Alnylam Pharmaceuticals Inc (ALNY) 2017 Q3 法說會逐字稿

Ladies and gentlemen, thank you for standing by. Welcome to the Alnylam Pharmaceuticals conference call to discuss the third quarter 2017 financial results. (Operator Instructions) Please be advised that this call is being taped at the company's request. I will now turn the call over to the company.

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; Yvonne Greenstreet, Executive Vice President, Chief Operating Officer; Akshay Vaishnaw, Executive Vice President of R&D; and Manmeet Soni, Chief Financial Officer. In addition, Barry Greene, President, is available for Q&A.

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. The press release and related financial tables, including a reconciliation of GAAP to non-GAAP net loss that we will discuss today, can also be found on the Investor page of our website. We believe non-GAAP net loss provides useful information to management and investors regarding our financial conditions and results of operations.

During today's call, as outlined in Slide 2, John will provide some introductory remarks and give some general context. Akshay will review the recent clinical update, Manmeet will review our financials 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. 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.

Thanks, Christine, and thank you, everyone, for joining us this afternoon. The third quarter of 2017 and recent period were truly transformative in our overall efforts to advance RNAi therapeutics through clinical trials and toward the market as part of our overall Alnylam 2020 strategy, where we remain on track to build a multiproduct, commercial-stage company with a deep and sustainable clinical pipeline by the end of 2020.

Arguably, we believe this period was also the most significant in our company history, as it marks a critical milestone in our 15-year journey aimed at bringing RNAi therapeutics to patients as a whole new class of innovative medicine.

I'd like to begin today's call with some overall context. First, we are thrilled to have reported positive results from our APOLLO Phase III trial of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. This is great news for patients, great news for RNAi therapeutics and certainly great news for Alnylam.

As you heard on our conference call last week and as Akshay will briefly review again on this call, we believe the data from APOLLO could position patisiran, if approved, to become the best-in-class treatment option for appropriate patients living with ATTR amyloidosis. We now plan to rapidly advance patisiran toward regulatory filings and remain on track to complete our NDA submission to the FDA by year-end and submit our Marketing Authorization Application, or MAA, to the EMA shortly thereafter. We're also preparing for commercialization and the next stage of our company.

As you've heard from us in the past, we have enabled our supply chain, medical and commercial organization in the U.S. and Western EU for a successful launch in 2018. Of course, raising awareness of hATTR amyloidosis and our ability to help healthcare professionals identify patients will be key determinants of our success in benefiting as many patients as possible following approval. We've been involved with the hATTR amyloidosis community for nearly a decade, and as we now prepare for commercial launch of patisiran, we plan to build on our efforts with the addition of roughly 150 U.S. and EU Canada employees in customer-facing activities across medical affairs, patient services and commercial to maximize our prospects of improving patient outcomes.

Access is another key priority, and we are engaged in appropriate pre-approval discussions with payers about RNAi therapeutics, the burden of hATTR disease and our APOLLO data. Together with our partners at Sanofi Genzyme, we have the goal of making patisiran, if approved, available to patients around the world. For us, a focus on customers and patients is not an afterthought; it's in our RNA.

Second, we also made great progress over the quarter and in the recent period with givosiran, our investigational RNAi therapeutic in development for the treatment of acute hepatic porphyrias, including exciting news we announced just this morning. Specifically, we have initiated the ENVISION Phase III study in patients with acute hepatic porphyrias who experience recurring porphyria attacks. This study will include an interim analysis that will be based on reduction of levels of urinary aminolevulinic acid, or ALA, as a surrogate endpoint reasonably likely to predict clinical benefit. Based on this design, we expect to have data from the interim analysis in mid-2018, and assuming positive results, to be in a position to submit an NDA at or around year-end 2018, representing a significant acceleration in our efforts to advance givosiran to patients. This positions Alnylam with the potential for sequential NDA submissions, and if approved, sequential launches of 2 potentially transformative medicines for patients.

We also continue to focus our efforts on other late-stage programs that we believe also have significant potential for patients. As you're aware, we had a setback with our fitusiran program in hemophilia earlier in the fall. But we've established a risk mitigation approach that we and our investigators believe will enable safe resumption of dosing in our Phase II open-label study and our ATLAS Phase III studies. We'll soon be completing our discussions with regulatory authorities with the goal of resuming fitusiran dosing as soon as possible.

Together with our partners at The Medicines Company, we are pleased to have now started the ORION-11 study of inclisiran, an investigational RNAi therapeutic targeting PCSK9, in development for the treatment of hypercholesterolemia. ORION-11 is one of a number of trials comprising the broad ORION Phase III program for inclisiran that will together enroll approximately 3,400 patients with heterozygous familial hypercholesterolemia or with atherosclerotic cardiovascular disease, or ASCVD, with or without additional risk equivalents. These studies build on the very promising results from the ORION-1 Phase II study that showed over 50% time average reductions in LDL cholesterol with a biannual dosing regimen and an encouraging safety profile.

Next up for Phase III development is ALN-TTRsc02, our subcutaneously-administered investigational RNAi therapeutic in development for the treatment of both wild-type and hereditary ATTR amyloidosis. We're excited by the clinical data we've generated in this program showing potent knockdown of TTR at very low doses with a durability profile that supports a quarterly and possibly biannual dose regimen. This program is slated to move into Phase III in 2018.

