrates a robust treatment effect in significantly reducing the annualized rate of composite attacks in AHP patients relative to placebo, specifically givosiran met the primary efficacy endpoint with a 74% mean and 90% median reduction relative to placebo in the annualized rate composite porphyria attacks in patients with AIP over six months.

Turning to safety and tolerability results, AEs were reported in 89.6% of givosiran patients and 80.4% of placebo patients in the pivotal study. Sales adverse events were reported in 20.8% of givosiran patients and 8.7% of the placebo group. One patient with givosiran arm, as previously mentioned, discontinued treatment due to an AE. Three SAEs in the givosiran group were reported as related to study drug, a single case each of pyrexia, abnormal liver function test and chronic kidney disease. We were very pleased in the second quarter to complete the rolling submission of the NDA with the US FDA and to submit the MA with the European Medicines Agency, and we announced just yesterday that both applications have now been accepted and that the FDA has gone to the project review setting a PDUFA date of February 4, 2020. The FDA has also indicated that they do not foresee a need for an Advisory Committee meeting at this time.

Finally, with respect to the givosiran, we've now enabled an expanded access program to potentially make givosiran available to qualified AHP patients following requests from healthcare providers.

I'll now turn to recent progress with lumasiran, an investigational RNAi therapeutic in development for the treatment of primary Hyperoxaluria type 1 or PH1. At the Oxalosis and Hyperoxaluria Foundation Meeting in June, we presented final results from a Phase I-II study, an interim data from the Phase II OLE study of lumasiran. In these studies, we continue to see robust lowering of urinary oxalate to normal or near normal levels and an encouraging tolerability profile. As you know, we are now conducting the ILLUMINATE-A Phase III study of lumasiran. This is a randomized, double blind, placebo-controlled study in PH1 patients ages six or older with mild to moderate renal impairment. We completed enrollment in this pivotal trial and remain on track to report top line results from ILLUMINATE-A in late 2019 and if positive to submit regulatory filings beginning in early 2020. Also in the second quarter, we initiated ILLUMINATE-B, a Phase III study of lumasiran in PH1 patients under the age of six. We plan to start the third Phase III trial ILLUMINATE-C in PH1 patients with severe renal impairment later this year.

In addition to progress we've made with our wholly and late stage assets, our partners at The Medicines Company and at Sanofi have also been advancing our partner Phase III assets. In May, the Medicines Company reported interim results from the ongoing ORION-3 OLE study of inclisiran, an investigational RNAi therapeutic targeting PCSK9 that was showing sustained lowering of LDL cholesterol by more than 50% with no material safety issues observed in the study. We now look forward to seeing topline results from the inclisiran ORION 11, then 9 and then 10 pivotal studies starting in the second half of the third quarter and I have been encouraged by the more than 3500 patient years of safety data from the Phase III program that had been reviewed on seven separate occasions by the Independent Data Monitoring Committee with no recommended changes to study conduct. Notably, this is the largest human experience for an investigational RNA therapeutic and positive results if achieved will be an important milestone for the entire field.

So with that, let me now turn the call over to Manmeet to review our financials. Manmeet?

Manmeet S. Soni -- Chief Financial Officer

Thanks, Akshay, and good morning everyone. Please refer to our press release issued earlier today for a summary of our financial results for the second quarter of 2019. I would like to take this opportunity to provide a brief overview of three key areas. Our cash position, our second quarter 2019 results, and our updated 2019 financial guidance.

Let me start with our cash balance. We ended the second quarter with a strong balance sheet of approximately $1.97 billion in cash, cash equivalents, marketable debt securities and restricted investments. Our cash balance includes proceeds of $800 million received in the second quarter attributed to our Regeneron collaboration. Moving now to our revenues, total second quarter revenues were $44.7 million. We recorded $38.2 million of ONPATTRO net product global revenue during the second quarter of 2019 which represents 45% growth from first quarter net product global revenues of $26.3 million.

