Ionis Pharmaceuticals, Inc. (IONS) Earnings Call Transcript & Summary

Good morning, everyone. Welcome. Thank you for joining us on this very first edition of the Ionis Rare Disease Webinar Series. I'm Kenneth Newman. I'm Vice President of Clinical Development and the Franchise Leader for the Pulmonary Immunology area here at Ionis. Today, we'll be discussing hereditary angioedema, which is a debilitating and severe disease for which there are currently limited effective treatment options. I'm really honored and thrilled to have joining me today, Dr. Danny Cohn, who's an internist at the Amsterdam University Medical Center and the primary investigator for the Ionis PKK LICA program, and also 1 of the 2 global leaders in the diagnosis and treatment of HAE. Ionis antisense therapy is designed to target and treat the root cause of HAE. Danny?

Thank you very much for the kind introduction, Ken, and it's great to be here. I really look forward to have a very interesting discussion with you and, of course, also the patient who you are about to introduce and I also look forward to their questions from the audience. And I would like to thank you very much for the invitation, which helps in creating more awareness of this debilitating disorder.

I'm also really honored to be joined by our very special guest, [ Mitch ]. [ Mitch ] is a patient of Dr. Cohn, who's been living with HAE for many years, and I think he provides a very unique and important perspective for us here.

Thanks for having me, Ken, and I'm glad that I can share my story, hopefully, to be of some assistance to raising some awareness for the disease though. Thank you.

Yes. We have a few housekeeping items before we begin. First of all, we're going to have a live question-and-answer period at the end of our discussion. If you have a question for consideration, please submit it through the Q&A feature, and the team will select a few of these for response. Please be sure to note if the question is for [ Mitch ], Dr. Cohn or myself. This webinar is being recorded, and the video replay will be available on the Ionis website at ionispharma.com. We've invited [ Mitch ] and Dr. Cohn here to share their perspectives on living with and treating HAE, as we said, a debilitating rare disease that impacts the lives of patients, their loved one and their friends. Our goal is to help inform viewers about what it's like to live with these rare diseases like HAE, but also educate about the potential treatments for these diseases. Collaborating with patients, caregivers and health care providers is a critical part of the drug development process. We know that patients depend on us to deliver innovative therapies. We also know for anyone living with a debilitating disease every moment matters. That drives our sense of urgency, that all of us at Ionis have to discover and that we have to use every day. So having done our introduction, let's start our discussion. Danny, what's hereditary angioedema and what causes it?

I can see we just lost Dr. Cohn. I think I'm the only one that has his personal number. What do you prefer, Ken? Should we start the interview with my story, my questions, or should I try to contact him?

No. Let's talk with you, [ Mitch ]. I think you're the critical person on this call anyway.

Not the one with the most knowledge. I will tell you that.

The most personal knowledge, for sure. So [ Mitch ], what was your personal journey like? How did you get to where you are today?

Well, I'd like to take you back to the beginning. Well, my name is [ Mitch ] as you can. I'm 29 years old, and I live in the Netherlands. I live with my girlfriend. I have a 1-year-old son and a dog, Dora, which we all enjoy during these pandemic times. And I want to take you back to the beginning. When I was about 10 years old, I was diagnosed with HAE, and it took a lot of time to get the correct diagnosis, but it also took about the same amount of time to accept the clinical picture for myself. As being confronted with living with a potentially life-threatening disease is something that you have to give a place in your emotional and personal life. And after many hospital visits and missing school parties before, I was diagnosed, I was very lucky to get diagnosed because my family doctor had visited a meeting like this, about some rare diseases, and he linked the dots for me, so that I was very lucky to get diagnosed at a pretty young age. The diagnosis was made on-site at that time by a physician before Danny Cohn in the Amsterdam Hospital and I got prescripted with the medicine that made the swelling go away at that moment. So I walked into the hospital with a swollen face. I took the tranexamic acid and the swelling would just flow away. So my parents were really delighted at that time because I think I've seen 4 doctors before that who thought they knew that I had and gave me some kind of drug that did not work. And when the right diagnosis was made, it was great, but on the other hand, it was kind of -- it may be very anxious because at that time, I knew it would not only be a swollen face or a stomach attack, but it could also possibly be the laryngeal attack, and it could possibly be deadly. So it was pretty lucky. I never had a laryngeal attack before I get diagnosed. And I have been living with the possibility of getting an attack at any time. So I always have to keep my medicine ready and always have to be on the lookout and not losing control for myself personally, not as an example, not drinking too much because you always want to be on the lookout. Oh, I see, we have Danny back.