Finally, it's worth mentioning that we have made great progress on our earlier-stage clinical programs as well. This includes cemdisiran for complement-mediated diseases and lumasiran for primary hyperoxaluria type 1. And we formed a partnership with Vir for our HBV and other infectious disease efforts. These efforts together exemplify the robustness of our pipeline.

As we move our late-stage programs through pivotal trials and toward the market, we also aim to generate exciting data from our earlier-stage efforts and also new IND filings. Of course, we intend to remain strategic in pursuing programs in disease areas with very high unmet need, where our medicines can make a significant impact. Consider, for example, our exciting results from just last week with lumasiran, where we are achieving substantial reductions in urinary oxalate, the disease-causing metabolite in this severe fatal disease. All this progress is enabled by having an R&D engine that continues to generate new investigational candidates and a modular and highly reproducible R&D strategy that can allow us to streamline development of RNAi therapeutics. Hereto, we continue to further optimize our platform, as exemplified by presentation of data at the recent OTS Meeting on our ESC+ conjugate technology. We believe these important advances in our earlier-stage pipeline and in our research platform overall will enable us to achieve sustainable growth for the long term.

We expect that this work, combined with the commercial initiatives I described earlier, will enable Alnylam to transition from a late-stage R&D company into a fully-integrated R&D and commercial company.

With those introductory comments, I'd like to now turn the call over to Akshay to review our pipeline progress in more detail. Akshay?

Thanks, John, and good afternoon, everyone. As John noted, we've made strong progress with our pipeline of investigational RNAi therapeutics. We're advancing 7 investigational RNAi therapeutics in clinical development, including 4 programs in late and 3 in earlier-stage development. By the end of this year, we expect to have our first program submitted for registration.

Let's begin with our programs in ATTR amyloidosis, which include patisiran and ALN-TTRsc02. This was certainly a big period for patisiran, with positive results from the APOLLO Phase III study. We reported these full results just last week at the European ATTR amyloidosis meeting in Paris.

As a reminder, APOLLO was a randomized, double-blind placebo-controlled study of patisiran in patients with hATTR amyloidosis with polyneuropathy. This was the largest ever study in this indication and one that recruited the most heterogeneous and representative study populations in this global disease. Patisiran met the primary endpoint with a 34-point mean difference relative to placebo at 18 months. This difference was highly statistically significant, with a p value of 9.26 x 10 to the power of -24. Furthermore, patisiran resulted in a negative 6-point mean change in mNIS+7 relative to baseline in 18 months -- at 18 months, signifying a substantial improvement of neurological impairment as compared to a 28-point mean increase reported for the placebo group, signifying the expected worsening in disease progression. All subcomponents of the mNIS+7 score showed improvement with patisiran treatment as compared with placebo. In addition, improvement in mNIS+7 resulting from patisiran treatment was also observed across all patient stratification subgroups, including age, sex, race, geographic region, baseline neuropathy impairment, genotype, prior TTR stabilizer use, baseline FAP stage and inclusion in the cardiac subpopulation. Patisiran also met the key secondary endpoint, the Norfolk Quality of Life Diabetic Neuropathy score, with a mean 21.1-point treatment benefit compared to placebo at 18 months. This difference was also highly statistically significant, with a p value of 1.1 x 10 to the power of -10. As with mNIS+7, the mean change from baseline in Norfolk-QOL was a negative 6.7-point change, indicating a significant and clinically meaningful improvement commensurate with the mNIS+7 result. In a prespecified binary analysis, 56% of patisiran patients had an improvement in mNIS+7 compared with 4% of placebo patients. Similarly, 51% of patisiran patients had an improvement in Norfolk-QOL versus 10% for placebo. Both of these results were highly statistically significant.

Looking at the other secondary endpoints, which further flesh out the full clinical meaningfulness of the mNIS+7 and the Norfolk-QOL data, patisiran demonstrated statistically significant improvements over placebo in all other secondary endpoints at 18 months, including: NIS-W, which measures muscle strength, with an approximately 18-point improvement for patisiran relative to placebo; R-ODS, a patient-reported outcome measuring activities of daily living, with a 9-point improvement for patisiran relative to placebo; timed 10-meter walk tests assessing ambulatory ability and gait speed, with an approximately 0.3 meter per second change with patisiran relative to placebo; and BMI, assessing nutritional status, with an approximately 116-unit change for patisiran relative to placebo. And finally, COMPASS-31, a patient questionnaire assessing autonomic disease symptoms, with an approximately 8-point improvement for patisiran relative to placebo.

We also reported favorable and significant changes in several exploratory cardiac measures in patisiran-treated patients in the prespecified cardiac subpopulation. These included NT-proBNP, certain echocardiographic parameters and the 10-meter walk time. Notably, with NT-proBNP there was a median 49.9 pg/ml decrease or improvement in the patisiran arm compared with a 320 pg/ml increase or worsening in the placebo arm. This over 300 pg/ml difference between patisiran and placebo is considered a clinically meaningful difference. Similarly, the effects on left ventricular wall thickening and longitudinal strain are also clinically meaningful. Of note, these changes in biomarker and echocardiographic measures also associated with an improvement in functional status, as documented with the 10-meter walk time. Here, patients in the cardiac subpopulation had a statistically significant and clinical meaningful 0.35-meter per second improvement in this measure. Changes relative to baseline were also measured for troponin I, LV mass and LV ejection fraction were not statistically significant at the 18 point -- 18-month time frame. So overall, for a majority of patients, we are seeing reversal of disease progression and improvement in their disease symptoms.

