Alnylam Pharmaceuticals Inc

NASDAQ:ALNY

Earnings Call Transcript 2017-Q4

[Operator]

Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals Conference Call to discuss the Fourth Quarter and Year End 2017 Financial Results. [Operator Instructions] 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.

[Christine Lindenboom]

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, Executive Vice President of R&D; and Manmeet Soni, Chief Financial Officer; and Yvonne Greenstreet, Executive Vice President and Chief Operating Officer.

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 the recent clinical pipeline update, Manmeet will review our financials, Barry will provide an update on our commercial readiness efforts and Yvonne will provide 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 constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995.

Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent quarterly report on file with the SEC.

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 provides useful information to management and investors regarding our financial conditions and results of operations.

In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements.

With that, I will now turn the call over to John.

[John Maraganore, Chief Executive Officer]

Thanks, Christine, and thank you, everyone, for joining us this morning. The fourth quarter of 2017, a recent period, were marked by a number of notable milestones for RNAi, for Alnylam and for the patients we serve. In this period, we have come closer than ever to delivering on the promise of RNAi and have taken a big step towards fulfilling our Alnylam 2020 strategy of building a multi-product global commercial stage company with a deep and sustainable clinical pipeline and a robust product engine by the end of 2020

A company profile rarely achieved in biotech history. Indeed, we are now at a critical turning point in the Company's 15-year journey of bringing RNAi therapeutics to patients with a whole potential new class of innovative medicines.

To begin, I'd like to set the stage with some overall context. First, the big news for the quarter was our report of the positive results from our APOLLO Phase 3 trial of patisiran. Based on these results, we have now completed our regulatory filings with the U.S. and European Health Authorities, notably, in less than 90 days after the announcement of our top line results.

I am really proud of our team's execution on these filings, and this highlights Alnylam's sense of urgency and commitment to excellence that we believe will soon be manifest in our commercialization efforts. We also received a number of important regulatory designations for patisiran, including break-through therapy, priority review status as well as an expanded orphan drug designation for ATTR amyloidosis, all by the FDA, and then, accelerated assessment by the EMA and promising innovative medicine designation by the UK's MHRA.

We believe that all of these regulatory accolades reflect a very promising profile of patisiran seen in APOLLO and a very high unmet need in hATTR amyloidosis patients. The review process is now fully underway and we announced last week that we have a PDUFA date of August 11, although we expect an expedited review that could lead to an earlier approval.

We believe the APOLLO results highlight the potential impact of patisiran across the full spectrum of hATTR amyloidosis disease, and we believe that the results support a broad label for the product. Assuming regulatory approvals, we remain on track for commercial launch in the U.S. in mid-2018 and in Europe in late 2018.

The second point I wanted to cover in my introductory comments is that we're very pleased to have entered recently into a strategic restructuring of our Sanofi Alliance. As a part of the restructuring, we gave full control of our TTR programs, acquiring the rest of world rights to commercialize patisiran and global rights for ALN-TTRsc02, a very promising once quarterly subcutaneously administrator investigational RNAi therapeutic for ATTR amyloidosis.

With this restructuring, we're now gearing up for a Phase 3 start for TTRsc02 late in 2018 in a compressive program that is aimed at evaluating this promising agent across the broadest spectrum of ATTR amyloidosis disease, including patients with wild-type disease and asymptomatic hereditary ATTR carriers, all with the goal of realizing the fullest potential for Alnylam's leadership in this field

In turn, Sanofi will obtain global rights to patisiran in hemophilia. In light of their planned acquisition of Bioverativ, Sanofi appears destined to become a powerhouse in the highly competitive $10 billion hemophilia market. And we believe that this has the potential to significantly benefit commercialization efforts of patisiran when it reaches the market, which we would expect, potentially, in 2020.

Moreover, with 15% to 30% royalties on patisiran, we stand to benefit from their success, just as Sanofi stands to benefit from our success on our TTR programs. Now, a preparation for our global launch for patisiran, we plan on filing the Japanese NDA in mid-2018 and filing in one or more additional country by the end of the year.

Further, we have initiated a stage-build of global medical and commercial capabilities to expand our reach and ensure that patients and physicians are educated about the hATTR disease and the safety and efficacy profile of patisiran upon market approval. Barry will discuss some of this further later in the call.

The third point I'd like to make is that we also made important progress over the quarter and in the recent period with our other late stage clinical programs. Specifically, we initiated Phase 3 development for givosiran. Then, our partner at The Medicines Company has moved inclisiran into Phase 3 development. And then following successful removal of a clinical hold, we have reinitiated Phase 3 development for patisiran.

We're particularly excited about givosiran, our RNAi therapeutic for the treatment of acute hepatic porphyrias. Here, we initiated the ENVISION Phase 3 study in patients with acute hepatic porphyrias that experience recurring attacks. This study will include an interim analysis based on reduction in levels of a urinary biomarker aminolevulinic acid, or ALA, as a surrogate endpoint reasonably likely to predict clinical benefit.

And we expect to have top line interim analysis data in mid-2018, leading to the potential for an NDA filing at year-end 2018. For Alnylam, we believe this represents the enviable and exciting opportunity for back-to-back NDA submissions and back-to-back global launches, with two potentially transformative medicines for patients. We're also very excited about inclisiran, where our partners at The Medicines Company have started 3 Phase 3 studies, ORIONs-9, 10 and 11 in patients with atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia.

A week or so ago, Medco announced that they've already completed enrollment of approximately 1,500 patients in the ORION-11 study in just 11 weeks after they started that study. The ORION Phase 3 studies are expected to read out in 2019, paving the way for the potential entry of inclisiran into the multibillion dollar hypercholesterolemia market if the studies are positive.