I'm terribly sorry. I don't know what happened, why the connection was lost. And I...

No problem. We're just going to talk to [ Mitch ] for a little while, and then we'll circle back. So [ Mitch ], we were just talking a little earlier how lucky you were. You were between when you first had symptoms and when you were diagnosed in your case, was pretty short. It was less than 2 years, right?

No, it was approximately 4 to 5 years.

4 to 5.

Yes. But the problem really was that as a child, I mainly had stomach aches. Well, if you can name a child without stomach aches, then I think that's pretty wonderous. So it was a journey from where does it come from? Is it stress related? Or is it just a regular stomach ache? While it felt for me sometimes like I was -- the stomach aches were so intense that I was floating in between being conscious and being unconscious. So my parents, they pretty early had the idea that this was not a normal stomach ache. Only the swelling, at peak moments, it only lasts a couple of days. So at the moment, I was in the hospital to get a check or get a scan, most of the time the swelling would go away. So the doctors at the time could not make the right diagnosis based on that hospitalization.

Do you remember the first time you had swelling in an extremity or on your back? And how you felt -- you must have been really frightened.

Yes. It was pretty scary. And I don't really remember the first swelling on my -- on any extremity or hands or foot, but I do really remember at times always before an exciting school trip or swimming lessons or something like that, that I would wake up with a big hand. And at that time, I would always sleep on my belly, sleep on my hands. So yes, my father and my mother always thought, you might want to stop doing that and try to sleep on your back, things like that. And then it become obvious that the trigger wasn't sleeping because my hand would swell up anyway regardless of sleeping on it or not.

So how often do you have these attacks, especially before you went on treatment?

Yes, it differs. I normally have about 2 attacks a month. And in my case, I'm very lucky to have even that if I speak to other patients -- some patients have attacks weekly, sometimes more attacks -- more than 1 attack in a week. But the 2 attacks in a month are also pretty, yes. I don't exactly know the right word, but they always keep you on edge. You always have to anticipate what's going to happen, when it's going to happen, do I have the correct medicine, all those things.

Have you figured out what triggers them in your case?

Well, through the years, I have found some triggers. The triggers are psychologically, but they're also physically. In my case, it's very unique or it's very unique or weird or a, it doesn't really fit the normal -- get the normal role of the disease. But in my case, the swelling mostly comes after a stressful event. So when I had a really stressful week, Friday night, I would come home, I would put my bag and my working clothes away, and then I would sit on the couch. And then I can feel it, starting to tingle, and the next morning, I wake up with 1 or 2 swollen feet or hands. And the physical triggers, yes, that's just -- that's so weird, I can punch a punching bag 3 nights a week without having a single swelling and I can just bump my feet to the side of the bed, and then it would swell up. So that's really weird. But there are physical and psychological triggers, yes.

And it must be so nerve racking anxiety provoking to have to worry about where the next attack is going to be.

Yes. I'm very glad through some psychological help and through great doctors and physicians that try to give you the best treatment and that I could give it a place in my life. But for my parents and during my puberty, it was -- well, I think nerve-racking is the right word. Not being able to go on a holiday with your friends because you're always anxious. Do I have my medicine? My medicine needs to be -- my current medicine needs to be cooled. Do you have the cooling facilities? Where do you store it? Where is the closest hospital that's not nice, that's not something you want for someone in puberty just developing and searching, wanting freedom.

And have you had to go to the hospital or the emergency room for this?

Yes. I've been hospitalized a few times. I can remember 2 times for stomach attack, where it was just my stomach attacks were so intense that I couldn't eat. I could not drink. I got clocked up. I got obstipated and then I was dehydrated because I couldn't drink. And my energy levels were so low at one moment that it became quite dangerous, so I had to be hospitalized. And I remember 2 other cases being hospitalized for thinking I had a laryngeal attack.

Yes. And you've been lucky enough from what you were saying, never to have had a laryngeal attack, but yet, the thought of it must be also very nerve-wracking?

