Alnylam Pharmaceuticals, Inc. (ALNY) Q4 2018 Earnings Conference Call Transcript

Alnylam Pharmaceuticals, Inc. (ALNY -1.55%)
Q4 2019 Earnings Conference Call
Feb. 7, 2017, 4:30 p.m. ET

Contents:

• Prepared Remarks
• Questions and Answers
• Call Participants
  
  See all our earnings call transcripts.

Prepared Remarks:

Operator

Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals conference call, Fourth Quarter and Full Year 2018 Financial Results. There will be a question and answer session to follow. Please advise that this call is being taped at the company's request. I would now like to turn the call over to the company.

Christine Lindenboom -- Vice President, Investor Relations and Corporate Communications

Good afternoon. 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; and Manmeet Soni, Chief Financial Officer. Yvonne Greenstreet, our Chief Operating Officer, is traveling today and will not be available for today's call.

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. During today's call, as outlined in Slide 2, John will provide some introductory remarks and provide some general context. Akshay will review recent clinical updates, Barry will provide an update on our commercial progress, Manmeet will review our financials, and John will wrap up with a brief summary of upcoming milestones before opening the call for your questions.

I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans, and prospects, which constitutes forward-looking statements for the purpose 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 that are in our most recently quarterly report on file with the SEC. In addition, any forward-looking statements represent our views only as to the date of this reporting. It should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements.

Please also note that the press release and related financial tables including a reconciliation of GAAP to non-GAAP measures that we will discuss today can also be found on the investor page of our website. We believe non-GAAP measures provide useful information to management and investors regarding our financial condition and results of our operation. With that, I'll turn the call over to John.

John Maraganore -- Chief Executive Officer

Thanks, Christine, and thank you, everyone, for joining the call today. I'm gonna keep my remarks relatively brief so we can dive into the meat of the call. We believe 2018 was a banner year for Alnylam in which we saw the approval and subsequent launch in the U.S. and E.U. of ONPATTRO, heralding the arrival of RNAi therapeutics as a whole new class of innovative medicines. Barry will get into the specifics later, but while still early, we're pleased with how the launch is going. With over 200 patients receiving treatment with commercial ONPATTRO in the U.S. and E.U. as of the end of 2018, we believe we are seeing strong patient and physician demand as well as excellent commercial execution by our U.S. and E.U. teams.

While we're focused in the near term on launching ONPATTRO into the market of hATTR amyloidosis patients with polyneuropathy, we're also excited about the significant growth potential of our ATTR franchise in the mid and longer term. This includes potentially expanding the ONPATTRO label into the hereditary and wild-type cardiomyopathy segments with the APOLLO-B study as well as advancing our investigational RNAi therapeutic Vutrisiran initially for hATTR polyneuropathy patients through our HELIOS-A study. Then, longer term, we're committed to developing Vutrisiran for the treatment of hereditary and wild-type cardiomyopathy patients with the HELIOS-B outcome study that we expect to start later this year. Akshay will summarize how our clinical development efforts can potentially help realize this growth.

The bottom line here is that over the next few years, we anticipate having thousands of ATTR amyloidosis patients on either commercial product or in a development program with an investigational RNAi therapeutic. All-in-all, we believe that this provides significant opportunity for patient impact and allows Alnylam to achieve sustained and continued growth with potential value creation for shareholders.

Now, beyond ONPATTRO and Vutrisiran, we're also advancing a large number of additional programs, building what we believe to be the foundation for yet further patient impact and company growth. In particular, we believe that we're positioned, assuming positive study results, to have essentially annual launches of innovative medicines over the next several years including Givosiran and Lumasiran, where we have global rights, and then Inclisiran and Fitusiran, which are being advanced by our partners.

And beyond these Phase 3 programs that are nearing potential commercialization, we have a rich pipeline of yet additional programs and clinical [inaudible] clinical development. Altogether, we believe that this is a compelling profile for potential value creation very much in line with our Alnylam 2020 goal of becoming a multiproduct commercial biopharma company with a deep clinical pipeline fueled by a robust discovery engine for sustainable innovation, a profile rarely achieved in the biotech industry.

So, with that, I'll turn it over to Akshay now to review our latest pipeline progress in more detail. Akshay?

Akshay Vaishnaw -- President, Research and Development

Thanks, John, and good afternoon, everyone. Let me start with patisiran, which is the nonbranded name for ONPATTRO. We announced last month our plan to pursue potential expansion of the ONPATTRO label to include hereditary and wild-type ATTR cardiomyopathy. As you know, last September, we were pleased to have exploratory cardiac endpoint data following the APOLLO Phase 3 study published in the journal circulation. This data highlighted the potential for patisiran that favorably impacts certain cardiac manifestations of hATTR amyloidosis and support continued evaluation through clinical research.

These encouraging exploratory cardiac data have led us to now reach alignment with FDA in a new study, APOLLO-B, which is designed as a randomized, double-blind, placebo-controlled study of ONPATTRO with 6-minute walk distance as the primary endpoint after 12 months. APOLLO-B is expected to enroll about 300 patients with either wild-type or inherited ATTR amyloidosis with cardiomyopathy including patients who either naïve to TTR stabilizers or who are progressing while receiving TTR stabilizers. We expect this study to start in the middle of this year, and if positive, we believe it will support an expanded label for ONPATTRO in the '21 to '22 timeframe.

As you know, we're also advancing Vutrisiran as a potentially best-in-class therapeutic for ATTR amyloidosis. Vutrisiran is our investigational subcutaneously delivered TTR lowering agent. We believe that a once-quarterly low-dose, low-volume subcutaneous injection can achieve an approximately 90% knock-down of TTR and is generally well tolerated, could be a very effective option for patients.

Late last year, we initiated the HELIOS-A Phase 3 study of Vutrisiran in hATTR patients with polyneuropathy. It's an open-label study where we're looking at neurological impairment and quality of life at nine months and comparing the results in Vutrisiran-treated patients to the placebo arm of the APOLLO study. This innovative study design is aimed at bringing Vutrisiran to the market as rapidly as possible.

