TNKase®

(Tenecteplase)

DESCRIPTION
TNKase® (Tenecteplase) is a tissue plasminogen activator (tPA) produced by recombinant DNA
technology using an established mammalian cell line (Chinese Hamster Ovary cells).
Tenecteplase is a 527 amino acid glycoprotein developed by introducing the following
modifications to the complementary DNA (cDNA) for natural human tPA: a substitution of
threonine 103 with asparagine, and a substitution of asparagine 117 with glutamine, both within
the kringle 1 domain, and a tetra-alanine substitution at amino acids 296–299 in the protease
domain. TNKase is a sterile, white to off-white, lyophilized powder for single intravenous (IV)
bolus administration after reconstitution with Sterile Water for Injection (SWFI), USP. Each vial
of TNKase nominally contains 52.5 mg Tenecteplase, 0.55 g L-arginine, 0.17 g phosphoric acid,
and 4.3 mg polysorbate 20, which includes a 5% overfill. Each vial will deliver 50 mg of
Tenecteplase.

CLINICAL PHARMACOLOGY
General
Tenecteplase is a modified form of human tissue plasminogen activator (tPA) that binds to fibrin
and converts plasminogen to plasmin. In the presence of fibrin, in vitro studies demonstrate that
Tenecteplase conversion of plasminogen to plasmin is increased relative to its conversion in the
absence of fibrin. This fibrin specificity decreases systemic activation of plasminogen and the
resulting degradation of circulating fibrinogen as compared to a molecule lacking this property.
Following administration of 30, 40, or 50 mg of TNKase, there are decreases in circulating
fibrinogen (4%–15%) and plasminogen (11%−24%). The clinical significance of fibrin-
specificity on safety (e.g., bleeding) or efficacy has not been established. Biological potency is
determined by an in vitro clot lysis assay and is expressed in Tenecteplase-specific units. The
specific activity of Tenecteplase has been defined as 200 units/mg.

Pharmacokinetics
In patients with acute myocardial infarction (AMI), TNKase administered as a single bolus
exhibits a biphasic disposition from the plasma. Tenecteplase was cleared from the plasma with
an initial half-life of 20 to 24 minutes. The terminal phase half-life of Tenecteplase was 90 to
130 minutes. In 99 of 104 patients treated with Tenecteplase, mean plasma clearance ranged
from 99 to 119 mL/min.

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 The initial volume of distribution is weight related and approximates plasma volume. Liver
metabolism is the major clearance mechanism for Tenecteplase.

CLINICAL STUDIES
ASSENT-2 was an international, randomized, double-blind trial that compared 30-day mortality
rates in 16,949 patients assigned to receive an IV bolus dose of TNKase or an accelerated
infusion of Activase® (Alteplase).1 Eligibility criteria included onset of chest pain within 6 hours
of randomization and ST-segment elevation or left bundle branch block on
electrocardiogram (ECG). Patients were to be excluded from the trial if they received
GP IIb/IIIa inhibitors within the previous 12 hours. TNKase was dosed using actual or estimated
weight in a weight-tiered fashion as described in DOSAGE AND ADMINISTRATION. All
patients were to receive 150–325 mg of aspirin administered as soon as possible, followed by
150–325 mg daily. Intravenous heparin was to be administered as soon as possible: for patients
weighing ≤ 67 kg, heparin was administered as a 4000 unit IV bolus followed by infusion at
800 U/hr; for patients weighing > 67 kg, heparin was administered as a 5000 unit IV bolus
followed by infusion at 1000 U/hr. Heparin was continued for 48 to 72 hours with infusion
adjusted to maintain aPTT at 50–75 seconds. The use of GP IIb/IIIa inhibitors was discouraged
for the first 24 hours following randomization. The results of the primary endpoint (30-day
mortality rates with non-parametric adjustment for the covariates of age, Killip class, heart rate,
systolic blood pressure and infarct location) along with selected other 30-day endpoints are
shown in Table 1.

