Alnylam Pharmaceuticals, Inc. Annual Report 2018

Form 10-K (NASDAQ:ALNY)

Published: February 15th, 2018

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UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549

Form 10-K

☑ ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the fiscal year ended December 31, 2017 OR ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from to Commission File Number 001-36407

ALNYLAM PHARMACEUTICALS, INC. (Exact Name of Registrant as Specified in Its Charter)

Delaware 77-0602661 (State or Other Jurisdiction of (I.R.S. Employer Incorporation or Organization) Identification No.) 300 Third Street, Cambridge, MA 02142 (Address of Principal Executive Offices) (Zip Code) Registrant’s telephone number, including area code: (617) 551-8200 Securities registered pursuant to Section 12(b) of the Act:

Title of Each Class Name of Each Exchange on Which Registered Common Stock, $0.01 par value per share The Nasdaq Global Select Market Securities registered pursuant to Section 12(g) of the Act: None

Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☑ No ☐ Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐ No ☑ Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes ☑ No ☐ Indicate by check mark whether the registrant has submitted electronically and posted on its corporate Web site, if any, every Interactive Data File required to be submitted and posted pursuant to Rule 405 of Regulation S-T (§ 232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit and post such files). Yes ☑ No ☐ Indicate by check mark if disclosure of delinquent filers pursuant to Item 405 of Regulation S-K is not contained herein, and will not be contained, to the best of the registrant’s knowledge, in definitive proxy or information statements incorporated by reference in Part III of this Form 10-K or any amendment to this Form 10-K. ☐ Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer ☑ Accelerated filer ☐ Non-accelerated filer ☐ (Do not check if a smaller reporting company) Smaller reporting company ☐ Emerging growth company ☐

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐ Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act). Yes ☐ No ☑ The aggregate market value of the registrant’s common stock, $0.01 par value per share (“Common Stock”), held by non-affiliates of the registrant, based on the last sale price of the Common Stock at the close of business on June 30, 2017, was $7,243,192,478. For the purpose of the foregoing calculation only, all directors and executive officers of the registrant are assumed to be affiliates of the registrant. At January 31, 2018, the registrant had 99,867,820 shares of Common Stock outstanding. DOCUMENTS INCORPORATED BY REFERENCE Portions of the registrant’s definitive proxy statement for its 2018 annual meeting of stockholders, which the registrant intends to file pursuant to Regulation 14A with the Securities and Exchange Commission not later than 120 days after the registrant’s fiscal year end of December 31, 2017, are incorporated by reference into Part II, Item 5 and Part III of this Form 10-K.

ALNYLAM PHARMACEUTICALS, INC. ANNUAL REPORT ON FORM 10-K For the Year Ended December 31, 2017 TABLE OF CONTENTS

PART I ITEM 1. BUSINESS 1 ITEM 1A. RISK FACTORS 39 ITEM 1B. UNRESOLVED STAFF COMMENTS 64 ITEM 2. PROPERTIES 65 ITEM 3. LEGAL PROCEEDINGS 65 ITEM 4. MINE SAFETY DISCLOSURES 65

PART II ITEM 5. MARKET FOR REGISTRANT’S COMMON EQUITY, RELATED STOCKHOLDER MATTERS AND ISSUER PURCHASES OF EQUITY SECURITIES 66 ITEM 6. SELECTED CONSOLIDATED FINANCIAL DATA 68 ITEM 7. MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS 69 ITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK 85 ITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA 86 ITEM 9. CHANGES IN AND DISAGREEMENTS WITH ACCOUNTANTS ON ACCOUNTING AND FINANCIAL DISCLOSURE 126 ITEM 9A. CONTROLS AND PROCEDURES 126 ITEM 9B. OTHER INFORMATION 126

PART III ITEM 10. DIRECTORS, EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE 127 ITEM 11. EXECUTIVE COMPENSATION 127 ITEM 12. SECURITY OWNERSHIP OF CERTAIN BENEFICIAL OWNERS AND MANAGEMENT AND RELATED STOCKHOLDER MATTERS 127 ITEM 13. CERTAIN RELATIONSHIPS AND RELATED TRANSACTIONS, AND DIRECTOR INDEPENDENCE 127 ITEM 14. PRINCIPAL ACCOUNTANT FEES AND SERVICES 127