Our global gross to net or GTN percentage during the second quarter of 2019 was in mid-20s. Cost of goods sold was $4.3 million for the second quarter, which is approximately 11% as a percentage of net product revenues. We recognized $6.5 million of collaboration revenue during the second quarter of 2019 as compared to $29.9 million during the second quarter of 2018. As expected, the decrease in collaboration revenues is primarily due to a decrease in reimbursable activities in connection with our collaboration agreements with Sanofi Genzyme and Vir. Moving to other operating costs and expenses, GAAP R&D expenses were $163.9 million for the second quarter of 2019 as compared to $137.6 million for the second quarter of 2018. Non-GAAP R&D expenses were $148.6 million as compared to $126 million for the second quarter of 2018. The increase in non-GAAP R&D expenses was due to increased license fees related to our collaboration agreement with Regeneron and increased compensation expenses and facility expenses as a result of growth in the number of our late-stage programs and higher headcount and clinical trial expenses during the period as we continue to expand and advance our development pipeline. This increase was offset by a decrease in manufacturing expenses related to reduce batches of drug substance and raw materials.

Turning to SG&A, GAAP SG&A expenses were $104.8 million as compared to $84.7 million for the second quarter of 2018. Non-GAAP SG&A expenses were $97.4 million as compared to $74.1 million for the second quarter of 2018. The increase in non-GAAP SG&A expenses was due primarily to an increase in commercial and medical affairs head count in connection with the continued global launch of ONPATTRO. We are pleased today to have updated our 2019 annual non-GAAP R&D expense guidance to be in the range of $550 million to $575 million compared to our previously guided range of $550 million to $590 million. We are also pleased to have tightened our 2019 annual non-GAAP SG&A expense guidance to be in the range of $390 to $400 million as compared to our previously guided range of $390 to $410 million.

Finally, on a personal note today is my last earnings call with Alnylam team, I have thoroughly enjoyed my time as part of the team, and I'm proud of the many contributions made to the launch of the Company as a commercial enterprise and support its global expansion across multiple geographies. I am confident that the foundation created over the past few years will serve Alnylam for many years to come. I've also enjoyed working with Jeff Poulton on the CFO transition.

I will now hand it over to Jeff to highlight some of his perspectives. Jeff?

Jeff Poulton -- Incoming Chief Financial Officer

Thanks Manmeet and thanks for your help in the transition. I'd like to make just a few brief remarks as I prepare to formally assume the CFO role next week. I'm very excited to be joining Alnylam at this stage in its growth as it establishes its global commercial operations. I'm really impressed with Alnylam's technology and team and the company's potential to make a difference in patients' lives with this new frontier of medicine. I strongly believe that with its first commercial product today, prospects for many more commercial products in the coming years beginning in 2020 and a deep clinical pipeline and robust organic product engine for the future, Alnylam is positioned to emerge as a top tier biopharmaceutical company. Consistent with John's earlier comments, the key focus for me will be working with my new colleagues to create a roadmap for the financial self-sustainability as Alnylam becomes a successful global commercial organization with significant top line growth fueled by a deep R&D pipeline. I look forward to this challenge and communicating our plans in the future.

With that, I'll now turn the call over to Yvonne to review our goals for the remainder of the year. Yvonne?

Yvonne Greenstreet -- Chief Operating Officer

Thanks, Jeff, and welcome to the team. We couldn't be happier to have you on board. I'm really thrilled with the progress we've made in 2019 so far, but we still have a number of exciting milestones to look forward to in the remainder of the year. For starters we plan to continue our global commercialization of ONPATTRO including launching in Japan and other countries. We also look forward to initiating the APOLLO-B Phase III study in mid-2019 aimed at securing an expanded commercial label for patisiran to include wild-type and hereditary cardiac amyloidosis. With vutrisiran, we plan to continue enrolling the HELIOS-A Phase III trial throughout the year and expect to initiate HELIOS-B, an outcome study in wild-type and hereditary ATTR cardiac amyloidosis patients in late 2019. With givosiran, we plan on having additional data from ENVISION presented at the ICPP meeting in early September.

Turning to the lumasiran, with enrollment in the ILLUMINATE-A Phase III study now complete, we plan to report top line results from that study in late 2019. We will also continue enrolling pediatric patients in ILLUMINATE-B and plan to start the ILLUMINATE-C study in PH1 patients with severe renal impairments later in 2019. With inclisiran, we expect our partners at The Medicines Company to report top line results from the ORIONs 9, 10 and 11 studies beginning later this quarter and assuming positive data to submit an NDA for inclisiran by the end of the year. And of course we'll continue advancing our pipeline of earlier stage clinical efforts as well as exciting preclinical efforts and we'll highlight those milestones throughout the rest of the year as they occur. In particular, you should expect data readouts from a number of our early and mid-stage clinical programs.