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 Table 1
ASSENT-2
Mortality, Stroke, and Combined Outcome of Death or Stroke
Measured at Thirty Days

Accelerated Relative Risk

TNKase Activase TNKase/Activase
30-Day Events (n = 8461) (n = 8488) (95% CI)
Mortality 6.2% 6.2% 1.00
(0.89, 1.12)
Intracranial Hemorrhage (ICH) 0.9% 0.9% 0.99
(0.73, 1.35)
Any Stroke 1.8% 1.7% 1.07
(0.86, 1.35)
Death or Nonfatal Stroke 7.1% 7.0% 1.01
(0.91, 1.13)

Rates of mortality and the combined endpoint of death or stroke among pre-specified subgroups,
including age, gender, time to treatment, infarct location, and history of previous myocardial
infarction, demonstrate consistent relative risks across these subgroups. There was insufficient
enrollment of non-Caucasian patients to draw any conclusions regarding relative efficacy in
racial subsets.

Rates of in-hospital procedures, including percutaneous transluminal coronary angioplasty

(PTCA), stent placement, intra-aortic balloon pump (IABP) use, and coronary artery bypass graft
(CABG) surgery, were similar between the TNKase and Activase (Alteplase) groups.

TIMI 10B was an open-label, controlled, randomized, dose-ranging, angiography study which
utilized a blinded core laboratory for review of coronary arteriograms.2 Patients (n = 837)
presenting within 12 hours of symptom onset were treated with fixed doses of 30, 40, or 50 mg
of TNKase or the accelerated infusion of Activase and underwent coronary arteriography at
90 minutes. The results showed that the 40 mg and 50 mg doses were similar to accelerated
infusion of Activase in restoring patency. TIMI Grade 3 flow and TIMI Grade 2/3 flow at
90 minutes are shown in Table 2. The exact relationship between coronary artery patency and
clinical activity has not been established.

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 Table 2
TIMI 10B Patency Rates
TIMI Grade Flow at 90 Minutes

Activase <100 mg TNKase 30 mg TNKase 40 mg TNKase 50 mg

(n=311) (n=302) (n=148) (n=76)
TIMI Grade 3 Flow 63% 54% 63% 66%

TIMI Grade 2/3 Flow 82% 77% 79% 88%

95% CI (77%,86%) (72%,81%) (72%,85%) (79%,94%)

(TIMI 2/3 Flow)

The angiographic results from TIMI 10B and the safety data from ASSENT-1, an additional
uncontrolled safety study of 3,235 TNKase-treated patients, provided the framework to develop a
weight-tiered TNKase dose regimen.3 Exploratory analyses suggested that a weight-adjusted
dose of 0.5 mg/kg to 0.6 mg/kg of TNKase resulted in a better patency to bleeding relationship
than fixed doses of TNKase across a broad range of patient weights.

The Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous
Coronary Intervention (ASSENT 4 PCI) was a Phase IIIb/IV study designed to assess the safety
and effectiveness of a strategy of administering full dose TNKase with a single bolus of 4000 U
of unfractionated heparin in patients with ST segment elevation AMI, in whom primary
percutaneous coronary intervention (PCI) was planned, but in whom a delay of 1-3 hours was
anticipated before PCI. The trial was prematurely terminated with 1667 randomized patients (75
of whom were treated in the United States) due to a numerically higher mortality in the patients
receiving TNKase prior to primary PCI versus PCI without TNKase (median time from
randomization to balloon of 115 minutes). The incidence of the 90-day primary endpoint, a
composite of death or cardiogenic shock or congestive heart failure (CHF) within 90 days, was
18.6% in patients treated with TNKase plus PCI versus 13.4% in those treated with PCI alone
(p = 0.0055; OR 1.39 (95% C.I. 1.11−1.74)).

There were trends toward worse outcomes in the individual components of the primary endpoint
between TNKase plus PCI versus PCI alone (mortality 6.7% vs. 5.0%, respectively; cardiogenic
shock 6.1% vs. 4.8%, respectively; and CHF 12.1% vs. 9.4%, respectively). In addition, there
were trends towards worse outcomes in recurrent MI (6.1% vs. 3.5%, respectively; p = 0.03) and
repeat target vessel revascularization (6.6% vs. 3.6%, respectively; p = 0.005) in patients
receiving TNKase plus PCI versus PCI alone.

