From Partnered ASO Therapies To A Wholly-Owned Pipeline With Ionis's Brett Monia, Ph.D.

On this week's episode of the Business of Biotech, Brett Monia, Ph.D., CEO at Ionis Pharmaceuticals, talks about how antisense oligonucleotides (ASO) graduated from a late-1980s lab concept to real RNA-targeting medicines, and why Ionis stuck with a difficult modality despite multiple setbacks. Brett describes the company's shift from a partner-first model to building a wholly-owned pipeline, commercial function, and an expanded manufacturing operation, and how he as a founding scientist-turned-CEO bridged a skills gap in finance and investor relations. 

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Transcript

Welcome And Guest Introduction

Ben Comer 0:03

Welcome back to the Business of Biotech. I'm your host, Ben Comer, Chief Editor at Life Science Leader, and today I'm speaking with Brett Monia, Ph.D., founding scientist, CEO, and board member at Ionis, an RNA therapeutics company and pioneer of antisense oligonucleotide therapies or ASOs. Brett became CEO in 2020, succeeding longtime CEO Stanley Crooke, and I'm excited to speak with him about his journey to the CEO chair and the strategy he put in place as the company's leader, what's unique about ASO therapies and what challenges they present, how Ionis shifted its focus from partnered therapies to a wholly- owned pipeline with commercialization capabilities, and what's next for the company. Thank you so much for being here, Brett. It's great to be here, Ben.

Brett Monia, Ph.D. 0:56

I'm really looking forward to the conversation.

Falling In Love With Antisense

Ben Comer 0:58

Well, I'm glad to have you. Um, I want to start off with uh some background, Brett. You received uh a PhD in pharmacology from the University of Pennsylvania School of Medicine. You did a postdoc fellowship with Smith, Kline & French, now Glaxo Smith Kline, of course. What initially sparked your interest in anti-sense oligonucleotide technology?

Brett Monia, Ph.D. 1:24

Um, yeah, uh it's it's uh um something I've always been very excited about that is to be in the pharmaceutical business. You know, I've always had a love for science throughout high school and so on. And and I always wanted to um be um part of applying science to for drug discovery for human therapeutics. Um that's always been the case. Um, you know, when I was growing up in high school through the 70s, biotech was undergoing a revolution. It was it was exploding. And uh it got me very excited. And I, you know, I made the decision that I wanted to go to graduate school, college, and then graduate school for um to apply that, uh, to apply biotech for drug discovery. Um, and you know, I went to undergrad and got dual degrees to help support that in one in chemistry, one in molecular biology. And then I went to the University of Pennsylvania um uh seeking a pharmacology degree, as you mentioned, um uh a PhD, uh, because I thought that would be the you know the right, the right course to do what I wanted to do. But I chose Penn, you know, Ben, um uh out of several opportunities that I had purposefully to help uh augment accelerate my my uh introduction to biotech. And and that is because I recognized that um uh they had a uh adjunct uh relationship with several professors at the Smith Klein of French at the time, which is now Glaxo Smith Klein, as you mentioned. And the um the head of uh the president of R&D was Stanley Crooke at Smith Kline. He was also an adjunct professor at at the University of Pennsylvania. So I said, wow, what better opportunity would I have to get exposure to biotech in pharmaceuticals in that case, but to, you know, to to get in the in the industry and some exposure. Uh if I could do that, if we can, you know, get along and have a have a good relationship. And and that's what happened. Uh we have we we forged a fantastic relationship. Um uh I did did my Ph.D. with Stan um uh at the University of Pennsylvania, doing most of my lab work at Smith Kline at the time. And um, and you know, uh one of the things we were doing, uh, well, first of all, the the the on concept of antisense technology was really taking off at the time. Like people were really, really recognizing that this could be a paradigm shift.

Ben Comer 3:46

Like And this was the what, the late 80s?

Founding Ionis In The Late 80s

Brett Monia, Ph.D. 3:49

Yes. Uh this was the late 80s. And and it rec and it looked like a potential paradigm shift uh in drug discovery. Do something entirely different. Instead of targeting proteins with small molecules or antibodies, uh, maybe we could target RNA, the messenger, that can coach for the proteins. And um, and you know what? Uh we were actually doing some of the first anti-sense experiments in the labs at Smith Klein at the time because we were beta testing some of the first ever DNA synthesizers. So we were making little segments of DNA and testing them uh for their ability to conduct anti-sense effects in cell culture and so on. It got me really excited. Uh, and um the potential was enormous uh for human therapeutics, and Stan decided to start a company and he and he invited me to help join it as a founding scientist.

Ben Comer 4:40

Well, that answers my question about uh how you met Stanley Crooke. Um, for listeners, he is now at the N. Lorem Foundation, uh focused on, I think what he's calling uh nano-rare diseases, so diseases that are affecting a very small number of people. Um so you you met you met Stanley uh and you you moved out to California as founding as founding scientist. Uh was you were you concerned at all? You know, uh were you were you scared, you know, at that point that that you know this brand new field might not pan out?