Yes. It's the process that I'm very aware of the way my voice sounds, the way I feel here, if I have a cough or if I have a cold, you're always on edge. If I wake up after a party or something like that, my throat is sore and my voice is a little bit deformed, you go straight to thinking, well, my medicine, are they in the cooler, the dates are right, everything is set. I have a clean working environment if I need the intravenous injection. So it's a lot of planning and a lot of thought that goes to it.

So how are you managing your disease now?

At this moment, I'm very glad to participate in a new study, and those results are looking very promising. And on the other hand, I have medicine that works pretty good in case of an attack. So I don't have a real good prophylactic treatment. But I do have a medicine, which is guaranteed to work in case of an attack. So that's -- well, it's not great. And the fact that you have to inject it intravenous means that you always have to have the clean working environment. You have to be prepared. You have to know what you're doing when you inject yourself in a stressful situation. So it's not great, but I can't manage.

Do you have a port in to give yourself an intravenous injection?

No, no.

So you have to have -- inject, you have to find a vein and start an IV each time you want to give yourself an injection?

Yes.

Wow.

Yes. And that's a choice I made from my own because it's an expensive -- very expensive drug. And I don't want to use the drug every time. I want to use the drug if I have an attack, which has severe symptoms. So if I just have a swelling in my hand or my foot, I won't use it. I only use it for bad stomach ache or in case I have the fear of having a laryngeal attack.

So what would an ideal treatment look like for you?

The ideal treatment would just give the freedom back of not having the really hard way of administering the drug and would, of course, be a prophylactic drug, which you can take and then just be free of symptoms. That would be, in my case, the ideal treatment. It being a pill or a monthly injection or something like that. Because the problem with the current treatment is that you have to go through all these procedures, all these steps of injecting the medicine in a situation that's kind of stressful. So if you have the stress of getting a laryngeal attack or having a bad stomach ache, when you wake up and then having to lay out the table and finding the vein and then injecting with one hand. I've had some situations sitting in the next room, doing it early in the morning by myself and thinking just -- it's not a great feeling, no.

Yes. So Dr. Cohn. Thank you for sharing your delightful patient with us. We really appreciate that. So can you tell us a little bit about what HAE is and what causes it?

Absolutely. So HAE is a rare genetic disorder that is characterized by recurrent unpredictable swellings that can occur at almost any location, as you have already heard also from [ Mitch ]. And the symptoms and signs, they depend on the localization where the swelling occurs. So for instance, facial tics, they can give disfiguration; abdominal attacks, so swellings of the intestine, they can be extremely painful and a common cause of absence at school or missed days at work; and swellings of hand and feet. In the genital region, they can be really bothersome and the most commonly localization feared is, of course, the laryngeal attacks, so selling of the upper airways, which can lead to asphyxiation and a potential cause of death. It is caused by a single gene mutation, most commonly in the C1 inhibitor gene. C1 inhibitor, it is a protein that controls a certain system. And I won't make this too difficult. But once the body loses control over the system, which is called the kallikrein-kinin system, then this ultimately leads to a leakage of the blood vessel, which leads to their swelling in HAE. And [ Mitch ] also mentioned a variety of triggers. There is a large variety of triggers, including stress, exogenous hormones and surgery and injury and also common infections like common cold or flu can lead to these swellings. And I think it's very important to stress that although symptoms can start early in life, there is -- the disease remains under recognized. And there is a long delay usually between the first signs of symptoms, the first swellings and it can lead to delays of up to a decade or even more before the true diagnosis made.

[ Mitch ], I meant to ask you earlier, when you have one of these attacks, how long do they last? Whether you -- if you don't treat it, and also if you do treat it?

If I don't treat it and even if I do treat it, the duration of the attack can vary pretty much. I've had some attacks that would not make my hand swell up to the extreme point that it reaches sometimes. So it can vary if I have to say a certain length of time. I think about 3 to 4 days, in total, if I do not treat it. And if I treat it quickly, it can take 1.5 or 2 days, something like that.

And can you go to work during that time? Or do you pretty much stay at home?