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 There was no difference in in-hospital major bleeding between the two groups (5.6% vs. 4.4%
for TNKase plus PCI vs. PCI alone, respectively). For patients treated with TNKase plus PCI,
in-hospital rates of intracranial hemorrhage and total stroke were similar to those observed in
previous trials (0.97% and 1.8%, respectively); however, none of the patients treated with PCI
alone experienced a stroke (ischemic, hemorrhagic or other).

INDICATIONS AND USAGE

TNKase® (Tenecteplase) is indicated for use in the reduction of mortality associated with acute
myocardial infarction (AMI). Treatment should be initiated as soon as possible after the onset of
AMI symptoms (see CLINICAL STUDIES).

CONTRAINDICATIONS
TNKase therapy in patients with acute myocardial infarction is contraindicated in the
following situations because of an increased risk of bleeding (see WARNINGS):
• Active internal bleeding
• History of cerebrovascular accident
• Intracranial or intraspinal surgery or trauma within 2 months
• Intracranial neoplasm, arteriovenous malformation, or aneurysm
• Known bleeding diathesis
• Severe uncontrolled hypertension

WARNINGS
Bleeding
The most common complication encountered during TNKase therapy is bleeding. The type of
bleeding associated with thrombolytic therapy can be divided into two broad categories:
• Internal bleeding, involving intracranial and retroperitoneal sites, or the gastrointestinal,
genitourinary, or respiratory tracts.
• Superficial or surface bleeding, observed mainly at vascular puncture and access sites (e.g.,
venous cutdowns, arterial punctures) or sites of recent surgical intervention.

Should serious bleeding (not controlled by local pressure) occur, any concomitant heparin or
antiplatelet agents should be discontinued immediately and treated appropriately.

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 In clinical studies of TNKase, patients were treated with both aspirin and heparin. Heparin may
contribute to the bleeding risks associated with TNKase. The safety of the use of TNKase with
other antiplatelet agents has not been adequately studied (see PRECAUTIONS: Drug
Interactions). Intramuscular injections and nonessential handling of the patient should be
avoided for the first few hours following treatment with TNKase. Venipunctures should be
performed and monitored carefully.

Should an arterial puncture be necessary during the first few hours following TNKase therapy, it
is preferable to use an upper extremity vessel that is accessible to manual compression. Pressure
should be applied for at least 30 minutes, a pressure dressing applied, and the puncture site
checked frequently for evidence of bleeding.

Each patient being considered for therapy with TNKase should be carefully evaluated and
anticipated benefits weighed against potential risks associated with therapy. In the following
conditions, the risk of TNKase therapy may be increased and should be weighed against the
anticipated benefits:
• Recent major surgery, e.g., coronary artery bypass graft, obstetrical delivery, organ biopsy,
previous puncture of noncompressible vessels
• Cerebrovascular disease
• Recent gastrointestinal or genitourinary bleeding
• Recent trauma
• Hypertension: systolic BP ≥ 180 mm Hg and/or diastolic BP ≥ 110 mm Hg
• Acute pericarditis
• Subacute bacterial endocarditis
• Hemostatic defects, including those secondary to severe hepatic or renal disease
• Severe hepatic dysfunction
• Pregnancy
• Diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions
• Septic thrombophlebitis or occluded AV cannula at seriously infected site
• Advanced age (see PRECAUTIONS: Geriatric Use)
• Patients currently receiving oral anticoagulants, e.g., warfarin sodium

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 • Recent administration of GP IIb/IIIa inhibitors
• Any other condition in which bleeding constitutes a significant hazard or would be
particularly difficult to manage because of its location

Thromboembolism
The use of thrombolytics can increase the risk of thrombo-embolic events in patients with high
likelihood of left heart thrombus, such as patients with mitral stenosis or atrial fibrillation.

Cholesterol Embolization
Cholesterol embolism has been reported rarely in patients treated with all types of thrombolytic
agents; the true incidence is unknown. This serious condition, which can be lethal, is also
associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular
surgery) and/or anticoagulant therapy. Clinical features of cholesterol embolism may include
livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits, hypertension,
pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery
occlusion, bowel infarction, and rhabdomyolysis.