While we're preparing for global commercialization of patisiran in 2018 and advancing our Phase 3 development pipeline toward the market for expected the launches in 2019 and 2020, we're also investing in the future, with both of our early to mid-stage clinical pipeline and in our research efforts to fuel sustainable growth in 2021 and beyond.

To that end, in addition to advancing TTRsc02 with the Phase 3, as I mentioned earlier, we will also have important readouts for our cemdisiran complement and our lumasiran primary hyperoxaluria programs later this year. We are also planning on one or more CTA filings in 2018, including our AATO2 program for alpha-1-antitrypsin deficiency liver disease. And we're making strong progress in other late preclinical programs, including our HPV program in collaboration with VIR.

During the recent period, we were also very excited to announce our participation in the UK Biobank consortium in collaboration with Regeneron and a few other pharmaceutical companies. This industry leading exome sequencing initiative will help us strengthen our target identification and validation efforts and fuel our R&D engine.

As part of this collaboration, we're aiming to sequence 0.5 million exomes that are linked to medical records by the end of 2019, creating the world's richest source of human phenome data. We're convinced that this has the potential to generate a large number of promising opportunities for future Alnylam RNAi therapeutics programs.

Finally, as described in our release this morning, we are for the first time providing financial guidance on 2018 non-GAAP R&D and SG&A expenses in addition to our traditional guidance on year-end cash. We will remain in a significant investment mode at Alnylam for the next several years, as we execute on and advance what we believe to be one of the strongest pipelines in the biotech industry today, with potential annual launches starting in 2018 and sustainably thereafter.

We also plan to invest significantly in our global commercialization efforts to secure market leadership. In short, it is our firm belief that maximizing impact for patients and value for shareholders over the mid-to-long-term is best achieved by making the needed yet disciplined investments in R&D and SG&A in the near term. With that, I'd like to now turn the call over to Akshay to review our pipeline progress in more detail. Akshay?

[Akshay Vaishnaw, Executive Vice President-R&D]

Thanks, John, and good morning, everyone. As John highlighted, we've had a productive quarter with many firsts for the company. Let's begin with our programs in hATTR amyloidosis, which include patisiran and ALN-TTRsc02.

This undoubtedly was a transformative period for patisiran, with our positive results from the APOLLO Phase 3 study. To recap, patisiran met its primary efficacy endpoint, the change from baseline in the modified neuropathy impairment score, mNIS+7, with a remarkably significant p value of 9.26 x 10-24 and hit all secondary endpoints as well, including the Norfolk Quality of Life score with equally notable statistical significance with a p value of 1.10 x 10-10 at 18 months.

The combination of secondary endpoints, which included not only the Norfolk-QOL, but additional readouts in muscle strength, activities of daily living, walking speed, BMI and autonomic function, show the potential for patisiran to uniquely impact patients' lives in a clinically meaningful fashion. In the prespecified cardiac subpopulation, patisiran treatment was also associated with improvement in cardiac structure and function, including a marked improvement in gait speed.

These data make patisiran the only therapy, whether investigational or approved, for the treatment of hereditary TTR amyloidosis with evidence of disease reversal in a majority of patients. Based on these data, we recently completed our rolling submission of an NDA to the FDA, where we have breakthrough therapy designation and have also submitted our MAA to the EMA, where we have accelerated assessment status.

As John mentioned, we completed both of these regulatory filings in record time and both agencies have accepted our filing. Our PDUFA date from the FDA is August 11. On that note, I too would like to congratulate and thank our teams for these remarkable achievements.

Based on these submissions, we expect potential regulatory approvals in the U.S. in mid and in the EU in late 2018. With our recently obtained global rights for patisiran, we're also preparing for global submissions, including the goal of a Japanese NDA in mid-2018 and the filing in one or more additional countries by the end of the year.

With 99% of eligible patients from APOLLO having enrolled into the global open-label extension, or OLE, study, we're also looking forward to generating longer-term data for patisiran on safety and efficacy. In addition to patisiran, we're also developing ALN-TTRsc02, and as an investigational RNAi therapeutic for ATTR amyloidosis.

TTRsc02 uses our ESC-GalNAc-conjugate platform and allows for subcutaneous route of administration. Earlier reported results in healthy volunteers suggested that a once quarterly fixed dose of either 25 or 50 milligrams could provide the same level of TTR knockdown observed with patisiran. With respect to safety, TTRsc02 was generally well-tolerated, supporting further advancement of this investigational RNAi therapeutic.

We believe that these positive results position TTRsc02 to be a promising potential option for ATTR amyloidosis patients. And in light of the unequivocal validation of the TTR knockdown hypothesis from APOLLO, we might as well look forward to advancing TTRsc02 as our next Phase 3 program in late 2018.

As John noted earlier, we're excited about the potential for TTRsc02 across the broad spectrum of patients with ATTR amyloidosis. To this end, we're planning on a comprehensive Phase 3 development program that will include studies aimed at confirming safety and efficacy in patients with hATTR amyloidosis, in other words the APOLLO population, and also in patients who are asymptomatic hATTR mutation carriers and the patients with wild-type ATTR amyloidosis.

These two later patient groups represented the potential to substantially expand the number of patients who may benefit from TTR knockdown with our investigational RNAi therapeuticTTRsc02.

With that, let's now turn to our givosiran program, where we've also made significant progress in recent months. As you know, givosiran is in development for the treatment of hepatic porphyrias. As a reminder, the hepatic porphyrias are a group of ultra orphan diseases caused by genetic defects in the heme biosynthetic pathway. They are a devastating family of disorders with enormous unmet need and economic burden.

In porphyria, buildup of toxic heme intermediaries leads to incapacitating and potentially fatal attacks with symptoms that includes severe abdominal pain, peripheral and autonomic neuropathy and neuropsychiatric manifestations. Porphyria attacks are relentless, typically lasting for days and requiring hospitalization. Moreover, many patients suffer from disabling chronic pain in between attack.