Brett Monia, Ph.D. 5:15

Um I wouldn't say scared, but certainly I recognize that the um the hurdles were enormous, right? We were really starting from a blank piece of paper, if you will, like right from the beginning. Um, although, as I mentioned, there was a lot of excitement about the concept of targeting RNA for human therapeutics, anti sense. Um uh nothing was known with respect to um whether the drugs would work, whether they would get into cells, how to manufacture them, what is the proper medicinal chemistry? Will they be toxic? Will the will there be safety concerns? Um, how potent can they be? Can we manufacture them at scale if we are successful? And so on. Absolutely zero was known. So I recognized that. Um, and I I so I recognized that the hurdles would be um were enormous. But I also recognized the fact that um we had a crop of core scientists that led to the foundation of ISIS Pharmaceuticals, which is now Ionis. That was our original name.

Ben Comer 6:14

Right.

Brett Monia, Ph.D. 6:15

Um, and I knew that if anyone would be able to do to do it, to do the right experiments, to turn over every rock and to understand what the limitations were and to be able to address those limitations, I felt we had the right group. And at the very least, I knew that we were going to do the right stuff to to test the hypothesis of whether antisense can work or not. And we were gonna do great science together. Um it was hard, it was very hard uh for decades. Uh the expectations that this was gonna be the magic bullet for for human diseases, chronic diseases, um, the the expectations were um off the charts uh and unrealistic, of course. Uh we had to create something that had never been done before. Um and no and we were pretty much doing it alone. Um so it took a long time. We had we had a lot of setbacks, very significant setbacks. There are times at which we didn't know if we were gonna be able to keep the lights on in the company. We were gonna be able to fund the company. Um we had, I'm sure we had reservations of whether we were going down the right path. Um, but we persevered and uh we continued and we had we finally got some breakthroughs and and we proved for the first time that antisense can work and it can work very effectively in humans, and we've since then have continued to optimize, uh modify and optimize, further refine the platform to to you know improve drug-like properties across the board. And and today we've proven it, and um and the and the proof is in the the tremendously effective medicines that are changing the course of the course for human disease across many different diseases. So we're very proud of that, but we still but with that said, we still have a lot more to do.

Ben Comer 8:04

Yeah, right. Uh so ISIS was was founded as a company, I think went public pretty shortly after that, right? Like a year or two later after it was founded, the company went public. Is that is that correct?

Brett Monia, Ph.D. 8:16

Yeah, about two years later, I believe it was 1991. We were founded in 1989.

Ben Comer 8:21

And um I wonder if you could say maybe a little bit more of some of the kind of initial challenges that you faced. Maybe, you know, uh it could have just been scientifically, you know, exploring these, you know, brand new drug modality. Uh you don't know exactly what's going to happen in in early clinical trials. Um, but we're, you know, what give me a sense of like what some of those initial obstacles uh were that that you guys faced early on in the company.

Brett Monia, Ph.D. 8:49

Sure. Um uh scientifically, I mean, obviously financially, we had to finance the company, but scientifically, um uh boy, where to begin? There are so many obstacles. Let me back up a little bit, Ben. Um so the the idea of anti sense, the concept of antisense is focused on RNA, like we talked about. Um uh what we're using are small snippets of chemically modified DNA or RNA that bind to RNA through a hybridization mechanism with tremendously high fidelity, right? Specificity. Um and and the idea was that if we bind the RNA, we can tackle the RNA and prevent it from producing a protein um that is toxic uh to the cell, causes a disease, right? Um and uh there are many advantages to that, potentially theoretical at the time, but what we didn't know is whether or not I think one of the biggest the problems was trip challenges was whether they would actually get into cells. Um uh so we can we can show that mechanism can work in a cell-free system, but will it actually get into cells? Um what cell types do they get into effectively if they do get into cells? Once they bind to that RNA, what happens? Right? Binding is nice, but does it destroy the RNA? Does it block the RNA from translating the the genetic code into protein? Um and um and are are they safe? You know, when you when you inject them into animals, um, will they be safe? Uh we don't know. Will they elicit an immune response that could be catastrophic? Um and then last thing I'll touch on is and and I mentioned this very briefly before, uh if we are successful, how can we m scale this? How can we make kilos of these molecules that are cost effective um, you know, for the industry and so on? So um it was a slog. Um, but uh but it you know, but we we per we persevered.

Ben Comer 10:51

Well, to stay at it for as long as you have, you you must have uh you must have found it really compelling to be working in this at the time white space. I mean, was there ever a moment where you felt like you know we we could develop a small molecule or or an antibody or and you know follow some kind of well-tread paths uh to to market? I mean, you must have you must have found it compelling to be operating in this space where really you you were having to pioneer it uh your yourselves.