On the safety side, patisiran showed an encouraging safety and tolerability profile relative to placebo with up to 18 months of dosing. The most commonly reported adverse events that occurred more frequently in patisiran-treated patients were generally mild to moderate and included peripheral edema and infusion-related reactions. The frequency of death and serious adverse events was similar in the patisiran and placebo groups, with respect to infrequency of events being consistent with the underlying disease, hATTR amyloidosis. There were no safety signals related for steroid premed regimen and also no signals with regard to thrombocytopenia, hepatic or renal dysfunction. Patisiran also showed an encouraging safety and tolerability profile in the cardiac subpopulation. With 99% of eligible patients now enrolled into the global OLE study, we look forward to generating longer-term results for patisiran on safety and efficacy.

We view the APOLLO results as truly impressive, and they highlight how TTR knockdown with patisiran has the potential to have a significant and clinically meaningful effect across a broad spectrum of clinical symptoms and manifestations in this multisystem disease. Indeed, as shown here on Slide 13, we believe we see evidence for a broad-based effect of patisiran toward multiple dimension -- multiple disease manifestations of hATTR amyloidosis when we consider the effects of patisiran on specific study endpoints, ranging from neurologic to cardiac, and when we also consider the lower incidence of the number of AEs in the patisiran arm and substantially lower discontinuations in the patisiran arm. These findings overall highlight why we believe that patisiran can potentially become a transformational therapy for patients with hATTR amyloidosis.

Now in addition to patisiran, we're also developing ALN-TTRsc02 as an investigational RNAi therapeutic for ATTR amyloidosis, including both hereditary and wild-type forms of the disease. ALN-TTRsc02 uses our ESC-GalNAc-conjugate platform and is aimed at providing a subcutaneous RNAi treatment alternative to patients with ATTR amyloidosis.

At our patisiran RNAi roundtable in August, we provided updated results from our TTRsc02 Phase I study, which are shown here on Slide 14. In this 80-subject, single ascending dose study, TTRsc02 showed what we believe to be a highly encouraging potency toward TTR knockdown and a durability of effect. Indeed, our results suggest that a once-quarterly or possibly semi-annual fixed dose of either 25 or 50 milligrams could provide the same level of TTR knockdown as observed with patisiran. Regarding safety results, TTRsc02 was generally well-tolerated, supporting further advancement of this investigational RNAi therapeutic.

We believe that these positive results position TTRsc02 for accelerated development, and we very much look forward to advancing this program into planned Phase III studies in 2018, particularly in light of the significant de-risking of the TTR knockdown hypothesis from APOLLO.

With that, let's now turn to our givosiran program, where we've made some very significant progress in recent months. As you know, givosiran is in development for the treatment of acute hepatic porphyrias. As a reminder, hepatic porphyria is a group of ultra-orphan diseases caused by genetic defect in the heme biosynthetic pathway. They are a devastating family of diseases with enormous disease 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 typically last for days and require hospitalization. Moreover, many patients suffer from chronic symptoms in between attacks.

This morning, we were pleased to announce initiation of the ENVISION Phase III study of givosiran. ENVISION will be a randomized, double-blind placebo-controlled study in approximately 75 acute hepatic porphyria patients. The primary endpoint will be change in annual attack rate relative to baseline for patients treated with givosiran versus those treated with placebo at 6 months of treatment. We will, of course, be measuring the more chronic aspects of porphyria like pain, since patients with porphyria suffer from disease symptoms between attacks.

The ENVISION study design has been supported by the FDA, EMA and the Japanese FDA or PMDA, and we've reached alignment with the FDA on an interim analysis in approximately 30 patients using reduction in urinary levels of ALA at 3 months as a biomarker surrogate endpoint that's likely -- reasonably likely to predict clinical benefit. This was based on data in the literature on the role of ALA in porphyria attacks, as well as data shown here on the left-hand side of the slide from our Phase I study that demonstrates the graded relationship between ALA lowering and attack reduction. In our current Phase I and Phase II early studies, as shown here on the right-hand side of the slide, we already demonstrated robust lowering of ALA, with over 80% reduction in this biomarker relative to baseline. So we look forward to potentially confirming this in our Phase III interim analysis, which we expect to report in mid-2018. If the interim analysis is positive, and pending regulatory support, we would then be in a position to file an NDA for an [excised] approval based on the interim study results at or around year-end 2018, representing a significant acceleration of our efforts to bring this potentially promising investigational medicine to patients.

Turning to our fitusiran program, an RNAi therapeutic for the treatment of hemophilia and rare bleeding disorders. Here, we've had a mixed set of results in recent months. As a reminder, fitusiran is an investigational RNAi therapeutic targeting antithrombin, or AT, that's designed to increase thrombin generation and thus provide hemostasis in people with hemophilia.

