It Takes a Village: Developing Treatments for Rare Disease

WEBINAR TRANSCRIPT

LAUREN: Hello, everyone, and welcome to Rare Perspectives, a new online roundtable series that is dedicated to uniting the rare disease community by fostering conversations on the unique challenges associated with diagnosing and treating rare diseases. I’m Lauren Chunn, the editorial director for Rare Perspectives, and I’m excited to have you join our first roundtable discussion on rare disease drug development and patient advocacy!
Before we get started, I encourage you to participate in the poll to let us know a bit more about you and your role in the rare disease community. In addition, you can use the questions window in the control panel to the left of the webinar screen to post any questions you have for the panelists during their discussion, which we will answer during the Q&A session as time permits. Please note that this webinar is being recorded, and you will receive a link to the on-demand recording after this event.
Now, to introduce our panelists! Today, we have with us Samantha Parker, the chief patient access officer at InnoSkel, and the vice chair of the international rare disease research consortium. Dr. Al Garfield, who is head of translational sciences and strategy at Rectify pharma. Last but certainly not least, Dr. Mark Kiel, the chief science officer and vice president of product strategy here at Genomenon. Now, I’d like to give a moment for our panelists to tell you a bit more about themselves, and why they are passionate about rare diseases. We will start with Sam — if you would like to turn on your camera and introduce yourself.

SAM: Hi, thanks! I’m Sam Parker, as was introduced. I’m chief patient access officer at InnoSkel. I’m also vice chair of the international rare disease research consortium. Passionate, I think that’s a word we come across a lot, for people that are working in the rare disease field. I certainly have been close to 25 years. I’ve been working from early-stage to commercial, from small molecules to gene therapy. If I had to think about where I wanted to put my energy in any occupation, I think, here, where there’s such a high unmet need, where we understand that rare diseases affect, often times, children, and they’re most often very severe, with little therapies currently available. Therefore, this is the area that I’ve always wanted to be in, and I’m an adamant believer that rare disease research should be conducted on principles of patient centricity, harmonization, and collaboration. That’s how I believe that we can accomplish many of the challenges that there are in rare disease still today. Thank you for inviting me to the meeting!

LAUREN: Great, thank you, Sam, and great to have you today! Al, if you would like to turn on your camera and introduce yourself as well.

AL: Hi, Lauren. Good to be back! That was a superb entry by Sam. I’m not sure I can live quite up to that. What I will say is that rare disease has been a focus of mine, professionally, scientifically, for about two decades now. I’ve had a number of different guises within that role, from the academic side, as a know-it-all phD student working on the molecular basis of genomic imprinting disorders, which are a very small, very rare subset of rare disease. Listeners may be familiar with disorders such as Prader-Willi syndrome or Engelmann Syndrome. From there, I grew into more of the industry side and novel target identification, really trying to find the entry points into the biology which are going to be important for changing disease progression, in particular, in rare pediatric forms. From there to my role now, which is now having identified a set of really valuable targets that lend themselves to the pathogenesis of rare disorders, and also as therapeutic targets. In particular, Rectify pharma focuses on a class of genes called ABC transporters.
Now, we’re trying to actually develop the chemistry that will enable us to treat those that need patient populations. Then, to where we all want to be, which is at the sharp end of the process, where we’re actually in clinical development. There, delivering precision therapeutics for patients with rare genetic forms of obesity. I’ve been lucky enough to be part of a team that delivered on the hope and the promise that, as a drug development industry, we carry for patients and for their families, and actually brought a drug to regulatory approval. To the testament of your title, the number of people that must have touched that drug — from the moment somebody conceptualized of the biology and why it was important, all the way through to actually getting the drug approved — the sheer number of people on that probably 10 year journey cannot be estimated. Or, it probably could be, but my brain isn’t big enough to be able to do it.
To Sam’s point, it is about collaboration between people with different experiences, different expertise, different focuses. We need the diversity and the passion, the different people bring for different elements of what is a very integrated, multidisciplinary process, to then deliver on the ultimate end goal. Just touching on my quote here, I think it’s two things: one, it’s organizing people, but it’s also organizing data. We live in a brave new world where there’s a lot more of that, and we really need to make sure we’re utilizing it, and it’s in the right hands of the right people, because it will transform the care of patient populations that are very often overlooked. Thank you for having me!

