CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`210922Orig1s000
`
`LABELING
`
`Moderna Ex 1023-p. 1
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`ONPATTRO™ safely and effectively. See full prescribing
`information for ONPATTRO.
`ONPATTRO (patisiran) lipid complex injection, for intravenous
`use
`Initial U.S. Approval: 2018
`-----------------------INDICATIONS AND USAGE----------------------
`ONPATTRO contains a transthyretin-directed small interfering RNA
`and is indicated for the treatment of the polyneuropathy of hereditary
`transthyretin-mediated amyloidosis in adults. (1)
`------------------DOSAGE AND ADMINISTRATION------------------
`• For patients weighing less than 100 kg, the recommended dosage
`is 0.3 mg/kg every 3 weeks by intravenous infusion. For patients
`weighing 100 kg or more, the recommended dosage is 30 mg
`(2.1)
`• Premedicate with a corticosteroid, acetaminophen, and
`antihistamines (2.2)
`• Filter and dilute prior to administration (2.3)
`Infuse over approximately 80 minutes (2.4)
`•
`-----------------DOSAGE FORMS AND STRENGTHS----------------
`Lipid Complex Injection: 10 mg/5 mL (2 mg/mL) in a single-dose
`vial (3)
`
`-------------------------CONTRAINDICATIONS-------------------------
`None (4)
`-------------------WARNINGS AND PRECAUTIONS------------------
`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 (5.1)
`• Reduced serum vitamin A levels and recommended
`supplementation: Supplement with the recommended daily
`allowance of vitamin A. Refer to an ophthalmologist if ocular
`symptoms suggestive of vitamin A deficiency occur (5.2)
`--------------------------ADVERSE REACTIONS-------------------------
`The most frequently reported adverse reactions (that occurred in at
`least 10% of ONPATTRO-treated patients and at least 3% more
`frequently than on placebo) were upper respiratory tract infections
`and infusion-related reactions (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact
`Alnylam Pharmaceuticals at 1-877-256-9526 or FDA at 1-800-
`FDA-1088 or www fda.gov/medwatch.
`See 17 for PATIENT COUNSELING INFORMATION
`
`Revised: 8/2018
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Dosing Information
`2.2 Required Premedication
`2.3 Preparation Instructions
`2.4 Infusion Instructions
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Infusion-Related Reactions
`5.2 Reduced Serum Vitamin A Levels and Supplementation
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Immunogenicity
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`
` 8.4 Pediatric Use
` 8.5 Geriatric Use
` 8.6 Hepatic Impairment
` 8.7 Renal Impairment
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
` 12.1 Mechanism of Action
` 12.2 Pharmacodynamics
` 12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
` 16.1 How Supplied
` 16.2 Storage and Handling
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing
`information are not listed
`
`Reference ID: 4305330
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`Moderna Ex 1023-p. 2
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`IPR2019-00554
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`

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`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`ONPATTRO is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in
`adults.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dosing Information
`ONPATTRO should be administered by a healthcare professional.
`ONPATTRO is administered via intravenous (IV) infusion. Dosing is based on actual body weight.
`For patients weighing less than 100 kg, the recommended dosage is 0.3 mg/kg once every 3 weeks.
`For patients weighing 100 kg or more, the recommended dosage is 30 mg once every 3 weeks.
`Missed Dose
`If a dose is missed, administer ONPATTRO as soon as possible.
`If ONPATTRO is administered within 3 days of the missed dose, continue dosing according to the patient’s
`•
`original schedule.
`If ONPATTRO is administered more than 3 days after the missed dose, continue dosing every 3 weeks thereafter.
`
`•
`
`2.2 Required Premedication
`All patients should receive premedication prior to ONPATTRO administration to reduce the risk of infusion-related
`reactions (IRRs) [see Warnings and Precautions (5.1)]. Each of the following premedications should be given on the day
`of ONPATTRO infusion at least 60 minutes prior to the start of infusion:
`Intravenous corticosteroid (e.g., dexamethasone 10 mg, or equivalent)
`•
`• Oral acetaminophen (500 mg)
`Intravenous H1 blocker (e.g., diphenhydramine 50 mg, or equivalent)
`•
`Intravenous H2 blocker (e.g., ranitidine 50 mg, or equivalent)
`•
`For premedications not available or not tolerated intravenously, equivalents may be administered orally.
