Access and support

Welcome everybody.

Please stand by as we give a few minutes to allow more attendees to join us.

We will begin in just a few moments.

Thank you.

Welcome! My name is Kishan Mistry, and I am an Associate Director in Global Regulatory Compliance at Ionis Pharmaceuticals.

It is my distinct honor today to present this live broadcast on the FDA approval of TRYNGOLZA—the first and only FDA-approved therapy indicated as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome, or FCS.

This presentation is sponsored by, and the speakers are presenting on behalf of, Ionis Pharmaceuticals, Inc.

With me today, it is my pleasure to introduce our guests: Dr. Seth Baum, Dr. Christie Ballantyne, and Amanda Davis.

Dr. Baum is the Chief Medical Officer of Flourish Research and serves as a Clinical Affiliate Professor of Cardiology at the Charles E. Schmidt College of Medicine at Florida Atlantic University. He is deeply passionate about advancing research in cardiovascular and metabolic health, with a focus on improving patient outcomes and fostering innovation in the field.

Dr. Ballantyne is joining us virtually from Houston, TX. Dr. Ballantyne is one of the nation’s foremost experts on lipids, atherosclerosis, and heart disease prevention. He is the JS Abercrombie Chair for Atherosclerosis and Lipoprotein Research, and Professor of Medicine at Baylor College of Medicine in Houston, TX. Dr Ballantyne also serves as Chief of Cardiology and Cardiovascular Research at Baylor College of Medicine, and Director for the Center for Cardiometabolic Disease Prevention.

Amanda Davis is an Associate Director and Patient Education Manager at Ionis. She is a Registered Nurse and received her Bachelor of Science in Nursing from the University of Iowa. Amanda has over 20 years of experience providing direct patient care and clinical education in a variety of disease states throughout her career.

Welcome to you all, and thank you for being here with us for this exciting presentation. During today’s presentation, we will be discussing the burden of living with FCS and the associated risks; the TRYNGOLZA mechanism of action; Ionis’ pivotal trial of TRYNGOLZA, Balance, including safety and efficacy; and our patient support program, Ionis Every Step™.

We will close today’s discussion with audience questions. To submit a question any time during the presentation, click inside the questions box, type your question or comment, and then click the submit button.

You can also text your questions to 912-378-1244.

Our panel will address as many questions as time permits right up to the end of this program.

Please see Important Safety Information for TRYNGOLZA throughout this presentation.To download the TRYNGOLZA Prescribing Information, please go to the Important Safety Information section on the right side of your screen, or visit TRYNGOLZAHCP.com.

Now that we’re all settled in, let’s have Dr. Ballantyne start the presentation by taking us through the unmet need faced by people living with FCS.

Thank you, Kishan. It is my pleasure to join you here today.

Familial chylomicronemia syndrome—known familiarly as FCS—is an underdiagnosed form of severe hypertriglyceridemia. It affects 1-13 in 1 million people in the US. FCS can result in a variety of symptoms including recurrent acute or chronic pancreatitis. Patients with FCS may face debilitating physical and psychosocial symptoms, social withdrawal, and difficulty maintaining employment. Diagnosis is through established clinical criteria, supported by genetic testing. Please note that not all genetic variants associated with FCS have been identified. So, genetic testing can be supportive of a clinical FCS diagnosis, even with indeterminate results.

Patients with FCS can have triglycerides 10 to 100 times the normal level. Acute pancreatitis prevalence in patients with FCS can be as high as 75%. In 1 study, the rate of hospitalization for acute pancreatitis was 58.6%. And the mortality rate from recurrent acute pancreatitis is reported to be as high as 6%. Before now, there have been no FDA-approved therapies specifically to lower triglycerides in people with FCS.

Thank you, Dr. Ballantyne. Dr. Baum, could you talk about how TRYNGOLZA works in adults with FCS?

Thank you, Kishan. Yes, I’d be happy to.

TRYNGOLZA is a GalNAc conjugated antisense oligonucleotide inhibitor of apolipoprotein C-III (apoC-III) production.