Recently, we announced the initiation of the ENVISION Phase 3 study of givosiran. ENVISION is a randomized double-blind placebo-controlled study in approximately 75 acute porphyria patients with recurrent attacks. The primary endpoint is the change in annual attack rate relative to baseline for patients treated with givosiran versus placebo at 6 months.

ENVISION study design has been endorsed by the U.S., European and Japanese regulatory authorities, and we've reached alignment with the FDA on an interim analysis approach in approximately 30 patients using reductions in levels of urinary ALA at three months as a surrogate endpoint that is reasonably likely to predict clinical benefit. The use of ALA as a biomarker predictive of clinical benefit is based on the role of ALA in porphyria attacks as documented in literature as well as our own data from the Phase 1 study that demonstrated a greater correlation between ALA lowering and diminished frequency of attacks, as seen on Slide 16.

In our Phase 1 and Phase 2 early studies, we've also demonstrated over 80% reduction in ALA relative to baseline. So we look forward to potentially confirming this in our Phase 3 interim analysis, which we expect to report in mid-2018. If the interim analysis are positive and pending regulatory support, we'll then be in a position to file an NDA for an accelerated approval based upon the interim study data at or around year-end 2018, representing a significant acceleration in our efforts to bring this promising investigational medicine to patients.

We're also announcing today that our interim analysis will include a blinded assessment of the rate of porphyria attacks to enable potential adjustment in the study sample size from approximately 75 to approximately 94. We believe this is a prudent measure to ensure that the study is robustly powered and to guard against patients in either arm that might have fewer porphyria attacks compared to those studied in our Phase 1/2 program.

Because this interim analysis is conducted on a blinded basis, a robust treatment effect in the drug arm might also lead to a decision to add additional patients, resulting in an overpowered study, which, of course, is always a good thing. Accordingly, we believe it's best for people to expect that we'll be triggering the study expansion to 94 patients. That said, even with adding 20 patients, we still fully expect the readout to be in 2019 and the study expansion will not impact the conduct or timing of our interim analysis of urinary ALA lowering in mid-2018 and if positive, our planned NDA submissions by year-end 2018.

Let's now turn to our fitusiran program, an investigational RNAi therapeutic for the treatment of hemophilia and rare bleeding disorders. As a reminder, fitusiran targets antithrombin, or AT, and is designed to increase thrombin generation and thus, provide hemostasis in peak with hemophilia.

In the fourth quarter, following a successful Type A meeting outcome with the FDA, we aligned on clinical safety and risk mitigation measures that include a protocol specified guidelines and additional investigator and patient education concerning reduced doses of replacement factor or bypassing agent to treat any breakthrough bleeds and education on sizes and symptoms of a clot.

This resulted in the lift of the temporary clinical hold on fitusiran and resumption of dosing in the Phase 2 early study late last year. We and our partners at Sanofi have now reinitiated our ATLAS Phase 3 program, with resumption of dosing expected in the coming weeks. As a reminder, ATLAS is a broad-based program that is designed to evaluate the efficacy and safety of fitusiran in patients with hemophilia A or B with or without inhibitors, where the patients are receiving on-demand or prophylactic replacement therapy.

ATLAS will enroll approximately 250 patients in three separate studies and over 100 clinical centers around the world. Under our restructured collaborations, Sanofi will assume global development responsibility and global commercialization rights for fitusiran and will oversee patient enrollment in ATLAS following an approximately six-month handover period.

As a once monthly subcutaneous medicine without peaks and troughs of replacement factor therapy, we and our partners at Sanofi remain very excited about the potential for fitusiran in hemophilia and other rare bleeding disorders. We fully expect that Sanofi's recent announcement to acquire Bioverativ will not only assist in maximizing fitusiran's commercial prospects, but will also aid in the efficient and timely development of this promising investigational medicine.

Another late stage state program in our pipeline is inclisiran, our investigational RNAi therapeutic targeting PCSK9, is being developed collaboration with our partners at The Medicines Company. Recently, we and The Medicines Company announced initiation of a comprehensive Phase 3 program for inclisiran, consisting of ORION-9, -10 and -11 trials in patients with heterozygous familial hypercholesterolemia or with ASCVD, with or without additional risk factors.

As John mentioned, Medco has guided that the timelines to complete patient enrollment have exceeded previous expectations, with the ORION-11 trial completing randomization of 1,500 patients in just 11 weeks, about 17 weeks sooner than expected. ORION-9 and -10 trials are actively enrolling, also ahead of schedule, and are expected to complete enrollment during the first half of 2018.

Of interest, the FDA also recently granted inclisiran orphan drug status for the treatment of homozygous familial hypercholesterolemia, underscoring the potential of inclisiran in the highest unmet need population in addition to unmet need in the broader secondary prevention hypercholesterolemia market. Inclisiran remains a very important product opportunity for Alnylam in light of our significant economic participation in the value of the program. In addition, we stand to benefit greatly from the substantial safety data we obtained from the program and how it supports the overall safety profile of our ESC-GalNAc-conjugate platform.

To this end, we have a close working relationship with Medco related to safety monitoring in the ORION program and we're encouraged by the safety reports we've reviewed to-date. During the fourth quarter and recent period, we also made good overall progress in some of our earlier stage programs, most notably with lumasiran, formerly known as ALN-GO1, showing exciting initial efficacy in a small number of patients with primary hyperoxaluria type 1, or PH1.

As a reminder, PH1 is an ultra-rare orphan disorder, in which oxalate crystals build up in the kidney, leading to painful and recurrent kidney stones and damage to extrarenal tissues, primarily in children. Treatment options are limited and typically involve chronic dialysis and often a dual liver and kidney transplant. Lumasiran targets the enzyme glycolate oxidase, thereby depleting the substrates necessary for the production of oxalate, which directly contributes to the pathophysiology of PH1.

