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Hi and welcome to this Genentech educational podcast created for healthcare professionals I'm Abby and my co-host today is Adrian. We are AI created podcast hosts, not real people, we have been designed to sound like real people to share information from Genentech. Today, we will have a brief discussion about the Alteplace compared to Tenecteplase study, also known as the Act study, which led to FDA approval of TNKase for the treatment of acute ischemic stroke in adult patients.

Hi everyone, Adrian here. Also an AI created podcast host, not a real person; I'm designed to sound like a real person to share information from Genentech. So I heard you say that TNKase, also known as tenecteplase, is indicated for the treatment of acute ischemic stroke (AIS) in adults. But, Abby, before we start, does TNKase have any contraindications?

I’m glad you asked, Adrian, the contraindications are also something that should be considered prior to treatment. TNKase is contraindicated in any patients with active internal bleeding; intracranial or intra-spinal surgery or trauma within 2 months; known bleeding diathesis; current severe uncontrolled hypertension; presence of intracranial conditions that may increase the risk of bleeding (eg, intracranial neoplasm, arteriovenous malformation, or aneurysm). TNKase is contraindicated in AIS patients with active intracranial hemorrhage. We'll go over the rest of the important safety information later.

Thanks so much for that, Abby.

Sure, thanks Adrian. Would you like to start by explaining the specifics of the act study to our listeners?

So Act was a large, randomized, controlled clinical trial. It was an open-label study with blinded outcome assessment that investigated the non-inferiority of TNKase to alteplase in the treatment of acute ischemic stroke. Patients experiencing a stroke were eligible for the study if they had a disabling neurological deficit and were eligible for intravenous thrombolysis. Although the trial enrolled patients who were treated within 0 to four and a half hours of stroke symptom onset, the subset of patients treated within 0 to 3 hours was used to assess efficacy of TNKase because the comparator, alteplase, is approved for use within 0 to 3 hours of stroke symptom onset.

Ok and how many patients were included in the study?

The intent-to-treat population consisted of eleven hundred forty seven patients who were treated within 3 hours of symptom onset.

Very interesting. And what about randomisation?

Patients were randomized one to one to receive either TNKase or alteplase. Due to the differences in administration, this was an open‐label study with blinded outcome assessment.

That makes sense. What can you tell our listeners about the dosing and administration in the study?

TNKase was administered as a single 5 second IV bolus, whereas alteplase was given, ten percent as an IV bolus over one minute and the remaining 90 percent as a 1 hour infusion. TNKase was given at the body-weight–tiered recommended dosage. The maximum dose of TNKase for stroke treatment is 25 milligrams.

Great. I think we're ready to talk about the endpoints of the study now.

Yes. Efficacy of TNKase was assessed as the proportion of patients treated within 3 hours of symptom onset achieving a modified Rankin Scale score of 0 to 1, at 90 to one hundred and twenty days.

What can you tell us about the patients included and how they compared across both arms?

That's such a great question and so important to understand these details before we get to the study results. The intent-to-treat population included a broad population that was consistent across both treatment arms. The mean age was 72 years. 53 per cent of patients were male, and 47 per cent were female. The median baseline NIHSS score was 10.

How about large vessel occlusions or LVO? I know our listeners have patients who may present with an LVO.

The presence of a large vessel occlusion was detected in approximately 27 per cent on baseline CT angiography, and the median time from stroke onset to thrombolysis was one hundred and eight minutes.

Thanks Adrian. I think we're ready to discuss the results. What do you think?

Results from Act showed no significant difference between treatment groups, with 36.6 per cent of the 592 patients treated with TNKase and 35.9 per cent of 555 patients treated with alteplase having achieved excellent functional outcomes, defined as a modified Rankin Scale score of 0 to 1, 90 to 120 days following a stroke. The unadjusted risk difference was zero point 7% and the 95% confidence interval was negative 4.9% to 6.3%.

And how does that compare across all the different patient demographics we discuss earlier in the study design?

You're really asking the good questions, Abby. Thank you. It's so important to discuss all the details and not just top-line results. So, similar efficacy was observed across exploratory subgroups defined by age, gender, and baseline NIHSS score. And safety data were comparable across treatment arms.

Safety data. Another really important part of this conversation for our listeners. What else can you tell me about safety from this study?

You may want to look at the www.tnkase.com or the TNKase prescribing information to better visualize this but, let me tell you some details about the adverse reactions of the five hundred and ninety two TNKase patients and the five hundred and fifty five alteplase patients treated for AIS within 0 to 3 hours from symptom onset. I'm going to tell you about the rates we saw of each adverse reaction for the TNKase group and the alteplase group respectively. Rates of death were 15.0 per cent in both groups. Symptomatic intracranial hemorrhage was three point four percent and three point one percent respectively. Specifically, intracerebral hemorrhage that, in the opinion of the investigator, was temporally related to and directly responsible for worsening of the neurological condition. Extracranial bleeding requiring blood transfusion 1.0 percent and zero point seven percent, and orolingual angiodema 1.0 percent and one point four percent respectively.

Approximately 3% of patients experienced symptomatic intracerebral hemorrhaging within 24 hours of treatment with either TNKase or alteplace. A question for our listeners to think about... how does that compare with your experience treating with thrombolytic agents?

Now, I think I'll try to summarize if that's ok with you, Adrian.

Yes, I think it would be helpful for everyone. I know that was a lot of information for our listeners.

In summary, TNKase is administered as a single 5‐second IV bolus. Data from the act trail demonstrated no significant differences between treatment groups in achieving excellent functional outcomes 90 to one hundred and twenty days post stroke. Similarly, the safety profile of TNKase was demonstrated to be comparable to alteplase, with approximately 3% of patients experiencing 24-hour symptomatic intracerebral hemorrhage in both treatment arms.

Thanks Abby. Finally, if our listeners are interested in learning about the body- weight-tiered dosing and administration of TNKase for acute ischemic stroke in adults, they can find a downloadable Dosing Card and a full video demonstrating each step of the process at tnkase.com. You can also select the option to contact a representative on tnkase.com. Now, we need to make sure we discuss the important safety information.

Thanks Adrian. Here is the rest of the TNKase important safety information I mentioned earlier.

The following are the warnings and precautions associated with TNKase use.

Bleeding. TNKase can cause significant, sometimes fatal, internal or external bleeding, especially at arterial and venous puncture sites. Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. Avoid intramuscular injections and trauma to the patient while on TNKase. Perform arterial and venous punctures carefully and only as required. To minimize bleeding from non-compressible sites, avoid internal jugular and subclavian venous punctures. If an arterial puncture is necessary during TNKase administration, use an upper extremity vessel that is accessible to manual compression, apply pressure for at least 30 minutes, and monitor the puncture site closely. Should serious bleeding that is not controlled by local pressure occur, discontinue any concomitant heparin or antiplatelet agents immediately and treat appropriately.