LAUREN: Thanks, Al! Love to have diverse perspectives on the panel, it’s great to have you here as well as Sam. Last, we’ll invite Mark to turn on his camera and introduce himself as well.

MARK: Hi. Thanks, Lauren! Beautiful introductions, both Sam and Al. I am the chief science officer and founder of Genomenon, and my background is as an MD-PhD with a focus on molecular genetic pathology, but that was a former life. Actually, for the past 10 years, beginning with the founding of Genomenon in 2013, I have been working as the chief science officer, liaising with both our clinical users as well as some of our pharmaceutical clients in maximizing the value of genetic and genomic data that we’ve amassed and we deliver through software, data, and services. I was personally motivated to found Genomenon, which is Greek, and means “born out of need,” because I myself am a rare disease patient.
You wouldn’t know to look at me now, because I benefited greatly from the work of patient advocacy groups, most notably the NFED for ectodermal dysplasia. They helped me get my smile. They worked very closely with my mother for my twin brother and I when my mom felt bereft of options. It was the first taste that I got of this collaborative nature, and the spirit that unites a lot of rare disease initiatives is this collaborative, cross-functional work. I became very interested in genetics and genomics at that stage, but particularly, with a pragmatic outlook of how to get things done. That was the inspiration for founding Genomenon. I have been fortunate enough to recruit wonderful employees like Lauren, who has worked with Al and had many conversations with Sam in the past, and who spun out this rare disease perspectives webinar.
So Lauren, thank you so much for the introduction! Sam, I’d invite you to join the round table. I will serve as the moderator. I said somewhat facetiously, I’ll try to keep up, because I know that Sam and Al have a lot to say. We rehearsed things a bit last week, and even some just this morning. There’s a lot of content to get through.
Just to set expectations for the audience, there’s three major touch points that I want to get to, and multiple details in between. I will invite questions to come in as you have them. We’ll have some time at the end for a Q&A, and we invite some audience participation, but the major touch points that we want to cover for the next half hour or so will be how drug programs and diseases of focus are selected (what are some of the parameters? what are the some some of the contingencies and challenges in selecting diseases and drug programs to go after in the context of rare disease?) as well as, as was touched on by Al and Sam, how to foster collaborations.
I have experienced in my own engagements, both with pharma and with patient advocacy groups, the vital role that patients play. I believe, Sam, you talked about patient centricity. I’ve seen that play out to the great benefit of these programs, and obviously, the patient communities. Then, finally, ending the diagnostic odyssey. I remember learning about this in my early training, the zebras in med school that you hear about quite often. It’s interesting, though, when you’re training as a medical student, the suggestion is that you pay attention to the horses first and not the zebras, and here I am, focused on the zebras, which was actually where my passion lied in med school altogether.
That’s the sort of tripartite nature of the conversation, and we’ll just see where we go. As I said, I know that our minds are full. Sam, I’d invite you to take the lead here. I’m very cheered and encouraged every time I hear about the great work that IRDiRC does. If you can describe that in some more detail, particularly, a recent and fascinating study promulgated by the Chrysalis task force that was published in Therapeutic Advances and Rare Disease. If you could touch on those two things to get the ball rolling here for our round table.