`For patients who are tolerating their ONPATTRO infusions but experiencing adverse reactions related to the
`corticosteroid premedication, the corticosteroid may be reduced by 2.5 mg increments to a minimum dose of 5 mg of
`dexamethasone (intravenous), or equivalent.
`Some patients may require additional or higher doses of one or more of the premedications to reduce the risk of IRRs [see
`Warnings and Precautions (5.1)].
`
`
`Reference ID: 4305330
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`2.3 Preparation Instructions
`ONPATTRO must be filtered and diluted prior to intravenous infusion. The diluted solution for infusion should be
`prepared by a healthcare professional using aseptic technique as follows:
`• Remove ONPATTRO from the refrigerator and allow to warm to room temperature. Do not shake or vortex.
`Inspect visually for particulate matter and discoloration. Do not use if discoloration or foreign particles are
`•
`present. ONPATTRO is a white to off-white, opalescent, homogeneous solution. A white to off-white coating
`may be observed on the inner surface of the vial, typically at the liquid-headspace interface. Product quality is not
`impacted by presence of the white to off-white coating.
`• Calculate the required dose of ONPATTRO based on the recommended weight-based dosage [see Dosage and
`Administration (2.1)].
`• Withdraw the entire contents of one or more vials into a single sterile syringe.
`• Filter ONPATTRO through a sterile 0.45 micron polyethersulfone (PES) syringe filter into a sterile container.
`• Withdraw the required volume of filtered ONPATTRO from the sterile container using a sterile syringe.
`• Dilute the required volume of filtered ONPATTRO into an infusion bag containing 0.9% Sodium Chloride
`Injection, USP for a total volume of 200 mL. Use infusion bags that are di(2-ethylhexyl)phthalate-free (DEHP-
`free).
`• Gently invert the bag to mix the solution. Do not shake. Do not mix or dilute with other drugs.
`• Discard any unused portion of ONPATTRO.
`• ONPATTRO does not contain preservatives. The diluted solution should be administered immediately after
`preparation. If not used immediately, store in the infusion bag at room temperature (up to 30°C [86°F]) for up to
`16 hours (including infusion time). Do not freeze.
`
`•
`
`2.4 Infusion Instructions
`• Use a dedicated line with an infusion set containing a 1.2 micron polyethersulfone (PES) in-line infusion filter.
`Use infusion sets and lines that are DEHP-free.
`Infuse the diluted solution of ONPATTRO intravenously, via an ambulatory infusion pump, over approximately
`80 minutes, at an initial infusion rate of approximately 1 mL/min for the first 15 minutes, then increase to
`approximately 3 mL/min for the remainder of the infusion. The duration of infusion may be extended in the event
`of an IRR [see Warnings and Precautions (5.1)].
`• Administer only through a free-flowing venous access line. Monitor the infusion site for possible infiltration
`during drug administration. Suspected extravasation should be managed according to local standard practice for
`non-vesicants.
`• Observe the patient during the infusion and, if clinically indicated, following the infusion [see Warnings and
`Precautions (5.1)].
`• After completion of the infusion, flush the intravenous administration set with 0.9% Sodium Chloride Injection,
`USP to ensure that all ONPATTRO has been administered.
`
`Reference ID: 4305330
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`Moderna Ex 1023-p. 4
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`3 DOSAGE FORMS AND STRENGTHS
`Lipid Complex Injection: 10 mg/5 mL (2 mg/mL) white to off-white, opalescent, homogeneous solution in a single-dose
`vial.
`
`4 CONTRAINDICATIONS
`None.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Infusion-Related Reactions
`Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO. In clinical studies, all patients
`received premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) to reduce the risk
`of IRRs. In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of
`placebo-treated patients. Among ONPATTRO-treated patients who experienced an IRR, 79% experienced the first IRR
`within the first 2 infusions. The frequency of IRRs decreased over time. IRRs led to infusion interruption in 5% of
`patients. IRRs resulted in permanent discontinuation of ONPATTRO in less than 1% of patients in clinical studies. Across
`clinical studies, the most common symptoms (reported in greater than 2% of patients) of IRRs with ONPATTRO were
`flushing, back pain, nausea, abdominal pain, dyspnea, and headache [see Adverse Reactions (6.1)]. One patient in the
`ONPATTRO expanded access program had a severe adverse reaction of hypotension and syncope during an ONPATTRO
`infusion.