The concomitant administration of heparin and aspirin with and following administration of TNKase for the treatment of acute ischemic stroke during the first 24 hours after symptom onset has not been investigated. Because heparin, aspirin, or TNKase may cause bleeding complications, carefully monitor for bleeding, especially at arterial puncture sites. Hemorrhage can occur 1 or more days after administration of TNKase, while patients are still receiving anticoagulant therapy.In the following conditions, the risks of bleeding with TNKase therapy for all approved indications are increased and should be weighed against the anticipated benefits: recent major surgery or procedure, (eg, coronary artery bypass graft, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels); cerebrovascular disease; recent intracranial hemorrhage (if not contraindicated); recent gastrointestinal or genitourinary bleeding; recent trauma; hypertension: systolic BP above 175 mm Hg or diastolic BP above 110 mm Hg; acute pericarditis; subacute bacterial endocarditis; hemostatic defects including those secondary to severe hepatic or renal disease; significant hepatic dysfunction; pregnancy; diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions; septic thrombophlebitis or occluded AV cannula at seriously infected site; advanced age; patients currently receiving anticoagulants; or any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location.

Hypersensitivity.

Hypersensitivity, including urticarial/anaphylactic reactions, have been reported after administration of TNKase (eg, anaphylaxis, angioedema, laryngeal edema, rash, and urticarea). Monitor patients treated with TNKase during and for several hours after administration. If symptoms of hypersensitivity occur, initiate appropriate therapy (eg, antihistamines, corticosteroids, or epinephrine).

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 in patients treated with thrombolytic agents. Investigate cause of any new embolic event and treat appropriately.

Arrhythmias. Coronary thrombolysis may result in arrhythmias associated with reperfusion. It is recommended that anti-arrhythmic therapy for bradycardia and/or ventricular irritability be available when TNKase is administered.

Adverse Reactions: The most common adverse reaction is bleeding.

DRUG INTERACTIONS

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.

PATIENT COUNSELING INFORMATION

Bleeding

Inform patients that bleeding can occur 1 or more days after administration of TNKase. Instruct patients to contact a healthcare provider if they experience signs or symptoms consistent with bleeding (eg, unusual bruising; pink or brown urine; red, black, or tarry stools; coughing up blood; vomiting blood or blood that looks like coffee grounds) or symptoms of a stroke.

You may report side effects to the FDA at 1-800-332-1088 or www.fda.com/medwatch. You may also report side effects to Genentech at 1-888-8352-555. Please see full Prescribing Information for additional Important Safety Information.

Hi and welcome to this Genentech educational podcast created for healthcare professionals. I'm Abby and my co-host today is Adrian. We are AI created podcast hosts, not real people but we have been designed to sound like real people to share information from Genentech. This podcast will cover the dosing and administration of TNKase but is not a substitute for dedicated practice in nursing. Please listen to the important safety information at the end of the podcast.

Thanks Abby. Adrian here. Also an AI created podcast host, not a real person; I'm designed to sound like a real person to share information from Genentech. So, TNKase (tenecteplase) is indicated for the treatment of acute ischemic stroke (AIS) in adults and is for intravenous (IV) administration only. But, Abby, before we start, does TNKase have any contraindications?

I'm glad you asked, Adrian, the contraindications are also something that should be considered prior to treatment. TNKase is contraindicated in any patients with active internal bleeding, intracranial or intraspinal surgery or trauma within two months. Known bleeding diathesis, current severe uncontrolled hypertension and presence of intracranial conditions that may increase the risk of bleeding. For example, intracranial neoplasm, arteriovenous malformation or aneurysm. TNKase is also contraindicated in patients for the treatment of AIS with active intracranial hemorrhage. Please listen to the rest of the important safety information at the end of the podcast.

Thanks for that Abby. And what is in the TNKase kit?

TNKase is approved in 25 milligram and 50 milligram vials. This podcast will focus on administration of the 25-milligram kit. The kit contains one 25-milligram vial of sterile lyophilized TNKase powder, a 5.2 milliliter vial of sterile water for injection. And a copy of the full prescribing information. Please be sure to review the included full prescribing information for TNKase. You will need to provide a sterile syringe, gloves, and alcohol swabs. You may also refer to the TNKase Dosing Card for guidance. TNKase uses weight-based tiered dosing. Use the table in the prescribing information to determine the appropriate dose for your patient. The maximum recommended dose is 25 milligrams, or five milliliters. Initiate treatment as soon as possible within three hours of stroke symptom onset. TNKase is for intravenous (IV) administration only, administered as a single bolus over 5 seconds. Individualize dosing based on your patient's weight per the table that I'll ask Adrian to describe.

Thanks Abby. For patients weighing less than 60 kilograms, the recommended TNKase dose is 15 miligrams and the volume of TNKase to be administered is 3 mililitres. For patients weighing 60 kilograms to less than 70 kilograms, the recommended TNKase dose is 17.5 miligrams and the volume of TNKase to be administered is 3 point five mililitres. Next For patients weighing 70 kilograms to less than 80 kilograms, the recommended TNKase dose is 20 miligrams and the volume of TNKase to be administered is 4 mililitres. For patients that weigh 80 kilograms to less than 90 kilograms, the recommended TNKase dose is 22.5 miligrams and the volume of TNKase to be administered is 4.5 mililitres . Finally for patients that weigh 90 kilograms or more, the recommended dose is 25 miligrams and the volume of TNKase to be administered is 5 mililitres.

Thanks Adrian. I'll continue with the next details. During and following TNKase administration for the treatment of AIS, frequently monitor and control blood pressure. In patients without recent use of oral anticoagulants or heparin, TNKase treatment can be initiated prior to the availability of coagulation study results. If the pre-treatment international normalization ratio is greater than 1.7 or the activated partial thromboplastin time is elevated, closely monitor patients.

Did you get all that Adrian? I am going to tell you about preparation now. Using a sterile syringe, aseptically withdraw five point two milliliters of sterile water for injection from the diluent vial. Only use the supplied sterile water for injection diluent vial. Please note: if you are using the fifty milligram TNKase vial, withdraw 10 milliliters of sterile water for injection. Aseptically reconstitute the TNKase vial with sterile water for injection by directing the stream into the lyophilized powder. The final concentration of TNKase should be 5 milligrams per milliliter. Slight foaming upon reconstitution is not unusual. Any large bubbles will dissipate if the product is allowed to stand undisturbed for several minutes. Without shaking, gently swirl until contents are completely dissolved. The reconstituted solution should be transparent and colorless to pale yellow. Because TNKase contains no antibacterial preservatives, reconstitute immediately before use. If the reconstituted TNKase is not used immediately, refrigerate the TNKase vial at 2 degrees Celsius to 8 degrees Celsius, 36 degrees Fahrenheit to 46 degrees Fahrenheit, and use within eight hours. Once you have determined the appropriate dose of TNKase, withdraw this volume in milliliters from the reconstituted vial with a syringe. Discard any unused solution.

Now we will go over the Administration of TNKase. Visually inspect the reconstituted product in the syringe for particulate matter and discoloration prior to administration. Precipitation may occur when TNKase is administered in an intravenous line containing dextrose. Flush dextrose-containing lines with 0.9 per cent sodium chloride injection solution prior to and following single-bolus administration of TNKase. Using sterile technique, connect the syringe directly to the intravenous port. Administer reconstituted TNKase as a single intravenous bolus over five seconds. Dispose of the syringe using established procedures. Adrian, can you talk us through considerations post administration?