Later in 2019, we also plan to initiate an outcome study for Vutrisiran which will be called HELIOS-B. If successful, we believe HELIOS-B will facilitate Vutrisiran's entry into the significant and growing wild-type ATTR market opportunity.

Let's move on to Givosiran, an investigational RNAi therapeutic in development for the treatment of acute hepatic porphyrias. We're now just about a month away from reporting topline results from the ENVISION Phase 3 study, and we're very excited to soon see these important results from the first ever Phase 3 study of a GalNAc conjugator of siRNA.

As a reminder, patients with porphyria have enormous disease burden and can suffer from frequent life-threatening porphyria attacks, often requiring hospitalization. This is a frail population with significant underlying disease manifestations and complications from therapy including an iron overload from chronic hematin administration. Recurrent attack porphyria patients also exhibit neuropathy with chronic pain, fatigue, and also liver disfunction, and renal disease. Clearly, there's a very high unmet need for new therapies to help these patients.

The ENVISION study overenrolled with 94 porphyria patients and also enrolled much more rapidly than we had a reason to expect it. Topline results to be reported next month will include data on the primary endpoint of annualized attack rate and safety. Both study results are expected to be presented in an oral presentation at the European Society for the Study of the Liver, or EASL, on the morning of Saturday, April 13th in Vienna. If the study results are positive, we plan to complete our rolling NDA permission in the middle of this year, which could support an approval for Givosiran in late 2019-early 2020. We also expect to open a global EAP to make Givosiran available to patients prior to regulatory approvals and reimbursement decisions.

In the meanwhile, we're extremely pleased just yesterday that the New England Journal of Medicine published results from our Phase 1 study of Givosiran, and we believe this publication in such a highly esteemed peer-reviewed journal reflects the enormous potential of Givosiran to transform the lives of patients with acute hepatic porphyria. We're proud that this is now the sixth New England Journal paper to describe clinical results for an RNAi therapeutic coming from our scientists, clinicians, and collaborators.

I will now turn to recent progress with Lumasiran, an RNAi therapeutic we're developing for Primary Hyperoxaluria Type 1, or PH1. Based on very promising Phase 1 and 2 study results, we were pleased to initiate the ILLUMINATE-A Phase 3 study last year. This is a randomized, double-blind, placebo-controlled study in approximately 50 patients with PH1. Primary endpoint in this study is the reduction of urinary oxalate at six months relative to baseline in the Lumasiran group relative to placebo.

We expect to report topline results from ILLUMINATE-A in late 2019, and if positive, to submit regulatory filings beginning in early 2020. In addition to the scheduled file, we intend to initiate in mid-2019 both the ILLUMINATE-B study in patients less than six years of age with preserved renal functions and ILLUMINATE-C study in patients with more severe renal impairment.

Outside of the four Phase 3 programs I just highlighted, we have two additional programs currently in Phase 3 trials. Vutrisiran in development for the treatment of hemophilia is being advanced by our partner Sanofi in the ATLAS Phase-3 program. Inclisiran in development for hypercholesterolemia is being advanced by our partner at The Medicines Company in the ORION Phase 3 program.

Finally, one area that we're especially excited about is the progress that we've made at Alnylam in the delivery of our RNAi therapeutics to the central nervous system and the eye. This opens up an exciting new landscape of disease opportunities that we can pursue by leveraging our RNAi therapeutics platform.

And with that, I'll turn it over to Barry to review our commercial and med affairs progress. Barry?

Barry Greene -- President

Thanks, Akshay. As John said, we're extremely pleased with the supply chain commercial and medical affairs capability we've built and our progress on the ONPATTRO launch. In terms of our commercial performance, as you've read, we've achieved $12.1 million in global net revenues for ONPATTRO in Q4 and $12.5 million for the full-year 2018. We're very pleased that as of year-end 2018, we had over 200 patients on commercial ONPATTRO worldwide. Now, if you include patients receiving patisiran in our clinical studies and our expanded access program, we had about 550 patients receiving the drug as of year-end 2018, representing the future pool of patients that we expect over time to come onto commercial ONPATTRO.

To get some additional color on market dynamics in the United States, we can look at Start Forms that we've received in our Alnylam Assist patient hub. As a reminder, our U.S. Start Forms represent most but not all of our U.S. patient demand since many patients also receive ONPATTRO outside of Alnylam Assist via supply through our distribution channel.

From launch through year-end 2018, we received 250 Start Forms. We were very pleased to see that we're now getting a growing number of Start Forms from patients who did not participate in the Expanded Access program. We're also very pleased to see that we have a mix of physician prescribers for ONPATTRO, including neurologists, cardiologists, hematologists, and other specialties. We truly speak to the multisystemic nature of hATTR amyloidosis.

In terms of the payer mix, approximate 62% of Start Forms, as we expected, in the United States are from patients covered by Medicare, while approximately 32% were from patients covered by commercial insurers. Importantly, we have not encountered significant headwinds on reimbursement for ONPATTRO in the U.S. In fact, we currently have patients on commercial drug from each one of the top five U.S. payers. We also are making solid progress on value-based agreements, or VBAs, and expect to have around 90% of commercial patients covered by VBAs.

Now, let me turn to the E.U. where we've also made good progress advancing pricing and reimbursement procedures with authorities in 15 countries across Europe, together representing the vast majority of hATTR amyloidosis patients with polyneuropathy in Europe. Recent examples of our progress include positive technology assessment reports from authorities in Germany and Sweden, the special innovation designation of ONPATTRO by Italian authorities, and favorable reimbursement alignment with authorities in the Netherlands.

On the medical affairs front, one of the biggest challenges in this rare disease is raising awareness and improving diagnosis of hATTR amyloidosis with polyneuropathy. As we've highlighted previously, our Alnylam program is a third-party genetic screening initiative aimed as facilitating improved diagnosis of patients suspected of having hATTR amyloidosis. As of February 6th, more than 10,900 samples have been submitted out of which 726 have tested positive for a pathogenic TTR mutation. We've also seen success with our patient advocacy initiatives as well as our digital disease awareness campaigns.