Let me now turn it back to Christine to coordinate our Q&A session. Christine?

Christine Regan Lindenboom -- Vice President of Investor Relations and Corporate Communications

Thank you, Yvonne. Operator, we will now open the call for questions to those dialed in. We would like to ask you to limit yourself to one question each, and then get back in the queue if you give additional question.

Questions and Answers:

Operator

Thank you. [Operator Instructions] Our first question is from Alethia Young from Cantor Fitzgerald.

Alethia Young -- Cantor Fitzgerald -- Analyst

Hey guys, thanks for taking my question, and congrats on the progress as you continue this launch. Just one from me, maybe I might have a little bit of a follow-on question, but can you just talk a little bit about tafamidis and what you're seeing and hearing from how doctors make decisions since like 50% of your docs are cardios? And then, just kind of tagging on to that, can you talk a little bit more about how the presence of both the Alnylam's drug and the Pfizer drug and have driven diagnosis. Can you give any quantitative metrics or is there any other color you can give us around that? Thanks.

John Maraganore -- Chief Executive Officer

Great, thanks, Alethia. Barry, you want to handle it?

Barry Greene -- President

Yeah. So Alethia we are -- on the emerging landscape, it's too early to give specifics around increased diagnosis and increased speed of diagnosis other than the color that we are gaining more and more new prescribers every quarter, which is a sign that new people are learning about disease, seeing the disease and then are comfortable diagnosing and holding on to their patients. So, anecdotally, we are definitely seeing increase of awareness and having multiple players at every Cardiology Congress educate that there is -- disease of ATTR amyloidosis has certainly been helpful for patients in raising awareness.

Now on to tafamidis specifically again, it's too early in their launch to understand their particular dynamics but our market research is telling us is that physicians who understand hereditary TTR amyloidosis even in those mixed phenotype with polyneuropathy, ONPATTRO is the drug of choice, particularly in United States. And then for those that are wild-type, clearly tafamidis is a choice. In Europe were tafamidis has been present for a number of years, physicians understand the progression of tafamidis and we're seeing a number of patients that are switched -- hereditary patients from tafamidis to ONPATTRO in the major markets where tafamidis has been used. So does that answer your question, Alethia?

Alethia Young -- Cantor Fitzgerald -- Analyst

Yes. Thanks.

John Maraganore -- Chief Executive Officer

Great, thank you.

Operator

We'll go next to Gena Wang from Barclays.

Gena Huidong Wang -- Barclays -- Analyst

Thank you for taking my questions and first one also regarding the ONPATTRO commercial, a question, for all the 500 patients on commercial drugs, how many were from ex-US and also following Alethia's question, 49% demand from cardiologist, how's the payer coverage for these patients?

John Maraganore -- Chief Executive Officer

Great. Let me, let me quickly address the first one and then I'll hand it over to Barry for the second one. We're not breaking out patient numbers by region. We are for the first time breaking out revenues and we're reporting $28.2 million in the US and $10 million in rest of world, CEMEA in this case. So, that's unfortunate, we're limited for really competitive reasons. Barry, you want to answer the second question.

Barry Greene -- President

Yeah, in terms of US payer coverage, which we reported, I mean, we remarkably have external reports saying that 98% of our patients who if prescribed ONPATTRO will be reimbursed ONPATTRO, is actually quite remarkable. We have not to date had a patient rejected by the payer.

John Maraganore -- Chief Executive Officer

Just to add to that, Gena, we're -- we've a very strong belief that the proactive and high quality approach that we took in engaging with payers as we introduced ONPATTRO to the market and continue to have discussions with payers, even to this day around value based agreements, these are all elements of what has I think been a very successful market access story for this important medicine in the US market.

Gena Huidong Wang -- Barclays -- Analyst

Thank you.

Operator

Moving on, our next question will come from Whitney Ijem from Guggenheim.

Whitney Ijem -- Guggenheim Securities -- Analyst

Hey guys, thanks for taking the questions. The first one, I guess, I am going to ask them on givosiran, so the first one in terms of the greater than $500 million for givosiran opportunity, any color you can give us on what that assumes in terms of use in sporadic versus recurrent patients either kind of in terms of how the drug will be used or relative breakdown of patients in either bucket?