It depends when I have a stomach ache and I treat it too late, so it reaches a peak, I can't do anything, but lay in bed and just feel terrible. If I treat it at the right point, then I can go to work. You will have the feeling in your stomach, not feeling well, but again, can go to work. But I do realize that I have a desk job, and I'm very glad to have that. Because if I had a physical job, then it would not be possible. I've more than once jammed my swollen feet in my shoe and then just humping to work, sit at my desk, do my thing and then go home. I don't know why I do that. It feels like some kind of self-torture, but you just want to go on and you don't want to sit on the couch and think about look at my feet, or I can't do anything today.

Must be tough to type with swollen hand, too?

Yes, that's weird. And I have had some weird situations where I had a business interview or something like that. And I had to shake someone's hand, and I would still go to the meeting, and I would have -- I'd be super self-conscious about having a swollen hand, just reaching and shaking someone's hand and then going to hide the head under a desk and do the meeting. It's -- yes, you do it, but it's not nice.

Yes. I think the point you made, Ken, is very important because there are also other much more common forms of angioedema, which developed really fast and go away really fast. These are the allergic types of angioedema. And that's a true distinction between this form of angioedema, which has really slow onset and a long time to relieve.

Exactly. So Danny, how likely is it that someone who has HAE is going to pass it on to their children?

So it is a genetic disorder, and there is a 50% chance of passing it over to the progeny. However, it is important to stress that up to 25% of patients with HAE do not have a typical family history. So they are the first in the family. They have a new onset mutation, but also in these patients, there is a 50% chance of passing it on to the progeny.

So I'm curious, Danny, how do you end up interested in HAE? What -- how did you get to where you are?

So I've started taking care of the patients with hereditary angioedema over 4 years ago, and I was and [ Mitch ] can agree in perm that I was truly touched about their stories. And I was really curious because many patients, they just settled with the situation they were in. They said, I had recurrent attacks. And there is, of course, I'm worried about new attacks, that there is some kind of treatment -- on-demand treatment if there is an attack. Hopefully, I can treat myself, and let's move on. They didn't even treat all the attacks because they thought it was too expensive to treat attacks which occurs and is something that is really difficult to understand if you just want every patient to have 0 attacks and to be in full control of their disease. So I was touched on their stories, and I wanted an individualized optimal care for these patients. And they were possible -- there are opportunities because there are new treatments in development which have increased efficacy as compared to the usual treatments that we have now. And the future looks bright. I really believe that patients can be in charge of their disease and live a normal life.

So can you talk us through very briefly some of the current therapies and how they work and what their limits are?

Yes, of course. So I think it's important to make a distinction between on-demand treatments, which are treatments that are being used to treat an acute attack, and then there are treatments that are used prophylactically, so to avoid any attacks for occurring. And especially with the later, that will give patients control over their disease. The most used forms have been used for a couple of decades even, but they are not as effective as you want them to be. So patients experience breakthrough attacks, for instance, attenuated androgens have been used for a very long time and are still being used in many countries across the world, especially because they are not very expensive. But patients keep having and usually having angioedema attacks, and they have limited tolerability. So mood disturbances, skin abnormalities and even the long-term risk on cardiovascular or hepatic diseases, not completely known. Tranexamic acid is no longer a treatment of choice and has very low efficacy. And of course, then there are the substitutions of the C1 inhibitor concentrates. These have to be administered in most cases, intravenously. So that gives -- as [ Mitch ] also mentioned stress in the acute situations. But if you continuously treat yourself 3 or 4 times a week with IV administration, then it can also lead to blood access problem and infections. And despite treating 3 times a week with these concentrates, patients still experience attacks in many cases. And there are now also available subcutaneously administered C1 inhibitor concentrates, which are more effective than the IV administered concentrates, but still patients need to administer twice a week. And that also makes them think about the disease continuously. And therefore, the -- I think the new perspectives are administered therapies that are less frequently administered. For instance, once a month or even less frequently, where they can -- and if these therapies are very effective, then this will allow patients to live a normal life.

Thank you. So for the 2 of you, thinking about what your experiences have been, what advice would you give to other patients living with HAE? Let's start with [ Mitch ].

Yes. A tip I want to give to the other patients is to really emerge yourself in the clinical picture, try to understand and try to find your own personal triggers. And then you have to be very strict, having all your medicine in order, having all the precautions taken. But when that's done, try as best as you can to forget it and live a normal life. Because if you truly do get caught up in the anxious process of always thinking about the things that can happen, you effectively do not have a life and cannot carefree enjoy the things that you're doing. So it's a mix. Be strict, have your things in place. And then when that's the case, try to let it go as best as you can.