As we've discussed previously, another potential driver of improved diagnosis is the availability of new therapies. Post launch, we're hearing many anecdotal stories from patients and their physicians about their positive experience with ONPATTRO. We believe these positive patient and positive physician experiences will contribute to raising awareness, improving diagnosis, and supporting earlier treatment of hATTR amyloidosis patients with polyneuropathy.

With that in mind, we've launched a new promotional campaign that highlights ONPATTRO's ability to reverse the polyneuropathy manifestations of ATTR amyloidosis, as demonstrated in addition to other benefits in the APOLLO Phase 3 study. We believe this effort will help highlight the clinical benefits and unique characteristics of ONPATTRO.

I'll now turn the call over to Manmeet to review our fourth quarter and full year performance. Manmeet?

Manmeet Soni -- Chief Financial Officer

Thanks, Barry, and good afternoon, everyone. Please refer to our press release issued earlier today for a summary of our financial reserves for the fourth quarter and full year 2018. Let me start with our cash balance.

We maintained a solid balance sheet ending 2018 with approximately $1.13 billion in cash, cash equivalents, marketable debt securities, and restricted investments excluding equity securities. Following our noted and public offering last month, we currently have a pro forma cash balance of approximately $1.5 billion.

Moving now to our revenues, we recorded $12.1 million of ONPATTRO net product total revenue during the fourth quarter of 2018 and $12.5 million since the middle of August U.S. launch date through the end of the year. As expected, our gross-to-net discount in the U.S. was approximately 23% mostly delivered to mandatory discounts for 340(b) entities and reserve for Medicaid patients. Also, as expected, our gross-to-net in the E.U. was generally higher than in the U.S. We will continue to update on our expected gross-to-net discounts as we profit with the launch of ONPATTRO and actual payer mix.

Cost of goods sold were $1.8 million for the full year, which equates to approximately 14.5% as a percentage of net product revenues. In the long run, we expect normalized cost of good sold to be in the mid- to high-teens as a percentage of ONPATTRO product revenues, including all of these paid to third parties.

Moving to other operating costs and expenses, I will refer you to our full year 2018 results. GAAP R&D expenses were $505.4 million for the full year 2018 as compared to $390.6 million for the prior year. Non-GAAP R&D expenses were $424.9 million as compared to $338.8 million for the prior year. This lies in the lower-end range of our non-GAAP R&D guidance of $420 million to $460 million. The increase in non-GAAP R&D expenses was due to increased compensation and related expenses as a result of increased manufacturing expenses associated with our late-stage programs and increased headcounts during the period as we continued to expand and advance our development pipeline.

Turning to SG&A, GAAP SG&A expenses were $382.4 million as compared to $199.4 million for the prior year. Non-GAAP SG&A expenses were $305 million as compared to $158 million for 2017. We ended within the midpoint of our non-GAAP SG&A expense guidance range of $280 million to $320 million for 2018. The increase in non-GAAP SG&A expenses was due primarily to an increase in commercial and medical affairs headcount and commercial related services to support corporate growth and the launch of ONPATTRO in 2018 and potential additional country launches of ONPATTRO in 2019. Non-GAAP SG&A expenses also exclude stock-based compensation expense.

With respect to guidance for 2019, we expect our annual non-GAAP R&D expenses will range between $520 million and $560 million and annual non-GAAP SG&A expenses will range between $390 million and $420 million. We expect that our current cash, cash equivalence, and marketable debt securities will support company operations for approximately two years based upon our current operating plan.

As of now, we will not be providing any new guidance for 2019. We will continue to evaluate the possibility of providing guidance once we have better visibility on the ramp of the launch, market data mix, and key metrics over the next several quarters.

I will now hand it back to John to review our 2019 goals. John?

John Maraganore -- Chief Executive Officer

Thanks, Manmeet. As I mentioned earlier, 2018 was a landmark year for Alnylam, and we envision 2019 shaping up to be equally transformative. Overall, we're executing on six Phase 3 programs, expect to report three Phase 3 data readouts, and if positive, expect to file two NDAs.

More specifically, starting with ONPATTRO while we continue our global commercial execution, we'll also be planning to initiate our APOLLO-B Phase 3 study in mid-2019, which is aimed at supporting a potential expansion of the ONPATTRO label to include both hereditary and wild-type cardiomyopathy.

With Vutrisiran, we plan to enroll the HELIOS-A Phase 3 study throughout the course of the year and initiate our HELIOS-B outcome study in late 2019.

Moving to Givosiran, as Akshay highlighted, we expect to report topline results from the ENVISION Phase 3 study very, very soon in March, and of course, if the results are positive, we'll plan on completing our rolling NDA submission as well as filing an MAA in mid-2019.

With Lumasiran, we expect to complete enrollment in the ILLUMINATE-A study in the middle of the year and to report topline results from that study in late 2019.

With Inclisiran, our partners at The Medicines Company have guided to have topline results from the ORION-9, 10, and 11 studies in mid and late 2019, and assuming positive data to submit an NDA for Inclisiran by the end of the year.

Of course, we'll also continue advancing the rest of our pipeline as well as exciting preclinical efforts, and we'll highlight those milestones throughout the course of the year as they occur.

So with that, let me now turn the call back to Christine to coordinate our Q&A session. Christine?

Christine Lindenboom -- Vice President, Investor Relations and Corporate Communications

Thank you, John.

...

Operator, we are ready to 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 have additional questions.

Questions and Answers:

Operator

Yes, ma'am. Thank you. If you would like to ask a question, please signal by pressing *1 on your telephone keypad. If you are using a speakerphone, please make sure that your mute function is turned off to allow your signal to reach our equipment. Again, that is *1 to ask a question, and our fist question will come from Paul Matteis with Stifel.

Paul Matteis -- Stifel Financial Corp -- Managing Director

Thanks so much and congrats on all the progress. One question for Barry. Barry, I was wondering if you could comment on the time to get drugs that you're seeing in the channel for patients starting ONPATTRO, what the trajectory looks like and how this has been changing at all with your progress on reimbursement? Thanks.

John Maraganore -- Chief Executive Officer

Barry, go ahead.