John Maraganore -- Chief Executive Officer

Sure, great question. Maybe just for the benefit of others on the call, obviously, the recurrent patient population that we have estimated to be approximately a 1,000 patients in the US and Europe and there're about estimated to be 5,000 patients with sporadic disease defined as three attacks or less. Keep in mind that any patient that experiences at attack can experience attack that can be life threatening. So, it doesn't lessen the importance of their disease if they are sporadic patient. But with that, Barry, do you want to comment a little bit about how we get to the belief at around greater than $500 million opportunity.

Barry Greene -- President

Yeah, John you outlined it very, very well. As with many ultra-rare orphan diseases where patient journeys can last 13 to 15 years, and patients show up with three to four unnecessary surgery, are misdiagnosed by about a dozen physicians in their journey. We believe that there are probably many more patients than the number that John highlighted out there. An interesting fact is as little as three years ago the porphyria consortium which has been studying this disease for 20 years, did not have the benefit of an industry partner doing natural history and by working with them, we've all now understood that two-thirds of patients experienced debilitating chronic pain between attacks. So, as John said, it's not just about the attack rate, number of attacks, it's about the overall devastating nature of the disease. So when you take the 1000 and 5000 likely a growing and multiply that by an orphan price point, we think there is a very significant opportunity. Now, of course we're going to take the same proactive nature driven by our patient access philosophy with givosiran as we've taken with ONPATTRO and we'll be very proactive with payers to ensuring we put the right value based agreements in place so that patients in the United States and frankly around the world have access to an important medicine for their devastating disease.

Whitney Ijem -- Guggenheim Securities -- Analyst

Great. And one quick follow-up on ONPATTRO, any color you can give on the relative ex-US price versus US at this point?

John Maraganore -- Chief Executive Officer

Yeah, Barry, you want to comment?

Barry Greene -- President

Well, as I think Whitney, as we highlighted on previous calls, we've held the price band very, very tight on a per vial basis and then of course price varies because it is weight based dosing. So, in countries with bigger people, it's more of dollars per patient per year and smaller people, it's less, but the vial price is very, very tight.

Whitney Ijem -- Guggenheim Securities -- Analyst

Thank you.

John Maraganore -- Chief Executive Officer

Thank you, Whitney.

Operator

We'll go next to Anupam Rama from JP Morgan.

Anupam Rama -- J.P. Morgan -- Analyst

Hey, guys. Thanks so much for taking my question and congratulations on all the progress here.

John Maraganore -- Chief Executive Officer

Thank you.

Anupam Rama -- J.P. Morgan -- Analyst

In the US like you've outlined here, you're getting about 50% of the ONPATTRO demand coming from cardiologists. Wondering if you could provide any color on some of the OUS prescribing trends and then maybe any color on the gating factors to starting HELIOS-B for vutrisiran? Thanks so much.

John Maraganore -- Chief Executive Officer

Great. So, let's have Barry talk little bit about the ex-US trends on prescribers, and then Akshay, you can handle the next -- the second question. So, Barry?

Barry Greene -- President

Yeah, thanks Anupam. As you highlighted, we said about 50% from the US prescribers are cardiologists and interestingly enough, the number of additional specialties including primary care physicians, nurse practitioners is growing, a real sign that as a healthcare providers become familiar with the disease via patients, they understand how to diagnose and clearly what to prescribe at least in our case with ONPATTRO. Ex-US, it really depends on the country. There are some countries like France that are -- that are highly coordinated with centers and there are named centers where a neurologist or cardiologist takes care of those patients and in places like Germany, it's primarily neurology driven. So, it really depends ex-US on the country and how the centers are established. Turning to Japan, which we mentioned earlier, we believe that the primary prescribers, at least the initial launch in Japan will be neurologists, because those are the folks that manage the overall disease symptomatology. Now of course dynamic back to United States really is the V122I patient population. So in parts of the world where patients of Western African descent, we probably will see a bigger uptick in cardiology at least in a hereditary space.

Akshay Vaishnaw -- President, Research and Development

Just following up -- Anupam following up on the HELIOS-B question, essentially the main gating factor was getting aligned with -- getting aligned with regulatory agencies globally, and I think we're in great shape now, as we reported this morning. So we're looking forward to a vigorous start from that program in the second half of this year now and that as you know we know all the [Phonetic] ATTR products [Phonetic] globally and we're excited to start enrolling wild-type patients as well as of course in that study.