We recently presented initial patient data from Part B of the ongoing Phase 1/2 study of lumasiran. Part B is a randomized single-blind placebo-controlled study designed to enroll up to 24 PH1 patients aged 16 to 19 years of age, representing our first ever pediatric experience. In the initial two cohorts, lumasiran achieved substantial reductions in the urine oxalate levels in all patients, supporting the hypothesis that RNAi-mediated inhibition of GO1 can reduce and potentially normalize hepatic oxalate production, thus, potentially halting PH1 disease progression.

In the first lowest dose cohort, urinary oxalate levels were reduced by up to 74%, with all patients reaching the normal urinary oxalate levels. With respect to safety, lumasiran was generally well tolerated, with no treatment-related serious adverse events or study discontinuations up to seven months after initial dosing. We aim to discuss these data with the regulators and rapidly advance lumasiran towards Phase 3 clinical studies.

Notably, we believe that the level of urinary oxalate could be considered a surrogate endpoint for approval. In the meanwhile, lumasiran is a potential global pick for Sanofi as part of our 2014 agreement, in which case Sanofi would assume the development and commercial lead of the program with Alnylam receiving significant milestones and royalties up to 20%. We have now triggered the process whereby Sanofi will consider opting in, and we expect to hear of their response in the next few months.

Of course, Sanofi may also decline their option for any number of reasons, including for portfolio reasons related to their recent acquisitions. Of course, if Sanofi elects to decline its opt-in, we would keenly advance lumasiran towards Phase 3 studies, potentially, later this year. Finally, as John mentioned, we're also advancing our cemdisiran program in complement-mediated diseases, advancing one or more CTAs in 2018 and continuing to invest in our future with bold initiatives such as the UK Biobank consortium.

In summary, we've had a very exciting final quarter in 2017 and in the recent period. Having now advanced the pipeline with four programs in Phase 3, with one under regulatory review and multiple earlier stage programs.

With that, I'll now turn the call over to Manmeet for a review of our financials. Manmeet?

[Manmeet Soni, Chief Financial Officer]

Thanks, Akshay, and good morning, everyone. I will be referring to Slide 21 for a discussion of our fourth quarter and year-end 2017 financial results and 2018 financial guidance. We maintained a strong balance sheet, ending the fourth quarter and the year of 2017 with approximately $1.73 billion in cash, cash equivalents, marketable securities and restricted investments.

Our revenues were $37.9 million in the fourth quarter of 2017, as compared to $17.5 million in the fourth quarter of 2016. Revenues for the fourth quarter of 2017 included $20.1 million from the Company’s alliance with The Medicines Company, $13.4 million from the Company’s alliance with Sanofi Genzyme, and $4.4 million from other sources.

Revenues were $89.9 million in the year ended December 31, 2017, as compared to $47.2 million in the year ended December 31, 2016. Revenues for the year ended December 31, 2017 included $54.6 million from the Company’s alliance with Sanofi Genzyme, $30.2 million from the Company’s alliance with The Medicines Company, and $5.1 million from other sources.

The increase in revenues during the year was due to increased services performed by us in connection with our clinical development programs for which Sanofi Genzyme had opted in and the achievement of $20 million milestone under our agreement with The Medicines Company upon initiation of its Phase 3 study for inclisiran in early November 2017.

Moving to expenses, our GAAP R&D expenses were $117.8 million in the fourth quarter of 2017, as compared to $105 million in the fourth quarter of 2016. GAAP R&D expenses were $390.6 million in the year ended December 31, 2017 as compared to $382.4 million for the prior year.

Non-GAAP R&D expenses were $102.9 million in the fourth quarter of 2017, as compared to $95 million in the fourth quarter of 2016. Non-GAAP R&D expenses were $338.8 million in the year ended December 31, 2017 as compared to $339.4 million for the prior year. Non-GAAP R&D expenses exclude stock-based compensation expense. Our non-GAAP R&D expenses increased during the quarter due primarily to increased compensation and related expenses as a result of an increase in headcount during the period, as we expand and advance our development pipeline.

GAAP G&A expenses were $67.5 million in the fourth quarter of 2017 as compared to $27.9 million in the fourth quarter of 2016. GAAP G&A expenses were $199.4 million in the year ended December 31, 2017 as compared to $89.4 million for the prior year.

Non-GAAP G&A expenses were $55.2 million in the fourth quarter of 2017 as compared to $17.2 million in the fourth quarter of 2016. Non-GAAP G&A expenses were $158.4 million in the year ended December 31, 2017 as compared to $56.8 million for the prior year. Non-GAAP G&A expenses also exclude stock-based compensation expense. Our non-GAAP G&A expenses increased significantly during the quarter and the year due primarily to an increase in commercial and medical affairs headcount and commercialization building-related services to support corporate growth and prepare for potential commercial product launches.

Turning to losses. The net GAAP – our net GAAP loss for the fourth quarter of 2017 was $142.2 million, as compared to a net loss of $112.9 million for the same period in the previous year. For the year ended December 31, 2017, the net loss was $490.9 million, as compared to a net loss of $410.1 million for the prior year.

The non-GAAP net loss for the fourth quarter of 2017 was $115.1 million, as compared to a non-GAAP net loss of $92.3 million for the same period in the previous year. The non-GAAP net loss for the year ended December 31, 2017 was $398.1 million, as compared to a non-GAAP net loss of $334.6 million for the prior year.

With respect to guidance for 2018, we expect that balance of cash, cash equivalents, marketable securities, restricted cash and investments will be approximately $1 billion at December 31, 2018. We believe this provides Alnylam with a strong balance sheet at the end of 2018 to support the achievement of our Alnylam 2020 goals.