`Patients should receive premedications on the day of ONPATTRO infusion, at least 60 minutes prior to the start of
`infusion [see Dosage and Administration (2.2)]. Monitor patients during the infusion for signs and symptoms of IRRs. If
`an IRR occurs, consider slowing or interrupting the ONPATTRO infusion and instituting medical management (e.g.,
`corticosteroids or other symptomatic treatment), 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.
`Some patients who experience IRRs may benefit from a slower infusion rate or additional or higher doses of one or more
`of the premedications with subsequent infusions to reduce the risk of IRRs [see Dosage and Administration (2.2)].
`
`5.2 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 of vitamin A is advised for patients taking ONPATTRO. Higher doses than the recommended daily allowance
`of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as
`serum vitamin A 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 ADVERSE REACTIONS
`The following clinically significant adverse reactions are described elsewhere in the labeling:
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`•
`
`Infusion-Related Reactions [see Warnings and Precautions (5.1)]
`
`6.1 Clinical Trials Experience
`Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical
`studies of ONPATTRO cannot be directly compared to rates in the clinical studies of another drug and may not reflect the
`rates observed in practice.
`A total of 224 patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR
`amyloidosis) received ONPATTRO in the placebo-controlled and open-label clinical studies, including 186 patients
`exposed for at least 1 year, 137 patients exposed for at least 2 years, and 52 patients exposed for at least 3 years. In the
`placebo-controlled study, 148 patients received ONPATTRO for up to 18 months (mean exposure 17.7 months). Baseline
`demographic and disease characteristics were generally similar between treatment groups. The median age of study
`patients was 62 years and 74% were male. Seventy-two percent of study patients were Caucasian, 23% were Asian, 2%
`were Black, and 2% were reported as other. At baseline, 46% of patients were in Stage 1 of the disease and 53% were in
`Stage 2. Forty-three percent of patients had Val30Met mutations in the transthyretin gene; the remaining patients had
`38 other point mutations. Sixty-two percent of ONPATTRO-treated patients had non-Val30Met mutations, compared to
`48% of the placebo-treated patients.
`Upper respiratory tract infections and infusion-related reactions were the most common adverse reactions. One patient
`(0.7%) discontinued ONPATTRO because of an infusion-related reaction.
`Table 1 lists the adverse reactions that occurred in at least 5% of patients in the ONPATTRO-treated group and that
`occurred at least 3% more frequently than in the placebo-treated group in the randomized controlled clinical trial.
`Table 1: Adverse Reactions from the Placebo-Controlled Trial that Occurred in at Least 5% of
`ONPATTRO-treated Patients and at Least 3% More Frequently than in Placebo-treated Patients
`ONPATTRO
`Placebo
`N=148
`N=77
`%
`%
`29
`21
`Upper respiratory tract infections a
`Infusion-related reaction b
`19
`9
`8
`4
`Dyspepsia
`8
`0
`Dyspnea c, d
`8
`1
`Muscle spasms c
`7
`0
`Arthralgia c
`7
`3
`Erythema c
`7
`3
`Bronchitis e
`5
`1
`Vertigo
` 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.
`
`Adverse Reaction
`
`
`
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`e Includes bronchitis, bronchiolitis, bronchitis viral, lower respiratory tract infection, lung infection.
`
`
`
`Four serious adverse reactions of atrioventricular (AV) heart block (2.7%) occurred in ONPATTRO-treated patients,
`including 3 cases of complete AV block. No serious adverse reactions of AV block were reported in placebo-treated
`patients.
`Ocular adverse reactions that occurred in 5% or less of ONPATTRO-treated patients in the controlled clinical trial, but in
`at least 2% of ONPATTRO-treated patients, and more frequently than on placebo, include dry eye (5% vs. 3%), blurred
`vision (3% vs. 1%), and vitreous floaters (2% vs. 1%).
`Extravasation was observed in less than 0.5% of infusions in clinical studies, including cases that were reported as serious.
`Signs and symptoms included phlebitis or thrombophlebitis, infusion or injection site swelling, dermatitis (subcutaneous
`inflammation), cellulitis, erythema or injection site redness, burning sensation, or injection site pain.