PART IV ITEM 15. EXHIBITS AND FINANCIAL STATEMENT SCHEDULES 128 ITEM 16. FORM 10-K SUMMARY 133 SIGNATURES 134

This annual report on Form 10-K contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, that involve risks and uncertainties. All statements other than statements relating to historical matters should be considered forward- looking statements. When used in this report, the words “believe,” “expect,” “plan,” “anticipate,” “estimate,” “predict,” “may,” “could,” “should,” “intend,” “will,” “target,” “goal” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these words. Our actual results could differ materially from those discussed in the forward-looking statements as a result of a number of important factors, including the factors discussed in this annual report on Form 10-K, including those discussed in Item 1A of this report under the heading “Risk Factors,” and the risks discussed in our other filings with the Securities and Exchange Commission. Readers are cautioned not to place undue reliance on these forward-looking statements, which reflect management’s analysis, judgment, belief or expectation only as of the date hereof. We explicitly disclaim any obligation to update these forward-looking statements to reflect events or circumstances that arise after the date hereof.

PART I

ITEM 1. BUSINESS Overview We are a global biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. RNAi is a naturally occurring biological pathway within cells for sequence-specific silencing and regulation of gene expression. We are harnessing the RNAi pathway to develop a potential new class of innovative medicines, known as RNAi therapeutics. RNAi therapeutics are comprised of small interfering RNA, or siRNA, and function upstream of today’s medicines by potently silencing messenger RNA, or mRNA, that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

Our research and development strategy is to target genetically validated liver-expressed genes that have been implicated in the cause or pathway of human disease. We utilize a lipid nanoparticle, or LNP, or N-acetylgalactosamine, or GalNAc, conjugate approach to enable hepatic delivery of siRNAs. Our focus is on clinical indications where there is a high unmet need, early biomarkers for the assessment of clinical activity in Phase 1 clinical studies, and a definable path for drug development, regulatory approval, patient access and commercialization.

Specifically, our broad pipeline of investigational RNAi therapeutics is focused in three Strategic Therapeutic Areas, or “STArs:” Genetic Medicines; Cardio-Metabolic Diseases; and Hepatic Infectious Diseases. We are committed to the advancement of our Alnylam 2020 strategy, which is to achieve a company profile with three marketed products and ten RNAi therapeutic clinical programs, including four in late stages of development, across our three STArs by the end of 2020. In December 2017, we filed our first new drug application, or NDA, and marketing authorisation application, or MAA, for patisiran. In January 2018, we announced that the European Medicines Agency, or EMA, has accepted the MAA and initiated its review. Patisiran was previously granted an accelerated assessment by the EMA. In early February 2018, we announced that the United States Food and Drug Administration, or FDA, has accepted our NDA and granted our request for priority review, with an action date of August 11, 2018. If approved, we expect to launch patisiran and begin generating product revenues in 2018.

Finally, based on our expertise in RNAi therapeutics and broad intellectual property estate, we have formed alliances with leading pharmaceutical and life sciences companies to support our development and commercialization efforts, including Sanofi Genzyme, the specialty care global business unit of Sanofi, The Medicines Company, or MDCO, and Vir Biotechnology, Inc.

Key 2017 Highlights Investigational Clinical Pipeline • Patisiran - Hereditary Transthyretin-Mediated (hATTR) Amyloidosis, or hATTR Amyloidosis o Reported positive, final results from APOLLO Phase 3 study o EMA granted accelerated assessment status o FDA granted Breakthrough Therapy Designation o FDA expanded Orphan Drug Designation, or ODD, to treatment of ATTR amyloidosis o Completed submission of NDA with FDA o Completed submission of MAA with EMA

• Givosiran - Acute Hepatic Porphyrias o Aligned with FDA and other regulatory authorities on Phase 3 trial design, including, with the FDA, on an interim analysis based on reduction of urinary aminolevulinic acid, or ALA, as surrogate endpoint reasonably likely to predict clinical benefit o Initiated ENVISION Phase 3 clinical study with interim analysis data readout expected mid-2018 and potential for NDA filing at or around year-end 2018

• Fitusiran - Hemophilia A and B, With and Without Inhibitors o Initiated ATLAS Phase 3 study o Suspended dosing due to a fatal thrombotic event reported in September o Aligned with FDA on clinical risk mitigation measures; clinical hold lifted by FDA in December o Resumed dosing in Phase 2 open-label extension, or OLE; expect to dose in ATLAS Phase 3 study in early 2018

• Inclisiran - Hypercholesterolemia o Reported with MDCO positive data from the ORION-1 Phase 2 study o MDCO initiated comprehensive ORION Phase 3 program

