Clinical Profile FOR. Indication. Important Safety Information

Transcription

1 Clinical Profile FOR The first and only FDA-approved RNAi treatment for the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. 1 Indication ONPATTRO (patisiran) is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. Important Safety Information Infusion-Related Reactions Monitor for signs and symptoms during infusion. Slow or interrupt the infusion if clinically indicated. Discontinue the infusion if a serious or life-threatening infusion-related reaction occurs. Please see Important Safety Information on the following pages and accompanying Full Prescribing Information. 1

2 Hereditary ATTR amyloidosis is rapidly progressive and life-threatening 2-4 Hereditary transthyretin-mediated (hattr) amyloidosis is caused by a mutation in the transthyretin (TTR) gene that results in the accumulation of amyloid deposits in multiple organs of the body, including the nerves, heart, and GI tract. 2-4 hattr amyloidosis is a multisystem disease with heterogeneous symptom presentation 3 Peripheral sensory-motor neuropathy (e.g., neuropathic pain, paresthesia, weakness) Autonomic dysfunction (e.g., orthostatic hypotension, recurrent urinary tract infections) GI manifestations (e.g., diarrhea, nausea, vomiting) Cardiovascular manifestations (e.g., conduction abnormalities, arrhythmias, heart failure) More than 120 different TTR gene mutations have been identified, with predominant symptom presentation varying by genotype 5 The most common mutations in the US are V122I, T60A, and V30M 6 Some mutations are more common in certain populations, including those of Portuguese, Swedish, Japanese, African, and Irish descent 7,8 GI=gastrointestinal. Please see Important Safety Information on the following pages and accompanying Full Prescribing Information. 2

3 hattr amyloidosis can have a debilitating impact on a patient s life Symptoms of hattr amyloidosis can progress quickly, leading to significant disability and dysfunction 7,9 Decreased ambulation 10 : Inability to walk unaided Wheelchair-bound or bedridden Decline in daily function : Impairment in self-care Impairment in ability to perform usual activities Pain/discomfort Social burden 14 : Anxiety Depression hattr amyloidosis can lead to premature death in 4.7 years. 15,a a Median survival following diagnosis.

4 ONPATTRO (patisiran) targets the pathogenic protein in hattr amyloidosis What is ONPATTRO? ONPATTRO is a double-stranded small interfering ribonucleic acid (sirna) formulated for targeted delivery to hepatocytes, the primary source of TTR protein in circulation.1,16 TTR protein in a patient with hattr amyloidosis16 Liver: Primary site of TTR production Mutations lead to misfolding of TTR protein Misfolded TTR protein forms amyloid deposits in tissues Progressive symptoms ONPATTRO targets the liver Liver TTR protein Misfolded TTR Amyloid deposits ONPATTRO Fewer amyloid deposits in tissues ONPATTRO ONPATTRO harnesses the endogenous RNAi pathway to target TTR mrna for degradation and reduce production of TTR protein1 Reducing the TTR protein leads to a reduction in the amyloid deposits that accumulate in tissues1,17 RNA=ribonucleic acid; RNAi=RNA interference. Please see Important Safety Information on the following pages and accompanying Full Prescribing Information. 4

5 In the APOLLO study... Treatment with ONPATTRO led to a reduction of serum TTR The mean serum TTR reduction after 18 months was 84% 1,18,a,b -20 Mean Change in Serum Transthyretin (%) ONPATTRO Placebo Weeks From New England Journal of Medicine, Adams D, Gonzalez-Duarte A, O Riordan WD, et al, Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis, 379(1). Copyright 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. TTR protein reduction of ~80% occurred within days following a single dose of ONPATTRO 1 The mean maximum serum TTR reduction was 88% from baseline over 18 months 1 Similar TTR reductions were observed regardless of TTR mutation, sex, age, or race 1 In an ongoing open-label extension study, serum TTR reduction was maintained up to 24 months with continued dosing 19 a Evaluated in patients with hattr amyloidosis with polyneuropathy treated with 0.3 mg/kg ONPATTRO via intravenous infusion once every 3 weeks. 1 b Bars represent SEM (standard error of the mean). Important Safety Information Reduced Serum Vitamin A Levels and Recommended Supplementation ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking ONPATTRO. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum levels do not reflect the total vitamin A in the body. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g. night blindness).