Brett Monia, Ph.D. 11:21

Yeah. No, we never really um uh we we never talked about um changing course small molecules and bodies. Other companies did. Um, you know, one of our our fiercest competitor at the time, um, you this may come as a surprise to you. Um in the antisense field was Gilead uh science. Really? Yeah. Uh it got hard, they quit. And they're a very successful small molecule uh company today. Absolutely. Uh, but they didn't create a new paradigm for, you know, like like a drug discovery paradigm. Um, I give Stan a lot of credit for keeping us focused on um uh we're gonna we're gonna see this through. We're if um if if anyone is gonna do this, it's gonna be us because no one else is everyone else has given up. Um so we persevered. No, we never we never considered changing course. Uh as I mentioned, there were times in which we didn't know if we were gonna be successful and we didn't know if um we can finance the company because as I said, the original uh um expectations were just you know off the charts and and unreasonable. Um and and and I since fell out of favor um eventually after a few years uh because we had so much to understand and to to to learn. Um uh but we've stuck with it and and that perseverance paid off. I mean, you know, we we've delivered some breakthrough medicines and we're on we're on the verge of so many more for diseases that have no treatment uh had no treatment options prior to the delivery, you know, what Anisense has been able to deliver.

Why Ionis Never Switched Modalities

Ben Comer 13:00

Yeah, I and I want to talk a little bit about that in a few minutes. You you guys have um six products on the market, six marketed products that that were discovered and and maybe initially developed at Ionis today. Is that is that number right?

Brett Monia, Ph.D. 13:15

Yeah, that's correct. Um, and uh we're expecting um three more drug approvals this year.

Ben Comer 13:22

Wow, okay. And uh the the other name that uh I think of when I think about uh pioneering um companies working in this space uh is Al nylam. And I think they are a little bit different from you in in terms of their focus. I don't think it's ASO with them, but um, and I I know that you've worked with uh Al nylam and even spun out a company, Regulus, that I think was acquired by Novartis for $1.7 billion uh not too long ago. Um give me just uh from you know, for my information, what what's the difference, I guess, between Al nylam's focus and and Ionis's focus?

ASO Versus siRNA And What’s Next

Brett Monia, Ph.D. 14:00

Uh so Alnylam was founded um to cre to pursue a uh a similar approach um called siRNA, not antisense uh um oligonucleotides, but siRNA, um, which works very similarly to antisense oligonucleotides. It binds the the RNA, it targets the RNA through Watson Crick hybridization, high fidelity, as I mentioned before, but um it ends up um causing the degradation of the RNA, the target RNA, through a different mechanism than what antisense oligonucleotides do. Antisense oligonucleotides promote the degradation through a different mechanism called RNase H. siRNA uses a mechanism called RISC. Um however, there are far more similarities uh between the two mechanisms than there are differences, how they work, how you manufacture them, their distribution, getting them into cells, and so on and so forth. Um, you know, uh at Ionis today, uh, we actually uh because there are there are so many similarities um uh between the the two technologies, um, and there could be advantages for one over the other for specific applications, and there could be advantages for the other for specific applications, that I made a decision back in um when I moved into the CEO role to expand and diversify our drug discovery capabilities to not only include um anti sense, to improve upon antisense through new chemistries and and and and and more, um, but to also expand it to siRNA as well. So we have several SIs, siRNAs in the clinic today that were where we think that they could offer better um a better profile over an antisense drug, vice versa. We have antisense drugs that offer better profile than SIs. And we're also beginning to delve into gene editing. Um, because again, um there are there are far more similarities between these approaches than there are differences. And you know, I'm biased, I'll tell you, Ben, but I believe that we have the greatest research organization in oligonucleotide therapeutics, uh bar none. And um when I made that decision, it was like uh releasing the hounds. Uh the medicinal chemists, the biologists, uh everybody, manufacturing, dev/chem, uh just ran it, ran with it. And and I think we're making some of the greatest progress in all these areas um uh today uh uh for for you know for discovery and development of new drugs.

The Path From Scientist To CEO

Ben Comer 16:31

When did you know, Brett, uh, that you wanted to move uh from a very science-focused RD role and your you know, your your title grew, you you were promoted into uh you know higher and higher levels of responsibility throughout your time uh over these years. But at what point did you realize that you had something to offer as a leader, as CEO of the company?

Brett Monia, Ph.D. 16:56

Uh yeah, that's a great question. Um so um, you know, as you said, my my roles at Ionis um grew um uh and expanded uh very very quickly and and substantially over the many years I've been here. You know, I began by creating the our first formal drug discovery group, um, identifying those tissues, those cell types where our drugs work best and pursuing them. Uh that essentially created the pipeline that we have today um uh and set the foundation for the continued growth of that pipeline. Um, as you say, development, I I um my experience in development um expanded substantially. I ran several phase three programs that were successful. Um in addition, uh I mentioned earlier about some of the challenges we had in financing the company over the years. Uh um to support and finance the drug discovery programs that I was really, really um uh attached to, that I was really excited about, I went out and did business development. I I started uh the you know, I created the foundation for most of our partnerships today uh because I needed we needed the money to fund those programs. Uh my point is that my role uh, and I never left research. So my role uh expanded into business, into development, into research over the years. Um and um and it was about 2017, I think it was, that um Stan was uh was talking about um uh stepping down as CEO, retiring. And um, and he was kind of like uh, if you will, a little bit coy. Um, but I think he had me in mind the whole time. And but he was he never directly asked me. He was just saying, what do you think about potential successors and this kind of thing? I think he was waiting for me to raise my hand. Yeah, which um eventually I just like it was becoming so obvious uh that I that I said, okay, yeah, um let's talk about this more directly. Um I actually was not that thrilled with the opportunity uh at the beginning because I saw myself as a chief scientific officer or head of RD and you know, at Ionis or something like that. Um, but the more and more I thought about it, and then the rest of the board approached me and they got it, you know, they were very encouraging for me to strongly consider this. They recognized the long-standing experience I had at Ionis and RD and business um development and so on. That um I um, you know, I give it a lot of thought, obviously. And I started to begin to think that um with their encouragement, that maybe I could make a difference. Maybe I could take Ionis to a new level, um, at least pursue some new things um that could really great bring great value to patients, to the um uh clinical medicine, um, as well as to Ionis. So I think it was announced in 2018 that I would be the successor, and I spent a couple of years working on plans, getting to know, filling the gaps that um I had um that I would need to uh you know, need to be capable of for in a CEO role investing.