• Early to mid-stage programs

o Reported positive preliminary results from Phase 1 study of ALN-TTRsc02 for the treatment of ATTR amyloidosis

o Reported positive interim results from Phase 1/2 study for lumasiran (ALN-GO1) for treatment of primary hyperoxaluria type 1, or PH1

o Initiated Phase 2 trial for cemdisiran (ALN-CC5) for treatment of atypical hemolytic-uremic syndrome, or aHUS

Corporate Highlights • Finance o Completed two successful public offerings raising $1.14 billion in net proceeds o Ended 2017 with $1.73 billion in cash, cash equivalents, fixed income marketable securities and restricted investments

• Business o Formed strategic alliance with Vir Biotechnology to advance RNAi therapeutics for infectious diseases • Commercial/Medical Affairs o Enabled our supply chain, medical, quality, compliance and commercial organizations in the U.S. and Western Europe o Established or enhanced existing diagnostic screening and patient/physician education initiatives to detect disease and raise awareness

Commercial Readiness In preparation for a potential global commercial launch of patisiran in 2018 and potentially subsequent global product launches in 2019 and beyond, we are: • Expanding the organization with approximately 250 new hires deployed in customer facing activities across the world, initially in the United States and major European countries, followed by Canada and Switzerland, with a phased approach to the Asia Pacific, Latin American and Middle Eastern regions, with broad experience in marketing, sales, patient access, patient services, distribution and product reimbursement, in particular for orphan diseases; • Expanding our commercial capabilities with incorporation of appropriate quality systems, compliance policies, systems and procedures, and implementation of internal systems and infrastructure in order to support global commercial sales and establish patient-focused programs; and • Planning to expand our global footprint in major European markets and beyond with the continued hiring of country general managers, medical experts, market access professionals and marketing and sales professionals.

Recent Developments Sanofi Genzyme Restructuring On January 6, 2018, we and Sanofi Genzyme entered into an amendment to our 2014 collaboration, which is structured as an exclusive relationship for the worldwide development and commercialization of RNAi therapeutics in the field of Genetic Medicines. In connection and simultaneously with entering into the 2018 amendment to the 2014 Sanofi Genzyme collaboration, we and Sanofi Genzyme also entered into an Exclusive License Agreement with respect to all TTR products, including patisiran, ALN-TTRsc02 and any back-up products, referred to as the Exclusive TTR License, and the ALN-AT3 Global License Terms with respect to fitusiran and any back-up products, referred to as the AT3 License Terms.

Under the 2014 Sanofi Genzyme collaboration, Sanofi Genzyme has certain rights to our current and future Genetic Medicine programs that reach human proof-of-principal study completion, or Human POP, by the end of 2019, subject to extension to the end of 2021 in various circumstances. Under the 2014 Sanofi Genzyme collaboration, we were leading development and commercialization of patisiran in the United States, Canada and Western Europe (Alnylam Territory), while Sanofi Genzyme had rights to develop and commercialize the product in the rest of the world (Sanofi Genzyme Territory). Sanofi Genzyme also had a right to opt in to co-develop and co-promote ALN-TTRsc02 in the Alnylam Territory along with its regional opt-in rights. In addition, Sanofi Genzyme had opted in to co-develop and co-promote fitusiran in the Alnylam Territory, as well as develop and commercialize fitusiran in the Sanofi Genzyme Territory.

The 2018 amendment, together with the Exclusive TTR License and the AT3 License Terms, revise the terms and conditions of the 2014 collaboration to (i) provide us with the exclusive right to pursue the further global development and commercialization of all TTR products, including patisiran, ALN-TTRsc02 and any back-up products, (ii) provide Sanofi Genzyme the exclusive right to pursue the further global development and commercialization of fitusiran and any back-up products and (iii) terminate the previous co-development and co-commercialization rights related to revusiran, ALN- TTRsc02 and fitusiran under the 2014 Sanofi Genzyme collaboration.

Sanofi Genzyme continues to have the right to opt into our other rare genetic disease programs for development and commercialization in territories outside of the Alnylam Territory as contemplated in the 2014 Sanofi Genzyme collaboration, as well as one right to a global license.

The transaction is subject to customary closing conditions and clearances, including clearance under the Hart-Scott- Rodino Antitrust Improvements Act. We expect the transaction to close during the first quarter of 2018.