On the one hand, we've been very pleased with data we presented at the ISTH meeting in Berlin in July, where we presented new results from our ongoing Phase II early study.

Here, fitusiran administration resulted in a low median ABR of 1 in all patients and 0 in inhibited patients, with a median treatment duration of 14 months. On the safety side, most AEs were mild to moderate with up to 20 months of dosing. Asymptomatic ALT elevations more than 3x supplement normal were observed in HCV antibody patients -- HCV antibody positive patients, with all either having resolved or resolving at the time of the data cutoff.

Also on the positive side, we're happy to have initiated our ATLAS Phase III program for fitusiran. 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, whether patients are on-demand or prophylactic therapy. ATLAS is designed to enroll approximately 250 patients in 3 separate trials at over 100 clinical centers around the world. Notwithstanding this encouraging progress, we recently reported a case of a fatal thrombotic event in a patient with severe hemophilia A without inhibitors in the Phase II early trial.

As a result of this unfortunate event, we elected to temporarily suspend dosing in all fitusiran clinical studies, including the Phase II early study and the ATLAS Phase III trials. We've now completed a comprehensive review of the safety event and have worked with our KOLs to define a risk management approach that we believe will enable resumption of dosing in our studies.

Specifically, we believe that a lower level of replacement factor or bypassing agent needs to be used for treatment of any breakthrough bleeding event. We're now in discussions with the regulators to reach agreement on the risk mitigation plan with the goal of resuming dosing of fitusiran studies as soon as possible. We look forward to updating you upon restart of the studies as soon as possible, which we're aiming to do by the end of this year or fairly early next year.

Another late pipeline program is inclisiran, our investigational RNAi therapeutic targeting PCSK9 that's being developed in collaboration with our partners at The Medicines Company. We're pleased to recently announce with The Medicines Company initiation of patient dosing in the ORION-11 trial, one of a number of trials comprising the broader ORION Phase III program for inclisiran in patients with heterozygous familial hypercholesterolemia or with ASCVD, with or without additional risk factors. Inclisiran remains a very important product option for Alnylam in light of our significant economic participation in the value of the program. In addition, as John mentioned earlier, we 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. During third quarter and recent period, we also made good overall progress in some of our earlier-stage programs, including cemdisiran, formerly known as ALN-CC5, where we initiated a new Phase II study in patients with atypical hemolytic-uremic syndrome or aHUS; and lumasiran, formerly known as ALN-GO1, where we reported exciting initial efficacy data and an encouraging safety profile in patients with primary hyperoxaluria type 1, or PH1. In the interest of time, I'll just briefly touch on the results we just reported from lumasiran, which we consider to be quite promising. As a reminder, PH1 is an ultra-orphan disease in which oxalate crystals build up in the kidney, leading to painful and recurrent kidney stones, and also damage to extrarenal tissues. Sadly, PH1 is a disease that is more prevalent in children and typically is treated with chronic dialysis, and in the most severely affected, often requires a dual liver and kidney transplant.

Lumasiran targets the enzyme glycolate oxidase, thereby depleting the substrate necessary for the production of oxalate, which directly contributes to the pathophysiology of PH1. Just last week at the American Society of Nephrology Kidney Week in New Orleans, we presented initial patient data from Part B of the ongoing Phase I/II study of lumasiran. Part B is a randomized, single-blind placebo-controlled study in PH1 patients aged 16 to 19 years old. Of note, this study is the first we've performed with an RNAi therapeutic in the pediatric population.

In the 2 initial cohorts, lumasiran achieved substantial reductions in urinary oxalate levels in all patients, supporting the hypothesis that RNAi-mediated inhibition of GO1, that 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 the mean maximum reduction of 66% and with all patients reaching urinary oxalate levels previously shown to be associated with a reduced risk of progression to end-stage renal disease. Regarding safety, lumasiran was generally well-tolerated, with no treatment-related serious adverse events or study discontinuations up to 7 months after initial dosing. The only drug-related adverse event was a mild and transient injection site reaction. We now aim to discuss this data with regulators and advance lumasiran toward Phase III clinical studies. We believe this program can move quickly, and we do believe that urinary oxalate levels can be considered a surrogate endpoint for approval, although we have yet to confirm this with global regulatory authorities.

Finally, while we don't have sufficient time to review details, we also made exciting progress on our platform technology efforts. Specifically, we presented data at the OTS Meeting on our ESC+ conjugate platform, where we've engineered an approach to improve the therapeutic index for our GalNAc-siRNA conjugate. Going forward, we plan on using our ESC+ platform for future clinical programs. And this will begin next year with our ALN-AAT02 for Alpha-1 antitrypsin deficiency liver disease, an area of significant unmet medical need. We look forward to updating you on this progress in the future.

In summary, we had a very exciting third quarter and recent period, having now advanced the pipeline with 4 programs in Phase III, including one advancing towards registration and multiple earlier-stage programs with significant progress as well. And with that, I'll now turn the call over to Manmeet for a review of our financials. Manmeet?