ApoC-III is known to:

• Inhibit lipoprotein lipase (LPL) activity, the primary mechanism by which plasma triglycerides are hydrolyzed
• ApoC-III also regulates the metabolism of triglyceride-rich lipoproteins through LPL-independent pathways, which plays an important role in patients with FCS who have a substantial deficit of LPL activity

GaINAc conjugation enables targeted delivery to the liver, where apoC-III mRNA is generated. TRYNGOLZA is designed to work by selectively binding to apoC-III mRNA and degrading apoC-III mRNA, which then reduces serum apoC-III protein. The reduction in apoC-III results in reduced triglyceride levels. Reducing apoC-III promotes the metabolism and hepatic clearance of the triglycerides through both LPL-independent and LPL-dependent pathways.

Sustained reductions in fasting apoC-III were observed from baseline over 1 year. ApoC-III is a regulator of triglyceride metabolism and is the primary biomarker of TRYNGOLZA activity. In Balance, there was a mean reduction in fasting apoC-III from baseline of 57% at Month 1, 69% at Month 3, 72% at Month 6, and finally, 80% at one year.

It is important that I also share SELECT IMPORTANT SAFETY INFORMATION which includes

CONTRAINDICATIONS.

TRYNGOLZA is contraindicated in patients with a history of serious hypersensitivity to TRYNGOLZA or any of the excipients in TRYNGOLZA. Hypersensitivity reactions requiring medical treatment have occurred.

Dr. Baum, could you also take us through the pivotal Balance trial of TRYNGOLZA in adults with FCS?

Of course, I’d be happy to do that.

The efficacy of TRYNGOLZA 80 mg was evaluated in 45 adults with FCS in the Balance trial. Participants were randomized to receive TRYNGOLZA or placebo once every 4 weeks for 6 months for the primary analysis, and were continued over a 12-month treatment period. There were 23 participants in the placebo arm and 22 in the TRYNGOLZA arm.

Here are some key inclusion criteria for Balance, which included fasting triglyceride levels at or higher than 880 mg/dL. The primary endpoint was the mean percent change in fasting triglycerides from baseline to Month 6 compared with placebo.

Here you can also see select secondary and additional endpoints, including adjudicated pancreatitis events and the number of participants affected during the treatment period.

Here we see that patient demographic and baseline characteristics were generally similar across treatment groups, including body mass index, history of acute pancreatitis, type 1 or 2 diabetes, hypertension, triglyceride level, apoC-III level, and non-HDL cholesterol level. Additionally, most participants were on stable background lipid-lowering therapy, such as statins, omega-3 fatty acids, or fibrates.

Participants in the TRYNGOLZA group saw a significant -42.5% mean change in fasting triglycerides compared with placebo at Month 6. In the secondary endpoint at Week 53, there was a -56.9% mean change in triglycerides compared with placebo.

Changes from baseline in triglyceride levels were observed as early as Week 5 with TRYNGOLZA and were sustained over 1 year as seen in median values here.

Now I’d like to share SELECT IMPORTANT SAFETY INFORMATION that includes WARNINGS AND PRECAUTIONS for Hypersensitivity Reactions.

Hypersensitivity reactions (including symptoms of bronchospasm, diffuse erythema, facial swelling, urticaria, chills, and myalgias) have been reported in patients treated with TRYNGOLZA.

Here we see the changes that were observed in fasting total apoB, apoB-48, non-HDL cholesterol, and LDL cholesterol levels.

The TRYNGOLZA vs mean percent change in total apoB was 11.7% at month 6. For apoB-48, the only specific marker of intestinal chylomicrons, the mean percent change was -75.9% at month 6. For non-HDL cholesterol, the mean percent change was -23.4% at month 6. For LDL cholesterol, the mean percent change was 55% at month 6. Mean LDL cholesterol levels increased, but remained within normal range for most participants. 74% of participants had LDL-C levels less than 70 mg/dL. The reductions observed in apoB-48 and non-HDL cholesterol continued over one year.

In Balance, the numerical incidence of acute pancreatitis in participants treated with TRYNGOLZA was lower, compared with placebo. There was 1 event of acute pancreatitis in 1 participant treated with TRYNGOLZA, compared with 11 events in the placebo group seen in 7 patients. Additionally, as you can see, the first event of acute pancreatitis in the TRYNGOLZA group occurred a year into treatment. While in the placebo group, the first acute pancreatitis event took place on Day 9.

Again, I’d like to share the SELECT IMPORTANT SAFETY INFORMATION which includes

WARNINGS AND PRECAUTIONS for Hypersensitivity Reactions. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to promptly seek medical attention and discontinue use of TRYNGOLZA if hypersensitivity reactions occur.