The 2014 Sanofi Genzyme collaboration, as amended in January 2018, as well as the Exclusive TTR License and the AT3 License Terms, are described below under the heading “Strategic Alliances.”

UK Biobank Consortium In December 2017, we entered into a 'pre-competitive' consortium together with Regeneron Pharmaceuticals, Inc., or Regeneron, AbbVie Inc., AstraZeneca PLC, Biogen Inc. and Pfizer Inc., to fund the generation of exome sequence data from the 500,000 volunteer participants who make up the UK Biobank health resource by the end of 2019. We and each of the other collaborators agreed to commit $10.0 million to enable an acceleration of sequencing timelines. Regeneron will conduct the sequencing effort and the data will be paired with detailed, de-identified medical and health records within the UK Biobank resource, to create a comprehensive resource for linking human genetic variations to human biology and disease. All consortium members will have a limited period of exclusive access to the sequencing data, before the data will be made available to other health researchers by UK Biobank. Consortium members have committed to make all significant research findings public. We believe that the broad and ongoing access to detailed health and full exome sequencing data for the 500,000 UK Biobank participants will greatly enhance our target identification and validation efforts, contributing to the sustainability of our RNAi therapeutics product engine.

RNAi Therapeutics – A Potential New Class of Innovative Medicines RNAi is a natural cellular process that was discovered in 1998 and was recognized with the award of the 2006 Nobel Prize for Physiology and Medicine to Dr. Andrew Fire and Dr. Craig Mello.

RNAi therapeutics harness the natural RNAi pathway to silence disease-associated genes and knock down production of disease-causing proteins, representing the opportunity to create a potential new class of innovative medicines. RNAi therapeutics exert their biological effects through a highly potent, catalytic mechanism. This unique mechanism of action confers a number of attributes that we believe have the potential to provide meaningful differentiation and distinct value for our investigational RNAi therapeutics relative to other drug classes.

Key Features of Alnylam Investigational RNAi Therapeutics Potential Attributes for Differentiation and Value • Potential to silence any disease-associated gene, including so-called “undruggable” targets, where conventional therapeutic modalities (e.g., small molecule drugs and biologics) have not been successful • Demonstrated potential in clinical trials to achieve robust clinical activity with up to 99 percent target gene knockdown in some cases • Clamped pharmacodynamic effect that has potential to provide improved and consistent efficacy compared with intermittent and transient effects often achieved with other drug classes

• Demonstrated durability of effect in clinical trials that enables once-monthly, once-quarterly and, in some cases, possible bi-annual dose regimens • Ability to be administered via subcutaneous injection when using our proprietary GalNAc-conjugate delivery platform • Potential for room temperature stability, avoiding the inconveniences, costs and global challenges of a cold chain distribution

We believe that the combination of these attributes represents a very promising profile for our investigational therapeutics, even in competitive markets, and in December 2017, we filed the first ever regulatory applications with the FDA and the EMA for approval of an RNAi therapeutic. We have reported on our advances in developing RNAi therapeutics as potential drugs in a large number of peer-reviewed publications and many scientific meetings, including publications by Alnylam scientists in the journals Nature, Nature Medicine, Nature Biotechnology, Cell, Proceedings of the National Academy of Sciences, The New England Journal of Medicine and The Lancet.

Our Product Platform We believe that we have created a reproducible and modular platform for drug discovery, development and commercialization of innovative medicines.

Alnylam Reproducible and Modular Platform Strategic Framework for Innovative Medicines • High unmet need population Genetically validated, liver-expressed target 1 • Opportunity for highly competitive profile gene • Delivery with GalNAc-conjugate platform

• Blood- or urine-based Biomarker for human proof-of-concept in 2 • Informative disease correlation Phase 1 • Establish dose/regimen for late stage development • Clinical development plans with established Definable path to potential approval and 3 endpoints market • Demonstrable value for payors

Delivery of RNAi Therapeutics In recent years, a tremendous amount of progress has been made in effectively delivering RNAi therapeutics to targeted organs and cells, and we believe Alnylam has been the leader of this advancement. This delivery success is now enabling execution on our Alnylam 2020 strategy.

Early efforts focused on delivery of RNAi therapeutics utilizing LNPs, where siRNA molecules are encapsulated in specific lipid-based formulations. This technology enables systemic delivery with intravenous drug administration. Results with LNP-based investigational RNAi therapeutics demonstrated potent, rapid and durable target gene silencing in pre- clinical and clinical studies. Further, LNP-based investigational RNAi therapeutics have been found to be generally well tolerated in clinical studies conducted to date. Our lead product, patisiran, is formulated utilizing LNPs.