SAM: Thanks so much, Mark! Just a bit of background as well, because I’m not sure that everybody knows who IRDiRC is: IRDiRC exists to make rare disease research efforts more efficient and collaborative around the world. That’s our statement. It was founded some years ago by the European commission and the NIH, and it has 60 or 70 members, including regulatory authorities, FDA, we have task forces with EMA, with different people, with NIH, throughout the world. People that are funding into research, but also patient organizations and academics. It’s all about the collaborative nature. I love the fact that that’s something that’s come out in everything that we’ve said so far in the first few minutes.
The founders behind IRDiRC were particularly interested to see where there may be gaps in funding for drug development programs, and they wanted to understand what was influencing pharmaceutical or biotech companies into the choices they made in drug development. They did a survey and targeted interviews, so it was quite a long process. I’m coming off from work for my colleagues, because I didn’t actually do those interviews, so I’m going from publication, which was done to 38 companies. They came out with some of the prioritizations for different companies. The first one that comes out is the high patient unmet need. This is what we all said in our introduction; there’s a massive unmet need in rare diseases.
From personal experience, I do feel that this is such an important one, because it generally translates into strong collaboration with the patient organization. It also means that you can work collaboratively, you can recruit more easily to clinical trials. Because there’s such a strong unmet need, you understand that the potential for therapies is quite transformative in terms of clinical design.
The second thing that came out of this study was, if companies were looking at a particular therapy or molecule, the availability of preliminary scientific data. So that might be animal models, it might be cellular models, but I want to tag one particular thing that I’m passionate about as well, the importance of natural history and understanding of diseases. I think we’ll touch on that at different moments in this discussion, the importance of setting up natural history, but the importance also of working collaboratively in terms of natural history. There might be natural history already available in certain diseases, and it’s how you pull that together, as well as doing your own natural history study.
The third point was the lack of current treatment. That kind of joins the unmet need, but also, competitive landscape, so that’s something that companies would look at in terms of their choices in prioritizing different products.
Also — and this came a little low on the list, I thought it would be higher, but gladly it’s not— the potential for global market size. We’re talking here about the incidence and prevalence of disease. Particularly, there was a need for higher prevalence in high income countries. There was also discussion around costs of goods, I think, again, very relevant when we’re looking at very small, ultra-rare diseases and gene therapy trials, where the COGS are obviously high, and opportunities to be able to expand to other indications would be a strong motivator.
Things that came up but that were almost more general to the whole of rare diseases rather than specific to a disease area were the regulatory incentives. Also, companies would be interested if it was a drug that was developed in a therapeutic area that they were already involved in. Some economies of scope in those terms. Something that’s, I think, very warming to us all, having worked so long in this field, that the people that we work with, we do see a lot of passion in rare diseases. In general, companies considered that patient communities were the critical collaborators in quantifying the disease burden. There was an overwhelming reason that companies entered into the rare disease space. There’s a lot of things that we can learn in this panel discussion, but over to the both of you, I think you might want to build on some of those points.

MARK: Certainly. Beautiful, I recommend all of our audience members to follow the link to the publication from the Chrysalis group that Sam brought up. Al, I know that you read it, I can give you a provocative prompt if you’d like, but I bet you’ve got stuff to say abut what Sam just laid out.

AL: (LAUGHTER) Provoke me later, when we feel like we’re running out things to say! No, it was a beautiful summary of what we live with every single day in drug discovery. I come from the scientific side, so I’m always going to be earlier in the process. What I would say is, we make it about choices, but it’s actually about priorities. We have to prioritize our focus and our effort. You may be a company that is based on a particular therapeutic area, you’re a liver company, you may be a company whose expertise is in a particular target class or a particular technology.
Within that, to create the perception of that value, you’re always looking for all of the places where you can bring something transformative to bet. What you end up with, especially in my world, where I’m constantly surveying the scientific landscape to rationalize where drugs may fit best, you are trading off between options. I never want to say we take something off the table, we just have to move it further down the list so that we get successful at the beginning, and we can get to the next ones and the next ones as we learn more, as the community brings more forward. It’s about prioritization, especially in the world that I live in.
Then, the prioritization is largely based on risk. You’re trying to take risk off the table as quickly as possible, you want to be as sure as you can be that what you are doing is the right thing for the right set of patients, and ultimately that it’s going to end up working. The more we know about the patients, the more there are models out there that we know we can put our drugs into, and be able to predict what’s going to happen in the clinic, the more we understand about disease progression. To Sam’s point about natural history, those things will always rise an option further up the list.
Now, of course, at the same time, it’s not just so true for one company, it’s going to be true of every other company, so then you create competition, but actually, that’s a good thing as well. To Sam’s point, there will always be unmet need in rare diseases. With the exception of some completely curative therapies, like more modern genetic therapies, there will always be an unmet need. It’s good to have the competition. It’s good for the advocacy organizations, the patients, to have multiple things to think about, multiple companies to engage with. For me, it comes down to prioritization, and how do we prioritize as companies? Everything that Sam said is part of the calculation that we have to go through to then float the most likelihood of success further up the top.