We expect that 2018 annual non-GAAP R&D expenses should be in the range of $400 million to $440 million. Non-GAAP R&D expenses for 2018 include acceleration of our Phase 3 drug candidates towards the market of – our market for expected launches in 2019 and 2020. Further, as John mentioned, we're also investing in the future, with both of our early to mid-stage clinical pipeline and in our research efforts to fuel sustainable growth in 2021 and beyond.

We expect that 2018 annual non-GAAP SG&A expenses will range between $280 million to $320 million. 2018 non-GAAP SG&A expenses are related to growth in our global operations, including the continued build-out of our global commercial infrastructure and field team in preparation for our anticipated first product launch and multiple successive global launches thereafter.

With that, I will now turn the call over to Barry. Barry?

[Barry Greene, President]

Thanks, Manmeet. As you heard from John and Akshay, the company has picked up remarkable momentum in the fourth quarter and recent period. We're now very focused on preparing for the commercialization of patisiran on a global scale, with an initial focus on United States and Western European territories. For patisiran, the pathway to reach global markets is very clear. As you've already heard from John and Akshay, in the U.S. and EU, we filed our NDA and MAA, and expect decisions in mid-2018 and late 2018 respectively.

We plan to begin a global expansion with a Japanese NDA submission to the PMDA in mid-2018 and expect to also file in one or more countries throughout the course of 2018 and beyond. Now we can refer to our APOLLO study population as the basis for an initial blueprint to map out our global reach beyond U.S. and Western Europe. In APOLLO, we enrolled 225 patients in 19 countries across the globe. The diversity of the APOLLO patient demographic highlights significant potential for commercial opportunities in Central and Eastern Europe and in markets like Asia Pacific and Latin America.

Now while not in APOLLO, we also see significant opportunities in the Middle East in countries like Turkey, Israel and United Arab Emirates. Our build of the Alnylam commercial and medical customer facing organization is well underway, with planned onboarding of over 250 employees, including medical affairs, patient services, access, marketing and sales professionals in a staged approach tied to regulatory approvals and reimbursement.

In the U.S., as things stand, we have our entire field and customer facing team onboard and in training. We plan to be launch ready in Western Europe later in the year, starting in Germany, we have hired and will soon begin to onboard our field and customer facing team. All of this work sets the stage for potential for subsequent commercial launches in countries around the world in a stepwise manner.

Outside of the U.S. and Europe, we also plan to have an Alnylam presence in Japan later this year. We intend to expand our ongoing patient identification and physician education efforts in the U.S. and EU to a global scale in accordance with the rules and regulations of each country. Similarly, we intend to expand our manufacturing and supply chain capabilities currently in place in U.S. and Europe on a global basis.

As you're well aware, there is precedent for successful global launches of orphan drugs from pioneers like Genzyme and Alexion, and there are many learnings that can be used as a framework for globalization of patisiran. Raising disease awareness and improving care through Centers of Excellence, are important priorities in our efforts to bring patisiran to patients. We have been working to improve diagnosis through a number of initiatives, for example, Alnylam Act, which is a free genetic testing services in the U.S. and Canada, where over 3,000 samples have been tested, leading to identification of mutant TTR in about 300 patients. It's a very good hit rate.

We're also improving education of healthcare providers and patients with targeted websites aimed at providing resources for disease awareness, accurate diagnosis and patient care. Among other efforts, we're also pleased to have an active expanded access program in the U.S. and compassionate use program in many European countries, providing early access to patisiran in response to request from treating physicians for eligible patients in an effort to address the urgent need for hATTR amyloidosis treatment option.

As announced this morning, to-date, we've fulfilled physician requests for more than a 100 patients, who are now being treated with patisiran in these early access programs in the United States and many European countries. And finally, as announced last year, we've established a set of patient access principles that provide the foundation for our discussions with private and government payers. With respect to pricing, we're reviewing analogues to other therapies for rare conditions and high unmet needs. As part of our patient access principles, we plan on being proactive on value-based agreements which certain payers have already indicated – are of considerable interest.

To that end, we'll also have a clear value dossier to instruct the appropriate framework to private payers and with government payers around the world. We're following a launch plan we established with the right focus on patient advocacy, access, disease education, patient finding, and supply chain. We understand fully that our patients and their caregivers require education, information and services in addition to access to patisiran, and plan to be prepared with appropriate offerings. So we're incredibly excited for the potential first launch of RNAi therapeutic in history, and we're on track for launch readiness.

With that, I'll now turn the call over to Yvonne to review our key 2018 goals and objectives. Yvonne?

[Yvonne Greenstreet]

Thanks, Barry. To echo the sentiments you've heard from my colleagues, the fourth quarter of 2017 and the beginning of this year have been exciting periods of the company. And we're now looking forward to a very eventful 2018. In 2018, most importantly, we expect to transition to a commercial-faced company, with an expected U.S. approval and launch for patisiran in mid-2018, and in the EU in late 2018. We will also start our global effort from patisiran, with a JNDA filing expected in mid-2018 and one or more rest of world regulatory submissions by year-end.

In addition, we intend to continue to cement our leadership in the ATTR amyloidosis field with the initiation of a comprehensive Phase 3 development program for ALN-TTRsc02 starting in late 2018. Beyond our ATTR amyloidosis programs, important highlights for the year include our top line interim analysis Phase 3 results for givosiran in acute hepatic porphyrias, leading to a potential year-end NDA submission.

Also, we'll be advancing our additional Phase 3 programs together with our partners with fitusiran in the ATLAS program and inclisiran in the ORION program. We expect Phase 3 readouts for fitusiran and inclisiran in 2019, leading to potential approvals in 2020. And as Manmeet said, we're now providing our year-end 2018 financial guidance, which we expect to end with approximately $1 billion in cash.