More recently, we began advancing proprietary technology that conjugates a sugar molecule called GalNAc to the siRNA molecule. This simpler delivery approach enables more convenient, subcutaneous administration of our drug candidates, a key aspect of our platform. Results from our Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform demonstrated a substantial increase in potency over our earlier standard template chemistry (STC)- GalNAc-conjugate approach in pre-clinical and clinical studies, and a durability of effect that we believe, based on our clinical results, supports once-monthly, once-quarterly, and in some cases, possibly even bi-annual subcutaneous dose regimens. Due to this increased potency and durability, as well as a wide therapeutic index, this conjugate platform has become our primary approach for development of investigational RNAi therapeutics. During 2017, we continued to invest in the enhancement of this platform and reported pre-clinical results from our ESC Plus (ESC+) GalNAc-conjugates. ESC+ GalNAc-conjugates utilize advanced design features to further improve specificity, including a glycol nucleic acid, or GNA, modification in the antisense seed region of the siRNA, while maintaining potency and durability, further improving our already wide therapeutic index by six-fold. The ESC+ design is now being applied to all of our pre-clinical programs and has shown successful translation of potency from rodents to non-human primates. We intend to employ our ESC+ GalNAc- conjugate platform in future development programs.

We have extensive human safety experience with our investigational RNAi therapeutics. Our data demonstrate that to date, RNAi therapeutics have been generally well tolerated with minimal platform-related safety findings. Based on data as of December 2016, in over 1,000 patients or volunteers dosed for over three years in more than ten clinical programs, the safety findings, set forth below, occur at a low incidence and are monitorable. They are also generally asymptomatic and reversible even with continued dosing. As noted, as of December 2016, these findings include: • Low incidence (2.2 percent) of generally mild, asymptomatic, reversible liver function test increases greater than three times the upper limit of normal • Low incidence (15.2 percent) of generally mild, transient injection site reactions, or ISRs

In our view, this is an acceptable tolerability profile in the high unmet need indications that we pursue. Continued review of data across our programs since December 2016 has not led to any meaningful change in human safety with respect to our RNAi platform.

In October 2016, we observed an apparent imbalance in mortality in the treatment arm of the ENDEAVOUR Phase 3 study for revusiran, our first generation, subcutaneously administered, investigational therapeutic for the treatment of cardiomyopathy due to hATTR amyloidosis, which utilized our STC-GalNAc-conjugate delivery platform. With patient safety at the forefront, the ENDEAVOUR study was discontinued and a comprehensive investigation into the causality of this imbalance was conducted.

The investigation revealed no overall baseline imbalance, although there was a greater number of older patients randomized to the revusiran arm. There was no clinical evidence for revusiran-mediated cardiotoxicity or findings that would suggest that the mortality imbalance was the result of revusiran pharmacokinetic or pharmacodynamic effects. While our investigation could not fully exclude a possible drug-related cause, there was some evidence for imbalance due to a lower- than-expected mortality rate in the placebo arm at the time of study discontinuation.

Due to lack of evidence of any broader platform issue, the decision to discontinue development of revusiran did not affect patisiran, which utilizes our LNP delivery platform, or any of our other investigational RNAi therapeutic programs in development, which utilize our ESC-GalNAc-conjugate or ESC+ GalNAc-conjugate delivery platform.

We believe RNAi therapeutics represent a simplified and efficient potential new class of innovative medicines. We have achieved human proof of concept in multiple clinical trials of our investigational candidates, providing strong support for our approach to drug development. Moreover, we believe that our reproducible and modular platform will support the achievement of our 2020 goals, such that by the end of 2020, we can grow into a multi-product commercial stage company with a deep and sustainable pipeline that can fuel continued growth for the future.

Our Product Pipeline Our broad pipeline of investigational RNAi therapeutics is focused in three STArs: Genetic Medicines; Cardio- Metabolic Diseases; and Hepatic Infectious Diseases. The chart below is a summary of our product development programs as of January 31, 2018. It identifies those programs in which we have achieved human proof-of-concept, or POC, by demonstrating target gene knockdown and/or additional evidence of activity in clinical studies, those programs for which we have received Breakthrough Therapy Designation from the FDA, the development stage of our programs, and our commercial rights to such programs:

We have spent substantial funds over the past three years to develop our product pipeline and expect to continue to do so in the future. We incurred research and development expenses of $390.6 million in 2017, $382.4 million in 2016 and $276.5 million in 2015.