6 APOLLO the largest controlled study of hattr amyloidosis 20 Global, randomized, double-blind, placebo-controlled study of 225 patients 1,18,20 Population 225 hattr amyloidosis patients with polyneuropathy a 2:1 Randomization ONPATTRO 0.3 mg/kg IV q3w (n=148) OR Placebo IV q3w (n=77) Primary Endpoint Change in mnis+7, a measure of neuropathy impairment, from baseline at 18 months Key Secondary Endpoint Norfolk QoL-DN Select Additional Endpoints Serum TTR 10MWT COMPASS 31 mbmi R-ODS EQ-5D-5L NIS-W 93% of patients treated with ONPATTRO (patisiran) and 62% of patients treated with placebo completed 18 months of the assigned treatment 1 Patients who completed their participation in the 18-month APOLLO study were eligible to enroll in the open-label extension (OLE) study 18 99% of eligible patients elected to enter the OLE study a Study patients had a diagnosis of hattr amyloidosis with polyneuropathy caused by any TTR mutation, had FAP stage 1 or 2 disease, had a neuropathy impairment score (NIS) of 5-130, and were permitted to have previously used tetramer stabilizers. 10MWT=10-meter walk test; COMPASS 31=Composite Autonomic Symptom Score 31; EQ-5D-5L=EuroQoL 5 Dimensions 5 Levels; FAP=familial amyloid polyneuropathy; mbmi=modified body mass index; mnis+7=modified Neuropathy Impairment Score + 7; NIS-W=Neuropathy Impairment Score-Weakness; Norfolk QoL-DN=Norfolk Quality of Life-Diabetic Neuropathy; R-ODS=Rasch-built Overall Disability Scale. Please see Important Safety Information on the following pages and accompanying Full Prescribing Information. 6

7 Baseline characteristics of patients in the APOLLO study Global study 18, patients from 19 countries Broad age range to 83 years old (median: 62 years) Multiple mutations 1,18 39 different TTR mutations were represented in the study population Prior treatment 18 53% of patients had previously been treated with tafamidis or diflunisal Disease characteristics of overall patient population Stage I polyneuropathy 1 Unimpaired ambulation (mostly mild sensory, motor, and autonomic neuropathy in lower limbs) Stage II polyneuropathy 1 Assistance with ambulation required (mostly moderate impairment progression to the lower limbs, upper limbs, and trunk) Patients (%) a 46% 53% a FAP stage percentages do not add up to 100 due to inclusion of one stage III patient. 18

8 ONPATTRO (patisiran) improved polyneuropathy Primary Endpoint: Change from baseline in mnis+7, a specialized assessment of polyneuropathy in hattr amyloidosis 1,20 The modified Neuropathy Impairment Score + 7 (mnis+7) is a validated composite measure of motor, sensory, and autonomic neuropathy, with a score ranging from 0 (no impairment) to 304 points mnis+7 assessed motor strength, reflexes, sensation, nerve conduction, and postural blood pressure Change from baseline at 18 months for the ONPATTRO arm was compared with that of the placebo arm 35 Change in mnis+7 score 1,a-d LS Mean Change in mnis N=67 Difference at 9 months: e (ONPATTRO vs Placebo) -2.0 N= Difference at 18 months: f (ONPATTRO vs Placebo) -6.0 N=51 N=137 ONPATTRO Placebo p<0.001 Improvement in polyneuropathy Baseline 9 months 18 months At 18 months there was a mean change from baseline of -6.0 points (improvement) with ONPATTRO versus 28.0 points (worsening) with placebo 1 Difference at 18 months between placebo and ONPATTRO was points a Improvement defined as a decrease in mnis+7 compared to placebo. b Bars represent SEM (standard error of the mean). c Mean mnis+7 at baseline was 80.9 with ONPATTRO and 74.6 with placebo. 18 d N=number of evaluable patients. e 95% CI: -20.7, f 95% CI: -39.9, CI=confidence interval; LS=least squares. Please see Important Safety Information on the following pages and accompanying Full Prescribing Information. 8