Learning Finance And Investor Expectations

Ben Comer 20:20

Yeah, what were what were some of those gaps? What were things that you felt like you needed to develop before, you know, becoming CEO?

Brett Monia, Ph.D. 20:26

I needed to improve my financial um uh capabilities, experiences, like so running an organization from a financial standpoint, and I needed to um uh really understand the investor community much, much better. Um those are the two big ones. So I moved into a chief operating officer role um uh and uh got out on the road and and and met with investors, listened to them, what were their concerns, what did they like about the company. And I worked very closely with our chief financial officer um to really understand the financing needs of the company and and so on, and of course with Stan during that time. Um and um uh and while while continuing to, you know, oversee uh many development programs, research, and and and so on. So um those were the key gaps. Um and then uh when 2020, you know, and I and I felt like um I was prepared to make some changes to the company when I moved into the uh role of CEO in 2020.

Ben Comer 21:26

Yeah, let's let's talk about well uh before I ask you about you know your strategy coming into the CEO role and and the changes that that you wanted to make, I'm curious about, you know, did you did you enjoy the the financial aspect, getting, you know, getting to know the investor community? And and I ask this because I've I've spoken to a number of CEOs that come up, you know, on the scientific side of the house, and it's really a mixed bag. I I get some who will say, you know, I I have this right hand man or right hand woman who is really my uh my business mind and helps me out with a stuff because it's it's very different functions and and requires very different skills and and then i've talked to others who who really uh really enjoyed it found that they and you know liked learning that part of the business and and excelled at it and i'm i'm wondering kind of where you where you sit on that uh was it is is that part of the job uh something that that you find it enjoyable or is it do you see it more as just you know an an extremely important function of of growing a company um I didn't love it like I loved research and development uh Ben but um I greatly appreciated the importance of it and I learned a lot and I was I was lucky enough and fortunate enough to have um r really really experienced people to show me the way um particularly on the financing side um I had a you know a highly supportive board of directors with strong financing um experience I outstanding chief financial officer Beth Haugen I worked very closely with she taught me a great deal and on the investor uh side of things um uh there was a little bit different I was thirsty to understand what the feedback was what the thoughts were um from the investor community with respect to what they felt uh was working well at Ionis and um what um they thought that we we need to do a better job um to to create even greater value for the company.

Brett Monia, Ph.D. 23:28

Um I learned a great deal there uh do I love investor um relations I have a tremendous respect for our investors and our and our analysts analysts are very smart people and I and I as I said I learned a lot from them it's not my favorite part of the job um I'm still a scientist at heart and I love research and I love what we're doing in research and I love clinical development um but um but but you know I took it seriously and I I think that I I built really good capabilities on the finance side of thing in in in the investor community.

Ending The Partner Everything Model

Ben Comer 24:00

Well I'm sure it helps going out to investors you know when you have this kind of passion and belief in in the science that you're developing at at the company it's like you know it's much easier for for salesmen when they're selling a product that that they actually like guys that you know that your experience that that kind of helps uh helps bring you into those rooms when you know you know what that money could mean for your programs.

Brett Monia, Ph.D. 24:23

Yeah it it does uh the passion of course matters a great deal to them but the investor community wants wants uh wants you to deliver yeah right passion's nice promises are nice uh you got to deliver and um you know we're delivering today so they're they're all very happy um but the for those early years were were tough um in my in my role as as as CEO you know um uh we pursued a a brand new uh approach yeah let's talk about that what what were the changes that you wanted to institute coming into the CEO role yeah yeah so um that during that two year transition period as I referred to before um um I learned a great deal uh I I did a lot of homework on um what I felt was um holding our holding us back um why weren't all the medicines getting to patients that we conceive and discover um uh you know or getting there as as quickly as they should um why weren't we being um getting the valuation for the company that I felt we deserve um I saw advice from anyone who would give it but I I I proactively saw advice from leaders in biotech several leaders from different companies um from my board of directors from anyone who would who would who would answer questions that I had even the investor community analysts and so on um and um and the other thing is is I was I was I I really felt like um our previous business model was letting us down um you know as I said um uh well our our previous business model was to partner all of our programs right every every drug was partner was was a partner there was nothing being wholly developed internally to keep our I own as an RD company our development capabilities were really focused on early development but research and early development um and uh to partner all of our programs um and to do and and and the rationale uh you know I get it uh it it was it was I understood it and it made some sense that um we wanted to keep uh Stan wanted to keep the company small uh preserve the culture uh keep it a science driven company I totally respected all that um but I also um uh felt that um too many times our partners were letting us down Ben. I could I there I I don't want to get into specifics, but we've you know and these were drug discovery programs in many cases that I started running drug discovery and then developing these programs and we were first to deliver new medicines and um you know priorities change in large large pharmaceutical companies all the time and new CEO Yeah having nothing to necessarily to do with the science of that program.