John Maraganore -- Chief Executive Officer

Does that answer your question?

Anupam Rama -- J.P. Morgan -- Analyst

Yeah, it is great. Thank you for taking my questions.

John Maraganore -- Chief Executive Officer

Thank you.

Operator

Ritu Baral from Cowen has our next question.

Ritu Baral -- Cowen & Company -- Analyst

Good morning everyone, thanks for taking my question. I've already gotten a few emails this morning on some concerns around US specific growth, I think the assumption is that the Q1 number of -- the Q1 revenue number of $26.3 million was largely 95% driven by US, understanding, you don't want to comment on patient numbers, can you give us a little more comfort around the US growth rate. Can you comment on how things like HELIOS-A enrollment, how much of an impact that's having on the launch and things like persistence, a little more color on persistence of treatment, especially given the steroid free treatment?

John Maraganore -- Chief Executive Officer

Yeah, Ritu. First of all, I mean, the concern about US growth is completely wrong actually. We've had steady growth in the US and in Europe. Manmeet, you want to comment more specifically to provide -- to provide support for that?

Manmeet S. Soni -- Chief Financial Officer

Sure, John. So Ritu, as John mentioned, we had consistent growth and you saw the global revenue grew over approximately 45% from Q1 to Q2, but if I split out US and Europe, US was growing even higher [Phonetic] ranges [Phonetic], was growing at a 50% rate from Q1 to Q2. So, to give you numbers, which were not there and you would see them in the 10-Q filing when we file later today, this evening or tomorrow. For US, our last quarter, Q1 was approximately $18.8 million and this quarter is $28. So that shows a pretty strong growth of 50%. In Europe, we were last quarter at $7.5 million and now this is -- this quarter is $10 million. So, that also shows a 33% growth. But, as you know there are -- in Europe, the growth comes primarily as we launch new countries and we get the final pricing and reimbursement finalized. So, as Barry and John mentioned, we are showing the steady and continuous growth in our revenue and there is no concern on the both US-Europe and global revenue growth. [Speech Overlap] No, Barry. If there were some more questions on persistence on adherence --.

Barry Greene -- President

Yeah, Manmeet, I think you covered the growth incredible and just to emphasize, we are seeing continuous and steady growth in the United States and believe it will continue, maybe even a particular uptake in the out quarters because of awareness. In Europe, as when we highlighted, we're in countries were launched we continue to see growth and a number of new countries will come on late this year into 2020 and then Japan is coming on late this year and into 2020. So we do see new market entrants and then within each country steady growth within countries. So that dynamic will continue.

You asked about -- you asked about continuation. We see tremendous continuation of patients on ONPATTRO. Anecdotally, we hear tremendous reports about physician experience and patient experience and the adherence rate remains very, very high. It's still what -- way early into our launch to give specific numbers, but it remains very high.

Manmeet S. Soni -- Chief Financial Officer

And just to follow up on that Ritu, the APOLLO study itself, the very low dropout rate there, the high conversion rate to the only persistence in the early, it is all evidence that the risk benefit is being well tolerated in patients who are staying on drug. We know from early patients who've been on drug from 2013, '14 onwards actually from the original Phase II and then the Phase III we're five years into it. So this steroid comment, I don't think applies, and we have very good evidence accumulating now the patients are tolerating the steroid free regimen well, which by the way over the years has -- the dose has been considerably reduced as well.

John Maraganore -- Chief Executive Officer

Did that answer your question?

Ritu Baral -- Cowen & Company -- Analyst

Got it. And then the impact HELIOS-A on that as well -- on the launch -- enrollment of HELIOS-A on the launch?

Barry Greene -- President

Yeah, I mean, look, I mean, as we said from the beginning, obviously HELIOS-A patients are potential ONPATTRO patients, we know that and they are -- for every patient that goes into HELIOS-A, they could be a commercial patient of course, we understand that, but we're investing in that program for the benefit of having a new product offering for patients in the future -- in the not-too-distant future that we think will continue to drive growth of the franchise. So it is obviously a very eyes wide open type of decision to do that. Now we are importantly expanding just this past quarter significantly into sites outside the US and we are going to see the benefit of that in countries and markets where there is no reimbursement at the present time. So that will obviously balloon out any effect that might occur on the commercial ONPATTRO growth from clinical studies.