9 The majority of ONPATTRO -treated patients experienced reversal in neuropathy impairment 18 Reversal in neuropathy impairment from baseline 18,a,b Patients (%) % c N=137 ONPATTRO Placebo p< % d N=51 From New England Journal of Medicine, Adams D, Gonzalez-Duarte A, O Riordan WD, et al, Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis, 379(1). Copyright 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. a Odds ratio: 39.9 ( ). 18 b N=number of evaluable patients. c 95% CI: d 95% CI: <0 point change from baseline in mnis+7 In patients treated with ONPATTRO who did not experience reversal in neuropathy impairment from baseline, progression in neuropathy impairment was slowed compared to the placebo arm and the natural history of the disease 18 Maintenance of efficacy was demonstrated for up to 36 months in 2 OLE studies 19 Important Safety Information Infusion-Related Reactions Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO. In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of placebo-treated patients. The most common symptoms of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache. To reduce the risk of IRRs, patients should receive premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) at least 60 minutes prior to ONPATTRO infusion. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the infusion and instituting medical management as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed.

10 ONPATTRO (patisiran) significantly improved quality of life 1 APOLLO measured patient-reported changes in quality of life 1,11 The Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) is a patient questionnaire that was designed to capture the impact of hattr amyloidosis on a patient s quality of life related to: Activities of daily living Polyneuropathy symptoms Autonomic function Small fiber nerve function Physical functioning/large fiber nerve function Change from baseline at 18 months for the ONPATTRO arm was compared with that of the placebo arm 1 LS Mean Change in Norfolk QoL-DN Score Change in Norfolk QoL-DN score 1,a-e 7.5 N=65 Difference at 9 months: f (ONPATTRO vs Placebo) 14.4 Difference at 18 months: g (ONPATTRO vs Placebo) Baseline 9 months 18 months N=48 N=141 N=136 ONPATTRO Placebo p<0.001 Improvement in quality of life At 18 months there was a mean change from baseline of -6.7 points (improvement) with ONPATTRO versus 14.4 points (worsening) with placebo 1 Difference at 18 months between placebo and ONPATTRO was points a Possible total score ranges from -4 to b Improvement defined as Norfolk QoL-DN change from baseline <0 points. c Bars represent SEM (standard error of the mean). d Norfolk QoL-DN scores at baseline were 59.6 with ONPATTRO and 55.5 with placebo. 18 e N=number of evaluable patients. f 95% CI: -19.8, g 95% CI: -27.2, Please see Important Safety Information on the following pages and accompanying Full Prescribing Information.

11 More than half of ONPATTRO -treated patients experienced improvement in quality of life 18 Improvement in quality of life from baseline a,b ONPATTRO Placebo Patients (%) % c N= % d N=49 Improvement in Norfolk QoL-DN From New England Journal of Medicine, Adams D, Gonzalez-Duarte A, O Riordan WD, et al, Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis, 379(1). Copyright 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. a Odds ratio: 10.0 ( ). 18 b N=number of evaluable patients. c 95% CI: d 95% CI: Patients receiving ONPATTRO experienced similar improvement relative to placebo in mnis+7 and Norfolk QoL-DN score across all subgroups, including 18 : Age Sex Race Region NIS score V30M mutation status Prior tafamidis or diflunisal use Disease stage Important Safety Information Adverse Reactions The most common adverse reactions that occurred in patients treated with ONPATTRO were upper respiratory tract infections (29%) and infusion related reactions (19%).