Barry Greene -- President

Paul, great question. So, as we highlighted on previous calls, our intention is to get the time from many, many weeks to only a couple weeks, and we're seeing progress. We have examples now of a Start Form coming in and patients literally getting on drug in a couple weeks. It does depend on where they're being infused, what the insurance looks like, but those times are coming way down, and we're really excited about the progress we're making.

Operator

All right, thank you. Our next question will come from Alan Carr with the Needham Company.

Alan Carr -- Needham & Company -- Senior Analyst

Hi. Thanks for taking my questions. Wondering if you can talk about how things are going for ONPATTRO U.S. versus Europe. What's your expectations for the relative ramps between those two over the course of this year into next year?

John Maraganore -- Chief Executive Officer

That's a great question, Alan. Barry, you want to handle that?

Barry Greene -- President

So, Alan, we're not really giving a breakdown of guidance, as you're aware. We launched immediately in the United States after the August 10th approval. We had boots on the ground that Monday, and we had drugs ready to be shipped within 48 hours as we committed, and we've highlighted how well the overall launch is going. Europe's quite different because in certain countries like Germany, we can launch immediately. Other countries require us to work through the Health Technology Assessment process before naming our price and getting paid for it, so we're in the process, as highlighted in the call, of working through that in 15 different countries. And getting the right access by country will really determine the launch order and then how the trajectory in Europe progresses. But we're happy with the progress so far in Europe in what we're seeing.

John Maraganore -- Chief Executive Officer

I'll just add, Alan, that from our perspective, Europe is showing itself strong at this point and that there's strong patient demand, there's very strong KOL awareness with ONPATTRO and obviously the features that they've seen in the clinical studies, and that helps a lot in that effort.

Operator

All right, thank you. Our next question will come from Maury Raycroft with Jefferies.

Mitchell -- Jefferies, LLC -- Analyst

Hi, this is Mitchell on for Maury. Thank you for taking our question. For at-home infusion of ONPATTRO, how many patients have access? Are doctors providing the option to all patients? Can you walk us through how cost and reimbursement factor into this service?

John Maraganore -- Chief Executive Officer

Thanks, Mitchell. Barry, you wanna handle it?

Barry Greene -- President

So, in the United States and then in many countries in Europe, home infusion is immediately available. Obviously, in certain European countries, it's all paid for or mostly paid for and taken care of by the country as single payers. In the United States, home infusion is available to all the commercial plans right now, and it's offered by all the commercial plans. It is something that the physician talks to the patient about and is offered. For new patients, the physician is telling us they typically like to see the patient once or twice at their institution and infusion to check the patient out, and after that, happy to move to home infusion. It's interesting that, and we highlighted this at the J.P. Morgan conference, only about 25% of the patients on commercial drug have chosen home infusion. And in fact, what we hear in market research from patients is they're actually enjoying their infusion experiences. They've met people they enjoy, they meet other patients, their nurses, and they're actually enjoying the infusion experience, which is a pleasant surprise for us.

Mitchell -- Jefferies, LLC -- Analyst

Thank you.

John Maraganore -- Chief Executive Officer

Operator

All right, thank you. Our next question will come from Alethia Young with Cantor Fitzgerald.

Emma -- Cantor Fitzgerald -- Analyst

Hi, this is Emma on for Alethia. Are you seeing any patients switch from cemdis in some of these markets? I'm just wondering what you expect that dynamic to look like as the launch progresses.

John Maraganore -- Chief Executive Officer

That's a good question, Emma. Barry, do you wanna handle that?

Barry Greene -- President

So, we have to look at the United States differently than in many of the countries in Europe. As you know, the Phase 3 study in polyneuropathy missed the endpoint, was not approved in the United States, but given the endemic nature of the disease was approved in Europe and other countries around the world, so it's been used for multiple years. As we also know, again, and the fact of polyneuropathy is many physicians report significant progression in as little as six months in published literature on tafamidis, so they dynamic outside the United States is in fact patients looking for progression in patients, and when appropriate, assuming an on-label patient, switching them to ONPATTRO. We are seeing that dynamic and do anticipate more of that. Obviously, the whole dynamic in the United States is something we'll see in the future as tafamidis hits the U.S. market with different labeling.

John Maraganore -- Chief Executive Officer

I'll just add, Emma, or remind you that in our APOLLO Phase 3 study, about 50% of patients had previously been on a stabilizer, and many of those patients chose to come onto a randomized placebo-controlled study because they'd had either progressed on the stabilizer or they wanted to participate in the availability of a TTR silencer like patisiran, so that's an important and useful data point if you just look at our clinical trial experience alone.

Emma -- Cantor Fitzgerald -- Analyst

Great. And then are you able to provide any color on the pricing band from [inaudible] in Europe as you're going through some of these reimbursement discussion?

John Maraganore -- Chief Executive Officer

I missed your question there, Emma. Can you repeat that?

Emma -- Cantor Fitzgerald -- Analyst

On the pricing band in Europe.

John Maraganore -- Chief Executive Officer

Barry, you wanna comment on that?

Barry Greene -- President

As we've commented on previously, on a global basis, the per vial price, we're gonna keep it a very, very tight level.

Emma -- Cantor Fitzgerald -- Analyst

Thank you.

Operator

All right, thank you.

John Maraganore -- Chief Executive Officer

All right, thanks, Emma.

Operator

Our next question with come from Ritu Baral with Cowen.

Ritu Baral -- Cowen and Company -- Managing Director, Senior Biotechnology Analyst

Hi, guys. Thanks for taking the question. Apologies for the noise. I have a question that's really about APOLLO-B. Can you walk us through some of the design elements and the assumptions like [inaudible] how many wild-type patients you were expecting and potential timing around that, both enrollment and date?

John Maraganore -- Chief Executive Officer

Terrific. Akshay?