`
`6.2 Immunogenicity
`The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. In addition, the
`observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several
`factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and
`underlying disease. For these reasons, comparison of the incidence of antibodies to ONPATTRO in the studies described
`below with the incidence of antibodies in other studies or to other products may be misleading.
`Anti-drug antibodies to ONPATTRO were evaluated by measuring antibodies specific to PEG2000-C-DMG, a lipid
`component exposed on the surface of ONPATTRO. In the placebo-controlled and open-label clinical studies, 7 of
`194 (3.6%) patients with hATTR amyloidosis developed anti-drug antibodies during treatment with ONPATTRO. One
`additional patient had pre-existing anti-drug antibodies. There was no evidence of an effect of anti-drug antibodies on
`clinical efficacy, safety, or the pharmacokinetic or pharmacodynamic profiles of ONPATTRO. Although these data do not
`demonstrate an impact of anti-drug antibody development on the efficacy or safety of ONPATTRO in these patients, the
`available data are too limited to make definitive conclusions.
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Risk Summary
`There are no available data on ONPATTRO use in pregnant women to inform a drug-associated risk of adverse
`developmental outcomes. ONPATTRO treatment leads to a decrease in serum vitamin A levels, and vitamin A
`supplementation is advised for patients taking ONPATTRO. Vitamin A is essential for normal embryofetal development;
`however, excessive levels of vitamin A are associated with adverse developmental effects. The effects on the fetus of a
`reduction in maternal serum TTR caused by ONPATTRO and of vitamin A supplementation are unknown [see Clinical
`Pharmacology (12.2), Warnings and Precautions (5.2)].
`In animal studies, intravenous administration of patisiran lipid complex (patisiran-LC) to pregnant rabbits resulted in
`developmental toxicity (embryofetal mortality and reduced fetal body weight) at doses that were also associated with
`maternal toxicity. No adverse developmental effects were observed when patisiran-LC or a rodent-specific
`(pharmacologically active) surrogate were administered to pregnant rats (see Data).
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`In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically
`recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and
`miscarriage for the indicated population is unknown.
`
`Data
`
`Animal Data
`Intravenous administration of patisiran-LC (0, 0.15, 0.50, or 1.5 mg/kg) or a rodent-specific (pharmacologically active)
`surrogate (1.5 mg/kg) to female rats every week for two weeks prior to mating and continuing throughout organogenesis
`resulted in no adverse effects on fertility or embryofetal development.
`Intravenous administration of patisiran-LC (0, 0.1, 0.3, or 0.6 mg/kg) to pregnant rabbits every week during the period of
`organogenesis produced no adverse effects on embryofetal development. In a separate study, patisiran-LC (0, 0.3, 1, or
`2 mg/kg), administered to pregnant rabbits every week during the period of organogenesis, resulted in embryofetal
`mortality and reduced fetal body weight at the mid and high doses, which were associated with maternal toxicity.
`Intravenous administration of patisiran-LC (0, 0.15, 0.50, or 1.5 mg/kg) or a rodent-specific surrogate (1.5 mg/kg) to
`pregnant rats every week throughout pregnancy and lactation resulted in no adverse developmental effects on the
`offspring.
`
`8.2 Lactation
`
`Risk Summary
`There is no information regarding the presence of ONPATTRO in human milk, the effects on the breastfed infant, or the
`effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the
`mother’s clinical need for ONPATTRO and any potential adverse effects on the breastfed infant from ONPATTRO or
`from the underlying maternal condition.
`In lactating rats, patisiran was not detected in milk; however, the lipid components (DLin-MC3-DMA and PEG2000-C-
`DMG) were present in milk.
`
`8.4 Pediatric Use
`Safety and effectiveness in pediatric patients have not been established.
`
`8.5 Geriatric Use
`No dose adjustment is required in patients ≥65 years old [see Clinical Pharmacology (12.3)]. A total of 62 patients
`≥65 years of age, including 9 patients ≥75 years of age, received ONPATTRO in the placebo-controlled study. No overall
`differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of
`some older individuals cannot be ruled out.
`
`8.6 Hepatic Impairment
`No dose adjustment is necessary in patients with mild hepatic impairment (bilirubin ≤1 x ULN and AST >1 x ULN, or
`bilirubin >1.0 to 1.5 x ULN) [see Clinical Pharmacology (12.3)]. ONPATTRO has not been studied in patients with
`moderate or severe hepatic impairment.