Turning more specifically to expected milestones in new drug for the beginning of 2018. We expect to present additional data from the APOLLO Phase 3 study of fitusiran at the ISA meeting in March. We also expect to present additional Phase 1 and Phase 2 early study results for givosiran at EASL in April. Alnylam and Sanofi expect to enroll patients for the ATLAS Phase 3 program for fitusiran in patients with hemophilia A or B with and without inhibitors throughout the year with a resumption of dosing expected in early 2018.

And The Medicines Company has guided its intention to complete enrollment in the ORION-9 and -10 pivotal studies of inclisiran in early 2018, with ORION-11 already now fully enrolled.

With that, I will now turn the call back to Christine to coordinate our Q&A. Christine?

[Christine Lindenboom]

Thank you, Yvonne. Operator, we will now open the call for your questions. For 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.

[Operator]

Thank you. [Operator Instructions] And our first question comes from the line of Ted Tenthoff of Piper Jaffray. Your line is open.

[Ted Tenthoff, Piper Jaffray]

Great, thank you very much. Two quick ones, if I may. Firstly, with respect to commercial preparation, I appreciate the guidance that you're starting to give there. What – where will you be manufacturing drug? And what still has to be done to sort of get through manufacturing, ahead of manufacturing visit and clearance, ahead of review? And secondly, any thoughts on how long it may take to enroll the ATLAS studies? Thanks.

[John Maraganore, Chief Executive Officer]

Right. Those are two great questions. Let's have Barry do the first one and Akshay the second.

[Barry Greene, President]

Yes. So Ted, specifically for patisiran manufacturing, we're in very good shape. The global supply chain is established, as I remarked, for U.S. and Europe, and we're now expanding that to rest of the world. We are a number of drug substance manufacturers. We haven't talked about exactly who we use, but they're well-established manufacturers. As we've disclosed previously, our drug product is made by Alnylam here in our Alewife facility, and it's inspection-ready.

We won't comment on specifically, but we're engaged with the agencies on pre-approval inspections and see all that going very well for U.S. and Europe. So I'd say, overall, in terms of manufacturing, we filed everything with the NDA, we're inspection-ready in all of our sites and it's a matter of moving through inspections and timing with the agencies.

[John Maraganore, Chief Executive Officer]

Yes. And Akshay?

[Akshay Vaishnaw, Executive Vice President-R&D]

Yes. And on Atlas, Ted, we were delighted at the end of last year to get things fired up again after the lift of the temporary clinical hold. The filings globally at almost a 100 sites have gone well, the regulatory progress Atlas progress is good. We're expecting enrollment to begin eminently, and of course, the ultimate timing for the data, our Sanofi colleagues will be guiding on that carefully as enrollment progresses, but our plans, originally, were always to get data in the 2019 timeframe.

[Ted Tenthoff, Piper Jaffray]

Great. Excellent. I appreciate it.

[John Maraganore, Chief Executive Officer]

All right. Thanks, Ted.

[Operator]

Thank you. Our next question is from the line of Terence Flynn of Goldman Sachs. Your line is open.

[Terence Flynn, Goldman Sachs]

Hi. Thanks for taking the question. Maybe one on givosiran. Just wondering if the announcement today regarding the sample size adjustment, if that was based on the current event rate that you guys are seeing or is this just, again, you want to have an overpowered study?

And then the second question I had is, Pfizer has an upcoming Phase 3 readout for tafamidis in the cardiomyopathy patients, just wondering if you can could remind us how you're thinking about potential implications of that data set there for your TTR portfolio. Thank you.

[John Maraganore, Chief Executive Officer]

Great. Let’s start with givosiran interim analysis and sample size reestimation. Let me just start by saying that this was always actually in the plan, but we realized coming into the year that we haven't provided specific guidance on it, so we wanted to make sure people were aware of the fact that we had this interim analysis in place for resizing. It's a typical approach. And there is certainly no aspect of data that's driving that. That was done actually before enrollment was started in the study. Anything to add to that?

[Akshay Vaishnaw, Executive Vice President-R&D]

I don’t know. You covered it, John.

[John Maraganore, Chief Executive Officer]

Yes, good. And then on the ATTR-ACT study results, maybe Barry, you want to cover that?

[Barry Greene, President]

Yes. So just as context, and Terence, thanks for asking, Pfizer has a very large cardiovascular outcome all-cause mortality study running in mainly cardiomyopathy patients, both mutant and wild type for TTR amyloidosis. We don't know the outcome we anticipate hearing the results sometime early to mid-this year. And I think, either way, I think we're in good shape for patisiran, given the data we have.

If ATTR-ACT is, in fact, a positive, it's further confirmation that modulation of TTR is beneficial for these patients, and as you know, including cardiomyopathy subpopulation, we've shown reversal of disease in the majority of patients. And if ATTR-ACT is negative, then it demonstrates sort of the lack of efficacy we've already seen with tafamidis. So I think, either way, we're in good shape for patisiran.

[John Maraganore, Chief Executive Officer]

Yes, I don’t think it changes. Just one another thing to add. I think, Barry, that's all correct, but one thing to add, Terence, is it doesn't change the fact that TTR stabilization with tafamidis is a pretty weak approach. And I think we'll see what the results are, but we wouldn't expect the results to be any more impactful than what we've already seen from tafamidis. And of course, we know that TTR lowering is substantially a better as an approach, overall, and we would expect that to play out in the future.

[Operator]

Thank you. And our next question comes from the line of Vincent Chen of Bernstein. Your line is open.

[Vincent Chen, Bernstein]

Thank you for taking the question. I was wondering if you could provide some color on how you're thinking about the likelihood of a broad label for patisiran. I guess both you and I know it's submitted for a broad label since – do we know of advisory committee's plan? So regulators clearly think they have a view on the likely label, whether it ends indeed broader and roughly only.