Ben Comer 27:16

It could just be priorities the you know portfolio shifts, etc.

Launch Planning And Commercial Sticker Shock

Brett Monia, Ph.D. 27:21

Right. Um the new CEO comes in, changes priorities, new strategy we're out of that area, we're into a new area and that kind of thing. Oh it was too many times um I felt really left at the altar that um our drug didn't make it to patients. That was the number one thing. The second thing was the valuation for the company because you know when you rely on partnerships that's highly de-risking right you're not taking the phase three risk and the commercial risk but you're also uh not getting the valuation that the company deserves and of course with greater valuation then allows you to invest in more science. That was my rationale make more money invest in more science uh build a pipeline. So um uh moving into my CEO role I felt that I needed to um change the business model um to to build a um fully integrated biotech company right to build our commercial capabilities and to deliver the medicines that we conceive and discover directly to patients ourselves and not rely and depend on others to do so. That was um uh not what the board was expecting they did not um ask me in 2018 2019 to to be could move into this EO role because of my commercial uh excellence uh I had none I had no experience but um I also felt that honestly and and is that hell if we can create a new paradigm for drug discovery and do all the great science we're doing at Ionis, we could tackle commercialization too. How hard could it be? Well it was hard. Um and um but you know um I felt that we needed to do this in a measured manner take steps I I I said and and this was my pitch to the board was that we well for all those reasons I just laid out we need to do this it's and the time is right the culture is strong the science is proven um uh let's do it and um uh and I also recognize that the board didn't choose me because of my you know my commercial experience but they also had a lot of faith in me and and and that I that I I I can get it done. So I I was able to bring in some outstanding talent um and uh they had a great deal of experience in uh building a commercial organization as well as commercializing products and um uh you know it was a long haul it took about five years uh not only to build those capabilities and bring in the talent that we needed the talent was a very attracted to IMS because we have such a big pipeline right we're not a one and done company so that they see in this you know science and value there. Um so I was able to do that um but also um you know uh to to not only build the organization but to have have people with a pedigree of being able to deliver uh first-time treatments for for diseases and and and to be um uh successful there um but also and then I'll also add to that is um with a laser focus on bringing in experienced commercial people with a appreciation for culture for culture and science um which is in which is the you know which is what re which is the um foundation of the company so uh it took um obviously all of our par programs were partnered at the time or most of them were we had to build a strategy to build our wholly owned pipeline uh over time to not partner them and have the have the have the will not to partner because it's so inherent in our DNA because we've been doing it for very effectively for so many years. But to really uh you know not partner to build a wholly owned pipeline to focus on specific therapeutic areas where our drugs work best so we could and and and so that we can build experience in a therapeutic area. We selected cardiometabolic diseases and neurology um uh and that has paid off really well flash forward five years of building the organization and building the holy owned pipeline we launched our first two independent medicines last year um one for familial cholomicronemia syndrome FCS the first ever FDA approved medicine for this devastating genetic disease and a prophylactic treatment uh and that drug is Tringolza and uh and Donzera uh we launched in August of last year which is a is a prophylactic treatment for another genetic rare disease called hereditary angioedema and those launches are off to great starts and we're expecting two more launches this year um I wonder uh what your first experiences with commercialization were like you know it we've everybody has seen the statistic you know more than half of drug launches don't meet expectations I mean what what were some of the surprises some of the initial challenges with uh that first experience is with you know commercializing your own products well my first experience was was sticker shock on the budget yeah wow we gotta have to build all kinds I thought we were just gonna hire some salespeople um little did I know that all the all the backroom work and capabilities that needed to be developed and uh as well as medical affairs and commercial supply chain and all that it was a it was a you know a big ask from a financial stand uh position um but um you know the as far as the experiences uh uh leading up to um the launch uh how much planning was required with uh you know to identify to to establish a strategy that was going to be effective enough um and to in to support you know success on the launch to getting these drugs to patients um to um identifying those centers those sites where that are managing the patients most effectively pricing uh you know reason um uh responsible pricing uh commer as I mentioned commercial supply was a big thing um uh that we needed to sort out and so on.