Yes. Do not let the disease take control of you, but you need to take control of the disease.

Wise words. So I'm going to move on now to the question-and-answer period because I know we're starting to run short on time. So as mentioned earlier, for people that want to ask the questions, please utilize the Q&A feature to submit any questions. And then please let us know who you're directing the question to. So any questions that have come in so far.

I can see a question. I think it's directed at me. The question is, how does the condition affect your family life? Well, that's a good question. And I think that I have to answer that in 2 separate answers because firstly, the family life, when I was diagnosed was the family life, of course, with my parents, who are also quite anxious about their child getting diagnosed with a possible life-threatening disease. And my mother had a very hard time. She fought really hard getting the right diagnosis and just keep on taking me to all kinds of different doctors and always going with me to the hospital, being there every step of the way until I was like maybe 50 years, 60 years old and said, mom, I'm going to try to manage it myself. So please take a little bit -- take a little step back. But being a caring mother, that's not possible. So even now, if my mother heard from my girlfriend that I'm having an attack, she's still anxious, and she still lives it with me. And my family life now, which is, I think, the second part of the question is that I'm very glad that I have a supporting wife that understands me and can also administer the C1 inhibitor intravenously. So if I really have a stressful situation, she can help me. But on the other hand, it's quite stressful for her, too. Because every time you go to a seemingly care free trip or a family visit abroad or something like that, I always have to take a lot of precautions. So it's kind of a burden on her, too. Although she doesn't agree with me on that.

How do you take your medicine with you? Do you bring refrigerated packs?

Yes. Yes. I have a whole array of options from electrically refrigerators, which I can just plug into a socket. I have refrigerated little compartment in my car. And I even have a little battery pack, which I can put in my backpack when I go to the beach or something like that because it's hard when it's warm outside to just keep it at the right temperature.

[ Mitch ], I see you have another question.

Yes. What are you doing to prepare for this disease potentially being passed on to your son? And that's a very good question and a very hard question to answer, and that it has put a stamp on my life for, I think, the last 4 or 5 years. We are blessed with a little baby boy last year, March, 16th of March. So we just had his birthday around the corner. And given the 50% chance of the heredity, I had a lot of discussion with my wife at the time. What are we going to do? And luckily for us, it was made possible to conceive her some through preimplantation genetic diagnosis, which means that in the embryo stage, they saw the embryo, which did not have the disease. And then we conceived our son through that. So that was a very difficult and hard process with all kinds of psychologists, we had to visit and ethical commissions. And still, it was on the brink of being passed, but it eventually got passed in our situation. So yes, we have a little man here walking in the house who does not have HAE. So the line of heredity started with me because I acquired it myself, and the line is broken after me. So that makes it more bearable for me.

Sorry, go ahead, Danny. It's pretty amazing news, [ Mitch ].

It's very impressive, but I would like to emphasize that in the Netherlands, it is prohibited. It's not allowed to use it for this indication that they made an exception after a very long trajectory for [ Mitch ] and his wife. But is not a generally approved way of treatment.

And I see another question both for [ Mitch ] and Dr. Cohn.

And so the question is, do you foresee carrying acute therapy with you even when you are on prophylaxis. So yes, [ Mitch ], maybe you can first mention something you have been participating in the trial and your attack rate has really dropped incredibly, hasn't it?

Yes. My attack rate actually dropped to 0 for the last couple of months. From the moment I started with the new study. I walked in, having 2 swollen feet that was really a bad period. And after that, that was -- those were my less attacks. But on the other hand, while I'm on this study and I am HAE attack free at the moment, it still does not drop back to the back of my head. It's -- well, I should say, it's always in the back of my head. So yes, I always carry my medicine for acute treatment with me even on prophylactic medicine now.

Yes. So we currently still advise any patient, although they have very low or even absent of attacks to have on-demand treatment with them, so they can treat acute attacks. But we have noticed that patients start forgetting to bring the on-demand treatment with them because they get used to the idea that the attacks have disappeared. But indeed, every patient should possess on-demand treatment.

Danny, are there any interventions for acute attacks that don't require refrigeration that would be easier for somebody like [ Mitch ] to use?