12 Improvement in autonomic symptoms and ability to perform everyday activities 18 Autonomic symptoms: COMPASS 31 18,20,a,b Patients receiving ONPATTRO (patisiran) experienced a significant benefit relative to placebo in reduction of autonomic symptoms such as dizziness, constipation, diarrhea, vomiting, and incontinence Change in COMPASS 31 score Change From Baseline at 18 Months a N= N=53 ONPATTRO Placebo p<0.001 Decrease in symptoms Activities of daily living: R-ODS 18,20,b,c Patients receiving ONPATTRO saw a significant benefit relative to placebo in the ability to perform activities of daily living and everyday function, such as eating, bathing, dressing, and standing Change in R-ODS score 8 ONPATTRO Placebo Change From Baseline at 18 Months b N=138 p<0.001 Improvement in ability to perform everyday activities N=54 a COMPASS 31 is a 31-item questionnaire that evaluates autonomic function across 6 domains. Total possible weighted score ranges from ,21 b N=number of patients assessed at 18 months. c R-ODS is a 24-item scale that evaluates limitations on everyday activity. Total possible score ranges from ,22 12 Please see Important Safety Information on the following pages and accompanying Full Prescribing Information.

13 ONPATTRO (patisiran) improved other measurements of hattr amyloidosis 18 Significant improvement vs placebo across all secondary endpoints 1,18 Motor strength: NIS-Weakness (NIS-W) ONPATTRO-treated patients experienced a 0.1-point increase in NIS-W score compared to the placebo-treated patients whose score increased by 17.9 points (p<0.001) Gait speed: 10-Meter Walk Test (10MWT) Gait speed from baseline to 18 months improved in ONPATTRO-treated patients by 0.08 m/sec compared to placebo-treated patients whose speed worsened by m/sec (p<0.001) Nutritional status: modified Body Mass Index (mbmi) d ONPATTRO-treated patients maintained a better nutritional status at 18 months compared to placebo-treated patients as demonstrated by a 3.7-unit decrease in mbmi vs a 119-unit decrease in the placebo group (p<0.001) Improvement in mbmi vs placebo was seen in the ONPATTRO-treated patients as early as 3 months Patient mobility, self-care, usual activities, and pain/discomfort and anxiety/depression as measured by EQ-5D-5L 23,24,e ONPATTRO-treated patients showed improvement in these domains of EQ-5D-5L compared to placebo-treated patients 23,24 d mbmi: (BMI; kg/m 2 ) multiplied by serum albumin (g/l). e EQ-5D-5L was an exploratory endpoint in the APOLLO study. Important Safety Information Reduced Serum Vitamin A Levels and Recommended Supplementation ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking ONPATTRO. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum levels do not reflect the total vitamin A in the body. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g. night blindness).

14 Safety and tolerability profile in APOLLO Adverse reactions that occurred in at least 5% of patients treated with ONPATTRO (patisiran) and at least 3% more frequently than in patients treated with placebo 1 Adverse Reaction ONPATTRO N=148 % Placebo N=77 % Upper respiratory tract infections a Infusion-related reaction (IRR) b 19 9 Dyspepsia 8 4 Dyspnea c,d 8 0 Muscle spasms c 8 1 Arthralgia c 7 0 Erythema c 7 3 Bronchitis e 7 3 Vertigo 5 1 a Includes nasopharyngitis, upper respiratory tract infection, respiratory tract infection, pharyngitis, rhinitis, sinusitis, viral upper respiratory tract infection, upper respiratory tract congestion. b Infusion-related reaction symptoms include, but are not limited to: arthralgia or pain (including back, neck, or musculoskeletal pain), flushing (including erythema of face or skin warm), nausea, abdominal pain, dyspnea or cough, chest discomfort or chest pain, headache, rash, chills, dizziness, fatigue, increased heart rate or palpitations, hypotension, hypertension, facial edema. c Not part of an infusion-related reaction. d Includes dyspnea and exertional dyspnea. e Includes bronchitis, bronchiolitis, bronchitis viral, lower respiratory tract infection, lung infection. The safety profile of ONPATTRO was generally consistent across all subgroups 25,26 In ONPATTRO-treated patients, all IRRs were either mild (95%) or moderate (5%) in severity 27 One patient in the expanded access program experienced a severe IRR 1 Among ONPATTRO-treated patients who experienced an IRR, 79% experienced the first IRR within the first 2 infusions and the frequency of IRRs decreased over time 1 IRRs led to treatment discontinuation in <1% of patients 1 14 Please see Important Safety Information on the following pages and accompanying Full Prescribing Information.