Akshay Vaishnaw -- President, Research and Development

Hi. So, in terms of the length of the study, as you know from the original APOLLO study that at the nine-month endpoint, all the critical endpoints here, and so we're very confident that the 12-month time point is a suitable time point for 6-minute walk distance. We also know from the attack study that 6-minute walk distance has been fairly separated at significantly earlier than 12 months of tafamidis. So, clearly, this is a significant clinically relevant endpoint that is amenable to change at an earlier time point than potentially other endpoint if there's mortality or hospitalization. So, that was the rationale behind that. Now, with respect to the split between wild-type and mutant, obviously, there are many more wild-type patients than there are hereditary TTR patients, so I think the majority of the study would be filled with wild-type patients. Hard to say how much right now. Again, historical experience mostly [audio cuts out] three-quarters might be wild-type, but that's a speculation on my part at the moment. And then finally, with respect to [audio cuts out] the timing, with respect to the initiation of the study coming up, it's hard to comment on the exact timeline quite clearly, but as we have suggested, we anticipate approval in the '21 to '22 time frame, and we feel that [audio cuts out] consistent with that.

Ritu Baral -- Cowen and Company -- Managing Director, Senior Biotechnology Analyst

Great. Thanks.

John Maraganore -- Chief Executive Officer

And Ritu, if you can go on mute because you've got a lot of background noise. Thank you.

Operator

Thank you. And we have a question from Anupam Rama with J.P. Morgan.

Matt -- J.P. Morgan -- Analyst

Hey, guys. Thanks so much for taking the question. This is Matt on for Anupam. One for you, Barry. Just wondering about the ONPATTRO value-based agreements. How long do you anticipate it taking to get the remainder of those in place to get that 90% of commercialized covered? And then what does one of those agreements typically look like? Thanks so much.

John Maraganore -- Chief Executive Officer

Barry?

Barry Greene -- President

Thanks. So, as you know, part of our patient access philosophy was to proactively offer value-based agreements, and that strategy has proven incredibly useful in opening a dialogue with payers, and as we talked about in the call, even outside of finalizing value-based agreements, we're really not hitting the payer headwinds, so the partnership with the payers to try to find and treat their patients has been really spectacular and they've really stepped up on medical policies to really help educate and ensure that patients have access, so I give the payer community a lot of credit on the partnership we've seen. In terms of the value-based agreements we've highlighted, we've got three complete, and we anticipated by the end of the year having about 90% of patients covered by VBAs. It's hard to name timeframes because of the back and forth between the different back office folks to finalize the letter of the VBAs, but the conversations are going well, and I'd say it's a sort of end-of-year goal to have 90% of all the patients covered. It's important to note that even without the VBA in place, as I said, we are having great dialogue with payers and really not running into reimbursement issues with patients at this point.

Matt -- J.P. Morgan -- Analyst

Got it. Appreciate that.

Operator

All right, thank you. Our next question will come from Dave Lebowitz with Morgan Stanley.

David Lebowitz -- Morgan Stanley -- Senior Research Analyst, Biotechnology

Thank you very much for taking my question. How are you going to manage with the HELIOS-B and APOLLO-B trials starting later this year? Are they gonna be completely overlapping populations? Are they going to be at the same sites? Are you gonna manage those two groups?

John Maraganore -- Chief Executive Officer

That's a great question, David. Akshay, you wanna comment a little bit on APOLLO-B and HELIOS-B?

Akshay Vaishnaw -- President, Research and Development

There's certainly going to be some overlap between the study populations from those two protocols that involve patients with wild-type and hereditary TTR cardiomyopathy, but the situation is, what should I say, mitigated by several important factors. Firstly, there are a very significant number of wild-type patients that are currently on no treatment at all. Many of them, despite the potential approval of tafamidis in months to come may be in a territory where tafamidis may not be available or some other therapy may not be available for them. The availability of patients with hereditary TTR similarly varies by territory, and so between the need to do a robust study that encompasses a range of mutations and geographies that satisfies the regulators, the availability of the various drugs ended up being recently approved or about to be approved. We're confident that we can ensure enrollment without competing between the studies or competing between other goals in the company.

David Lebowitz -- Morgan Stanley -- Senior Research Analyst, Biotechnology

Thanks for taking my question.

John Maraganore -- Chief Executive Officer

Thanks, David.

Operator

All right, our next question comes from Gena Wang with Barclays.

Gena Wang -- Barclays Capital, Inc. -- Analyst

Thank you for taking my questions. One quick one regarding the 726 patients that a positive TTR mutation identified through Alnylam Act. Just wondering how many of these patients are addressable for ONPATTRO?

John Maraganore -- Chief Executive Officer

That's a great question, Gena. I mean, at a high level, we don't now because we don't have specific details on these patients. This is a service that we're providing for the medical community, and it's to help patients basically be able to get diagnosis. And so, we don't have any information about anything more specifically about those patients as a result. Barry, anything else to add?

Barry Greene -- President

No, you got it. As John said, this is a service that we offer for the benefit of patients to help improve overall diagnosis. The fact that we're seeing so many pathogenic hits demonstrates a major unmet need and a patient benefit. I will add that Alnylam Act doesn't represent all the genetic testing that's being done. There are other free genetic testing offered by other companies, and now that we have commercial drugs, many physicians are choosing to use commercial insurance to pay for genetic tests. So, we're delighted that genetic testing is being so well-amplified out in the community, representing the unmet need and the need to help find these patients with the genetic testing.

Gena Wang -- Barclays Capital, Inc. -- Analyst

Thank you.

Operator

Thank you. Our next question comes from Whitney Ijem with Guggenheim.

Whitney Ijem -- Guggenheim Partners -- Director, Senior Biotechnology Analyst

Hey, guys. Thanks for taking the questions. One on Givosiran headed into the Phase 3 data. I guess can you remind us, first of all, for the 1,000 and 5,000 patient numbers you talk about for recurrent and sporadic, are those based on identified or diagnosed patients, or is that an epidemiologic estimate? And then in terms of use of Givo on the two different populations, how do you think about that and what are, I guess, some of the endpoints in the Phase 3 data that we should look for to help us get a better sense of that?

John Maraganore -- Chief Executive Officer

Those are two great questions. Maybe, Barry, you can start with the epi, and then, Akshay, you can cover the second question on the data that we should look for to cover both sides? Go ahead.