Arrhythmias
Coronary thrombolysis may result in arrhythmias associated with reperfusion. These
arrhythmias (such as sinus bradycardia, accelerated idioventricular rhythm, ventricular premature
depolarizations, ventricular tachycardia) are not different from those often seen in the ordinary
course of acute myocardial infarction and may be managed with standard anti-arrhythmic
measures. It is recommended that anti-arrhythmic therapy for bradycardia and/or ventricular
irritability be available when TNKase is administered.

Use with Percutaneous Coronary Intervention (PCI)

In patients with large ST segment elevation myocardial infarction, physicians should choose
either thrombolysis or PCI as the primary treatment strategy for reperfusion. Rescue PCI or
subsequent elective PCI may be performed after administration of thrombolytic therapies if
medically appropriate; however, the optimal use of adjunctive antithrombotic and antiplatelet
therapies in this setting is unknown.

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 PRECAUTIONS
General
Standard management of myocardial infarction should be implemented concomitantly with
TNKase treatment. Arterial and venous punctures should be minimized. Noncompressible
arterial puncture must be avoided and internal jugular and subclavian venous punctures should
be avoided to minimize bleeding from the noncompressible sites. In the event of serious
bleeding, heparin and antiplatelet agents should be discontinued immediately. Heparin effects
can be reversed by protamine.

Readministration
Readministration of plasminogen activators, including TNKase, to patients who have received
prior plasminogen activator therapy has not been systematically studied. Three of 487 patients
tested for antibody formation to TNKase had a positive antibody titer at 30 days. The data
reflect the percentage of patients whose test results were considered positive for antibodies to
TNKase in a radioimmunoprecipitation assay, and are highly dependent on the sensitivity and
specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay
may be influenced by several factors including sample handling, concomitant medications, and
underlying disease. For these reasons, comparison of the incidence of antibodies to TNKase
with the incidence of antibodies to other products may be misleading. Although sustained
antibody formation in patients receiving one dose of TNKase has not been documented,
readministration should be undertaken with caution.

Hypersensitivity

Hypersensitivity, including urticarial / anaphylactic reactions, have been reported after

administration of TNKase (e.g., anaphylaxis, angioedema, laryngeal edema, rash, and urticaria).
Monitor patients treated with TNKase during and for several hours after infusion. If symptoms
of hypersensitivity occur, appropriate therapy should be initiated.

Drug Interactions
Formal interaction studies of TNKase with other drugs have not been performed. Patients
studied in clinical trials of TNKase were routinely treated with heparin and aspirin.
Anticoagulants (such as heparin and vitamin K antagonists) and drugs that alter platelet function

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 (such as acetylsalicylic acid, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of
bleeding if administered prior to, during, or after TNKase therapy.

Drug/Laboratory Test Interactions

During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may
be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is
an enzyme that, when present in blood in pharmacologic concentrations, remains active under
in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for
analysis.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals have not been performed to evaluate the carcinogenic potential, mutagenicity,
or the effect on fertility.

Pregnancy
TNKase has been shown to elicit maternal and embryo toxicity in rabbits given multiple
IV administrations. In rabbits administered 0.5, 1.5, and 5.0 mg/kg/day during organogenesis,
vaginal hemorrhage resulted in maternal deaths. Subsequent embryonic deaths were secondary
to maternal hemorrhage and no fetal anomalies were observed. TNKase does not elicit maternal
and embryo toxicity in rabbits following a single IV administration. Thus, in developmental
toxicity studies conducted in rabbits, the no observable effect level (NOEL) of a single IV
administration of TNKase on maternal or developmental toxicity (5 mg/kg) was approximately 7
times human exposure (based on AUC) at the dose for AMI. There are no adequate and
well-controlled studies in pregnant women. TNKase should be given to pregnant women only if
the potential benefits justify the potential risk to the fetus.

Nursing Mothers
It is not known if TNKase is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when TNKase is administered to a nursing woman.

Pediatric Use
The safety and effectiveness of TNKase in pediatric patients have not been established.