Following administration of TNKase, assess and monitor patients according to your institution's protocol. Check for bleeding and signs of hypersensitivity, monitor blood pressure, and perform neurological assessments. Consult the American Heart Association and American Stroke Association guidelines for acute ischemic stroke for more information. For more information please visit www.tnkase.com . Finally, if our listeners are interested in learning about the body weight-tiered dosing and administration of TNKase for acute ischemic stroke in adults, they can find a downloadable Dosing Card and a full video demonstrating each step of the process at tnkase.com. You can also select the option to contact a representative on tnkase.com. Now, we need to make sure we discuss the important safety information.

Thanks Adrian. Here is the rest of the TNKase important safety information I mentioned earlier. The following are the warnings and precautions associated with TNKase use. Bleeding. TNKase can cause significant, sometimes fatal, internal or external bleeding, especially at arterial and venous puncture sites. Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. Avoid intramuscular injections and trauma to the patient while on TNKase. Perform arterial and venous punctures carefully and only as required. To minimize bleeding from non-compressible sites, avoid internal jugular and subclavian venous punctures. If an arterial puncture is necessary during TNKase administration, use an upper extremity vessel that is accessible to manual compression, apply pressure for at least 30 minutes, and monitor the puncture site closely. Should serious bleeding that is not controlled by local pressure occur, discontinue any concomitant heparin or antiplatelet agents immediately and treat appropriately. Hypersensitivity. Hypersensitivity, including urticarial/anaphylactic reactions, have been reported after administration of TNKase (eg, anaphylaxis, angioedema, laryngeal edema, rash, and urti-caria). Monitor patients treated with TNKase during and for several hours after administration. If symptoms of hypersensitivity occur, initiate appropriate therapy (eg, antihistamines, corticosteroids, or epinephrine). 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 in patients treated with thrombolytic agents. Investigate cause of any new embolic event and treat appropriately. Arrhythmias. Coronary thrombolysis may result in arrhythmias associated with reperfusion. It is recommended that anti-arrhythmic therapy for bradycardia and/or ventricular irritability be available when TNKase is administered. The most common adverse reaction is bleeding. You may report side effects to the FDA at 1-800-332-1088 or www.fda.com/medwatch. You may also report side effects to Genentech at 1-888-835-2555. Please see full Prescribing Information for additional Important Safety Information.

Hi and welcome to this Genentech educational podcast created for healthcare professionals I'm Abby and my co-host today is Adrian. We are AI created podcast hosts, not real people, we have been designed to sound like real people to share information from Genentech. Today, we'll be discussing three unique patient cases, focusing on their backgrounds, medical history and current presentation and then we'll focus on TNKase eligibility. TNKase, also known as tenecteplase, is indicated for the treatment of acute ischemic stroke (AIS) in adults. These patients are hypothetical patients, with case histories created for educational purposes.

Hi everyone, Adrian here. Also an AI created podcast host, not a real person; I'm designed to sound like a real person to share information from Genentech. Abby, before we start, does TNKase have any contraindications?

I am glad you asked, Adrian, the contraindications are also something that should be considered prior to treatment. TNKase is contraindicated in any patients with active internal bleeding; intracranial or intra-spinal surgery or trauma within 2 months; known bleeding diathesis; current severe uncontrolled hypertension; presence of intracranial conditions that may increase the risk of bleeding (eg, intracranial neoplasm, arteriovenous malformation, or aneurysm). TNKase is contraindicated in AIS patients with active intracranial hemorrhage. We'll go over the rest of the important safety information later.

Thanks so much for that, Abby. Let's start with our first case study. Elsie. Abby shall I tell you a bit more about Elsie?

Sure, thanks Adrian.

Adrian: So Elsie is a 57-year-old piano teacher. With her children away at college, she's been ramping up her teaching schedule.

Abby: Ok and what about her symptoms. When did they start?

Adrian: Of note, she is right handed and is experiencing right arm paralysis. Her last known normal was two point five hours ago. She presents with a NIHSS score of 5 and a baseline mRS of 0.

Abby: And blood work and vitals? Do we have those details?

Adrian: Yes we do. Her glucose is within normal range at 110 milligrams per decilitre, and her blood pressure is 150 over 100 millimeters of mercury for which she takes Lisinopril 10 milligrams daily and states her blood pressure has been under control.

Abby: Is there anything else of note in her medical history?

Adrian: There is. Last year she also had a pulmonary embolism and has been taking a direct oral anticoagulant (Apixaban 2.5mg twice daily) since that time.

Abby: And do we have any imaging information you can share?

Adrian: Yes, her admission non-contrast CT is negative for bleeding.

Abby: What about Elsie’s history would make you think she may or may not be eligible for a thrombolytic? From here on, we will refer to thrombolytics as lytics. Is there any information you think still needs to be obtained before making a treatment decision?

Adrian: Well if you are thinking the apixaban may preclude her from receiving a lytic, you are correct. Her family were asked and we find that she has not taken her apixaban for the past 72 hours. Current 2019 AHA/ASA AIS Guidelines suggest IV thrombolytics for patients consuming DOACs in the last 48 hours prior to AIS, only if appropriate laboratory tests, such as aPTT, INR, platelet count, ecarin clotting time, thrombin time (<60 sec), or direct factor Xa activity assays are normal (<0.5U/ml).

Abby: So, healthcare professionals can consider Elsie eligible for TNKase, administered as a 5-second, single IV bolus to treat her acute ischemic stroke.

Great - thanks for that detailed discussion. Now let's move on to our second case, Katherine. What do we know about Katherine?

Adrian: Katherine is 68 years old and volunteers at a local art museum. She enjoys engaging with new people.

Abby: And what do we know about when Katherine’s symptoms started?

Adrian: Her symptoms began while she was shopping, and EMS was called after other shoppers noticed her unable to push her cart or take items from the shelf. Her family was also called and she was taken to the nearest hospital. On arrival to the ED she has an NIHSS of 9 then improves to 7. Her disabling symptom is complete hemianopsia and acute onset dizziness, making ambulation very difficult.

Abby: That’s a great amount of detail there. Do we have her blood work and vitals?

Adrian: Yes, her glucose is 120 milligrams per decilitre, and blood pressure is 145 over 95 millimeters of mercury. Medically, she has a history of ER positive breast cancer, treated with Tamoxifen 20 milligrams daily, and type 1 osteoporosis, for which she takes vitamin D and calcium supplements.

Abby: And I hope we also have imaging information for Katherine?

Yes, imaging on admission shows no sign of bleeding and her symptoms lead the physician to a diagnosis of a vertebrobasilar stroke.

Thank you. Is there any additional information needed to make a treatment decision?

Yes, I think it would be helpful to know her baseline mRS and current daily routine.

After Katherine’s family has arrived they confirm that her last known normal was two hours ago, and at the Emergency Department physicians determine her baseline mRS to be 1. Her family verifies that Katherine is an extremely active 68 year old and that these deficits would negatively impact her daily routine and her life. They state that Katherine would want a chance to return to her pre-stroke state.

Really interesting case. Based on her presentation, medical history and the fact that she remains disabled even though there has been a slight improvement in her NIHSS score, the healthcare professionals can still consider this patient, Katherine to be eligible for treatment with TNKase. They should act with urgency because time from onset of symptoms to treatment can impact outcomes and 5 second IV bolus TNKase administration should not be delayed while monitoring Katherine for further improvement.

Thanks Abby. Finally, let's discuss Raul.

Yes. What do we know about this patient?

So, Raul is a 74-year-old retired musician who enjoys singing at family gatherings, taking daily walks and participating in church events. His daughter called EMS shortly after symptom onset.