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`8.7 Renal Impairment
`No dose adjustment is necessary in patients with mild or moderate renal impairment (estimated glomerular filtration rate
`[eGFR] ≥30 to <90 mL/min/1.73m2) [see Clinical Pharmacology (12.3)]. ONPATTRO has not been studied in patients
`with severe renal impairment or end-stage renal disease.
`
`11 DESCRIPTION
`ONPATTRO contains patisiran, a double-stranded small interfering ribonucleic acid (siRNA), formulated as a lipid
`complex for delivery to hepatocytes. Patisiran specifically binds to a genetically conserved sequence in the 3’ untranslated
`region (3’UTR) of mutant and wild-type transthyretin (TTR) messenger RNA (mRNA).
`The structural formula is:
`
`A, adenosine; C, cytidine; G, guanosine; U, uridine; Cm, 2’-O-methylcytidine; Um, 2’-O-methyluridine; dT, thymidine
`ONPATTRO is supplied as a sterile, preservative-free, white to off-white, opalescent, homogeneous solution for
`intravenous infusion in a single-dose glass vial. Each 1 mL of solution contains 2 mg of patisiran (equivalent 2.1 mg of
`patisiran sodium). Each 1 mL also contains 6.2 mg cholesterol USP, 13.0 mg (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-
`tetraen-19-yl-4-(dimethylamino) butanoate (DLin-MC3-DMA), 3.3 mg 1,2-distearoyl-sn-glycero-3-phosphocholine
`(DSPC), 1.6 mg α-(3’-{[1,2-di(myristyloxy)propanoxy] carbonylamino}propyl)-ω-methoxy, polyoxyethylene (PEG2000-
`C-DMG), 0.2 mg potassium phosphate monobasic anhydrous NF, 8.8 mg sodium chloride USP, 2.3 mg sodium phosphate
`dibasic heptahydrate USP, and Water for Injection USP. The pH is ~7.0.
`The molecular formula of patisiran sodium is C412 H480 N148 Na40 O290 P40 and the molecular weight is 14304 Da.
`
`
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Patisiran is a double-stranded siRNA that causes degradation of mutant and wild-type TTR mRNA through RNA
`interference, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.
`
`12.2 Pharmacodynamics
`The pharmacodynamic effects of ONPATTRO were evaluated in hATTR amyloidosis patients treated with 0.3 mg/kg
`ONPATTRO via intravenous infusion once every 3 weeks.
`Mean serum TTR was reduced by approximately 80% within 10 to 14 days after a single dose. With repeat dosing every
`3 weeks, mean reductions of serum TTR after 9 and 18 months of treatment were 83% and 84%, respectively. The mean
`maximum reduction of serum TTR over 18 months was 88%. Similar TTR reductions were observed regardless of TTR
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`mutation, sex, age, or race. In a dose-ranging study, greater TTR reduction was maintained over the dosing interval with
`the recommended dosing regimen of 0.3 mg/kg every 3 weeks compared to 0.3 mg/kg every 4 weeks.
`Serum TTR is a carrier of retinol binding protein, which is involved in the transport of vitamin A in the blood. Mean
`reductions in serum retinol binding protein of 45% and serum vitamin A of 62% were observed over 18 months [see
`Warnings and Precautions (5.2)].
`
`12.3 Pharmacokinetics
`Following a single intravenous administration, systemic exposure to patisiran increases in a linear and dose-proportional
`manner over the range of 0.01 to 0.5 mg/kg. Greater than 95% of patisiran in the circulation is associated with the lipid
`complex. At the recommended dosing regimen of 0.3 mg/kg every 3 weeks, steady state is reached by 24 weeks of
`treatment. The estimated mean ± SD steady state peak concentrations (Cmax), trough concentrations (Ctrough), and area
`under the curve (AUCτ) were 7.15 ± 2.14 µg/mL, 0.021 ± 0.044 µg/mL, and 184 ± 159 µg·h/mL, respectively. The
`accumulation of AUCτ was 3.2-fold at steady state, compared to the first dose. In the placebo-controlled study, inter-
`patient variability in patisiran exposure did not result in differences in clinical efficacy (mNIS+7 change from baseline) or
`safety (adverse events, serious adverse events).
