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.
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 questions from the audience.
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 1 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 1 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.
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. I'd like to get us started with a question that our field team has been asked a few times, Dr. Baum and Dr. Ballantyne, can you explain what it means that a genetic testing can be supportive of a clinical diagnosis of FCS even with indeterminate results?
Sure. It's a very good question. Definitely very relevant and top of mind for clinicians. So the issue here is, first of all, we need to understand that in the balance study, all patients were genotyped and found to have genetically confirmed FCS. What that means is there are five genes that are currently known to play a role in causing FCS. LPL being, lipoprotein lipase, being the dominant one with greater than 80% of people having biallelic mutations. What happens if you don't find one of these mutations or two of the mutations? So in the case of FCS, as in the case of other disorders, phenotype trumps genotype, and what that means is on a clinical basis, you make the diagnosis of FCS even if the genetics don't confirm it. So what do we look for? Dr. Ballantyne mentioned some of the things we look at. We look at whether or not a patient has a history of elevated severe, severely elevated triglycerides greater than the 880 on multiple occasions, whether the use of lipid lowering therapies has not been effective, that there are no secondary causes of severe hypertriglyceridemia, and when the patient's phenotype starts really confirms or looks like FCS, we make that diagnosis even in the face of indeterminate genetic results.
Thank you, Dr. Baum.
How about you Dr. Ballantyne?
I agree with everything that Seth said. Another flag is if someone's had pancreatitis due to high triglycerides. That person, we hardly declared their risk to a certain extent. It's almost like thinking of secondary prevention after a heart attack. So if they've had pancreatitis, severely elevated triglyceride and you're not able to control it, and we always try with lifestyle and we try medications, but these people are extremely hard to treat. So this is why this is a breakthrough—I think it was a breakthrough designated by the FDA—because there hasn't been a therapy to be able to treat people. They lack lipoprotein lipase activity. So it's something to keep in mind. Now, if you're not certain, but you're suspicious, always find that you can get a consult with a lipidologist and they can go further on the evaluation for this. But it is something when you see that severely high triglyceride, you can't control it, and especially if they've had a history of pancreatitis, you should be thinking of this disorder.
Yeah, I'd add a couple of other thoughts actually. So FCS is very significantly underdiagnosed. Even though it's a rare disease, we're not diagnosing it enough. So what that means is we always have to be on high alert, and there are certain things in the literature that we'll see, such as these patients tend to be thinner, not obese, and though that's true just because you might see a patient who's overweight or obese and you think the patient has FCS, you shouldn't say that the patient doesn't have FCS because the patient is overweight. It's very similar to indeterminate genetic results. So be very careful about making the diagnosis of FCS, and I love Dr. Ballantyne’s suggestion. Speak to a lipidologist, speak to an endocrinologist, a preventive cardiologist who has expertise in FCS.
Perfect. Thank you Dr. Baum. Thank you, Dr. Ballantyne. Another question for you both. Can a patient on TRYNGOLZA relax their diet? How about you, Dr. Baum?
No. So the answer is no. So the diet is foundational, fundamental in the management of FCS. It's a very strict low fat diet, less than 20 grams a day of fat, and it's really essential that a patient maintain that diet while taking TRYNGOLZA. You know, people might want to say, hey, it would be great to relax the diet, but it is really not in the patient's best interest.
Remember in this study, this was done on top of the dieting, and when people were enrolled in the study, they didn't know if they were getting the placebo or the drug, and so we saw that very nice reduction in triglycerides, but unfortunately, these people, there's a lot of bouncing around and if someone has a bad weekend, they can go from 2,000 to 4,000 or 5,000 triglycerides, and so this is a very potent medication, but it's the same thing if someone has very high LDL and we treat them with a statin, we don't say forget lifestyle, it's still important. The lifestyle is still important. So it's the total picture here in terms of trying to re-optimize this, such a high risk for pancreatitis, and we know that it's very effective when this is combined with lifestyle.