And do we know when his symptoms began?

Yes, his last known normal was one and a half hours ago. His disabling symptoms include reduced consciousness/awareness, left sided weakness, facial droop and dysarthria. The patient arrived by EMS and the ED was informed he was having a stroke. This assessment in the field allowed the EMS team to transport the patient rapidly to the closest healthcare facility that would be able to administer TNKase. This hospital was only 20 minutes from his home versus 1.5 hours from his home to the nearest Comprehensive Stroke Centre.

Wow, that’s good to know. What happened next?

Well, the staff was prepared for him on arrival. He ended up presenting to the closest TNKase ready ED with an NIHSS of 17 and a baseline mRS of 2.

Ok, I think that’s the highest NHISS score of all these case studies?

Right. So then Raul is examined and lab work drawn. He is then taken to CT for initial imaging. Non-contrast CT showed no evidence of bleeding. He is now 2 hours from symptom onset and he continues with CTA and CTP. Imaging revealed an occluded middle cerebral artery.

Great imaging information. What about his blood and vitals?

Raul's glucose is 150 milligrams per decilitre, and his blood pressure is 165 over 100 millimeters of mercury. He has a history of a previous stroke 18 months earlier and takes Acetylsalicylic acid 81 milligrams daily. He also has type II diabetes, controlled with Glipizide 5 milligrams once daily, and hypertension managed with Chlorthalidone 25 milligrams once daily. He is a former smoker.

At this point Raul needs to be considered for TNKase treatment and set up to be transferred to a comprehensive stroke centre (CSC) and I’ll explain why:

Considerations at this point. Arrange for transfer to the closest CSC - it is approximately 75 minutes away - as soon as possible. Knowing that he will be out of the time window for a lytic when he arrives at the CSC, he should be considered for treatment of his stroke with TNKase as soon as possible and prior to transfer. His blood pressure is borderline high and he should be frequently monitored to ensure his BP parameters remain in the normal range

So we have three distinct cases here, each presenting unique challenges. I also think these case studies really highlight the importance of considering an Individual Disability Assessment - especially for patients with a lower NIHSS score. For more information about an Individual Disability Assessment or about TNKase data please visit www.tnkase.com. You can also select the option to contact a representative on tnkase.com. Now, we need to make sure we discuss the important safety information.

Here is the rest of TNKase important safety information I mentioned earlier.

The following are the warnings and precautions associated with TNKase use. Bleeding, TNKase can cause significant, sometimes fatal, internal or external bleeding, especially at arterial and venous puncture sites. Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. Avoid intramuscular injections and trauma to the patient while on TNKase.

Perform arterial and venous punctures carefully and only as required. To minimize bleeding from non-compressible sites, avoid internal jugular and subclavian venous punctures. If an arterial puncture is necessary during TNKase administration, use an upper extremity vessel that is accessible to manual compression, apply pressure for at least 30 minutes, and monitor the puncture site closely. Should serious bleeding that is not controlled by local pressure occur, discontinue any concomitant heparin or antiplatelet agents immediately and treat appropriately. Hypersensitivity. Hypersensitivity, including urticarial/anaphylactic reactions, have been reported after administration of TNKase (eg, anaphylaxis, angioedema, laryngeal edema, rash, and urticaria). Monitor patients treated with TNKase during and for several hours after administration. If symptoms of hypersensitivity occur, initiate appropriate therapy (eg, antihistamines, corticosteroids, or epinephrine). 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 in patients treated with thrombolytic agents. Investigate cause of any new embolic event and treat appropriately. Arrhythmias. Coronary thrombolysis may result in arrhythmias associated with reperfusion. It is recommended that anti-arrhythmic therapy for bradycardia and/or ventricular irritability be available when TNKase is administered. The most common adverse reaction is bleeding. You may report side effects to the FDA at 1-800-332-1088 or www.fda.com/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

Please see full Prescribing Information for additional Important Safety Information.

Hi and welcome to this Genentech educational podcast created for healthcare professionals. This is an audio version of the US prescribing information. You can also read the full prescribing information on TNKase.com. I'm Abby and my co-host today is Adrian. We are AI created podcast hosts, not real people but we have been designed to sound like real people to share information from Genentech. On today's podcast we'll be diving into the prescribing information for tenecteplase, a medication used in the treatment of acute ischemic stroke and acute ST-elevation myocardial infarction. We're going to be discussing the prescribing information for both indications. Medical information can be pretty dense sometimes, but we'll make sure to make it clear and, well, hopefully pretty interesting. This is meant to be a way to listen to information from the TNKase Prescribing Information but it is not meant to replace it. Please see the TNKase full prescribing information on TNKase.com. We will be discussing the latest version of the TNKase full prescribing information revised February of 2025.

Thanks Abby. Adrian here also created using artificial intelligence, so not a real person but designed to sound like a real person for educational purposes.

First things first. What is TNKase?

It's the brand name for tenecteplase and it's for injection, for intravenous use only.

And can you tell me what it's indicated for?

It's indicated for two main life-threatening conditions: acute ischemic stroke, or AIS, in adults, and to reduce the risk of death associated with acute ST elevation myocardial infarction, again in adults.

Now... time for the full prescribing information. And this is where it gets really interesting as we delve into the studies that led to FDA approval for tenecteplase. So, as we mentioned at the start, TNKase is indicated for both the treatment of acute ischemic stroke in adults and TNKase is also indicated to reduce the risk of death associated with acute ST elevation myocardial infarction (STEMI) in adults.

I think the next important topic is dosing and administration. Let's discuss AIS. Healthcare professionals should initiate treatment as soon as possible and within 3 hours after the onset of stroke symptoms. TNKase is for intravenous administration only, administered as a single bolus over 5 seconds. Individualize dosage based on the patient’s weight (see Table 1 in the prescribing information). The maximum recommended dose is 25 milligrams (5 milliliters).

As you said, Adrian, it's useful to refer to table 1 of the full prescribing information but don't worry, I'll talk you through it if you can't look at it right now. So Table 1 shows the Recommended Dosage for Acute Ischemic Stroke. For patients weighing less than 60 kilograms, the recommended TNKase dose is 15 milligrams and the volume of TNKase to be administered is 3 milliliters. For patients weighing 60 kilograms to less than 70 kilograms, the recommended TNKase dose is 17.5 milligrams and the volume of TNKase to be administered is 3 point five milliliters. Next For patients weighing 70 kilograms to less than 80 kilograms, the recommended TNKase dose is 20 milligrams and the volume of TNKase to be administered is 4 milliliters. For patients that weigh 80 kilograms to less than 90 kilograms, the recommended TNKase dose is 22.5 milligrams and the volume of TNKase to be administered is 4.5 milliliters . Finally for patients that weigh 90 kilograms or more, the recommended dose is 25 milligrams and the volume of TNKase to be administered is 5 milliliters.

Thanks Abby. That was a great walk-through of the dosing table.

I just want everyone to be aware that during and following TNKase administration for the treatment of acute ischemic stroke, they should frequently monitor and control blood pressure. In patients without recent use of oral anticoagulants or heparin, TNKase treatment can be initiated prior to the availability of coagulation study results. If the pretreatment International Normalized Ratio (INR) is greater than 1.7 or the activated partial thromboplastin time (aPTT) is elevated, closely monitor patients. We’ll have more details about that when we go over the contraindications.