Barry Greene -- President

The numbers that we quoted, the 1,000 and 5,000 are based on bums in seats, if you will. These are patients that the porphyria network believes they had in their coverage universe, and then we triangulate that at the various centers. The epidemiology represents much, much greater numbers, but of course, we don't all fully yet understand the penetrance. So, we feel pretty good about that. The other thing to keep in mind is that the attack rates are a way that we've been able to do a clinical study. As we move forward with data commercially, we're gonna look more at the severity of patients. The patient that may only have one attack, if I can say it that way, a year can be even more disabled than patients that have more attacks because of the severity of attack. So, we're gonna look at severity of patients and the overall manifestation of disease, and of course, the detailed readout of our data will help us understand just how many patients we may be able to benefit.

John Maraganore -- Chief Executive Officer

And so, Akshay, on the clinical studies question?

Akshay Vaishnaw -- President, Research and Development

So, I think they key aspect here is that we know that by targeting ALAS1, we are downregulating the key mediators of the acute hepatic porphyrias, namely aminolevulinic acid and porphobilinogen, or ALA and PBG. And it was the relationship between the levels of ALA and PBG in the previous position to attack that really convinced the FDA to allow us to proceed with the study and even encourage us to do the interim analysis that we did looking at those biomarkers. Now, whether you have 10 attacks a year or 20 attacks a year, and of course, there are patients who suffer greatly with that kind of frequency, or whether you have two attacks a year, which in and of itself is not trivial, those attacks are ameliorated by ALA and PBG. So, I think if the Phase 3 study reads out and convincingly shows consistent and durable reductions in ALA and PBG, which is what we anticipate based on the interim analysis, and these are indeed endpoints in the study, then that bodes well for very frequent attack patients or even those with more sporadic attacks. And let's recall that these patients suffer greatly not just from the acute attacks but even the symptomatology between attacks, and our hope, and we're gonna be measuring this with nausea, and fatigue, and pain scales, our hope is those inter-attack symptoms will also abate or reduce. Let's look at the data when they come out, but if they do, then again, that bodes well for patients that don't have the horrific 10-20 attacks a year but maybe have two or three because they too need help, and we believe this drug should help them.

Operator

All right, thank you. Our next question will come from Manny [inaudible] with SVB Leerink.

Manny -- SVB Leerink -- Analyst

Thanks for taking my question. I've got a quick one for Manmeet. So, regarding the two years of runway to operating plan, I'm scratching a little bit on what's baked into that plan because you've got a number of pivotal readouts, a number of launches. What is baked in in terms of potential expense to build up commercial infrastructure around Vutrisiran, to address the APOLLO-B population, the HELIOS population, and any additional incremental R&D buildout for assets that come out of the CNS liver off the portfolio? Then I have a quick follow up.

Manmeet Soni -- Chief Financial Officer

So, Manny, if you refer to our guidance on R&D, which we gave this optimum for $520 million to $560 million range, that covers all of the Phase 3 trials that are ongoing and the initial plan for building up inventory even for Givosiran. So, all of that is included into our guidance for 2019.

Manny -- SVB Leerink -- Analyst

And as a quick follow-up, should we think about the growth in the stock-based component of comp as approximately in line with the percentage year-over-year growth in non-GAAP R&D expense, non-GAAP SG&A expense? Is it approximately in line, and how should we think about any potential chunkiness around events this year?

Manmeet Soni -- Chief Financial Officer

I think that's the reason we are not able to guide our GAAP expenses and give [inaudible] measure to guide our non-GAAP expenses because it's very difficult to estimate your stock-based compensation expense realizing that some of our stock-base are dependent upon performance milestones. It depends on a couple other factors. But to highlight or to answer your question simply, you should expect pretty much end-range what we had in 2018 as our stock-base compensation for 2019. You should not expect a huge jump from here.

John Maraganore -- Chief Executive Officer

And Barry, you have any other comment?

Barry Greene -- President

Well, just to give some color here, Manmeet very well answered the R&D expenses and the fact that the expenses were baked in for the Phase 3s we had planned in the time horizon. In terms of preparation for launch of Givosiran, the capabilities that we built across supply chain medical affairs and commercial are all leverageable for the Givosiran launch, so very little has to be added in that respect. We will be adding additional customer-facing roles, but as a percent of our overall population base, that's a pretty small add to prepare for Givosiran.

John Maraganore -- Chief Executive Officer

And I mean, just to take it one step further, Manny, you mentioned our CNS and ocular investments as well. I mean, those are very small through the approximately two-year period of our cash balance in light of the fact that they'll be just starting clinical studies during that period of time, so that's not really a major part of the expense, but it is an area that we are advancing with strong focus.

Manny -- SVB Leerink -- Analyst

Great. Thanks, guys. That's really helpful. I've already asked two, so I'll hop back in the queue.

John Maraganore -- Chief Executive Officer

Great. Thank you.

Operator

All right, thank you. Again, to ask a question, please press *1. And our next question will come from Vincent Chen with Bernstein.

Vincent Chen -- Bernstein Research -- Senior Analyst, Small- and Mid-Cap Biotechnology

Great. Thank you very much for taking our question. Thinking toward the Givosiran readouts and trying to better understand the potential likelihood for additional liver function test elevations, could you help us better understand the typical characteristics of the LFT elevations you've seen to date with the siRNAs, both the one in the ENVISION study and also those in other programs which are thought to be attributed to a similar mechanism? I guess for example, when in the course of treatment do LFT elevations typically occur? Are these events that typically occur fairly early on in the course of treatment for a given patient or can they occur at various points [inaudible] throughout the course of treatment? And as you think about this right now, is this likely to be a one-time, highly rare event with Givosiran, or would you expect this is likely something where some minority of patients will have some sort of a response like this and those patients simply won't be amenable to Givosiran treatment, which is fine?

John Maraganore -- Chief Executive Officer

Vince, so thank you. Akshay?