Yeah, that's a great point, and the comparison to LDL is actually very interesting and important. So when we manage LDL, LDL levels do not fluctuate the way triglyceride levels fluctuate. So to Dr. Ballantyne’s point, triglyceride levels can fluctuate in the thousands with poor diet. So it really is important to reinforce to our patients, even on therapy, they should maintain a very tight control of their fat intake.
Thank you both, really appreciate that. Another question, how often is it recommended to check platelets on TRYNGOLZA once it's started? How about you, Dr. Baum?
Well, that's a great question, and frankly, I don't think that there is a recommendation right now to my knowledge for the frequency of checking platelets. If we look at the platelet results in the study, although there was a decrease in platelets, platelet levels in the vast majority of patients on TRYNGOLZA were not low. They were still within a normal range, and there was nobody who fell below 50,000 and there were no excess bleeding risks in the TRYNGOLZA arm.
I think it's reasonable to get a baseline CBC just to make sure they didn't have a low platelet before you started them because some people have low platelets from other disorders and everything else. So I think it's reasonable to get that, and you might get one in a follow up, but pretty much it's been very reassuring that the safety data in this study was, we didn't see–there were earlier generations. It is these antisense oligonucleotides have gotten better and better. It's like the example of monoclonal antibodies. Initially they were mirroring and then they were chimeric and then they were humanized and they're fully human. Well, Seth mentioned this GalNac, and so the dose is much lower. We don't seem to see the side effects we had earlier with this in terms of the low platelets for the other agents, but it's something obviously if there's a warning and if the patient says, gee, I've been having a lot more nosebleeds, you should check a platelet count. Anytime that someone complains of something, of a bleeding check, the platelet counts, and then if there was something that was markedly reduced, look at other secondary consultation, you might hold a dose to see what happens. I don't think there are, Seth, discrete recommendations right now, there's a lot of other ongoing larger studies with this same agent. We'll get more information, but we did not see in this study any really worrisome problems in terms of low counts that cause bleeding.
Yeah, I think it might also be important to mention that in this disease state, we do feel that platelet counts tend to be on the lower side and they also do fluctuate. So yeah, to Dr. Ballantyne’s point, it would be good. I don't think there's a formal recommendation, but it would be good to get a baseline and a follow-up. But again, to my knowledge, I don't know of a formal recommendation.
Thank you both. Another question, we have, will TRYNGOLZA only be available through the specialty pharmacy mentioned or will it eventually be available in commercial pharmacies? Amanda, do you think you can take that?
Yes, I sure can. Thank you. Panther RX is currently the exclusive pharmacy partner for TRYNGOLZA.
Thank you, Amanda. We have another question. How can I support my patient in staying on the diet?
Yep. So another very good pragmatic question that I think Amanda has answered very well. The Ionis programs are robust and there's tremendous support with nutritionists to help patients stay on an appropriate diet. There's also the reality that we as clinicians need to do our part to help encourage our patients to maintain a healthful diet, in this case, a very tough diet of less than 20 grams of fat a day.
One thing I find helpful is people respond to information. So when you start a therapy, you always see what the response is, what the triglycerides are. So in general, more frequent measurements of triglycerides. Seth mentioned the LDL cholesterol. It's pretty stable. We can measure LDL once a year and it doesn't change that much. Triglycerides are more of an issue, and in particular if somebody knows that they maybe overdid it on the weekend and they want to check their triglyceride, it's very reasonable because what happens is even with this disorder, if you go even super strict, I've had patients where before we had the medication, someone was pregnant, we would go clear liquids for 24 hours and they would drop down a lot. So it is important to give the people information. If someone slips a little bit on their diet, they may have to tighten up and they can do that, but they may have to get very, very strict. That's why it's been such a challenging disorder because it's pretty much unrelenting. If you mess up, you might get pancreatitis and someone goes to a birthday party or there's something. One thing important is that I've seen is alcohol is not something that's good because alcohol itself can cause pancreatitis and you don't want to have alcohol on top of high triglycerides as a part of the picture.
Thank you, Dr. Ballantyne. Thank you, Dr. Baum. Another question we have, can TRYNGOLZA be administered along with other lipid lowering medications like fibrates, Dr. Baum?