So that covers dosing for AIS only. Let's now discuss the recommended dosage for Acute STEMI. Initiate treatment as soon as possible after the onset of STEMI symptoms.

TNKase is for intravenous administration only, administered as a single bolus over 5 seconds. Individualize dosage based on the patient’s weight (see Table 2 in the prescribing information). The maximum recommended dose is 50 milligrams (10 milliliters).

It's useful to refer to table 2 of the full prescribing information but don't worry, I'll talk you through it if you can't look at it right now. So Table 2 shows the Recommended Dosage for Acute STEMI. For patients weighing less than 60 kilograms, the recommended TNKase dose is 30 milligrams and the volume of TNKase to be administered is 6 milliliters. For patients weighing 60 kilograms to less than 70 kilograms, the recommended TNKase dose is 35 milligrams and the volume of TNKase to be administered is 7 milliliters. Next For patients weighing 70 kilograms to less than 80 kilograms, the recommended TNKase dose is 40 milligrams and the volume of TNKase to be administered is 8 milliliters. For patients that weigh 80 kilograms to less than 90 kilograms, the recommended TNKase dose is 45 milligrams and the volume of TNKase to be administered is 9 milliliters. Finally for patients that weigh 90 kilograms or more, the recommended dose is 50 milligrams and the volume of TNKase to be administered is 10 milliliters.

Now we've discussed how to calculate the correct dose for each individual patient, shall we discuss preparation of TNKase? What does that look like?

So there are a few steps to prepare TNKase for administration. Let's jump into it. First of all, you should only use the supplied Sterile Water for Injection diluent vial for reconstitution. So for the 25 milligram vial strength you need to use a volume of 5.2 milliliters of sterile water for injection. For the 50 milligram vial strength you need to use 10 milliliters of sterile water for injection.

So for the actual process let's take it step by step. Using a sterile syringe aseptically withdraw the Sterile water for injection from the diluent vial and reconstitute the TNKase vial by directing the stream into the lyophilized powder to obtain a final concentration of 5 milligrams per milliliter. Slight foaming upon reconstitution is not unusual; any large bubbles will dissipate if the product is allowed to stand undisturbed for several minutes. Gently swirl until contents are completely dissolved, do not shake. The reconstituted preparation results in a colorless to pale yellow transparent solution.

So then I assume the final step is determining and withdrawing the correct dose?

Exactly right Abby. Determine the appropriate dose of TNKase (when doing this in practice, refer to full prescribing information table1 for AIS and table 2 for Acute STEMI) and withdraw the required volume (in milliliters) from the reconstituted vial into the syringe. Discard any unused solution.

Now we're ready to administer TNKase to the patient, right?

Yes we are. Follow these steps for administration. Visually inspect the reconstituted product in the syringe for particulate matter and discoloration prior to administration. Precipitation may occur when TNKase is administered in an intravenous line containing dextrose. Flush dextrose-containing lines with 0.9% Sodium Chloride Injection solution prior to and following single bolus administration of TNKase. Using sterile technique, connect the syringe directly to the intravenous port. Administer reconstituted TNKase as a single intravenous bolus over 5 seconds. TNKase contains no antibacterial preservatives so reconstitute immediately before use. If the reconstituted TNKase is not used immediately, refrigerate the TNKase vial at 2 degrees Celsius to 8 degrees Celsius (36 degrees Fahrenheit to 46 degrees Fahrenheit) and use within 8 hours. Dispose of the syringe per established procedures.

That was such a clear walk-through. Thank you Adrian. One question from me. Are there any chemical incompatibilities that healthcare professionals need to be aware of?

Yes, thanks for calling that out. TNKase is incompatible with dextrose containing solutions. When used together, precipitation may occur. Flush dextrose containing lines with 0.9% Sodium Chloride Injection solution before using TNKase.

And I think we've mentioned some of the dosage forms and strengths already but can you just confirm that TNKase is available for injection as 25 milligram or 50 milligrams as a white to pale yellow lyophilized powder in a single-dose vial for reconstitution with co-packaged Sterile Water for Injection, USP (diluent). Both vials will have 5mg/mL as the final mixture.

That's right. Thanks Abby. Ok, how do you feel? Ready to move on to discuss the contraindications and then warnings and precautions in more detail?

Sure.

There are several contraindications for TNKase. For both acute ischemic stroke and acute STEMI, TNKase is contraindicated in any patients with active internal bleeding, intracranial or intraspinal surgery or trauma within the past two months, known bleeding diathesis, or current severe uncontrolled hypertension.

TNKase is also contraindicated in the presence of intracranial conditions that may increase the risk of bleeding, for example intracranial neoplasm, arteriovenous malformation, or aneurysm. Adrian, are there any additional contraindications specific to either AIS or STEMI?

Yes, for acute ischemic stroke, TNKase is also contraindicated in patients with active intracranial hemorrhage, and for acute STEMI, it's contraindicated in patients with a history of intracranial hemorrhage or a history of ischemic stroke within the past three months.

Thanks for that recap. Now, pay attention, we're going to delve deeper into the warnings and precautions, starting with bleeding. TNKase can cause significant, sometimes fatal, internal or external bleeding, especially at arterial and venous puncture sites. Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. Avoid intramuscular injections and trauma to the patient while on TNKase. Perform arterial and venous punctures carefully and only as required. To minimize bleeding from noncompressible sites, avoid internal jugular and subclavian venous punctures. If an arterial puncture is necessary during TNKase administration, use an upper extremity vessel that is accessible to manual compression, apply pressure for at least 30 minutes, and monitor the puncture site closely. Should serious bleeding that is not controlled by local pressure occur, discontinue any concomitant heparin or antiplatelet agents immediately and treat appropriately. Because of the higher risk of intracranial hemorrhage in patients treated for acute ischemic stroke, limit treatment to facilities that can provide timely access to appropriate evaluation and management of intracranial hemorrhage. Aspirin and heparin have been administered concomitantly with and following administration of TNKase in the management of acute myocardial infarction, but the concomitant administration of heparin and aspirin with and following administration of TNKase for the treatment of acute ischemic stroke during the first twenty four hours after symptom onset has not been investigated. Because heparin, aspirin, or tenecteplase may cause bleeding complications, carefully monitor for bleeding, especially at arterial puncture sites. Hemorrhage can occur 1 or more days after administration of TNKase, while patients are still receiving anticoagulant therapy.

Such great information Abby. I also see that If serious bleeding occurs, treat appropriately. In the following conditions that I'll list in a few seconds, the risks of bleeding with TNKase therapy for all approved indications are increased and should be weighed against the anticipated benefits: Recent major surgery or procedure, (for example coronary artery bypass graft, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels), Cerebrovascular disease, Recent intracranial hemorrhage if not contraindicated, recent gastrointestinal or genitourinary bleeding, Recent trauma, Hypertension: systolic blood pressure above 175 millimeters of mercury or diastolic blood pressure above 110 millimeters of mercury, Acute pericarditis, Subacute bacterial endocarditis, Hemostatic defects including those secondary to severe hepatic or renal disease, Significant hepatic dysfunction, Pregnancy, Diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions. Septic thrombophlebitis or occluded AV cannula at seriously infected site, Advanced age, Patients currently receiving anticoagulants (for example warfarin sodium). Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location.