Ben Comer 33:23

Those were the biggest challenges but again I I was able to hire some really smart and experienced people um and I was able to work very closely with them and you know we didn't make all the right decisions but we made most of the decisions we made were the right ones and including the prioritization of the wholly owned medicines that we um elected to bring forward first which um you know when you do bring forward uh either a drug for a devastating disease um that's really having an impact on improving the lives of patients um it that helps a lot uh the launch right yeah we're not we're not developing me too drugs we're developing first time drugs or if it's not the first time to a market to tackle uh a a terrible disease it's it's addressing the and the the the needs of the patient where there's uh big gaps in in in in their in in the currently available treatments um for patients and when you do that that certainly helps the launch a lot because there's so much demand for for the drug what about the the manufacturing side I mean was that uh when you decided to make this shift to to a wholly owned uh internal pipeline that you're gonna develop and commercialize yourself did that did that change uh your your manufacturing in terms of what you had to do I mean were were your partners previously doing the bulk of manufacturing how did you how did you manage that?

Brett Monia, Ph.D. 34:51

Yeah so um you know we created the manufacturing um uh if you will sector for oligonucleotide therapeutics after decades and decades of of research into development chemistry, manufacturing and so on but our focus um was almost entirely for decades on supporting our clinical trials and supporting our research organization. So not commercial scale manufacturing commercial scale manufacturing um uh but you know and our and like you said our our partners where we partnered our programs were responsible for commercializing or you know commercial supply for the drugs that they licensed from us.

Winning Over Investors With Real Proof

Ben Comer 35:32

We had to um you know build those capabilities I mean we had the right people uh we certainly have the right people very smart and experienced people in manufacturing and we built um a an entire network of uh relationships strong relationships with with with CMOs manufacturing organizations around the globe US Europe Asia um so we were able to tap into all those experiences and uh relationships to then you know take it to the next step um the initial launches and uh and rare diseases were had its challenges supply chain and so on but we were able to handle it but those quantities were relatively low we're on the brink of launching into a um our first um disease indication that um is very very highly is highly prevalent millions of people in the United States alone for a disease called severe hypotriglyceridemia commercial supply just um uh the demands on commercial supply and the challenges just increase tenfold at least um uh we're on it we got it covered but we have to bring in a lot more people um and and and to really build on things that um uh build on things that we established previously and extend on those things to make sure that we're um being able to supply you know drug for millions of people um uh in the US alone um so um um it was a it's been a big challenge but I'm pleased to say that we have the right people and uh we're in a good position to be able to to to satisfy our our commercial supply needs well I mean the investment community uh seems to uh agree you know I I looked up uh uh Ionis's stock price yesterday just year over year it's up a hundred and and sixty percent uh from from the middle of last April and I'm curious about you know when you announced this strategy becoming CEO announced the wholly owned pipeline was that an immediate positive reaction from the investment community or or did it take some time you know did they kind of wait and see if you were going to be able to build this commercial organization scale up manufacturing how how did that play out uh they loved the words but it was a wait and see yeah yeah okay 30 years of of of basically you know not um uh you know emphasizing that um commercialization is not in our future um to change that mindset around and again i I'm not a I'm not a former chief commercial officer Ben right so it's not like oh look at this guy's track record yeah right right um so it was a wait and see it was a wait and see are you really gonna do it and are you gonna be successful um that changed really last year with the successful uh launches of of Trinco's uh in Don Sera and then um with several phase three readouts that um came out last year that were very positive which also sets us up um well from a commercial standpoint because again uh we're in a position to be first to market when you're first to market it's it's obvious um it's a hell of a lot easier to commercialize products that are are disease changing really impacting patients benefiting patients and your first um and that's what we we expect to be um uh this year with the with the two additional watches that I referred to can you give me a sense of uh how large your commercial organization is I guess just in terms of of people and then are you in in the process right now of of scaling that up for the the larger indication?

Brett Monia, Ph.D. 39:17

So the sales team is about a few hundred people about 300 people right now um and they're commercializing um uh two products today with the expectation um to commercialize um two more by the end of this year um the large indication that I referred to earlier severe hypertriglyceridemia that affects millions of people in the United States these are people that are at high risk for cardiovascular disease and most notably um they're at very high risk for a potentially fatal acute pancreatitis attack that causes destruction of the pancreas and so on. No effective treatments today for this disease. We made the decision um uh last year to hire our sales force for SHTG before approval um to do that in January of this year so that this team could be um fully prepared to take advantage of the this this really large launch that was coming up and we were confident we would get approval um uh based on the compelling data that we presented at the American Heart Association last year. But the other thing is is that this large indication is a is related to um the the earlier indication for the same drug that I referred to before familial chymomicronemia syndrome, a rare genetic disease. Both patient populations suffer from severely elevated triglycerides just one is genetic and rare and the other is common in non no known genetic causes that affect millions. So it's not like we were going from one disease brand to a brand new these these the sales team was able to now continue to promote FCS uh commercialization while educating on severe hypertriglyceredemia and getting ready for this launch. As we were hoping for um not only are we on track to get um an on time approval this year, we received priority review by the FDA which accelerated the approval and launch uh if everything you know assuming everything goes well by four months with a June uh Padufa date of approval date um of this year. So um uh across all the indications we're about 300 people in in in sales and and again we're just focused on the U.S. market um for IONAS commercialization today um I forget if I mentioned that before but that was also part of the plan for a measured careful approach it's a it's an approach to focus on the U.S. market first before expanding outside the U.S. Other companies biotechs have done the same and we'll expand eventually we have partners for outside the US but for the U.S.