`
`Distribution
`Plasma protein binding of ONPATTRO is low, with ≤2.1% binding observed in vitro with human serum albumin and
`human α1-acid glycoprotein. ONPATTRO distributes primarily to the liver. At the recommended dosing regimen of
`0.3 mg/kg every 3 weeks, the mean ± SD steady state volume of distribution of patisiran (Vss) was 0.26 ± 0.20 L/kg.
`
`Elimination
`The terminal elimination half-life (mean ± SD) of patisiran is 3.2 ± 1.8 days. Patisiran is mainly cleared through
`metabolism, and the total body clearance (mean ± SD) at steady state (CLss) is 3.0 ± 2.5 mL/h/kg.
`
`Metabolism
`Patisiran is metabolized by nucleases to nucleotides of various lengths.
`
`Excretion
`Less than 1% of the administered dose of patisiran is excreted unchanged into urine.
`
`Specific Populations
`Age, race (non-Caucasian vs. Caucasian), and sex had no impact on the steady state pharmacokinetics of patisiran or TTR
`reduction. Population pharmacokinetic and pharmacodynamic analyses indicated no impact of mild or moderate renal
`impairment (eGFR ≥30 to <90 mL/min/1.73m2) or mild hepatic impairment (bilirubin ≤1 x ULN and AST >1 x ULN, or
`bilirubin >1.0 to 1.5 x ULN) on patisiran exposure or TTR reduction. ONPATTRO has not been studied in patients with
`severe renal impairment, end-stage renal disease, moderate or severe hepatic impairment, or in patients with prior liver
`transplant.
`
`Drug Interaction Studies
`No formal clinical drug interaction studies have been performed. The components of ONPATTRO are not inhibitors or
`inducers of cytochrome P450 enzymes or transporters. Patisiran is not a substrate of cytochrome P450 enzymes. In a
`population pharmacokinetic analysis, concomitant use of strong or moderate CYP3A inducers and inhibitors did not
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`impact the pharmacokinetic parameters of patisiran. ONPATTRO is not expected to cause drug-drug interactions or to be
`affected by inhibitors or inducers of cytochrome P450 enzymes.
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Carcinogenesis
`Patisiran-LC was not carcinogenic in TgRasH2 mice when administered at intravenous (IV) doses of 0, 0.5, 2, or 6 mg/kg
`every two weeks for 26 weeks.
`
`Mutagenesis
`Patisiran-LC was negative for genotoxicity in in vitro (bacterial mutagenicity assay, chromosomal aberration assay in
`human peripheral blood lymphocytes) and in vivo (mouse bone marrow micronucleus) assays.
`
`Impairment of Fertility
`Intravenous (IV) administration of patisiran-LC (0, 0.03, 0.1, or 0.3 mg/kg) or a rodent-specific (pharmacologically
`active) surrogate (0.1 mg/kg) to male rats every two weeks prior to and throughout mating to untreated females produced
`no adverse effects on fertility.
`Intravenous administration of patisiran-LC (0, 0.15, 0.50, or 1.5 mg/kg) or a rodent-specific (pharmacologically active)
`surrogate (1.5 mg/kg) to female rats every week for two weeks prior to mating and continuing throughout organogenesis
`resulted in no adverse effects on fertility or on embryofetal development.
`Intravenous administration of patisiran-LC (0, 0.3, 1, or 2 mg/kg) to adult monkeys every three weeks for 39 weeks
`produced no adverse effects on male reproductive organs or on sperm morphology or count.
`
`14 CLINICAL STUDIES
`The efficacy of ONPATTRO was demonstrated in a randomized, double-blind, placebo-controlled, multicenter clinical
`trial in adult patients with polyneuropathy caused by hATTR amyloidosis (NCT 01960348). Patients were randomized in
`a 2:1 ratio to receive ONPATTRO 0.3 mg/kg (N=148) or placebo (N=77), respectively, via intravenous infusion once
`every 3 weeks for 18 months. All patients received premedication with a corticosteroid, acetaminophen, and H1 and H2
`blockers. Ninety-three percent of ONPATTRO-treated patients and 62% of placebo-treated patients completed 18 months
`of the assigned treatment.