Yes, it certainly can. I think we should emphasize though that fibrates are not effective in this patient population, so they inadequately reduce triglycerides, but there's certainly no problem administering both simultaneously.
How about you, Dr. Ballantyne?
Yes, agree with Seth. This was added on top of whatever the patients were taking.
Thank you. Thank you both. Dr. Baum, should clinicians be concerned that their patients will develop elevated LDL-C or total apo-b levels while they're on TRYNGOLZA?
No. They should not be concerned that patients will develop elevated LDL. We have to remember that in this patient population, LDL-C levels are very, very low to begin with. Typically less than 20 milligrams per deciliter. Apo-b levels are typically low as well or low normal. In the study, 74% of patients in the Balance study, 74% of patients maintained a LDL-C level that was less than 70 milligrams per deciliter. So it's good to check and to see what the LDL does, but we shouldn't worry about it.
Thank you. We have another question. So what would you say to FCS patients that postpone going to an ER with abdominal pain? Because they could have been repeatedly questioned about alcohol abuse?
So I would try to encourage the patient, if I'm getting this right, this is a patient who had alcohol abuse and was afraid to go to the ER with abdominal pain, I would encourage the patient to go to the ER. Pancreatitis is certainly a very serious issue, high mortality, and the patient needs to go to the ER. On a separate note, encouraging and helping the patient not to drink alcohol would be very valuable as well.
Thank you, Dr. Baum, how about you Dr. Ballantyne?
The other one that comes up. If someone, because the other possibility, someone doesn't drink alcohol, but every time they go they say, well, how much have you been drinking? I do think this is where if someone knows that they have FCS, it's an education issue that they tell the ER physician “By the way, I have a genetic disorder. It's called familial chylomicronemia syndrome, and it causes high triglycerides and pancreatitis.” I mean, I think Seth, the issue is that if they were drinking, but sometimes people might be accused of, you're back in here again with abdominal pain. This person drinks too much, and there may be some ER physicians who are not familiar with this disorder.
By the same token, I've heard patients say that when they go to the ER with pancreatitis or with abdominal pain, ER doctors often think that they're drug seeking, that they just want painkillers. That's where Christie, to your point, having the diagnosis being made, they can go in and say, hey, I have this genetic disorder, and perhaps the physicians will understand that they're not just seeking painkillers.
Yeah, that's one of the difficult aspects is that repeated episodes can lead to chronic pancreatitis, which is there's a lot of pain with that and complications if you have recurrent episodes and pancreatic dysfunction. So it can be the thing that Seth was pointing out. Those people might end up saying, well, they're pain seeking, but they're miserable is what it is. They're in pain.
Thank you both. Another question, were all patients genetically identified for FCS specific genes in the Balance study?
Yes, they were. So all patients were genotyped and found to have FCS genetically. Again, most of these patients had mutations in lipoprotein lipase, but there were others that had mutations in the four other genes that can be responsible for FCS.
You know, Seth, and I think there's one caveat is that the person who was looking at the genetics was, I think Rob Hegele is one of the world experts here. So 16% of them I think may have been considered indeterminate if you didn't have an expert calling because sometimes you have a well-described pathogenic variant, and then you may have what we would call a variant of unknown significance. But if you look carefully at that individual and if someone is knowledgeable as wrong and say, well, that actually is probably a pathogenic variant. So I think this is one of the things that–everybody has variants in genes. Some are disease causing, some don't cause disease, and sometimes you have a variant that maybe people don't know that it's pathogenic, but so you might say, oh, you have your heterozygous, you have one bad gene. I think one bad gene is not a good thing either. So it's not that you're out of the woods with that, but I do think is that it gets to this whole complexity of the, you don't always have a clear cut two pathogenic variants with it, so it's a rapidly moving field and there are other genes that can be problematic too.
Which brings us back to the earlier point that we made that phenotype trumps genotype, right? So if you end up, as Dr. Ballantyne just said, with an indeterminate result in your genetics and you clinically have FCS, then you have FCS.