Ritu Baral -- Cowen & Company -- Analyst

Got it. Super helpful and that was already three questions, so I'll get back in the queue before josh comes for me.

John Maraganore -- Chief Executive Officer

Great. Thank you. It's you're lucky day.

Operator

We'll take our next question from Paul Matteis from Stifel.

Unidentified Participant

Hey, this is [Phonetic] Ned [Phonetic] on for Paul, thanks for taking the question, maybe just -- just a quick one on -- on the 1,000 patients by year-end guidance. How are you getting confident in that number in terms of the de novo patient growth rate that you're seeing sequentially and then quick to clarify, does that 1,000 is that commercial drug or is that include patients in expanded access programs?

John Maraganore -- Chief Executive Officer

Yeah. It includes patients in our expanded access program and also in our ongoing open label study. So we do believe that we're on track to achieve that. We're roughly at this point over 750 patients within that universe and we're very much on track to hit that over 1,000 -- approximately 1,000-patient number by the end of the year. So that's encouraging.

Unidentified Participant

Great. And then the de novo patient growth rate just, I don't know if you can provide much detail on that sub-segment?

John Maraganore -- Chief Executive Officer

Well, I mean, Barry, can comment as well, but let's -- when we talk about growth, let's be clear, we understand the buckets of growth. One is new patient finding. De novo patients being identified and you could look at Alnylam Act. We are getting about a couple thousand samples per quarter and we're finding roughly 150 or so patients per quarter. And that's been very, very steady now for over a year of that program. Now those are not necessarily ONPATTRO patients. This is just a number that you can look at as a surrogate marker if you will for patient finding. But patient finding is ongoing and as Barry said earlier it's not just Alnylam Act, its other -- its other testing programs that are out there, some funded by companies, some that are not.

So there really is a significant amount of new patient finding happening and by the way that is just in the US right, in Canada as well. So it doesn't reflect new patient finding around the world, which is also getting better. So that's one source of growth.

The second important source of growth is our global expansion. And also in Europe is the expansion of market access on a country-by-country basis and that's a very important source of growth. Barry commented earlier around Japan, which we believe by the end of 2020 will be our second largest market and that's going to be an important source of growth in addition to what's going on in the US and what's going on in Europe and the rest of the world.

And the final source of growth, which I think it points to the, what we believe to be a remarkable profile of ONPATTRO, is the evidence generation activities that our medical affairs team and for longer-term our clinical development team are engaged in to really strengthen the differentiation of ONPATTRO to help patients understand or physicians understand on the best time to use ONPATTRO for their patients to help highlight some of the issues that may exist with other therapies that are out there like disease progression where ONPATTRO can be very helpful. Those type of activities will have both near-term and mid-term implications for growth.

So let me pause there. Barry, anything else to add?

Barry Greene -- President

No, you covered it completely.

John Maraganore -- Chief Executive Officer

Great, thank you.

Unidentified Participant

Super helpful. Thank you guys.

John Maraganore -- Chief Executive Officer

Terrific.

Operator

Next we'll go to Vincent Chen from Bernstein.

Vincent Chen -- Sanford C. Bernstein & Co. -- Analyst

Congratulations on progress and thanks for taking the question. I was wondering if you could provide a little more color on the folks identified in Alnylam Act with TTR amyloidosis who don't go on ONPATTRO. What are the reasons for this? Recognizing it's a third-party program but that you're certainly very plugged in with the TTR community. Could you give us a sense for how these patients break out? What portion of mutation is associated with neuropathy or mix disease versus a more pure cardiomyopathy phenotype or some ending up in trails, etc., or would you expect that many of them do eventually work their way onto ONPATTRO over time? And as a quick corollary, how does the patients new start forms look in the second quarter?

John Maraganore -- Chief Executive Officer

Yeah. So maybe just a couple of quick comments and then I'll hand it over to Barry. We don't have a lot of visibility on specific patients in Alnylam Act and that's by design. This is a program that's aimed to help physicians diagnose their patients. It's not anything other than that, and obviously, we believe that by improving medical education, improving patient diagnosis, that if ONPATTRO is identified as the right choice for treatment for these patients by their physicians, then that will follow. So that has been the philosophy. We just don't have a lot of color other than that in terms of Alnylam Act. So that's the answer to that one and then our start forms, as we said last quarter, we moved away from reporting start forms as is common in drug launches, because of the fact that it's an imprecise measure of patients, we have patients in the US who come into ONPATTRO therapy outside of start forms and of course start forms are a US specific measure to begin with. So it's not even reflecting true patient growth. The patient number is what you should focus on and obviously revenues. Barry, anything else to add to what I just said?