Yes, there are on-demand treatments also available that don't need to be refrigerated. The temperature should not exceed 25 degrees Celsius. I don't know how much that is in Fahrenheit, but these are available. And also with that respect, the future like bright, probably within the next couple of years, we will also have on-demand oral treatments probably available to be used.

Well, we have 2 more questions. And [ Mitch ], you are clearly the star of the show because all the questions are heading your way. So I'll read it to you. So has the disease ever gone into remission? Do you have periods where you have milder symptoms and less frequent symptoms?

Yes. I experienced some periods where I really had fewer attacks and I really try to analyze that. I keep logging from years and years when I have it, the periods, the seasons, trying to find the patterns. But I could not find a trend. There are periods my attacks are less frequent, but I can't find a reason for that.

You say normally, you have about 2 attacks a month. So during these less frequent, you may go a month or 2 without having an attack? Is that mild...

Yes, something like that. I can have 4 attacks a month. I can have multiple attacks at the same time. And I sent a message to Dr. Cohn 2 years back when I reached a sad point where I had 3 attacks at the same time with a swollen hand and 2 feet and I was not -- still at that moment, I did not want to inject the C1 inhibitor. But when all 3 attacks reached the peak point, I could smack myself in the head for not doing that -- because that was -- those were too terrible days.

Sounds horrible.

Yes.

So next question is also for you. Can you describe how an attack usually occurs? What's going on in your head when you feel one coming on?

The pattern is always the same. And it starts with a tingling sensation, a tingling feeling and after that comes my denial, so I try to say to myself, but I don't think it's an attack, which always follows the same process. And in the end, if it ends up being an attack, it starts to swell. First, in my hand, feels kind of heavy. And then at the end, it will become like almost balloon sized and really try -- really starts to hurt before going into -- before the attack into a remission again. It sometimes comes to the point that it's like my hand is 3 or 4 times the size it normally is. And at that peak point, it's really painful.

Next question is for Dr. Cohn. Is there a different treatment regimen for treating hereditary angioedema and nonhereditary acute attacks of angioedema?

So that's an excellent question and very important. Indeed, the most common form of angioedema is the allergic form of angioedema, which responds really well to antihistamines, which are anti-allergy therapies or corticosteroids or Adrenalin. And typically, all these treatments do not have any success in patients with hereditary angioedema. So this can lead to dangerous situations where patients with hereditary angioedema are receiving treatments that do not work in them. So therefore, establishing the diagnosis is of at-most importance to also have an approved and adequate treatment of these patients.

Thank you. Any final questions? I don't see anything else on our board here. If there are no other questions, do you guys have any final words that you'd like to put out there?

So I would like to thank you once again for this discussion. I apologize that the connection was lost for a few moments. And I'd like to create awareness amongst any physician and also patients because there are several reasons why the diagnosis is delayed for so long. It's, of course, a very rare disease. And there are other forms that also cause abdominal pain or maybe even swellings. And therefore, the diagnosis frequently missed. There are so many specialists out there that need to think about HAE. These are gastroenterologists, pediatricians and general physicians, emergency doctors, surgeons, if there is an acute abdominal attack. And I -- and actually maybe also even patients. Because patients, I can imagine if parents have, for instance, a child with a swollen hand that they may be reluctant to seek medical advice in fear of thinking that abuse would have led to this swollen hand for instance. So I think awareness is the key word in this session.

Thank you. [ Mitch ], any final words?

Yes, I do totally agree, Danny. And it's just really nice and gives much confidence to hear those things. And to participate in this webinar, creating that awareness. If I look back in the last 20 years, we really had some nice steps, and my treatment regimen has changed. So Danny, I really hope that the future does look bright in that case and that I can partially get my personal life back, but, of course, also for the other patients and the patients who are not diagnosed that there's more awareness for the disease. And I hope everyone participating in this webinar wants to help us spread the word.

Well, I can't thank you guys enough. This has really been fantastic. And thank you for sharing your perspectives on what it's like living with HAE or treating HAE. It's really been an incredible conversation, and I'm sure it's one that we're going to continue into the future. Thank you to the audience for joining us today. I hope it's been informative to all of you. So just as a note, our next rare disease webinar will focus on acromegaly, which is a hormonal disease that results from excessive production of growth hormone in adults. So until next time, everybody be well, be safe. Take care.