Thanks, Akshay. Good afternoon, everyone, and thanks for joining us today. I will be referring to Slide 24 for a discussion of our third quarter 2017 financial results. We maintained a solid balance sheet, ending the third quarter of 2017 with approximately $1.15 billion in cash, including restricted investments. Our GAAP revenues were $17.1 million in the third quarter of 2017 as compared to $13.7 million in the third quarter of 2016. Revenues for the third quarter of 2017 included $14.6 million from our alliance with Sanofi Genzyme, $2.3 million from our alliance with The Medicines Company and $0.2 million from other sources.

The increase in revenues in the quarter ended September 30, 2017 as compared to the prior-year period was due to increased services performed by us relating to our clinical development programs for which Sanofi Genzyme has opted in.

Moving to expenses. R&D expenses were $95.3 million in the third quarter of 2017 as compared to $97.9 million in the third quarter of 2016. The slight decrease in the R&D expenses for the quarter ended September 30, 2017 as compared to the prior-year period was due to a decrease in manufacturing expenses related in large part to our decision in October 2016 to discontinue the development of revusiran, partially offset by increased stock-based compensation expense for certain performance-based stock option awards.

We expect that R&D expenses will increase during the fourth quarter of 2017 as compared to the third quarter of 2017 as we continue to develop our pipeline, advance our product candidates into later-stage development and prepare regulatory submissions.

G&A expenses were $47.6 million in the third quarter of 2017 as compared to $22.4 million in the third quarter of 2016. The increase in G&A expenses for the quarter ended September 30, 2017 as compared to the prior-year period was due to an increase in commercial and medical affairs headcount to support corporate growth and to prepare for the potential launch of our first commercial product. We expect our G&A expenses will increase slightly during the fourth quarter of 2017 as compared to the third quarter of 2017 as we continue to grow our operations, including the continued build-out of our commercial infrastructure.

The GAAP net loss was $122.9 million in the third quarter of 2017 as compared to a GAAP net loss of $104.1 million for the same period in the previous year. The non-GAAP net loss for the third quarter of 2017 was $97 million as compared to a non-GAAP net loss of $88.5 million for the same period in the previous year.

With respect to guidance for 2017, we remain on track to end the year with greater than $1 billion in cash, including $150 million in restricted investments.

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

Thanks, Manmeet. As you heard from John and Akshay, we celebrated exciting clinical milestones in the third quarter and recent period. We were also pleased to announce recently a strategic alliance with Vir Biotechnology to advance RNAi therapeutics for infectious diseases. This agreement represents another step towards bringing RNAi therapeutics to patients who have limited or inadequate therapeutic options. Partnering with the exceptional, experienced team of Vir to advance investigational RNAi therapeutics in infectious diseases will expedite the development path for these medicines, while enabling Alnylam to maintain operational focus on a robust pipeline of later-stage programs.

A key value-creating feature of this alliance is our no-cost option prior to the start of Phase III to participate in a global profit share arrangement, thereby allowing Alnylam to retain substantial product value at a highly de-risked stage of product development.

Let's now turn to our remaining 2017 goals. With patisiran, our expanded access program remains open in the U.S. and we are receiving requests for compassionate use from many European countries. As discussed, we remain squarely on track to file our NDA at year-end, followed shortly by an MAA, putting us in a position, assuming regulatory approval, to launch the very first RNAi therapeutic in 2018. And as we've previously discussed, we're in building mode for a successful U.S. and Western EU launch. In fact, our U.S. business leadership is now in place and we are putting in place the remainder of our customer-facing organization.

With fitusiran, we're engaging with the regulators to discuss protocol amendments to our Phase II OLE and ATLAS clinical trials to implement our risk mitigation plan, with the goal of resuming dosing as soon as possible.

We also plan to share additional hemophilia data at the ASH Conference in December, including a very important abstract on an in silico modeling method that can accurately predict the impact of antithrombin lowering on thrombin generation, including doing an administration of replacement factor or bypassing agents to treat breakthrough bleeds. Finally, as Manmeet said, we expect to meet our guidance of ending 2017 with greater than $1 billion in cash, including restricted investments.

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

Thank you, Yvonne. Operator, we will now open the call for your questions. (Operator Instructions)

(Operator Instructions) Our first question comes from Terence Flynn from Goldman Sachs.

Maybe just on givosiran, I was wondering in the Phase III program if you guys have disclosed what percent reduction you'll need in ALA interim to be deemed a successful trial? And then if it is successful at the interim, will you continue it until the end to gather attack data from all patients, or will that be the end of the study?

Great question, Terence. Akshay, why don't you answer that?

We haven't formally disclosed it, to my knowledge, but I think we can say that with over 80% reduction in ALA and that rather important graded relationship that we've seen and that kind of level we can reproduce again, I think we can guide for that. We have an agreement with regulators and we should comfortably hit the necessary biomarker level.

And then the other question, Akshay, was whether patients continue on therapy. And the simple answer is yes, Terence. I mean, all the patients, the 30 patients that will be part of the interim analysis would comprise the -- a portion of the total of 75 or so patients that would be in the full study. And those 30 patients that would be part of the interim analysis would still continue for the final analysis that would be based on attack rate data.

And just to add, of course, though, we'll be rolling the patients over into a Phase III early study.

That's right, yes. For long-term data.

Okay. And then is the agreement consistent between U.S. and Europe regarding the endpoints in the interim? Or are there any key differences as you think about what the regulators in each geography would want?