`The primary efficacy endpoint was the change from baseline to Month 18 in the modified Neuropathy Impairment
`Score +7 (mNIS+7). The mNIS+7 is an objective assessment of neuropathy and comprises the NIS and Modified +7 (+7)
`composite scores. In the version of the mNIS+7 used in the trial, the NIS objectively measures deficits in cranial nerve
`function, muscle strength, and reflexes, and the +7 assesses postural blood pressure, quantitative sensory testing, and
`peripheral nerve electrophysiology. The maximum possible score was 304 points, with higher scores representing a
`greater severity of disease.
`The clinical meaningfulness of effects on the mNIS+7 was assessed by the change from baseline to Month 18 in Norfolk
`Quality of Life-Diabetic Neuropathy (QoL-DN) total score. The Norfolk QoL-DN scale is a patient-reported assessment
`that evaluates the subjective experience of neuropathy in the following domains: physical functioning/large fiber
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`Reference ID: 4305330
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`neuropathy, activities of daily living, symptoms, small fiber neuropathy, and autonomic neuropathy. The version of the
`Norfolk QoL-DN that was used in the trial had a total score range from -4 to 136, with higher scores representing greater
`impairment.
`The changes from baseline to Month 18 on both the mNIS+7 and the Norfolk QoL-DN significantly favored ONPATTRO
`(Table 2, Figure 1 and Figure 3). The distributions of changes in mNIS+7 and Norfolk QoL-DN scores from baseline to
`Month 18 by percent of patients are shown in Figure 2 and Figure 4, respectively.
`The changes from baseline to Month 18 in modified body mass index (mBMI) and gait speed (10-meter walk test)
`significantly favored ONPATTRO (Table 2).
`Table 2:
`Clinical Efficacy Results from the Placebo-Controlled Study
`ONPATTRO-
`Placebo
`Treatment
`Difference,
` LS Mean
`(95% CI)
`
`Endpointa
`
`Baseline, Mean (SD)
`
`Change from Baseline to
`Month 18, LS Mean (SEM)
`
`ONPATTRO
`N=148
`
`Placebo
`N=77
`
`ONPATTRO
`
`Placebo
`
`p-value
`
`Primary
`
`mNIS+7 b
`
`80.9 (41.5)
`
`74.6 (37.0)
`
`-6.0 (1.7)
`
`28.0 (2.6)
`
`-34.0
`(-39.9, -28.1)
`
`
`
`
`
`p<0.001
`
`p<0.001
`
`p<0.001
`
`Secondary
`Norfolk
`QoL-DN b
`10-meter
`walk test
`(m/sec) c
`
`59.6 (28.2)
`
`55.5 (24.3)
`
`-6.7 (1.8)
`
`14.4 (2.7)
`
`0.80 (0.40)
`
`0.79 (0.32)
`
`0.08 (0.02)
`
`-0.24 (0.04)
`
`-21.1
`(-27.2, -15.0)
`0.31
`(0.23, 0.39)
`116
`p<0.001
`-119 (14.5)
`-3.7 (9.6)
`990 (214)
`970 (210)
`mBMI d
`(82, 149)
`CI, confidence interval; LS, least squares; mBMI, modified body mass index; mNIS, modified Neuropathy Impairment Score; QoL-DN,
`Quality of Life – Diabetic Neuropathy; SD, standard deviation; SEM, standard error of the mean
`a All endpoints analyzed using the mixed-effect model repeated measures (MMRM) method.
`b A lower value indicates less impairment/fewer symptoms.
`c A higher number indicates less disability/less impairment.
`d mBMI: body mass index (BMI; kg/m2) multiplied by serum albumin (g/L); a higher number indicates better nutritional status.
`
`
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`Reference ID: 4305330
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`Moderna Ex 1023-p. 12
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`Figure 1:
`
`Change from Baseline in mNIS+7
`
`A decrease in mNIS+7 indicates improvement.
`∆ indicates between-group treatment difference, shown as the LS mean difference (95% CI) for ONPATTRO – placebo.
`
`
`Figure 2:
`
` Histogram of mNIS+7 Change from Baseline at Month 18
`
`
`
`
`mNIS+7 change scores are rounded to the nearest whole number; last available post-baseline scores were used.
`
`
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`Reference ID: 4305330
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`Moderna Ex 1023-p. 13
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`Categories are mutually exclusive; patients who died before 18 months are summarized in th