15 Dosing and administration ONPATTRO (patisiran) is administered via IV infusion once every 3 weeks 1 Dosing is based on actual body weight. For patients weighing <100 kg, the recommended dose is 0.3 mg/kg. For patients weighing 100 kg, the recommended dose is 30 mg. ONPATTRO should be administered by a healthcare professional. Patients should be given each of the following premedications on the day of the infusion, at least 60 minutes prior to the start of the infusion 1 : IV corticosteroid (e.g., dexamethasone 10 mg, or equivalent) Oral acetaminophen (500 mg) IV H1 blocker (e.g., diphenhydramine 50 mg, or equivalent) IV H2 blocker (e.g., ranitidine 50 mg, or equivalent) For premedications not available or not tolerated intravenously, equivalents may be administered orally. Some patients may require additional or higher doses of 1 or more of the premedications to reduce the risk of IRRs 1 For patients who are tolerating their ONPATTRO infusions but experiencing adverse reactions due to the corticosteroid premedication, the corticosteroid may be reduced by 2.5 mg increments to a minimum dose of 5 mg of dexamethasone (IV), or equivalent 1 Administration options to meet the needs of your patients Infusion Center Patients will visit an infusion center to receive their treatment with ONPATTRO. Home Infusion May be an option for some patients. The decision for a patient to receive home infusions should be made after an evaluation and recommendation by the treating physician, and may not be covered by all insurance plans. Some physicians may choose to have patients receive their first few infusions in the clinic prior to transitioning to home infusion.

16 Alnylam Assist is here to help Alnylam Assist offers a wide range of services to guide your patients through treatment with ONPATTRO (patisiran), including: A dedicated Case Manager Alnylam Assist will connect patients with a dedicated Alnylam Case Manager who can provide personalized support throughout the treatment process. Benefit verification Coverage for ONPATTRO will vary by plan and by patient. Alnylam Assist can help determine patient-specific coverage requirements. Treatment coverage Alnylam Assist can explain the requirements and processes for prior authorizations, claims, and appeals. Financial assistance for patients a Eligible patients may qualify for the Alnylam Assist Quick Start Program, Patient Assistance Program (PAP), or Commercial Copay Program. Disease and product education Patient Education Liaisons (PELs) are available to help patients gain a better understanding of the disease. Coding and billing A Field Reimbursement Director can provide education about billing, coding, and the reimbursement process for ONPATTRO. a Patients must meet specified eligibility criteria to qualify for assistance. Alnylam reserves the right to make eligibility determinations and to modify or discontinue the program at any time. 16 Please see Important Safety Information on the following pages and accompanying Full Prescribing Information.

17 Questions about how Alnylam Assist can help? A representative can assist you. 8am 7pm ET, Monday Friday : : To learn more about Alnylam Assist, visit

18 Efficacy endpoints in the APOLLO study Primary Endpoint modified Neuropathy Impairment Score + 7 (mnis+7) 1,20 Validated composite measure of sensory, motor, and autonomic neuropathy modified Neuropathy Impairment Score + 7 (mnis+7) Postural blood pressure Nerve conduction Reflexes Quantitative sensory testing Motor strength and weakness Increasing score indicates worsening impairment Key Secondary Endpoint Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) 1,11,12 Patient questionnaire designed to capture the impact of hattr amyloidosis on a patient s quality of life Score ranges from -4 to 136; higher score indicates worsening quality of life Assessed activities of daily living, polyneuropathy symptoms, small fiber function, large fiber function, and autonomic nerve function Sample questions from the questionnaire 12 : Have you felt unsteady on your feet? Have you had a problem walking down stairs? Have you had a problem with bathing or showering? Have you had a problem with dressing? Were you limited in the kind of work or other activities you could perform? 18 Please see Important Safety Information on the following pages and accompanying Full Prescribing Information.