Yes, Akshay, do you want to...?

We're still putting the finishing touches on that, but we're confident that we can have a consensus understanding of the endpoint we need to show for ALA and we're confident we can reach that.

Yes, I think to just to clarify that, there's alignment on the full study endpoint on the annualized attack rate, with the U.S. FDA, EMA and also the Japanese FDA. The interim analysis right now has been locked down with the U.S. agency, but we are continuing our dialogue with the Europeans on that front.

And feel confident that we should get to a common understanding.

Our next question comes from Vincent Chen with Bernstein.

At the ATTR conference last week, we heard a lot of excitement from folks about the potential of TTR-lowering drugs in the wild-type TTR amyloidosis indication, pointing out this could dwarf the size of the hereditary population. However, experts there didn't know that there were potential complications, notably if the Pfizer tafamidis ATTR-ACT trial reads out positively in early '18, could this require subsequent trials to be on top of tafamidis and potentially lead to a label for use on top of tafamidis, despite experts believing that patisiran is probably much more effective than tafamidis. How are you thinking about the path forward in the wild-type indication here? Is the design likely to use mortality and hospitalization endpoints, similar to the ATTR-ACT trial? Or could biomarkers or functional endpoint be sufficient? And would you wait for the tafamidis readout to -- or would you move forward in advance? And then finally, if Pfizer's ATTR-ACT trial were positive, how would you think about potentially running a trial on top of tafamidis or perhaps a head-to-head study? Or would neither of these be required?

Okay. Lots of good questions in there, Vincent. Let me just take the second one quickly first, which is that the expected date for the ATTR-ACT study is in early 2018. So we'll have those data in front of us before we lock down any definitive Phase III trial design, certainly for the wild-type ATTR population. So that's the answer to that one. Akshay, you want to handle the other 2? The first and second?

Yes. I mean, there are a number of approaches we could take. As you know, at least for the mutant TTR amyloidosis with associated cardiomyopathy, we've previously negotiated a 6-minute walk distance and TTR knockdown endpoint. That could certainly be entertained again, as could a variety of other approaches, and you started to outline them: head-to-head, on top of, et cetera. I think the most important thing is that we need to complete the dialogue with the FDA and others around our patisiran data set, come to a common understanding of how they think about our data in the cardiac subset with patisiran. I think that will be highly informative, as will the data that you mentioned from the ATTR-ACT Study. All of that will have to be computed before we put a path forwards for our drugs in the wild-type TTR space. Our greatest opportunity for that, of course, comes from ALN-TTRsc02, and we intend to put that into Phase III development by the end of next year. But by that time, I think we'll have much firmer plans that we can discuss with you.

And we certainly, Vincent, concur with your statement around the size of that wild-type population and the significant unmet need that exists there. So we're quite committed to be leaders in the ATTR space, broadly speaking, and that means advancing patisiran where appropriate from a patient population perspective as consistent with the label, but then also further innovation from our pipeline with TTRsc02.

If I could wedge in just one quick question, a little too tempting when you talk about being leaders in TTR space. So if I think of Alnylam, you guys are an RNA company with a rich scientific heritage there, but you're also likely to be soon the dominant TTR amyloidosis company with a leading commercial presence there as well. And there are other products in development in the TTR space, and this is actually a world where combination therapies could make sense, and you could actually be the best suited to commercialize some of these new drugs. Would you consider branching out of the RNA space and moving into areas like this, whether through L&A or internal R&D?

Well, let me look at Yvonne, who heads up our business development efforts in the company.

Yes. No, I think you made a very good point in our aspirations to be leaders in the amyloidosis space. We feel we have the best-in-class medicine here with patisiran, and I think it behooves us to keep a really close eye on what's happening in the amyloidosis environment in general. And we will continue to watch the space very carefully.

One thing that I could just add is that for the current generation of molecules like tafamidis and diflunisal, we know from our experience with the patisiran Phase II open-label extension study, that certainly, the combination there didn't provide any great benefit over patisiran alone, and I think that, along with the observations of patisiran as monotherapy, which we revealed in last week's show, really, the great potential of this drug to be of service to the vast majority of patients with a wide spectrum of disease, with polyneuropathy and significant cardiomyopathy.

We keep close tab on the field, Vincent. And the simple answer to your -- sort of the premise of your question is, we're not -- we're building a product company at Alnylam and we're certainly obviously foundationally driven by our RNAi therapeutics pipeline, but that's not the only way we'll build the company for the future.

Our next question comes from Ted [Tanashi] with Piper Jaffray.

Congrats on, really, all of the progress, from APOLLO to the Vir collaboration to starting the patisiran Phase III study. My question has to do first with CC5. I forget what that new one's called, I apologize. But what was the basis for the shift to aHUS versus PNH? Do you think there's some clinical differences there? Are there drug differences there that may benefit that? And then the second quick follow-up question is, with all the success that you're having in the liver, do any of these new targeting agents get to extrahepatic, with the ability to potentially treat beyond liver-synthesized proteins?

Well, those are 2 great questions. I'll just start. I'll let Akshay answer the first one. I'll potentially venture into the second one. I'll just start the first one by saying that the CC5 non-proprietary name is cemdisiran. And Akshay, you can comment a little bit on aHUS and the rationale there.