Thanks Adrian. How about I discuss 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 administration. If symptoms of hypersensitivity occur, initiate appropriate therapy (for example, antihistamines, corticosteroids, epinephrine).

Ok, next we have 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. Next let’s cover Cholesterol Embolization. Cholesterol embolism has also been reported in patients treated with thrombolytic agents. Investigate cause of any new embolic event and treat appropriately.

Arrhythmias also appear in the warnings and precautions: Coronary thrombolysis may result in arrhythmias associated with reperfusion. These arrhythmias (such as sinus bradycardia, accelerated idioventricular rhythm, ventricular premature depolarizations, ventricular tachycardia) 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.

The last of the TNKase warnings and precautions is STEMI specific. Increased Risk of Heart Failure and Recurrent Ischemia when used with Planned Percutaneous Coronary Intervention (PCI) in STEMI. In a trial of patients with STEMI, there were worse outcomes in the individual components of the primary endpoint between TNKase plus PCI versus PCI alone (mortality 6.7% vs. 4.9%, respectively; cardiogenic shock 6.3% vs. 4.8%, respectively; and CHF 12% vs. 9.2%, respectively). In addition, there were worse outcomes in recurrent MI (6.1% vs. 3.7%, respectively; p = 0.03) and repeat target vessel revascularization (6.6% vs. 3.4%, respectively; p = 0.0045) in patients receiving TNKase plus PCI versus PCI alone. 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.

So that covers warnings and precautions, let’s move on to the adverse reactions.

Absolutely. Great plan, Abby.

So, the following clinically significant adverse reactions are discussed in other sections of the label and I believe we've discussed them all already actually when I covered the warnings and precautions: Bleeding, Hypersensitivity, Thromboembolism, Cholesterol Embolization, Arrhythmias, Increased Risk of Heart Failure and Recurrent Ischemia when used with Planned Percutaneous Coronary Intervention (PCI) in acute ST-elevation myocardial infarction.

Actually Abby, before we discuss the clinical trials experience, something pretty interesting. Did you know that because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Did you know that the most frequent adverse reaction associated with TNKase in all approved indications is bleeding?

Ok Adrian, I'm really excited to look at the clinical trial data for TNKase in Acute Ischemic Stroke. So, in Trial 1, the safety of TNKase for the treatment of acute ischemic stroke (AIS) was evaluated in 592 patients who received TNKase at the recommended dosage within 0 to 3 hours of the onset of stroke symptoms (Alteplase compared to tenecteplase (act); Trial 1). Table 3 describes the incidence of adverse reactions in patients in Trial 1 in Patients Treated for Acute Ischemic Stroke Within 0 to 3 Hours from Symptom Onset. Adrian, for those who don't have the prescribing information in front of them, can you walk us through the table please?

My pleasure. Let's ground everyone with the number of patients in each arm. In the TNKase arm of the study there were 592 patients treated and in the Activase arm of the study there were five hundred and fifty five patients treated. First of all, incidence of death was 15.0% in both arms. Incidence of symptomatic intracerebral hemo-ridge that, in the opinion of the investigator, was temporarily related to and directly responsible for worsening of the neurological condition was 3.4% in the TNKase arm and 3.1% in the Activase arm. Extracranial (peripheral) bleeding requiring blood transfusion incidence were 1.0% in the TNKase arm and 0.7% in the activase arm and finally incidence of Orolingual angioedema was 1.0% in the TNKase arm and 1.4% in the alteplase arm.

Fascinating, Adrian. Maybe now is a good time to tell our listeners about the drug interactions for TNKase? 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. Let’s change topics a little and discuss Use in specific populations.

Ok Adrian, I feel like I should be the one to ask this. What do we know about use in a pregnant patient?

What's the risk summary?

There are risks to the mother and fetus from acute ST elevation myocardial infarction and acute ischemic stroke, which are medical emergencies in pregnancy and can be fatal if left untreated (see Clinical Considerations). Published data consisting of a small number of case reports involving the use of related thrombolytic agents in pregnant women have not identified an increased risk of major birth defects. There are no data on the use of tenecteplase during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. TNKase does not elicit maternal and direct embryo toxicity in rabbits following a single IV administration. 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 milligrams per kilogram) was approximately 7 times human exposure (based on AUC) at the dose for STEMI. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Great information. Super useful. And what are the clinical considerations, specifically I’d like to hear about Disease-Associated Maternal and/or Embryo/Fetal Risk?

That is a good question, I am glad you asked.: Acute ST elevation myocardial infarction and acute ischemic stroke are medical emergencies which can be fatal if left untreated. Life-sustaining therapy for the pregnant woman should not be withheld because of potential concerns regarding the effects of tenecteplase on the fetus.

Ok so that's for a pregnant patient. What about lactation? What's the risk summary related to lactation?

There are no data on the presence of tenecteplase in either human or animal milk, the effects on the breastfed infant, or the effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TNKase and any potential adverse effects on the breastfed infant from the TNKase or from the underlying maternal condition.

Ok and what about pediatric use? Do we have any information there?

No Abby, actually the safety and effectiveness of TNKase in pediatric patients have not been established.

And since I asked about pediatrics I'm also interested in geriatrics...

Ah yes, here we have a lot more data. Of the total number of TNKase patients treated within 0 to 3 hours in Trial 1 for acute ischemic stroke (AIS), four hundred and twenty six (72%) were 65 years of age and older, and two hundred and ninety (49%) were 75 years of age and older [see Clinical Studies (14.1)]. No overall differences in safety was observed between patients over 65 years old with AIS and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In the ASSENT-2 study, 41% (three thousand five hundred out of eight thousand four hundred and fifty eight) of STEMI patients who were treated with TNKase were aged 65 years or older. In this population, rates of 30-day mortality, stroke, intracranial hemo-ridge and major bleeds requiring blood transfusion or leading to hemodynamic complications were higher than in those less than 65 years old.

This is so much great information. I think I'd actually like to talk a bit more about tenecteplase itself. I mean. What is it exactly? What do we know about it? Will you go into its description?

It is a tissue plasminogen activator (tPA) produced by recombinant DNA technology using a mammalian cell line (Chinese Hamster Ovary cells). Tenecteplase is a five hundred and twenty seven-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. It has a molecular weight of fifty eight thousand seven hundred and forty two daltons. 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 per milligram.

TNKase, tenecteplase for injection is a sterile white to pale yellow lyophilized powder for intravenous bolus administration after reconstitution with Sterile water for injection, USP. Each 25 milligram single-dose vial of TNKase nominally contains 25 milligrams of tenecteplase, arginine (261 milligrams), phosphoric acid (approximately 80 milligrams), and polysorbate 20 (2 point zero milligrams). Following reconstitution with the supplied 5.2 milliliter single-dose vial of Sterile Water for Injection, USP, the final concentration is 5 milligrams per milliliter with a pH of approximately 7.3. Each 50 milligrams single-dose vial of TNKase nominally contains 50 milligrams of tenecteplase, arginine (522 milligrams), phosphoric acid (approximately 160 milligrams), and polysorbate 20 (4 point zero milligrams). Following reconstitution with the supplied 10 millilitre single-dose vial of Sterile Water for Injection, USP, the final concentration is 5 milligrams per millilitre with a pH of approximately 7.3.