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 Geriatric Use
Of the patients in ASSENT-2 who received TNKase, 4,958 (59%) were under the age of 65;
2,256 (27%) were between the ages of 65 and 74; and 1,244 (15%) were 75 and over. The
30-day mortality rates by age were 2.5% in patients under the age of 65, 8.5% in patients
between the ages of 65 and 74, and 16.2% in patients age 75 and over. The ICH rates were 0.4%
in patients under the age of 65, 1.6% in patients between the ages of 65 and 74, and 1.7% in
patients age 75 and over. The rates of any stroke were 1.0% in patients under the age of 65,
2.9% in patients between the ages of 65 and 74, and 3.0% in patients age 75 and over. Major
bleeding rates, defined as bleeding requiring blood transfusion or leading to hemodynamic
compromise, were 3.1% in patients under the age of 65, 6.4% in patients between the ages of 65
and 74, and 7.7% in patients age 75 and over. In elderly patients, the benefits of TNKase on
mortality should be carefully weighed against the risk of increased adverse events, including
bleeding.

ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in Section PRECAUTIONS of the
label:
• Hypersensitivity

Bleeding
The most frequent adverse reaction associated with TNKase is bleeding (see WARNINGS).

Should serious bleeding occur, concomitant heparin and antiplatelet therapy should be
discontinued. Death or permanent disability can occur in patients who experience stroke or
serious bleeding episodes.

For TNKase-treated patients in ASSENT-2, the incidence of intracranial hemorrhage was 0.9%
and any stroke was 1.8%. The incidence of all strokes, including intracranial bleeding, increases
with increasing age (see PRECAUTIONS: Geriatric Use).

In the ASSENT-2 study, the following bleeding events were reported (see Table 3).

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 Table 3
ASSENT-2
Non-ICH Bleeding Events

Accelerated Relative Risk for

TNKase Activase TNKase/Activase
(n = 8461) (n = 8488) (95% CI)
Major bleedinga 4.7% 5.9% 0.78 (0.69, 0.89)
Minor bleeding 21.8% 23.0% 0.94 (0.89, 1.00)
Units of transfused blood
Any 4.3% 5.5% 0.77 (0.67, 0.89)
1−2 2.6% 3.2%
>2 1.7% 2.2%
a
Major bleeding is defined as bleeding requiring blood transfusion or leading to
hemodynamic compromise.

Non-intracranial major bleeding and the need for blood transfusions were lower in patients
treated with TNKase.

Types of major bleeding reported in 1% or more of the patients were hematoma (1.7%) and
gastrointestinal tract (1%). Types of major bleeding reported in less than 1% of the patients were
urinary tract, puncture site (including cardiac catheterization site), retroperitoneal, respiratory
tract, and unspecified. Types of minor bleeding reported in 1% or more of the patients were
hematoma (12.3%), urinary tract (3.7%), puncture site (including cardiac catheterization site)
(3.6%), pharyngeal (3.1%), gastrointestinal tract (1.9%), epistaxis (1.5%), and unspecified
(1.3%).

Other Adverse Reactions

The following adverse reactions have been reported among patients receiving TNKase in clinical
trials. These reactions are frequent sequelae of the underlying disease, and the effect of TNKase
on the incidence of these events is unknown.

These events include cardiogenic shock, arrhythmias, atrioventricular block, pulmonary edema,
heart failure, cardiac arrest, recurrent myocardial ischemia, myocardial reinfarction, myocardial
rupture, cardiac tamponade, pericarditis, pericardial effusion, mitral regurgitation, thrombosis,
embolism, and electromechanical dissociation. These events can be life-threatening and may
lead to death. Nausea and/or vomiting, hypotension, and fever have also been reported.

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 DOSAGE AND ADMINISTRATION
Dosage
TNKase® (Tenecteplase) is for intravenous administration only. The recommended total dose
should not exceed 50 mg and is based upon patient weight.

A single bolus dose should be administered over 5 seconds based on patient weight. Treatment
should be initiated as soon as possible after the onset of AMI symptoms (see CLINICAL
STUDIES).

Dose Information Table

Patient Weight TNKase Volume TNKase* to be

(kg) (mg) administered (mL)
< 60 30 6
≥ 60 to < 70 35 7
≥ 70 to < 80 40 8
≥ 80 to < 90 45 9
≥ 90 50 10
*From one vial of TNKase reconstituted with 10 mL SWFI.