There are published clinical criteria for FCS, a couple of different ones. There's one recently for North America with it, but I do think it's this is one where it's important. Seth already mentioned the key clinical features is non-responsive to medications, triglycerides consistently over, at least persistently, you might have an occasional one that's a little lower, but it's 10 millimoles, which is 880, history of pancreatitis. These are the things that really alert you that boy, there's something going on here and that's when it's good to get perhaps referred to lipidologists, preventive cardiologists, endocrinologists who might have a little more expertise in this area.
Thank you Dr. Ballantyne, thank you Dr. Baum. We have another question for you both. For the FCS patients you treated, how were they identified or were they referred to you?
So for me, they were all referred, actually, they were referred for clinical trials, and I personally have seen seven patients with FCS. It's a fairly large number and all came through clinical trials from a variety of places. Thank you, Dr. Baum.
How about you? Dr. Ballantyne?
Same thing, referred. I have a lipid clinic that we've been doing for many years, and so people have seen this difficult to treat patients, and this is why we're saying that it's completely logical and a smart thing to do. If you have a difficult to treat patient who has severe triglycerides, you refer them to someone else and we do the other evaluations, genetic testing or other things, and frequently we can put them into trials or get the right therapy. There is sometimes even if it's just that, okay, I think they might have it, but I don't remember how to do the prior authorization and all these kinds of other things. Lipid, clinics, we're used to doing these things. So we have systems set up. It's painful for us just like it is for everybody else, but it still ends up that we're able to get the patients the drugs they need.
Thank you, Dr. Ballantyne. Thank you, Dr. Baum. Another question. Does GI tend to get early consults on these patients with the presentation of abdominal pain and pancreatitis?
Yeah, so yes, GI can do consultations, certainly in the setting of pancreatitis. The problem is that if GI sees these patients, often the diagnosis is not made. So it's nice in this setting of pancreatitis to bring others in. Clinical lipidologist, endocrinologist, who might have a better shot actually at making the diagnosis.
How about you, Dr. Ballantyne?
I think we miss cases sometimes because the focus is on the immediate pancreatitis, but the issue is maybe the triglycerides–the acute pancreatitis can sometimes also lead to high triglycerides. So there's a little confusion sometimes about this, and it's assumed it'll be taken care of in a follow-up, but it may not be. So I do think it's very important that GI docs be working with the lipidologist, endocrinologist, preventive cardiologists, and also be aware of the triglyceride issue so that the patient gets followed up. Most of them are not going to want to treat it, at least in my experience. It's not where you're not scoping. And the same thing, a lot of our cardiology friends don't want to treat lipids very much either. So they send the really tough ones to us because it's not what they do, but it's fine. That's fine. Everybody has different things that they do.
Thank you both. Last question, and are there any considerations you'd like to share with physicians who are thinking about starting a patient now? How about you, Dr. Ballantyne?
Yeah, so I think the important thing is going to be how did you make the diagnosis? You need to document that well. Was it genetics? Was it clinical scoring system or something that you heard the information about how to start a patient today? They'll be able to help you if you're not sure about that. And then you get the process initiated to go through this. So it is with everything, there's a patient physician discussion and you're going to talk about what's the benefits of the drug, what are the side effects of the drug? You want to make sure people understand the potential side effects. If you know what side effect, you can manage it. If you've never heard of the side effect, that's a problem. So that's part of the whole process of this patient physician discussion. Whenever you're thinking about a new therapy, somebody might say, well, I don't want to try that right now. Can we try lifestyle some more? That's fine, you can try it some more, but you raised it. And then when they come back, you may end up saying, okay, now I'm ready to take the medication.
I'd probably also add that it would be a good time to potentially speak to a lipidologist, get somebody else's input.
Thank you both. Well, that's all the time we have today. Thank you all so much for submitting such great questions. I'd like to thank all of you for being here with me today. You all had really some great information to share on TRYNGOLZA. Once again. For more information on TRYNGOLZA, please visit TRYNGOLZAHCP.com. Thank you to everyone who is tuned in from across the country. We hope you have thoroughly enjoyed this broadcast. From Ionis Pharmaceuticals, I'm Kishan Mistry. Take care.