Akshay Vaishnaw -- President, Research and Development

Thank you, Vincent, for the tripartite question. Turning first to the LFTs, I would say that it's not typical of the platform given that as we have been across the platform and reported about 2% to 4% of the patients may get LFT changes, and there very rather characteristically appear to be bumps in ALT, which are transient and reversible, not [inaudible] of course as is important to note, and when they do come on in that minority of patients, they tend to come on I would say within weeks or months of the initiation of the RNAi therapeutic. Now, we have plenty of examples of RNAi therapeutics that we put into clinic where we've had no significant LFT changes at all, and I think in that regard, the Inclisiran experience being reported by The Medicines Company is very important to note where over 3,000 patients I believe have been exposed to Inclisiran now, many of them for over a year. And as you've heard from them at J.P. Morgan, their last DFM being met and guided that they should take the significant Phase 3 studies, three of them, to completion, and that at that point, there appear to be no significant safety concerns including with respect to LFTs. So, I think that's a very stringent test of one of our drugs in a very large population, many of the patients being elderly and fragile. The last question of why this might happen and what we can do to attenuate it, if I interpreted your question properly, let's also remember that the LFTs that were reported often occur in patients that may be predisposed for one or more reasons. For example, in the context of porphyria, many of these patients have significant iron overload from hematin treatment, and in what way that may synergize with treatment or may in and of itself be causing [audio cuts out] disease predisposition's important and it causing the Fitusiran experience, we reported many of those patients are Hepatitis B, or rather Hepatitis C, as a background risk factor. So, as usual, it's complicated, but it seems to be a low [inaudible] event, transient reversible, and the couple of INDs we filed recently with ATO-2 and HPBO-2 are investigating the impact of this rather elegant DNA modification, the seed sequence to see whether we could attenuate off-target effects and thereby abrogate LFT changes, and so those are the interesting studies to follow this year. But overall, we're optimistic about the Givosiran outcome and the overall risk benefit I still think will be very much in favor of the drug [audio cuts out].

John Maraganore -- Chief Executive Officer

And I would just add, Vincent, that as a reminder, at the time of the interim analysis, there was only one discontinuation from study, and we'll obviously update you on the full results. That was at 50% of the enrollment. We'll update you with the full results in the coming weeks, and we'll just wait until then, but I concur with Akshay's comments on this as well.

Vincent Chen -- Bernstein Research -- Senior Analyst, Small- and Mid-Cap Biotechnology

Thank you very much.

John Maraganore -- Chief Executive Officer

Thank you.

Operator

Thanks. Next question comes from [audio cuts out] at Piper Jaffray.

John Maraganore -- Chief Executive Officer

Hello?

Operator

[Audio cuts out] just make sure you're not [audio cuts out].

Edward Tenthoff -- Piper Jaffray -- Managing Director, Senior Research Analyst

Thank you very much and-sorry, thanks. Thanks too for taking my question later in the call. Nice update. Two questions, if I may. Firstly, when it comes to tafamidis coming into market in cardiomyopathy, how would you guys detail ONPATTRO in those mixed patients? Do you get a sense that doc may be leaning more toward treating the cardiomyopathy? Do you think it'll be a situation where whichever manifestation is more prevalent? Do you think some patients may even get both? I mean, how are you guys thinking about tafamidis, certainly not in the polyneuropathy basins, but in those mixed where they do have the cardiac involvement? Thanks.

John Maraganore -- Chief Executive Officer

Ted, that's a great question. I'm gonna let Barry answer it, but I just need to remind you before Barry answers it, we are obviously not gonna get into any details around strategy because that is competitive, so I think, Barry, maybe you can make some high level comments on this without getting into any details.

Barry Greene -- President

Ted, I would've said the best defense is a good offence, but maybe the Super Bowl was different in that. Look, we are out there in the United States promoting on-label, which is that's approved to treat the polyneuropathy of hereditary TTR amyloidosis patients. Now, we are educating disease awareness broadly across multiple disciplines, and as you've seen, we have an interesting uptake with cardiology hematology representing the multisystem nature of the disease. So, very simply, if a patient is an on-label patient, we believe, recognizing that we have not done head-to-head studies that our on-label patients with polyneuropathy, we have the best drug for those patients based upon the APOLLO data and the lack of the polyneuropathy data for others, and that's sort of our approach is to make sure that on-label patients get an opportunity to get ONPATTRO. And what we're hearing, as I highlighted in the call, early and commercial launch is, and this isn't certainly every patient, but good patient stories and good physician experiences. And as you know, positive physician experiences often drive choice.

Edward Tenthoff -- Piper Jaffray -- Managing Director, Senior Research Analyst

Yes. And then are you able to discuss the APOLLO cardiac data with U.S. and/or European physicians?

Barry Greene -- President

So, discuss. So, in a promotional context, our salespeople can only promote on-label. In the United States, those data are not on-label, so the answer's no. In Europe, depends on the country and what the country rules allow, but in general, those are on-label, so when asked, it can be engaged. Now, of course, in the context of medical information, if physicians are interested in talking about the data, they're certainly free to ask questions, and we have a variety of techniques for scientific exchange. They can ask for medical information requests, which come in letter, they can ask for some person to physically show up and talk to them, but those are reactive only upon physician request.

Edward Tenthoff -- Piper Jaffray -- Managing Director, Senior Research Analyst

I appreciate that. That's really clear. One last one, if I may, just because I really like the program. How are things going with our friends Vir and the HPV program? And thanks for all the questions.

John Maraganore -- Chief Executive Officer

It's going great. I saw George Scangos just a couple weeks ago, and he was excited with the progress they're making, the dose escalation is proceeding in the human volunteer study, and we will look forward to having data from that effort later this year. It's an important program. As a reminder, Ted, we have an opt-in, a free opt-in, at the end of Phase 2 to have 50% of the value of that program, so we have very strong economic incentive in the success of that effort, and we look forward to data readouts later this year from that.

Edward Tenthoff -- Piper Jaffray -- Managing Director, Senior Research Analyst

Awesome. All right, thanks, guys.

John Maraganore -- Chief Executive Officer

Thank you.

Operator

Thank you. Our next question will come from Paul Matteis with Stifel.