19 Additional Endpoints Composite Autonomic Symptom Score 31 (COMPASS 31) 18,21 31-item questionnaire that evaluated patient-reported autonomic symptoms such as orthostatic hypotension, constipation, diarrhea, vomiting, and incontinence Score ranges from 0 to 100; lower score indicates fewer autonomic symptoms Covers 6 autonomic domains (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor) 21 Sample questions 21 : In the past year, have you ever felt faint, dizzy, goofy, or had difficulty thinking soon after standing up from a sitting or lying position? In the past year, have you ever noticed color changes in your skin, such as red, white, or purple? In the past 5 years, what changes, if any, have occurred in your general body sweating? In the past year, have you had any bouts of diarrhea? In the past year, have you ever lost control of your bladder function? Rasch-built Overall Disability Scale (R-ODS) 18,28 24-item scale that evaluated patient-reported ability to perform activities of daily living such as eating, bathing, dressing, and standing Score ranges from 0 to 48; higher score indicates less disability Sample questions 22,28 : Are you able to: Walk one flight of stairs? Carry and put down a heavy object? Take a shower? Do the shopping?

20 Efficacy endpoints in the APOLLO study Additional Endpoints Continued modified Body Mass Index (mbmi) 20,29 Nutritional status assessment based on body mass index and serum albumin (kg/m 2 x albumin [g/l]) Lower score indicates worsening of nutritional status mbmi is used as a tool to monitor disease progression and provide prognostic information, showing close correlation with time before death, duration of gastrointestinal disturbances, malabsorption, and functional capacity 10-Meter Walk Test 18 Measure of gait speed (m/sec) Increase in duration indicates worsening impairment EQ-5D-5L 24 Instrument used to measure health in 5 dimensions Mobility (walking) Self-care (washing or dressing) Usual activities Pain/discomfort Anxiety/depression 20 Please see Important Safety Information on the following pages and accompanying Full Prescribing Information.