Abby, let’s switch gears a little and discuss the clinical pharmacology. I am interested in hearing about the Mechanism of Action.

I’ve been waiting to discuss this topic Adrian. 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-mediated 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. The clinical significance of fibrin-specificity on safety (for example bleeding) or efficacy has not been established.

Wow. That was such incredible detail on the mechanism of action of tenecteplase. Can we talk about the pharmacodynamics?

We sure can. Following administration of 30, 40, or 50 mg of TNKase in patients with STEMI, there are decreases in circulating fibrinogen (4%–15%) and plasminogen (11%−24%).

And how about the pharmacokinetics?

Well, let’s start with distribution. In patients with STEMI, TNKase administered as a single IV bolus exhibits a biphasic disposition from the plasma. Volume of distribution at central compartment ranges from 4.22 to 5.43 L, approximating plasma volume. Steady-state volume of distribution was approximately 50% greater (6.12 to 8.01 L), suggestive of some extravascular distribution.

Ok, what about elimination?

After IV bolus administration in patients with STEMI, the terminal phase half-life of tenecteplase was 90 to 130 minutes. In 99 of 104 patients treated with TNKase, TNKase has linear PK with mean maximum concentrations increased in a dose-proportional manner and mean plasma clearance was similar for the 30, 40, and 50 mg doses ranging from 99 to 119 mL/min. And while we’re discussing elimination we should note that Liver metabolism is the major clearance mechanism for tenecteplase.

Before we leave the topic of PK, we need to cover Body weight.

A stepwise linear regression analysis indicated that total body weight explained 19% of the variability in plasma clearance and 11% of the variability in volume of distribution in patients with STEMI.

It makes me wonder what we know about Immunogenicity?

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of tenecteplase or of other tenecteplase products. In a study of subjects with STEMI, four of six hundred and twenty five (zero point six four per cent) STEMI patients tested for antibody formation to TNKase had a positive antibody titer at 30 days in studies with TNKase.

Let's finish this deep dive into the molecule itself with some nonclinical toxicology information. I think it's important for our listeners to know Studies in animals have not been performed to evaluate the carcinogenic potential, mutagenicity, or the effect on fertility.

Thanks Adrian. I'm really feeling like I'm getting such a fantastic level of understanding of TNKase.

Me too Abby. Ok. How do you feel about looking at the clinical studies? We can talk through the study designs and data?

That sounds like a good topic to move to next. How about I kick it off with Acute Ischemic Stroke, the latest FDA approved indication.

Great, thanks Abby.

So, The Alteplase compared to Tenecteplase (act) trial (NCT 0 3 8 8 9 2 4 9, Trial 1) was a registry-linked, multicenter, parallel group, open-label, randomized trial with blinded outcome assessment that investigated the non-inferiority of TNKase (tenecteplase) compared to Activase in treating patients with acute ischemic stroke (AIS) that presented with a disabling neurologic deficit. Endovascular thrombectomy was allowed if patients were eligible based on standard of care. A total of one thousand one hundred and forty seven patients were treated within 3 hours of symptom onset and were included in the intent to treat (ITT) population. In the ITT population, the mean age was 72 years, 53 per cent of patients were male, 24% were White, 5% were Asian, and 70% did not have a race reported or their race was unknown. Among the ITT population, the median baseline National Institute of Health Stroke Scale (NIHSS) score was 10, 27% of patients had a large vessel occlusion on baseline CT angiography, and the median stroke symptom onset to thrombolysis time was 108 minutes. Demographics and other baseline characteristics were generally balanced between the treatment groups. Patients were randomized (one to one) to receive a single IV bolus of TNKase or a one-hour infusion of 0.9 milligrams per kilogram of Activase (10 per cent administered as an IV bolus over 1 minute and the remaining 90% given as an infusion over 1 hour; maximum dose 90 milligrams). TNKase was dosed using actual or estimated weight in a body weight-tiered fashion at the recommended dosage [see Dosage and Administration (2.1)]. Administration of antiplatelet agents or other antithrombotic products were prohibited within the first 24 hours after administration of TNKase or Activase. In Trial 1, efficacy was assessed as a pre-defined favorable clinical outcome based on the proportion of patients that were treated within 3 hours of symptom onset who achieved a modified Rankin Scale (mRS) score of 0–1 at 90–120 days, as assessed by the Rankin Focused Assessment. The mRS is a 7-point scale which captures disability after stroke; higher scores indicate an increased amount of disability. A score of zero represents no symptoms or disability, where a score of 6 represents death. A score of 0 or 1 represents a favorable clinical outcome. The results comparing TNKase with Activase in patients treated within 3 hours of symptom onset are presented in Table 4. Study results demonstrated no significant differences between treatment groups. Although the trial enrolled patients who were treated within 0-4.5 hours of stroke symptom onset, the subset of patients treated within zero to three hours was used to assess efficacy of TNKase because the comparator, Activase, is approved for use within zero to three hours of stroke symptom onset.

Thanks. Such amazing detail there. How about I take our listeners through the efficacy data. So, if you have the prescribing information in front of you then please refer to table 4, Trial 1. Otherwise I'll talk you through it. So Table 4 shows the Efficacy Outcome Results in Patients with Acute Ischemic Stroke Treated Within 0-3 Hours of Symptom Onset (ITT Population). The endpoint was the Proportion of Patients with Modified Rankin Score (mRS) 0-1 at 90 to one hundred and twenty days and in the TNKase group there were five hundred and ninety two patients while in the alteplase group there were five hundred and fifty five patients. In the TNKase group, 36.6 per cent of patients had an mRS 0-1 at 90 to one hundred and twenty days vs. the alteplase group, with 35.9 per cent.

I can add a little about the results. Unadjusted Risk Difference percentage (ninety five percent confidence interval) across both arms was 0.7 per cent (with a range of minus 4.9 per cent to 6.3 per cent). It's also really interesting to note that a similar treatment effect in achieving a mRS score 0–1 was observed in exploratory subgroups defined by age, gender, and baseline NIHSS score.

Adrian, that covers the AIS clinical data. Can you talk us through the STEMI clinical data please?

Yes, happy to. The first study I will discuss is ASSENT-2. The Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) study was an international, randomized, double-blind trial that compared 30-day mortality rates in sixteen thousand nine hundred and forty nine patients assigned to receive an IV bolus dose of TNKase or an accelerated infusion of Activase (alteplase). 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 G P two b three a 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 (see section 2 point 2). All patients were to receive one hundred and fifty to three hundred and twenty five milligrams of aspirin administered as soon as possible, followed by one hundred and fifty to three hundred and twenty five milligrams daily. Intravenous heparin was to be administered as soon as possible: for patients weighing less than or equal to 67 kilograms, heparin was administered as a 4000-unit IV bolus followed by infusion at 800 Units per hour; for patients weighing more than 67 kilograms, heparin was administered as a 5000-unit IV bolus followed by infusion at 1000 Units per hour. Heparin was continued for 48 to 72 hours with infusion adjusted to maintain a P T T at 50–75 seconds. The use of G P two b three a 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 5.