I guess, two parts to the question, one, is it fair to say that the breadth of the label really hinges on how robustly regulators view cardiac substudy, for example, prespecified, robust mutual endpoint? And two, if so, what is your sense from your discussions with the regulators themselves and also with your regulatory consultants with respect to how the FDA is likely to view the robustness/efficiency of the cardiac substudy and the implications for the label?

[John Maraganore, Chief Executive Officer]

Okay. Those are great questions. Akshay, do you want to tackle?

[Akshay Vaishnaw, Executive Vice President-R&D]

Yes. Hi, Vincent, I mean, we’re obviously very hopeful that we can achieve a broad label based on just how comprehensive the data in APOLLO were speaking to all dimensions of the disease, and by that I mean the peripheral neuropathy, the autonomic neuropathy, the cardiac outcomes and all of that then supported by changes in very important secondary measures like Quality of Life, body mass, activities of daily living, et cetera.

So I think that is all going to be looked at very carefully by regulators. Equally, they'll want to – I imagine, if you're convinced that the input population that was studied in APOLLO is truly representative of the breadth of what is hATTR amyloidosis. We certainly believe it is. As you know, over 50% of patients had significant cardiomyopathy as well as the neuropathy, and we believe that we have very nicely tested the hypothesis of TTR reduction and its impact on the full breadth of the disease.

The cardiac data themselves will, of course, be very important, and I think the internal consistency of all the data will be important. So we've got to allow the regulators to work through all that stuff, of course. And I think that we're optimistic, but let's see where they end up.

[John Maraganore, Chief Executive Officer]

Yes, I would agree with that. And obviously, I think it goes without saying that APOLLO – the APOLLO data being as robust as they were and as amazingly consistent across all aspects of the disease is the key point here.

[Vincent Chen, Bernstein]

Would it matter at all that there wasn't a primary endpoint focused on sort of cardiac and that the primary was much more focused on the neuropathy? And is there a world where it would be potentially a shorter study just saying, let's redo a cardiac population with the primary really focused specifically on around the cardiac endpoints?

[Akshay Vaishnaw, Executive Vice President-R&D]

I think there are aspects to your questions which, obviously, we should allow regulators ultimately to answer. But from our perspective, what I would say is that the issue with the label is that you want to inform prescribers and those that will receive the drug, what is the capacity of this drug in terms of the efficacy can confer and what is the – what are the potential issues with safety. That's what we want to do with the label.

We feel, and I think most people will agree with, that the fact that the cardiac outcomes weren't the primary endpoint is not the issue here. We prespecified the cardiac outcomes, we've studied them rigorously, we find up to be entirely internally consistent with the other outcomes that we've measured.

And so I think in a rare disease population, in a complex disease where, in fact, the cardiac features are part of the predisposing factors to mortality, the regulators would want to look at that very carefully and make sure that they inform prescribers of what is this drug all about and what can it do for patients.

[Vincent Chen, Bernstein]

Great. Thank you very much.

[John Maraganore, Chief Executive Officer]

Thanks, Vincent.

[Operator]

Thank you. Our next question is from the line of Madhu Kumar of B. Riley. Your line is open.

[Madhu Kumar, B. Riley]

Thank you guys for taking my question. So thinking about patisiran and ATTR patient finding, what have you learned from the ex-U.S. launch of Vyndaqel that could aid in the genetic testing and expansion of patisiran beyond the initial patients set?

[John Maraganore, Chief Executive Officer]

Okay. Good question. Do you want to touch on that first, Akshay, maybe Barry?

[Akshay Vaishnaw, Executive Vice President-R&D]

Yes, I think some of the key lessons from the Vyndaqel experience sort of follows that, one, the disease is a complex multisystem disease. When most patients have neuropathy and cardiomyopathy and that the current batch of TTR stabilizers, tafamidis, diflunisal, really can't get to the full spectrum of manifestations of this disease. Secondly, the patients breakthrough.

And thirdly, the awareness that tafamidis is a therapy available for this disease has just allows more patients to emerge and come out and seek therapy. And we ourselves, on the back of that, are trying to take advantage of heightened awareness of the disease and launched a program, Barry commented on it, for genetic testing in Europe.

And we're equally optimistic that some of our early experiences over the last 18-plus months in U.S. will be reflected in the EU, actually even more so, because one of the interesting things in the EU is there are large pockets of patients, whether there's endemic disease by mutations or mutation is concentrated. Of course, Portugal is an example of that, Sweden is an example of that, parts of France are an example of that.

The Celtic population across the U.K. and Ireland is an example of that with T60a. And so we think that we will be identifying many patients because of the heightened awareness because of the emergence of new therapies and the availability of our genetic testing.

[John Maraganore, Chief Executive Officer]

Yes. I agree with everything Akshay said. I'd add a couple of things to that, which is that particularly now post the patisiran results, where a majority of patients have actually shown disease reversal, it's enhance the call to action. And what we want to happen in the marketplace is when a patient is identified and becomes, if you will, an index patient, they have a call to action that alerts the rest of their family about the disease. When there is nothing to do for a patient, they tend not to want to do that. When there is a probability that the disease can reverse, they can get better, there is a bigger call to action. So I think we're going to see a lot more of that call to action, which should lead to patients self-identifying and coming in for genetic testing.

The second thing, we've seen a phenomenon, and we're actually helping to make this happen, our Centers of Excellence. So if a patient comes in and sees a cardiologist who might miss the disease but doesn't see the neurologist who might see the disease or vice versa, that patient is hitting the healthcare system but then leaves the system. So with Centers of Excellence being established and multidisciplinary approaches, the chances of seeing that patient identifying this as hereditary ATTR improves. So in addition to what Akshay said, a couple of behavioral changes should prompt greater momentum in patient finding.