Yes, so with respect to cemdisiran, I think the initial studies that we shared with you last year revealed that this is really a very potent drug, giving up to 98% to 99% knockdown in C5. Now looking at that degree of knockdown in the non-nucleated red cells in PNH, which are highly susceptible to complement attack and require almost complete extinguishing of complement hemolytic activity, that level was not quite enough to get the level of efficacy that was required. However, we know through a number of lines of evidence, both from the literature and experience with other anti-C5 agents in aHUS and work we've done in vitro, that 98% to 99% knockdown in other indications where nucleated red cells, such as the endothelial cells in aHUS, which are under complement attack, should be sufficient to give a significant degree of protection. And so we're very encouraged by those rationales, and so we've advanced cemdisiran into a proof-of-concept Phase II study where we think an intermittently-administrated agent would really serve a very significant population there to prevent further attacks in that devastating renal disorder.

And on your extrahepatic question, Ted, it's -- obviously, we continue to explore those type of opportunities. It's not the core focus. The core focus remains on liver opportunities where we have many, many, many opportunities to prosecute and advance into the clinic for the foreseeable future. But our scientists continue to be leaders in the RNAi space and have made steadfast progress in extrahepatic delivery. We presented some data, in fact, at OTS using some antibody fragment-based approaches targeting tumors, for example. And we had previously shown data on muscle delivery of sRNAs and also ocular delivery of sRNAs. And I would not be surprised over the next 3 to 5 years to see new programs go into the clinic in those spaces based on the promising data. But in the meanwhile, we have our hands quite full with -- and are very flush with liver-based targets, where, of course, we have essentially 100% confidence, or as close to that as you can have, around our ability to engage those targets reliably. And that is exciting as an opportunity for us.

Our next question comes from Mike King with JMP Securities.

Sorry, I got a couple of conference calls going in the background. I just wanted to know, John or Akshay, coming out of the amyloidosis meeting, you got a question earlier about the wild-type TTR patients and I'm just wondering, I mean, I know mechanistically, patisiran shuts the entire gene down regardless of mutations, but I'm just concerned that in other territories, particularly Europe, where you may not have or you may have just a few wild-type patients in the population, that there might be a requirement to do a separate study to show the benefit of patisiran in a wild-type population. I just wonder if you could speak to that.

Yes, I mean, I think we never said that we wouldn't do another study in wild-type. In fact, we would expect to do another study in wild-type disease to get labeled there. So yes, absolutely. But I do think mechanistically, and Akshay should weigh in with his thoughts, that based on the encouraging data we have with hATTR amyloidosis, we feel confident that we'd be able to see encouraging results with wild-type disease as well. Akshay, anything to...?

Yes, I agree with that. The wild-type protein is certainly thought to be mechanistically very important in wild-type ATTR cardiomyopathy, and Professor Hawkins spoke to that last week on the IR call and reaffirmed his feelings that what we have shown in terms of the (inaudible) cardiac outcome with patisiran bode well for development of both patisiran and other anti-TTR agents in wild-type disease.

Our next question comes from Maury Raycroft with Jefferies.

So as kind of a follow-up, so as for Phase III trial with TTRsc02, what are some ways that you can look at designing the study that won't erode economics? And can you remind how much as a percent of patisiran's value do you own and how much for sc02?

So let me take part of that question and then have Akshay take it over from there. So as a reminder, with patisiran, we own 100% of North American rights and 100% of Western European rights, and Sanofi Genzyme is our partner for the Rest of World. So that's patisiran. With TTRsc02, the ownership share is essentially like patisiran. So it's 50-50 in North America and Western Europe and then Sanofi-Genzyme is Rest of World. Now we control development, and in fact, we control commercialization globally for development and in commercialization for our territories and therefore, whatever we do and however we develop TTRsc02 will always be done in a way in which we don't cannibalize or impair the value of our patisiran business. And so we're going to be very mindful of that, including ways to work closely with Sanofi Genzyme, even potentially restructuring those agreements. But for the most part, we do control development, we do control commercial in our territories even when we're 50-50, and therefore, we're going to be very mindful around how the development takes place to ensure the maximization of value for patients, first and foremost, and then for Alnylam. Now regarding development paths, Akshay, do you want to comment a little bit on different approaches?

Yes, the first thing to mention is that the patisiran data is a rich data set to analyze and understand very important relationships like degree of TTR knockdown and what impact that has on various outcomes. We know that we've had what looks to be a very important impact on neurologic, autonomic and cardiac outcomes in the patisiran population, where, just to remind everybody, the majority of patients have both cardiomyopathy and neuropathy. So with that, I think, that the first argument could be to discuss with regulators a biomarker-based approach looking at TTR knockdown and seeing whether that would be a path to approval. Another very important thing we've learned from the APOLLO experience is that, really, with that profound degree of knockdown associated with patisiran, you start seeing clinical benefit or what looks to be clinical benefit, really early in the course of disease. And certainly, by 9 months, all the endpoints we reported were statistically significantly different between the 2 arms of the study. So the size and shape and length of the studies that we would have to do in the future, I think will be significantly smaller and shorter. And so that part -- that points to other approaches, even potentially a placebo control approach if it was sufficiently short duration. And so there are a variety of ideas here. Our first goal is to discuss patisiran fully with regulators, seek approval for it, and I think from that, we'll be able to negotiate an expeditious path to develop sc02 in the broadest possible population where I think really the aim would be to study hATTR amyloidosis in its fullness.