Dr. Ballantyne, could you walk us through the safety profile, and administration of TRYNGOLZA?

Sure, I’d be happy to.

The safety of TRYNGOLZA was evaluated in 66 participants with FCS enrolled in the Balance trial. In this trial, 43 participants received at least 1 dose of TRYNGOLZA 50 mg (n=21) or 80 mg (n=22), and 23 participants received placebo. TRYNGOLZA 50 mg is not an approved dosing regimen for FCS. Here you will see adverse reactions that occurred in more than 5% of participants treated with TRYNGOLZA and at greater than 3% higher frequency than placebo. These included injection-site reactions, decreased platelet count, and arthralgia. Adverse reactions led to discontinuation of treatment in 7% of patients treated with TRYNGOLZA and 0% of patients treated with placebo. Two participants in the 80 mg TRYNGOLZA arm and 1 in the 50 mg TRYNGOLZA arm reported adverse events (diarrhea, vomiting, chest discomfort, chills, myalgia, trismus, and flushing) that led to treatment discontinuation. TRYNGOLZA is contraindicated in patients with a history of serious hypersensitivity to olezarsen or any of the excipients in TRYNGOLZA. Hypersensitivity reactions requiring medical treatment have occurred. Hypersensitivity reactions (including symptoms of bronchospasm, diffuse erythema, facial swelling, urticaria, chills, and myalgias) have been reported in participants treated with TRYNGOLZA. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to promptly seek medical attention and discontinue use of TRYNGOLZA if hypersensitivity reactions occur.

Ok, let’s talk a bit about dosing and administration. TRYNGOLZA is a subcutaneous injection delivered via a convenient autoinjector. It should be stored in the refrigerator, but it can also be stored at room temperature in its original carton for up to 6 weeks. This allows the patients to administer their once-monthly dose at home or away from home if necessary.

It can be injected in the areas seen highlighted here—self-administered into the front of the thigh or the abdomen, or if the patient needs help, by a healthcare professional or caregiver into the back of the upper arm. If a dose is missed, it should be administered as soon as possible after the missed dose. Patients should then resume dosing at monthly intervals from the date of the most recently administered dose. Prior to initiation, train patients and/or caregivers on proper preparation and administration. Please see the Instructions for Use for TRYNGOLZA, included in the full Prescribing Information available at TRYNGOLZAHCP.com.

Again, we’d like to share that the SELECT IMPORTANT SAFETY INFORMATION includes ADVERSE REACTIONS.

Most common adverse reactions (incidence >5% of TRYNGOLZA-treated patients and >3% higher frequency than placebo) were injection site reactions, decreased platelet count, and arthralgia.

Thank you so much Dr. Ballantyne and Dr. Baum.

I’d like to remind our audience that you can submit your questions throughout this broadcast in the chat box on the left side of the screen, or by texting your questions to 912-378-1244, and we will address them at the end of the presentation.

Ok, now that we’ve discussed the Balance trial results and the safety and efficacy of TRYNGOLZA in patients with FCS, I’d like to ask Amanda Davis, Patient Education Manager at Ionis, to tell us all about our patient support and access services.

Thank you, Kishan!

Ionis Every Step is our patient support program designed to help appropriate patients get started on TRYNGOLZA and promote adherence to therapy. The Ionis Every Step team and its various services can help navigate the insurance authorization process and offer eligible patients financial support, while also providing ongoing support to assist in overcoming access barriers and to aid patients in getting their medication.

Prescribing TRYNGOLZA is made easier with IONIS Every Step. To get a patient started on TRYNGOLZA, you can complete and fax the TRYNGOLZA Patient Enrollment and Prescription Form or you can e-prescribe to our single-source, exclusive specialty pharmacy partner, PANTHERx.

All patients who are prescribed TRYNGOLZA will receive core support services.

Patients who choose to sign up will have access to our suite of services and personal support from the Ionis Every Step team.

Patients can sign up for support services in several ways including, signing the patient consent section of the enrollment form, by visiting TRYNGOLZA.com to complete the form online, or by calling Ionis Every Step at the phone number listed on the screen.

The Ionis Every Step team are trained on FCS and understand the challenges associated with it. They are committed to simplifying the process to get a patient on TRYNGOLZA.