[Madhu Kumar, B. Riley]

Okay. Great. And then stepping back, so how much has the transition towards ESC+ RNAi technology versus the kind of change in the mix between R&D spend and SG&A spend affected the kinetics of new program IND or CTA filings?

[John Maraganore, Chief Executive Officer]

Madhu, I think that we took the purposeful decision last year to really focus on late stage execution of our pipeline versus filing new CTA or IND filings last year. We're going to have one or more filings this year. I'm pretty confident it's going to be more than one. And you're going to see that play out, because we have a lot of very important programs coming forward, and those programs will all be utilizing our ESC+ platform.

So it really was more of a explicit decision last year to really focus on late stage development more than any sort of need to pause and do something different.

[Madhu Kumar, B. Riley]

Thank you.

[Operator]

Thank you. Our next question is from the line of Alethia Young of Credit Suisse. Your line is open.

[Alethia Young, Credit Suisse]

Hey, guys. Thanks for taking my questions. Maybe a couple. Just can you talk a little bit about what maybe presented for givosiran at EASL and maybe specifically as it relates to pain? And then on TTRsc02, with the start late in 2018, can you just talk about kind of size details of that study and how you kind of prevent that from strategically impacting your upcoming launch? Thanks.

[John Maraganore, Chief Executive Officer]

Yes, okay. Great questions. Let me touch on both, and then Akshay can go a little bit deeper on the latter. So with givosiran at EASL, we'll be showing the full Part C dataset in around 15 patients as before. This is the cohorts of patients that were randomized into the double-blind placebo-controlled study. So you'll see the full Part C results, then you will see some I think will be pretty exciting set of data from the open-label extension study. So patients that have now been on therapy for over a year with givosiran, looking at how their disease control has played out and of course, safety as well. So it will be a pretty comprehensive review of that data.

And then on TTRsc02, it's – obviously, we haven't yet locked protocols with regulators, so we don't want to get ahead of our skis, I'm talking about patient numbers, but we can confidently expect to be enrolling patients around the world. And obviously, we'll be focusing on patients in territories where reimbursement hasn't happened, as part of the strategy to make sure that we're not limiting full access of patients into the commercial program with patisiran. So that will be one of the approaches that we take there.

I don't know, Barry or Akshay, anything else to add to what I just said?

[Akshay Vaishnaw, Executive Vice President-R&D]

No, you’ve covered it.

[John Maraganore, Chief Executive Officer]

Covered it?

[Akshay Vaishnaw, Executive Vice President-R&D]

Yes.

[John Maraganore, Chief Executive Officer]

Thanks, Alethia.

[Alethia Young, Credit Suisse]

Thanks.

[Operator]

Thank you. Our next question comes from the line of Maurice Raycroft of Jefferies. Your line is open.

[Maurice Raycroft, Jefferies]

Hi, good morning and thanks for taking my questions. To start, I was wondering if you can provide more specifics around practitioners' access to genetic testing through Alnylam Act and if you gaps where certain types of physicians or patients may not be using the free test. And if you can maybe provide a few more specifics around what you're doing to influence the call to action outside of Centers of Excellence.

[John Maraganore, Chief Executive Officer]

Okay. Those are two great questions. Akshay, you want to handle?

[Akshay Vaishnaw, Executive Vice President-R&D]

Yes, let me start off. So in terms of the access, we've made it open access to any specialty that wants to test the patient with suspicious symptoms of hATTR amyloidosis, and to date, we've been very successful. There are hundreds of doctors around the country in the U.S. who have accessed the system. As Barry said, we've had a pretty significant strike rate. And so it's great that patients are having quicker diagnosis, maybe a little more accurate diagnosis made for such a complex, high unmet need disease.

One of the – some of the initiatives around that where we're looking to expand things are calling on sites that are not just the expert sites for hATTR amyloidosis, but others with large collections of peripheral neuropathy patients, academic sites, other practitioners who have an interest in peripheral neuropathy, and also spreading to a much larger group of cardiologists. And so that work is underway and I think, can only increase the yield rate and allow more patients to be diagnosed. Of course, we're doing a similar thing in the EU as well now with that initiative there.

In terms of call to action, not only are we and our partners in the genetic testing vendors visiting sites and encouraging doctors to participate if they feel they want to act, as it's the first that rules. So highlighting hATTR amyloidosis at both cardiology and neurology conferences and via that, helping educate and inform a new generation of cardiologists, neurologist who really haven't been exposed to this disease of what the disease is all about and the potential emergence of new therapies and what they can do for patients. And that is also helping. So there is a lot of work going on now, and we anticipate a significant uptick in the number of tests.

[John Maraganore, Chief Executive Officer]

Yes. The only – I agree with that. The only thing I'd add to that is that as disease education becomes more prevalent with neurologists, neuromuscular specialists, heart failure centers, physicians are moving from a view of I've never seen one of those patients my entire life to maybe I have, let me understand the disease better and get somebody's tests ordered.

And then, Maurice, the big, big, big inflection point will come after labeling and after approval when we can actually promote. Keep in mind that right now, it's disease awareness, and our data are available via APOLLO results, but it's the label and really implementing our field force that allows to get out and reach people in a promotional capacity. And that should be a major inflection point for the field.

[Maurice Raycroft, Jefferies]

Great. Very helpful. Thank you.

[Operator]

Thank you. And that does conclude today's Q&A session. I would like to turn the call over to the company for their closing remarks.

[John Maraganore, Chief Executive Officer]

All right. Well, thanks, everyone, for joining us this morning. 2017 was obviously an amazing year for Alnylam, and we are just excited beyond belief around what's going to go on in 2018, as we turn commercial. So with that, thanks, everyone, and have a great day. Bye-bye.

[Operator]

Ladies and gentlemen, thank you for participation in today's conference. This does conclude the program. You may now disconnect. Everyone have a great day.