Ben Comer 41:56

it's about 300 people or so um and we're full we don't expect um significantly more hires uh this year for the two additional launches that are coming SHTG and our neurology drug um I want to ask about uh FDA well it sounds like you have a a a really good relationship with FDA given you know what you've just said and the accelerated approval uh and and fidufa date in June um at I guess a macro level there is still some ongoing debate uh some states you know have proposed legislation uh that would block certain mRNA therapies um for the most part vaccines although some of the states kind of say RNA therapeutics broadly other I guess portions of the population who are concerned about this portions of of the US the current administration that that are sort of concerned about this uh can can you speak to that at all Brett is Ionis uh you know are your products ever kind of caught up into this this larger uh debate about you know the safety of of RNA therapeutics or vaccines?

Brett Monia, Ph.D. 43:05

Yeah we're disappointed in the attitude um that has um that has emerged for you know in in some areas of by some people on um the negative play that has happened against um vaccines that are vaccines that are created by through RNA therapeutics. Um I don't believe that that's a criticism of RNA specifically it's just that that was really what tackled the COVID pandemic right was the efficiency of RNA-based vaccine development um allowed the creation of a vaccine in record time. Um it's more about people's uh some people's um uh lack of support for vaccinations, vaccines. So they just link it to RNA but that vaccine is a vaccine whether it's RNA derived or not I think that's really the issue. We were concerned that some of that would have a negative Impact on Ionis. But we took measures to counter that because we're not a vaccine company. We're not using RNA to create vaccines. We're actually targeting RNA. That's why we emphasize we our platform is RNA targeting. We modulate the function of RNA, but we don't use RNA to create vaccines. And we haven't had that much of a negative impact. Luckily so we prepared ourselves, but we haven't been caught up in in that to date. So that's a good thing. But again, I I you know I it's unfortunate that um RNA, um, even for even in the vaccine world, has um in certain areas, certain sectors of of the community have uh have been are viewed negatively when it's incredibly positive. Um the efficiencies that uh it delivers on the creation of new vaccines is is just remarkable.

Ben Comer 44:56

How are the uh the Ionis products generally administered?

Brett Monia, Ph.D. 45:01

Um using a um uh today uh we are administering them in two ways. Uh uh as I mentioned earlier, we have our cardiometabolic um programs, franchise pipeline, and our neurology um um drugs. Um we have um uh um for the approved products uh in the cardiometabolic space, they're administered um subcutaneously using a simple like uh auto injector that you don't even see the needle. Um and we admit and they are administered by the patient themselves.

Ben Comer 45:35

Oh, okay.

Brett Monia, Ph.D. 45:36

But using um uh a frequency of once per month, once every two months. And based on advancements we're making in the technology, uh that's gonna go to every six months or maybe once per year subcutaneous treatment. In the neurology space, uh they're administered directly to the CNS um into the uh um into the spinal cord using a procedure called intrathecal administration. That is because uh these drugs, SIRNA or ASOs, do not cross the protection that uh that protects the brain, the uh a structure called the blood-brain barrier. Uh it keeps out larger molecules. Uh so we administer them directly to the CNS using intrathecal administration. Um and today we're uh similarly, because of the advancements we've made in intrathecal administration, there are two approved products in the CNF space that came from Ionis, one for ALS and one for spinomuscular atrophy, um, and many more coming. Um we're now moving towards twice a year, once per year dosing for intrathecal administration as well. But we we're not stopping there. We have made tremendous progress in our research organization that is supporting our ability to administer subcutaneously, just like the cardiometabolic drugs, and overcoming fooling, tricking the blood-brain barrier to allow in our drugs into the CNS. Um, and we actually are now um have selected our first molecules that we think will work uh by sub Q for the CNS. Um, and they are marching towards clinical testing uh imminently.

When Partnerships Still Make Sense

Ben Comer 47:17

Um I want, I know that you're now um your priority is your your wholly owned pipeline, but I I do want to ask about partner strategy simply because uh there are a number of biotech companies out there today with the platform technology that would love to have some of the kinds of blue chip partnerships with some of the largest pharmaceutical companies in the world that that you've managed to have and still have uh over the years. Um what would you say about Ionis's success uh in in that context in terms of partnering and and maybe how you decide which assets to partner versus develop? And it sounds like most of the the new assets are are being you know moving straight into the wholly owned pipeline. But what what would you say about the the sick the the really successful uh I think it's fair to say partnership strategy that that Ionis has has done over the years?