Thanks Adrian. If our listeners can refer to table 5 in the prescribing information that would be useful. If not, I will describe it now. Table 5 ASSENT-2 Mortality, Stroke, and Combined Outcome of Death or Stroke Measured at Thirty Days. This table is more complex than the other tables we’ve discussed. There are four column headers. The first is 30-Day Events.Then the TNKase column (n equals eight thousand four hundred and sixty one). Followed by the Accelerated Activase column (n equals eight thousand four hundred and eighty eight). The last column header is Relative Risk with TNKase or Activase (ninety five per cent Confidence Interval). This table provides data about 4 different 30-day events. First, Mortality rate was 6.2% in both the TNKase and the accelerated activase arm. Relative Risk withTNKase or Activase was 1.00 with a 95% CI of zero point eight nine to one point one two. Second 30-day event, Rate of Intracranial Hemorrhage (ICH) was 0.9 in both the TNKase and accelerated activase arms with a relative risk of 0.99 and the 95% CI was 0.73 to 1.35). The third 30-day event is Any Stroke. The rate was 1.8% in the TNKase arm and 1.7% in the accelerated activase arm with a relative risk of one point zero seven and a 95% CI of 0.86, 1.35). Finally the rate of Death or Nonfatal Stroke was 7.1% in the TNKase arm and 7.0% in the accelerated activase arm with a relative risk of one point zero one and a 95% CI 0.91 to 1.13)

Thanks Abby. I'll add some more detail. 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 groups.

Ok the next study is called TIMI 10 B. TIMI 10B was an open-label, controlled, randomized, dose-ranging, angiography study which utilized a blinded core laboratory for review of coronary arteriograms. Eight hundred and thirty seven patients presenting within 12 hours of symptom onset were treated with fixed doses of 30, 40, or 50 milligrams of TNKase or the accelerated infusion of Activase and underwent coronary arteriography at 90 minutes. The primary endpoint was the rate of timmy Grade 3 flow at 90 minutes. The results showed that the 40 milligram and 50 milligram doses were similar to accelerated infusion of Activase in restoring patency. Timmy Grade 3 flow and TIMI ™Grade two slash three flow at 90 minutes are shown in Table 6. The exact relationship between coronary artery patency and clinical activity has not been established. Table 6 TIMI 10B Patency Rates TIMI Grade Flow at 90 Minutes. In the activase less than or equal to 100 mg arm there were three hundred and eleven patients. In the TNKase 30 milligram arm there were three hundred and two patients. In the TNKase 40 milligram arm there were one hundred and forty-eight patients and in the TNKase 50 milligram arm there were seventy six patients.

TIMI Grade 3 Flow rates with a 95% Confidence interval were 62.7% in the Activase arm (range fifty seven point one per cent, sixty eight point one per cent) and fifty four point three per cent in the TNKase 30 milligram arm (range forty eight point five per cent, sixty per cent) and sixty two point eight in the TNKase 40 milligram arm (range fifty four point five, seventy point six per cent) and sixty five point eight per cent in the TNKase 50 milligram arm (fifty four per cent, seventy six point three per cent). TIMI Grade two slash three Flow rates with a 95% Confidence interval were eighty one point seven per cent in the Activase arm (range seventy six point nine per cent, eight five point eight per cent) and seventy six point eight per cent in the TNKase 30 milligram arm (range seventy one point six per cent, eighty one point five per cent) and seventy nine point one per cent in the TNKase forty milligram arm (range seventy one point six per cent, eighty five point three per cent) and eighty eight point two per cent in the TNKase 50 milligram arm (range seventy eight point seven per cent, ninety four point four per cent) The angiographic results from timmy 10B and the safety data from ASSENT-1, an additional uncontrolled safety study of three thousand two hundred and thirty five TNKase-treated patients, provided the framework to develop a weight-tiered TNKase dose regimen. Exploratory analyses suggested that a weight-adjusted dose of zero point five to zero point six milligrams per kilograms of TNKase resulted in a better patency to bleeding relationship than fixed doses of TNKase across a broad range of patient weights. Adrian. there is one more study. Can you walk our listeners through that one?

Yes, sure. It's called ASSENT-4 PCI. The Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT-4 PCI) was a phase three b slash four study designed to assess the safety and effectiveness of a strategy of administering full dose TNKase with a single bolus of 4000 units of unfractionated heparin in patients with STEMI, in whom primary percutaneous coronary intervention (PCI) was planned, but in whom a delay of 1 to 3 hours was anticipated before PCI. The trial was prematurely terminated with one thousand six hundred and sixty seven randomized patients (75 of whom were 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 was one hundred and fifteen minutes in patients who were treated with TNKase plus PCI versus one hundred and seven minutes in patients who were treated with PCI alone). 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 equals zero point zero zero four five; R R one point three nine (95% Confidence Interval range one point one one to one point seven four). There were worse outcomes in the individual components of the primary endpoint between TNKase plus PCI versus PCI alone (mortality 6.7% vs. 4.9%, respectively; cardiogenic shock 6.3% vs. 4.8%, respectively; and CHF 12.0% vs. 9.2%, respectively). In addition, there were worse outcomes in recurrent MI (6.1% vs. 3.7%, respectively; p equals zero point zero three ) and repeat target vessel revascularization (6.6% vs. 3.4%, respectively; p equals zero point zero zero four ) in patients receiving TNKase plus PCI versus PCI alone ]. 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 hem-o-ridge and total stroke were similar to those observed in previous trials (zero point nine seven per cent and one point eight per cent , respectively); however, none of the patients treated with PCI alone experienced a stroke (ischemic, hemorrhagic or other).

Thanks Adrian. I will now discuss how TNKase is supplied, storage and handling. TNKase (tenecteplase) for injection is supplied as a sterile, white to pale yellow lyophilized powder in single-dose vials under partial vacuum, co-packaged with a single-dose vial of Sterile Water for Injection, USP, for reconstitution, as follows: TNKase Strength 25 milligram and Sterile Water for Injection Volume 5.2 milliliter with NDC 50242-014-03 and TNKase strength 50 milligrams and Sterile Water for Injection Volume 10 milliliter with NDC 50242-176-01. Storage and Handling: Store lyophilized TNKase at room temperature up to 30 degrees Celsius (86 degrees fahrenheit) or refrigerated at 2 degrees Celsius to 8 degrees Celsius (36 degrees fahrenheit to 46 degrees fahrenheit). Do not use beyond the expiration date stamped on the vial. For storage information for reconstituted TNKase, see Dosage and Administration (2.4 in the full prescribing information). I think one last important topic we need to mention is regarding patient counseling information related to bleeding. Healthcare professionals should Inform patients that bleeding can occur one or more days after administration of TNKase, you may recall that we went over that in the bleeding section of the Warnings and Precautions. Instruct patients to contact a healthcare provider if they experience signs or symptoms consistent with bleeding (for example unusual bruising; pink or brown urine; red, black, or tarry stools; coughing up blood; vomiting blood or blood that looks like coffee grounds) or symptoms of a stroke.

Good points. I'm glad you mentioned them. Well, that's it. We did it. Please read and review the full prescribing information on TNKase.com

We hope you enjoyed this podcast discussion. I was your host, Abby and my co-host was Adrian and we hope you get to hear us again sometime soon. TNKase (tenecteplase) is Manufactured by: Genentech, Inc. A Member of the Roche Group. Address: 1 DNA Way South San Francisco, California, 94080 - 4990 US License Number 1048. TNKase is a registered trademark of Genentech, Inc. This prescribing information is copyrighted 2025 Genentech, Inc.