The investigational therapeutics described below are in various stages of clinical development and the scientific information included about these therapeutics is preliminary and investigative. None of our investigational therapeutics have been approved by the FDA, EMA or any other health authority and no conclusions can or should be drawn regarding the safety or efficacy of these investigational therapeutics.

Late Stage Clinical Development Programs Patisiran — Hereditary Transthyretin-Mediated (hATTR) Amyloidosis Patisiran, our most advanced investigational RNAi therapeutic, is currently under priority regulatory review in the United States and accelerated assessment in the European Union, or EU, for the treatment of hATTR amyloidosis. If approved, we expect to make patisiran commercially available to patients in the United States in mid-2018 and in the EU in late 2018. We also plan to file for regulatory approval in Japan in mid-2018 and in one or more additional countries by the end of the year.

hATTR amyloidosis is a rare, progressively debilitating and often fatal disease affecting approximately 50,000 patients worldwide. It is caused by deposition of wild-type and mutant transthyretin, or TTR, in peripheral tissues, such as the nerves, heart and gastrointestinal tract. Thus, polyneuropathy and cardiomyopathy are two cardinal manifestations of this disease, with most patients exhibiting a spectrum of both. TTR protein is produced primarily in the liver and is normally a carrier of vitamin A. Patisiran targets wild-type and all known mutant forms of TTR, including the V30M and V122I, the most common disease-causing mutations, and therefore it represents a potential therapeutic approach for the treatment of hATTR amyloidosis.

hATTR amyloidosis is a progressive disease, with an overall survival of two to 15 years from symptom onset, but only two to five years in patients presenting with cardiomyopathy. Orthotopic liver transplant, or OLT, and TTR tetramer stabilizers, such as tafamidis (approved in Europe, Japan and certain countries in Latin America, specific indication varies by region), are the only approved treatment options. However, availability is limited and most patients continue to experience significant morbidity and mortality associated with disease progression. Palliative therapies directed at specific symptoms such as pain, nausea, vomiting and diarrhea have been the mainstay of treatment despite their limited effectiveness. Other investigational drugs in development for the treatment of hATTR amyloidosis include the TTR-targeting antisense oligonucleotide, or ASO, inotersen, which showed statistically significant slowing of neuropathy progression and improvement in quality of life relative to placebo in a randomized Phase 3 trial and is currently under regulatory review in the United States and the EU, and a fibril-disrupting drug combination of doxycycline and tauroursodeoxycholic acid, which to date has only been tested in small single-arm Phase 2 studies. Thus, there remains a high unmet medical need for a safe and effective therapy that can benefit the broad hATTR amyloidosis population.

APOLLO Phase 3 Clinical Trial Trial Design: Initiated in November 2013 and completed in September 2017, APOLLO is the largest pivotal study conducted to date in hATTR amyloidosis patients with polyneuropathy, with 225 patients enrolled, representing 39 TTR genotypes from across 19 countries. This randomized, double-blind, placebo-controlled, global study was designed to evaluate the efficacy and safety of patisiran in hATTR amyloidosis patients with polyneuropathy. The primary endpoint of the study was the change from baseline in the modified neuropathy impairment score, or mNIS+7, at 18 months. The mNIS+7 score is an evaluation of muscle weakness, sensory and autonomic function, and nerve conductance across a 304-point scale, where neuropathy progression leads to an increased score over time. A key secondary endpoint was the Norfolk Quality of Life Diabetic Neuropathy, or Norfolk QOL-DN, questionnaire, which is a validated instrument that measures clinical benefit. Additional secondary endpoints included: NIS-weakness, the subdomain of mNIS+7 assessing muscle strength; Rasch-built Overall Disability Scale, or R-ODS, a patient reported outcome measure of activities of daily living and disability; timed 10-meter walk test, assessing ambulatory ability and gait speed; modified body mass index, or mBMI, assessing nutritional status; and COMPASS-31, a patient questionnaire assessing autonomic disease symptoms. Exploratory endpoints measured the effects on cardiac structure and function. Patients were randomized 2:1, patisiran-to-placebo, with patisiran administered at 0.30 mg/kg once every three weeks for 18 months by intravenous infusion. 99 percent of patients who completed the APOLLO study rolled over into the Phase 3 OLE study, called the Global OLE.

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