21 Indication ONPATTRO (patisiran) is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. Important Safety Information Infusion-Related Reactions Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO. In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of placebo-treated patients. The most common symptoms of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache. To reduce the risk of IRRs, patients should receive premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) at least 60 minutes prior to ONPATTRO infusion. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the infusion and instituting medical management as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed. Reduced Serum Vitamin A Levels and Recommended Supplementation ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking ONPATTRO. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum levels do not reflect the total vitamin A in the body. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g. night blindness). Adverse Reactions The most common adverse reactions that occurred in patients treated with ONPATTRO were upper respiratory tract infections (29%) and infusion related reactions (19%). Please see the accompanying Full Prescribing Information for additional information. Resources: 1. ONPATTRO [package insert]. Cambridge, MA: Alnylam Pharmaceuticals, Inc; Adams D, Coelho T, Obici L, et al. Neurology. 2015;85(8): Conceição I, González-Duarte A, Obici L, et al. J Peripher Nerv Syst. 2016;21(1): Shin SC, Robinson-Papp J. Mt Sinai J Med. 2012;79(6): Rowczenio DM, Noor I, Gillmore JD, et al. Hum Mutat. 2014;35(9):E2403-E Maurer MS, Hanna M, Grogan M, et al. J Am Coll Cardiol. 2016;68(2): Ando Y, Coelho T, Berk JL, et al. Orphanet J Rare Dis. 2013;8: Reilly MM, Staunton H, Harding AE. J Neurol Neurosurg Psych. 1995;59(1): Dharmarajan K, Maurer MS. J Am Geriatr Soc. 2012;60(4): Coutinho P, Martins da Silva A, Lopes Lima JL, et al. Amsterdam: Excerpta Medica;1980: Vinik EJ, Vinik AI, Paulson JF, et al. J Peripher Nerv Syst. 2014;19: Vinik EJ, Hayes RP, Oglesby A, et al. Diabetes Technol Ther. 2005;7(3): Pruppers MHJ, Merkies ISJ, Faber CG, et al. J Peripher Nerv Syst. 2015;20(3): Lopes A, Fonseca I, Sousa A, et al. Amyloid. 2018;25(1): Swiecicki PL, Zhen DB, Mauermann ML, et al. Amyloid. 2015;22(2): Gertz MA. Am J Manag Care. 2017; 23(7 suppl):s107-s Adams D, Coelho T, Conceicao I, et al. Slides presented at: American Academy of Neurology; April 26, 2017; Boston, MA. 18. Adams D, Gonzalez-Duarte A, O Riordan WD, et al. N Engl J Med. 2018;379(1): Berk JL, Adams D, Suhr O, et al. Poster presented at: First European ATTR Amyloidosis Meeting (EU-ATTR) for Patients and Doctor; November 2-3, 2017; Paris, France. 20. Adams D, Suhr OB, Dyck PJ, et al. BMC Neurol. 2017;17(1): Sletten DM, Suarez GA, Low PA, et al. Mayo Clin Proc. 2012;87(12): van Nes SI, Vanhoutte EK, VanDoorn PA, et al. Neurology. 2011;76(4): Adams D, Gonzalez-Duarte A, O Riordan W, et al. Slides presented at: American Academy of Neurology; April 25, 2018; Los Angeles, CA. 24. Herdman M, Gudex C, Lloyd A, et al. Qual Life Res. 2011;20(10): Coelho T, Adams D, Gonzalez-Duarte A, et al. Slides presented at: European Academy of Neurology; June 16, 2018; Lisbon, Portugal. 26. Coelho T, Adams D, Gonzalez-Duarte A, et al. Poster presented at: XVIth International Symposium on Amyloidosis (ISA) Meeting; March 26-29, 2018; Kumamoto, Japan. Poster PC Polydefkis M, Adams D, Kristen A, et al. Poster presented at: Peripheral Nerve Society (PNS) Annual Meeting; July 22-25, 2018; Baltimore, MD. Poster Berk J, Lin H, Agarwal S, et al. Poster presented at: XVIth International Symposium on Amyloidosis; March 26-29, 2018; Kumamoto, Japan. 29. Suhr O, Danielsson A, Holmgren G, et al. J Intern Med. 1994;235(5):

22 ONPATTRO (patisiran) demonstrated a benefit versus placebo in the treatment of the polyneuropathy of hattr amyloidosis in adults across all endpoints 1,18 ONPATTRO treatment resulted in a mean serum TTR reduction of 84% at 18 months 1 ONPATTRO-treated patients showed significant improvement vs placebo in the primary endpoint of mnis+7, a composite measure of sensory, motor, and autonomic neuropathy (p<0.001) 1 56% of ONPATTRO-treated patients experienced reversal in neuropathy impairment from baseline at 18 months compared to 4% of placebo-treated patients, as measured by the mnis+7 score 18 51% of patients treated with ONPATTRO experienced an improvement from baseline in quality of life (Norfolk QoL-DN score) at 18 months compared with 10% of patients who received placebo 18 Patients receiving ONPATTRO showed improvement in motor strength, ability to perform everyday activities, gait speed, nutritional status, and autonomic symptoms compared to patients receiving placebo 18 To learn more about ONPATTRO visit Indication ONPATTRO is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. Important Safety Information Infusion-Related Reactions Monitor for signs and symptoms during infusion. Slow or interrupt the infusion if clinically indicated. Discontinue the infusion if a serious or life-threatening infusion-related reaction occurs. Please see Important Safety Information on the previous pages and accompanying Full Prescribing Information. ONPATTRO and Alnylam Assist are trademarks of Alnylam Pharmaceuticals, Inc Alnylam Pharmaceuticals, Inc. All rights reserved.ttr02-usa