Barry Greene -- President

I think you covered it well. Back to Alnylam Act, again just to reiterate, Alnylam Act is a free third party genetic tests that we and other companies -- other companies offer other tests for the benefit of patients. And just to give you some color, Vincent, what we often see is that a patient will come in after a multi-year journey finally, but be diagnosed with hATTR amyloidosis and through genetic counseling identified that they have disease to their siblings, children and others and those people often then will visit a physician for a genetic tests. So Alnylam Act really ease the burden for the benefit of patients to get these genetic tests. As John said, it's an arm's length relationship because it is there for the benefit of patients. Now some patients do not yet have penetrants of disease, but we believe that by raising awareness, remember, this is not about a portion of the pie, it is growing your overall pie, that will continue to benefit patients by raising awareness and speed to diagnosis.

Vincent Chen -- Sanford C. Bernstein & Co. -- Analyst

I see. Thank you very much.

Operator

Our next question today is from Ted Tenthoff from Piper Jaffray.

Edward Tenthoff -- Piper Jaffray -- Analyst

Great, thank you very much and congrats on the progress.

John Maraganore -- Chief Executive Officer

Thanks, Ted.

Edward Tenthoff -- Piper Jaffray -- Analyst

Yeah, really, really impressive global launch and just to comment, I love that you guys are breaking it out globally, it really gives us a sense of where the patients are coming from and where the growth is coming from. So thank you for that. I'm kind of looking at the vutrisiran and really considering sort of how this market could evolve, tell us a little bit more about where you think sort of IV versus subcu might be used and maybe even as, you know, there would be induction versus maintenance or just give us a little bit more of a sense of sort of how you see all of that playing out? Thank you.

John Maraganore -- Chief Executive Officer

Yeah. Thanks, Ted. And thanks for your -- thanks for your comments earlier. We're extremely excited about vutrisiran, it's a once quarterly, low dose, low volume, subcutaneous injection that we think is an exciting expansion of the overall ATTR opportunity, I mean, taking a step back, when you think about -- this market, you think about hereditary ATTR polyneuropathy where we are today and then in the future expanding into cardiomyopathy if our studies are successful and then you think about the wild-type setting again, we've studies like APOLLO-B and HELIOS-B assuming those studies are successful. We've got a remarkable opportunity for the overall franchise for many, many years to come. And I think without getting [Phonetic] heady or heddy [Phonetic] in terms of numbers, I mean, this really is a multi-billion dollar type of market opportunity, where Alnylam is poised to be a significant leader. So, vutrisiran really positions us with and -- with a product offering that really provides a great option for patients, in HELIOS-A, we'll bring [Phonetic] that [Phonetic] into patients, [Phonetic] prickly [Phonetic] rapidly that study is up and going enrolling. We expect that to readout in '21, '22 time period. That will be important for patients to get access to a subcu alternative like vutrisiran. And then Healios B, which will start out very shortly by the end of the year, that really addresses the larger commercial opportunity in the wild-type and hereditary cardiomyopathy setting. A very, very significant opportunity with a once quarterly subcutaneous option that we think is extremely competitive and we've done studies that show that it is even preferred over an oral agent given once a day or even less excitingly twice a day. So, -- these are really opportunities for market growth and expansion for Alnylam that is not that far away at all and very, very excited to look forward to. So, Barry, anything else to add to that?

Barry Greene -- President

No, I think you covered it well. I guess the only two things; one, an interesting analog to look at is how the MS market developed over the last 30 years. And if you think 30 years ago to today and project out the ATTR amyloidosis market over the next 10 to 15 years, we can see a dynamic where more prescribers are getting interested, diagnosis gets much earlier in disease, and patients benefit greater by an earlier diagnosis. So, just in addition to what John mentioned I see those same dynamics playing out with ATTR amyloidosis.

Edward Tenthoff -- Piper Jaffray -- Analyst

Great. I appreciate all the color, and you're building a great foundation on ONPATTRO. So, thanks so much.