Paul Matteis -- Stifel Financial Corp -- Managing Director

Thanks for taking the follow-up. Just a couple quick ones on cemdisiran. I saw you announced a program in IgA nephropathy. I was wondering if you could talk about the clinical rationale there and the plan's study design? And then secondarily on that same aspect, I was wondering if myasthenia gravis is on your radar given that the data for Soliris in gMG definitely suggests a different biological role for C5 and maybe suggests that cemdisiran could potentially have a comparable profile? Thanks so much.

John Maraganore -- Chief Executive Officer

Paul, those are two great questions. I'm gonna turn it over to our resident complementologist Akshay to comment on both.

Akshay Vaishnaw -- President, Research and Development

Thanks, John. [Inaudible] for cemdisiran in IgA nephropathy is rather straightforward, in addition obviously to the significant unmet need that IgA nephropathy represents globally. It's the most common inflammatory [audio cuts out] there is resulting in renal failure, and so there's no question that these folks need help. Even though many of them get better by themselves, there are hundreds of thousands of others globally in totality that suffer significantly the quite real impairment or renal failure. The evidence for complement activation is clear, and you see local complement deposits in the [inaudible] including C3 deposits and split complement products there. And finally, it's unsurprising that the complement is part of the pathos physiology because the intergenic basis of the disease has been well worked out now. We know that it's due to an autoantibody complex depositing in the renal [inaudible] and these complexes activate complement. We know new complexes activate complements. We think that in common with other inflammatory renal disorders, the rationale for complement is strong, and so we've initiated this study. There's a running period to the study to understand what's going on in terms of complement turnover and renal function, and then they get those with cemdisiran for a period of time. We're doing all of this, Paul, as a prequel to expanding cemdisiran studies into border range of indications, and with the proof of concept we hope for [inaudible] will expand to [inaudible] which as you [inaudible] validate and setting for complement inhibition. So, I hope that address some of your question.

Paul Matteis -- Stifel Financial Corp -- Managing Director

Thanks. And on myasthenia gravis, any additional thoughts there?

Akshay Vaishnaw -- President, Research and Development

As to whether we'll initiate? Was that the...?

John Maraganore -- Chief Executive Officer

No. Paul, I think Akshay sort of wrapped it into the last part of his question which is simply to say that we're obviously interested in that indication, the validation of complement's role in that indication, not only in the [inaudible] I've experienced, but I also think the recent raw data in that regard holds encouraging results for that regard. And yes, we do believe that if this thesis plays out, that it will be of interest to test Cemdisiran in that setting, so we certainly have it on our radar, but there's no specific guidance that we're giving at this point in time.

Paul Matteis -- Stifel Financial Corp -- Managing Director

Fair enough. All right, thank you both so much. Appreciate it.

Operator

Thank you. And our last question will come from Terence Flynn with Goldman Sachs.

Terence Flynn -- Goldman Sachs Research -- Lead Analyst, Large Cap US Biotechnology

Hi. Thanks for taking the question. Sorry, I jumped on late, so apologies if this was already asked, but any insight you guys can share on the ONPATTRO Start Forms in January versus December? And if you can't answer that, maybe can you tell us in terms of Givosiran, just how much data will actually be in the topline press release in March ahead of the EASL conference? I'm not sure how strict they are about data disclosure. I just wanna understand how much data will actually get in the press release. Thank you.

John Maraganore -- Chief Executive Officer

Terence, this is John. Let me answer both of those questions. We unfortunately can't give you any color on January because we'll need to wait for our first quarter results. But again, we're pleased with how launch is going as we reported our fourth quarter, and we're pleased with how it's going, so that's point No. 1. Point No. 2 on what we expect to report on the topline, look, I think a good example of what we will topline is what we did with patisiran when the APOLLO data were out, which is a P-value, commentary on primaries and secondaries that hit without any data per se, and then enough safety information, certainly not tables of safety data, but enough safety information on relevant safety findings so that investors can understand the full balance of the data. So, if you looked at the patisiran topline that we did in 2017, that's a good example of a template that we would look to. If there's any other things that emerge that we feel without compromising our presentation of the full data at EASL, we'll consider, but I think that's what I would guide you to look at as a good metric. Akshay, anything else to add to that?

Akshay Vaishnaw -- President, Research and Development

I think that's good. Thank you.

Terence Flynn -- Goldman Sachs Research -- Lead Analyst, Large Cap US Biotechnology

Thanks a lot.

John Maraganore -- Chief Executive Officer

Well, good. All right, well, thank you. Thank you. So, with, I wanna thank everybody for joining us this late afternoon. We're excited about 2019 and the progress that we are expected to make and look forward to updating you very soon, especially on the upcoming Givosiran data from ENVISION, so stay tuned. Thank you, everybody.

...

Operator

Thank you, ladies and gentlemen. This concludes today's teleconference, and you may not disconnect.

Duration: 59 minutes

Call participants:

Christine Lindenboom -- Vice President, Investor Relations and Corporate Communications

John Maraganore -- Chief Executive Officer

Akshay Vaishnaw -- President, Research and Development

Barry Greene -- President

Manmeet Soni -- Chief Financial Officer

Paul Matteis -- Stifel Financial Corp -- Managing Director

Alan Carr -- Needham & Company -- Senior Analyst

Mitchell -- Jefferies, LLC -- Analyst

Emma -- Cantor Fitzgerald -- Analyst

Ritu Baral -- Cowen and Company -- Managing Director, Senior Biotechnology Analyst

Matt -- J.P. Morgan -- Analyst

David Lebowitz -- Morgan Stanley -- Senior Research Analyst, Biotechnology

Gena Wang -- Barclays Capital, Inc. -- Analyst

Whitney Ijem -- Guggenheim Partners -- Director, Senior Biotechnology Analyst

Manny -- SVB Leerink -- Analyst

Vincent Chen -- Bernstein Research -- Senior Analyst, Small- and Mid-Cap Biotechnology

Edward Tenthoff -- Piper Jaffray -- Managing Director, Senior Research Analyst

Terence Flynn -- Goldman Sachs Research -- Lead Analyst, Large Cap US Biotechnology

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