Our next question comes from Gena Wang with Barclays.

And I managed to miss my flight, so I can ask the questions here. So I would just have one question on fitusiran. So just wondering, have you already submitted the protocol to the FDA? And in the protocol, do you have a detailed instruction to cover all the patients with different condition? Or just one universal protocol to cover as many patients as possible? And then regarding the time line of the trial resumption, just wondering how long the process would take from the document submission to the feedback from the FDA? Is it possible FDA could come back to request additional data?

Okay. Let's turn that to Akshay. I'll just say for starters, just to remind you the time line, Gena, the first step is to complete, and these are literally ongoing discussions, a type A meeting with the FDA. And then subsequent to that type A meeting, once we reach alignment with the FDA, we would be submitting specific protocols, protocol amendments. So Akshay, do you want to comment a little further?

Yes, with respect to the details of the protocol or protocols and what is or isn't codified, as you may recall, Gena, there are a number of Phase III studies in inhibitors, noninhibitors and in the prophylaxis population, each encompassing here for the A and B patients. And in each of those protocols, there are specific conditions for use codified and there will be educational around it as well for the use of rescue agents, whether it's Factor VIII, Factor IX or bypass agents as appropriate to the protocol. So all of that is being worked out in detail, and we're very confident that we can get alignment with regulators with all of that, given the level of understanding we now have of the serious adverse event that occurred and led to death.

Yes, I'll just add that we've been really reassured by the strong alignment that we've achieved with our KOLs and other experts on a path forward, and also reassured by the strong interest by the patient community for continued development of fitusiran, because there really are significant unmet needs across the spectrum of these patient populations and the support has been very reassuring.

So regarding the time line, what will be -- is there any like rough estimate how long it would take FDA to get a final green light to trial resumption by the time you submit the protocol?

Yes, we'll, Gena, we'll provide good color on all this so that people are aware of the time line, but our goal is to get back into dosing patients as soon as possible. And we're pleased with the level of urgency that we've seen from the FDA so far. So we are going to provide color as these dialogues continue. So stay tuned.

Our last question comes from Paul Matteis with Leerink Partners.

This is Ben Burnett. I'm on for Paul Matteis. I had 2 questions. But first, I just want to ask a follow-up to what Gena was asking. I guess with regards to restarting the ATLAS studies, given your progress with study investigators and the regulators, do you plan to initiate all 3 studies concomitantly or would it be possible or desirable to open these studies in a stepwise manner or separately?

Yes, I mean, Akshay, do you want to take those on?

Yes, our goal all along is to conduct the 3 studies in parallel, so we aim to do that.

Does that help you, Ben?

Yes, okay, that makes sense. I also want to ask about the givosiran study. So I guess, with regards to some of the secondary endpoints such as pain and impact to quality of life, I guess, how important are these secondary measures towards givosiran's commercial potential? And would these measures be included in the interim look?

Sure. Let me maybe turn it over to Yvonne to comment on the broader set of endpoints that we're collecting there.

Yes, I think, as you know, these patients, as well as having acute attacks of abdominal pain and a range of other symptoms, 65% of them we've seen have chronic symptoms, and this obviously is a very important kind of feature of the disease. And so I think looking at the number of secondaries around quality-of-life measures is actually going to be quite helpful in this patient population. I think Akshay has already talked about the endpoints that would be required for approval, both with respect to the interim analysis as well as the complete Phase III study. But I do think that these quality-of-life measures and measures of pain, et cetera, are going to be helpful to us as we take this medicine to patients, hopefully, post-approval.

And then, Ben, just on the interim analysis point, obviously, the interim analysis will be based on lowering of urinary ALA. That is what's been agreed to with the FDA, and we hope to reach that agreement with other global regulatory authorities. We'll submit all of the data we have at that point in time, both safety and efficacy data, as part of the interim analysis, but there's no requirement for, based on our discussions, for impact on those other measures as it relates to the interim analysis.

Okay. And I guess, just sort of on that, in terms of communicating that to the investor community, when would we get an update maybe on some of these other secondary measures? Would that be at the (inaudible)?

Yes, we probably will provide information on the study. I think the study design is going to be on ClinicalTrials.gov. There are some of those secondary endpoints will be listed there, Ben, as well. And in our corporate presentation, our slide covering ENVISION will capture some of those details as well. So that information will be out there for sure.

And ladies and gentlemen, this does conclude the Q&A portion of today's conference. I'd like to turn the call back over to our host.

All right. Well thanks, everyone, for joining us this afternoon. Obviously, 2017 has been just a remarkable year for Alnylam. I think it goes without saying that we remain so grateful to the patients, their families, caregivers and the investigators and study staff who participated in APOLLO and our earlier patisiran studies. We're excited to submit our first NDA in the coming weeks, and obviously, to bring this important medicine forward to patients as a commercial-stage company. So with that, thank you all and have a great rest of day. Bye-bye now.

Ladies and gentlemen, this does conclude today's presentation. You may now disconnect, and have a wonderful day.