John Maraganore -- Chief Executive Officer

Thank you, Ted.

Operator

And we'll go next to David Lebovitz with Morgan Stanley.

David Lebovitz -- Morgan Stanley -- Analyst

Thank you very much for taking my questions. Could you characterize the effort it takes to transition patients that are diagnosed in the Alnylam Act program to actually being patients on drug and noticing that there are certainly more patients that are from the cardio and I guess given that the drug is approved for polyneuropathy coming online for the drug, what would be driving the fact that so many cardio patients are coming on?

John Maraganore -- Chief Executive Officer

Sure, let's, Barry, you want to handle it?

Barry Greene -- President

Yeah, I mean, I guess more broadly, and just again to say that there is a number of things we're doing to increase awareness and diagnosis. Hereditary ATTR amyloidosis is unfortunately disease where patients can bump into cardiologists, neurologists other specialties who miss or misdiagnose the disease and that dynamic continues until awareness is raised. Now specifically on a cardiology front, if a patient presents with cardiovascular symptoms, there are tools the cardiologist has and are using now more and more, echo technetium scanning that helps point to amyloidosis, specifically TTR amyloidosis which is why we see the cardiology community so interested. And then of course, there are many, many wild-type patients, the segment that we're not yet penetrating commercially, we will in the future assuming positive data and because there are some of the wild-type patients, cardiologists are becoming more and more aware. Now importantly, we're also seeing on the neurology side more awareness of TTR amyloidosis hereditary and they are looking for the disease using the tools they have. So we see that all as positive signs of improved diagnosis and speedier diagnosis.

John Maraganore -- Chief Executive Officer

Right and Akshay?

Akshay Vaishnaw -- President, Research and Development

Yeah, I mean just to build on what Barry was saying, if we look at the US landscape in many senses, V122I is the commonest mutation, but the other important thing to bear in mind is that there's increasing awareness that a very significant proportion of those patients have neuropathy and suddenly what Barry has seen, I've seen when I've spoken to doctors is cardiologists are looking [Technical Issues]

neuropathy, they're collaborating with their neurologists and multi-functional teams to fully characterize the most systemic nature of the disease and as appropriate, if they have neuropathy, then to prescribe a rather than drug-like ONPATTRO. So, Barry is actually right, it is a journey. The education awareness is increasing and it's great that patients who have V122I and other mutations are getting more fully characterized, so physicians and patients understand the full burden of disease. And as I said [Indecipherable] neuropathy, then certainly ONPATTRO is an important choice for them.

John Maraganore -- Chief Executive Officer

So does that answer your question?

David Lebovitz -- Morgan Stanley -- Analyst

Thank you very much, I appreciate it.

John Maraganore -- Chief Executive Officer

Right. Thank you. Okay. So, go ahead, operator.

Operator

That's all the time we have for questions . I'll turn it back to the Company for closing remarks.

John Maraganore -- Chief Executive Officer

Great. Well, thanks everyone for joining us on the call. We're obviously very pleased with the R&D and commercial progress that we've been making. We are really excited about the Company that we're building, the impact we're making a patient lives. So, with that I look forward to updating you on our continued progress in the coming weeks and months. Have a great rest of the day everybody. Bye, Bye.

Operator

[Operator Closing Remarks]

Duration: 61 minutes

Call participants:

Christine Regan Lindenboom -- Vice President of Investor Relations and Corporate Communications

John Maraganore -- Chief Executive Officer

Barry Greene -- President

Akshay Vaishnaw -- President, Research and Development

Manmeet S. Soni -- Chief Financial Officer

Jeff Poulton -- Incoming Chief Financial Officer

Yvonne Greenstreet -- Chief Operating Officer

Barry Greene -- President

Alethia Young -- Cantor Fitzgerald -- Analyst

Gena Huidong Wang -- Barclays -- Analyst

Whitney Ijem -- Guggenheim Securities -- Analyst

Anupam Rama -- J.P. Morgan -- Analyst

Ritu Baral -- Cowen & Company -- Analyst

Unidentified Participant

Vincent Chen -- Sanford C. Bernstein & Co. -- Analyst

Edward Tenthoff -- Piper Jaffray -- Analyst

David Lebovitz -- Morgan Stanley -- Analyst


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