Brett Monia, Ph.D. 48:12

Um yeah, for decades, uh all of the drugs that we conceived in and move forward from our research organization were intended to be partnered at some point. Um that was that was the um uh that was the business model at the time. Uh today that's completely reversed. Uh all of the drugs that we pursue in research um are intended to we're intended to bring it to the finish line ourselves. We do not work on right out of the gate that we're saying, well, we'll partner this eventually. However, um uh you know, there are all kinds of reasons why um we may choose to partner a program um at some stage during its lifetime uh in research development or or even after approval. Um uh one could be that um something else has emerged that we weren't uh unex that we weren't expecting from our research organization. Or as I referred to earlier, partners sometimes uh change priorities. And all of our partnerships um require our partners to return assets, drugs, back to us if they um if they don't move them forward in a in a timely manner. So that happens sometimes. A program could be returned to us, and we say, wow, that's a heck of a lot more, you know, that's an exciting program. And and um we may need to uh so that we live within our means, our financial means, uh, and our bandwidth, people, number of people we have, um, we may choose to uh partner something that we weren't originally planning to partner. Um that can happen too. Um uh we also do different types of partnerships. Uh you know, we're all in on technology, science, expanding ASO, SIRNA technology. Uh, we're doing partnerships with companies to in-license technology to to, you know, that has enabled some of the work I mentioned before about overcoming the blood-brain barrier, for example. Um, we also have partnerships that are different today uh for commercialization. I mentioned earlier we're focused on the U.S. market today. Um uh so we have OUS commercial partners uh that are delivering our products uh to Asia, Europe, uh, Latin America, um, and Canada. Uh uh so you know this will continue to evolve. Um, but the but you know, I could I can tell you, Ben, that um anything in our almost every drug in our whole-owned pipeline, we could partner tomorrow if we wanted to. The interest, the enthusiasm, the attractiveness of those medicines uh is not lost on the farm industry. Um we get the people knocking on our doors all the time, but we're committed to building that wholly owned pipeline and to delivering the medicines that we bring forward ourselves.

2026 Priorities And Upcoming Readouts

Ben Comer 51:02

Great, right. Well, uh that's uh that's an excellent place to be. And I would say um we're we're running short uh on time here, Brett. But uh before I let you go, I want to ask about, you know, what you're most excited about, what your top priorities are for the rest of this year. I I suspect those late stage candidates are are probably right up there at the top. But uh, and did you say potentially three uh new approvals this year? Um yeah. Well how would you uh how would you describe your priorities and and uh you know what what you're really focused on for the remainder of 2026?

Brett Monia, Ph.D. 51:38

Well, I'm most excited about Ionis. I'm most excited and and and and um really, really um uh pleased with the organization today. The the the buzz here is just uh off the charts. Um people are really excited about discovering, developing, and now delivering um our medicines directly to patients. Um uh, you know, last year when we launched our first product, Ben, despite our rich scientific history in 30 years, was the first time the Ionis brand was on a prescription box, a product box in our history. And that that has really resonated well with the with the employees. They just love it. Um uh but more to your point, um uh we're expecting, you know, we're laser focused on the three drug approvals this year, particularly two that we're in full control of, the two holy own medicines, uh severe hypertrigly triglyceridemia with a PADUFA date, an approval date in late June that I mentioned earlier. But also the approval of our first holy owned neurology drug. Um it's for a rare, uh often fatal uh genetic disease leuchodystrophy called Alexander's disease. We ex we also received priority review for that drug. Um, and we're expecting um an approval, well, we have an approval date of late September. Uh that is incredibly important for the patient community, Alexander disease um community, which has no effective uh treatments available today. But it also represents the Ionus first uh launch, whole-owned launch uh for Ionis in neurology, a therapeutic area that we have validated with delivering products like spinrasa for spinal muscular atrophy or calcati for SOD1 ALS, licensed based on the previous business model to biogen, who are doing a fine job in commercializing, but now this is our first whole-owned neurology drug. The third one that I referred to earlier is partnered. That's with Glaxo Smith Klein, um, GSK, and um it's for um chronic HPV infection, a drug that we discovered and brought forward to GSK based on the previous business model. Um, and uh they ran the phase three programs and the results were incredibly positive. The results will be presented at a conference called ESL uh in May of this year. Um, cures, functional cures in chronic HBV, something that has never been conduct done before. Um and then uh also in addition, um, we're expecting um uh four additional uh phase three readouts this year um from our partnered pipeline. Um uh one two for cardiovascular disease, uh, one with AstraZeneca for a disease called TTR cardiomyopathy, and one with Novartis for um another cause of uh cardiovascular disease, pelicarsin for LP litol age and uh cardiovascular disease. Um and then um uh lastly a phase three uh program for another cause of ALS due to mutations in a gene called FUS. So, you know, the the um the drum keeps beating. Um we're expecting three approvals this year with launches um of more late-stage pipeline readouts and mid-stage pipeline readouts. Um, and and and and that will continue through 2027 and and beyond. So we have a lot of work to do here. We're excited about doing it. Um, we're pumped up and um uh and um but we are also very focused.

Ben Comer 55:08

Well, as busy as you are, uh you made time to come on the show, and I really appreciate that, Brett. It was a pleasure speaking with you.

Brett Monia, Ph.D. 55:15

Same here, Ben. I really enjoyed it. You take care.

Ben Comer 55:18

We've been speaking with Brett Monia, PhD CEO and board member at Ionis Pharmaceuticals. I'm Ben Comer, and you've just listened to the Business of Biotech. Find us and subscribe anywhere you listen to podcasts, and be sure to check out our weekly video cast of these conversations every Monday under the Business of Biotech tab at life science leader.com. We'll see you next week, and thanks as always for listening.