The Ionis Every Step Case Manager and Patient Education Manager are the key TRYNGOLZA team members with distinct roles to support your office and patients.

The Case Manager is the 'go-to' contact for your office. The Case Manager will help your staff navigate the insurance approval process, complete a benefits verification, identify plan-specific requirements, and provide prior authorization, appeal, and reauthorization support.

That’s really great, Amanda. Can you explain how a Patient Education Manager is different from a Case Manager?

Absolutely! A dedicated Patient Education Manager will provide patients with personal support throughout their treatment with TRYNGOLZA, including understanding and navigating the insurance process, injection training on the use of the TRYNGOLZA autoinjector in person, virtually, or by phone based on their preference, connecting patients with appropriate financial support programs to help with the cost of their medication, and nutritional support tools, resources, and education to maintain an FCS-friendly diet.

Ionis Every Step will assess each patient’s eligibility for our financial support programs and provide them with information on the appropriate programs if their insurance is not covering TRYNGOLZA.

Commercially insured patients may pay as little as $0 out of pocket per fill.

Terms, conditions, and limits of the programs apply.

Amanda, do you have an example of the autoinjector that you could show the audience?

In fact, I do have a demonstration device with me that I can show. You can see here that it’s just about the same size of a highlighter.

That’s great, thank you!

You’re welcome!

Ionis Every Step is committed to getting patients their TRYNGOLZA quickly and helping them to stay on treatment.

The Ionis Every Step team will coordinate overnight delivery of TRYNGOLZA with our specialty pharmacy partner, PANTHERx, and a dedicated Patient Education Manager will work with your patient to teach them how to use the TRYNGOLZA autoinjector.

Your patient will also receive a welcome kit with an empty demonstration autoinjector like the one I just showed, to practice and learn how to inject the TRYNGOLZA with support from their Patient Education Manager.

The Ionis Every Step team will also work with your patient to assist them with refill reminders, work with them to complete any steps needed for insurance reauthorization, and coordinate delivery of their TRYNGOLZA.

Ionis Every Step will stay connected with your patient to provide personal support as their needs may change throughout their treatment journey.

Ongoing support includes, follow up communication from their Patient Education Manager who will work with them to identify appropriate support programs and resources, answer questions regarding FCS and TRYNGOLZA, nutrition education and resources, and connection to appropriate financial assistance programs.

Other ongoing support services include insurance reauthorization support to help avoid treatment interruptions and help navigating health insurance changes in coverage.

Thank you, Amanda.

And thank you to our audience for your interest in TRYNGOLZA. As a reminder, you may download the TRYNGOLZA Prescribing Information that you’ve seen throughout the presentation by going to the Important Safety Information section on the right side of your screen, or by visiting TRYNGOLZAHCP.com.

Now it’s time for the Q&A session. Please feel free to type your question into the Q&A box on the left side of your screen and click the submit button or you can text your question to 912-378-1244. We will take as many questions as time permits.

OK, I’d like to get us started with a question that our field team has been asked a few times. Should clinicians be concerned that their patients will develop elevated LDL-C or total apo-B levels while they are on TRYNGOLZA?

Dr. Baum, could you address this question?

Yes, I can… [please refer to Objection Handler for appropriate responses]. Thank you, Dr. Baum. Next it looks like we have our first question from an audience member. They ask, “Do patients still need to be on a restrictive diet once they start TRYNGOLZA?”

Dr. Ballantyne, could you answer that?

Yes, I can… [please refer to Objection Handler for appropriate responses].

Thank you, Dr. Ballantyne. Our next audience member asks, “What happens if my patient’s genetic test doesn’t identify a genetic variant that labs use to qualify FCS?”

Dr. Baum, what are your thoughts on that?

Thanks Kishan. In that situation I would say… [please refer to Objection Handler for appropriate responses].

Thank you, Dr. Baum. It looks like our next question is related to the Ionis Every Step program. Amanda, our audience member is asking, “…”.

“Absolutely…”

Well, that’s all the time we have today. Thank you to all for submitting such great questions.

I’d like thank all of you for being here with me today—you all really had some great information to share on TRYNGOLZA. Once again, for more information on TRYNGOLZA, please visit TRYNGOLZAHCP.com.

Thank you to everyone who has tuned in from across the country! We hope you have thoroughly enjoyed this broadcast. From Ionis Pharmaceuticals, I am Kishan Mistry.

Take care!

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