The safety and efficacy of TNKase have only been investigated with concomitant administration
of heparin and aspirin as described in CLINICAL STUDIES.

The B-D ® 10 mL Syringe with TwinPak™ Dual Cannula Device

Reconstitution
NOTE: Read all instructions completely before beginning reconstitution and administration.
1. Remove the shield assembly from the supplied B-D® 10 mL syringe with TwinPak™ Dual
Cannula Device (see figure) and aseptically withdraw 10 mL of Sterile Water for Injection

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 (SWFI), USP, from the supplied diluent vial using the red hub cannula syringe filling
device. Do not use Bacteriostatic Water for Injection, USP.
Note: Do not discard the shield assembly.
2. Inject the entire contents of the syringe (10 mL) into the TNKase vial directing the diluent
stream into the powder. Slight foaming upon reconstitution is not unusual; any large
bubbles will dissipate if the product is allowed to stand undisturbed for several minutes.
3. Gently swirl until contents are completely dissolved. DO NOT SHAKE. The reconstituted
preparation results in a colorless to pale yellow transparent solution containing TNKase at
5 mg/mL at a pH of approximately 7.3. The osmolality of this solution is approximately
290 mOsm/kg.
4. Determine the appropriate dose of TNKase (see Dose Information Table) and withdraw this
volume (in milliliters) from the reconstituted vial with the syringe. Any unused solution
should be discarded.
5. Once the appropriate dose of TNKase is drawn into the syringe, stand the shield vertically
on a flat surface (with green side down) and passively recap the red hub cannula.
6. Remove the entire shield assembly, including the red hub cannula, by twisting
counterclockwise. Note: The shield assembly also contains the clear-ended blunt plastic
cannula; retain for split septum IV access.

Administration
1. The product should be visually inspected prior to administration for particulate matter and
discoloration. TNKase may be administered as reconstituted at 5 mg/mL.
2. Precipitation may occur when TNKase is administered in an IV line containing dextrose.
Dextrose-containing lines should be flushed with a saline-containing solution prior to and
following single bolus administration of TNKase.
3. Reconstituted TNKase should be administered as a single IV bolus over 5 seconds.
4. Because TNKase contains no antibacterial preservatives, it should be reconstituted
immediately before use. If the reconstituted TNKase is not used immediately, refrigerate the
TNKase vial at 2−8°C (36−46°F) and use within 8 hours.
5. Although the supplied syringe is compatible with a conventional needle, this syringe is
designed to be used with needleless IV systems. From the information below, follow the
instructions applicable to the IV system in use.
Split septum IV system: • Remove the green cap.
• Attach the clear-ended blunt plastic
cannula to the syringe.

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 • Remove the shield and use the blunt
plastic cannula to access the split
septum injection port.
• Because the blunt plastic cannula has
two side ports, air or fluid expelled
through the cannula will exit in two
sideways directions; direct away from
face or mucous membranes.
Luer-Lok® system: Connect syringe directly to IV port.
Conventional needle Attach a large bore needle, e.g., 18 gauge,
(not supplied in this kit): to the syringe’s universal Luer-Lok®.

6. Dispose of the syringe, cannula and shield per established procedures.

HOW SUPPLIED
TNKase® (Tenecteplase) is supplied as a sterile, lyophilized powder in a 50 mg vial under partial
vacuum. Each 50 mg vial of TNKase is packaged with one 10 mL vial of Sterile Water for
Injection, USP for reconstitution, the B-D® 10 mL syringe with TwinPak Dual Cannula
Device, and three alcohol prep pads. NDC 50242-120-01.

Stability and Storage

Store lyophilized TNKase at controlled room temperature not to exceed 30°C (86°F) or under
refrigeration 2−8°C (36−46°F). Do not use beyond the expiration date stamped on the vial.

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 TNKase [Tenecteplase]
Manufactured by:
Genentech, Inc. Initial US Approval June 2000
A Member of the Roche Group Revision Date 02/2018
1 DNA Way TNKase is a registered trademark
South San Francisco, CA 94080-4990
of Genentech, Inc.
U.S. License No.:1048 2018 Genentech, Inc.

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