MARK: Let’s build on that a bit. I’ll try to keep the question succinct, but also leave lots of room for conversation. I was actually not surprised either, Sam, about that scientific ballast for understanding the disease and the flavor of natural history. My world is genomic evidence, working at Genomenon. We traffic in that every day. We don’t have real direct touch points with patients, but we’re sort of behind the scenes with the evidence. In my work with patient advocacy groups and pharma alike, some of them are producing their own data. There’s opportunities to rely on data that predates you and your efforts from different researchers and different studies, versus needing to build it on your own.
I wonder — Sam first, and then Al — if you can talk to that, entering the calculus, particularly the rare and ultra-rare diseases, which don’t have a lot of scientific study behind them, who’s to be motivated to do that work and how to get that done? How to get that sort of second tier of the evidence in Al’s risk calculation replete, to make it a lucrative target?

SAM: That’s a really tough question, because it depends. I’m working at InnoSkel, at the moment, I’m working in a disease area that, really, there was nothing, there really has not been any. The only study that was published was retrospective, and there was no prospective collection. What we know from retrospective is, we’re not necessarily collecting endpoints that would be done outside of standard practice, and that’s actually what you need for clinical trial. As a company, we went in and set up our own natural history study. Then, I sit on a scientific advisory board for a patient organization, GM1 gangliosidosis, and this is a pretty rare disease. If I’m not mistaken, it’s one in 100,000, maybe one in 200,000. It’s quite a rare disease, and there’s silos of information all over the place. These natural history studies, and I’m combining retrospective, prospective into that kind of general real-world data. The silos, they’ve been developed by patient organizations. It’s been set up by academics. They’ve been set up by industry. You’ve got all these silos. Sometimes they’re looking at similar endpoints and things like that.
I think there’s now a massive piece of work, of how you pull that together in a pre-competitive space that we need to identify so that the whole of the community can benefit from that data. I don’t think I have an answer to your questioning, who should be setting it up, but I think it depends on what’s available. I just think it’s a shame to be setting up an additional natural history study when there’s already data available that hasn’t been made public. On the same side, it’s incredibly difficult for a company that invests, let’s face, it anything between two and four million into a natural history study to then say, “here you go, I’ll hand it over to my competitors.” I think we really need to think about — it’s the right thing to do, but how do we do that? How do we make that happen?

MARK: I was going to bring up the idea of better intercommunication, but you brought up a more salient challenge, this is hard work. Drug development is a business. If it’s not profitable, it’s hard to be motivated to develop drugs to treat these rare disease patients. That sort of challenges the idea that there could be collaboration, if you’ve invested time and money and energy into building out these natural history studies. It’s different, obviously, on the patient advocacy side and on the researcher side, where the intention was to get it out there, but I’ve seen both of those at play. Al, I wonder if, into that mix, you have anything to say from your perspective as an early drug discovery research-focused operant.

AL: It often takes time to get to where we know we need to be, but we can start with what we have access to earlier, and make the most of it as soon as we can. There’s a lot of places where there is organization within the clinical and the patient communities to centralize and codify data from a retrospective standpoint. Sam made the distinction between retrospective and prospective, and I think that is an important one. There is a lot to be learned from just organizing the data we already have in a way that helps, in particular, the early scientific phases. We can conclude, what is the patient population that we think we can address, scientifically, what’s the genotype-phenotype correlation that says, who are the patients, who are most at need, based on, for instance, their genetics?
As you start to get traction as a company, the risk starts to come come off the table as the energy goes up, because you’re being successful. You’ll want to put money and you’ll want to put effort into now driving those prospective efforts. Prospective natural history studies can take a very long time! Money is one thing, to sound point, but time is another. You’ve got to start them early, because you need the information to help inform when you’re getting to the point of your drug discovery process to increase your probability of success. From my end of the process, it’s “let’s organize what we already have, and make that data utile to the early phases.” Now, how we bring about industry-driven natural history studies and make sure that data is shared, that it has value for the competition, for everybody, that’s a bigger question, for somebody that’s not a scientist.

SAM: Can I add a point to what Al just said? I think, really, it’s a great point. Building on that data, something that can be done, and has been done in certain fields, is then to bring together, as you said earlier, oftentimes you’ve got several companies working in the same field or a similar field, where we can group some of the diseases together, and where people come together. It’s oftentimes driven by the patient groups. I hope I’m not skipping to the next topic.

MARK: That’s fine.

SAM: Patient groups, academics and industry, and start really looking at that data, and saying, “well, to do a clinical trial, what should the end points be?” because that’s the success of every drug development, is to have the right end points and to understand what the timing is of a clinical trial. How many clinical trials do we see that may have been better had they had different endpoints, or been designed slightly differently? If you can bring a group together then that says, “well, this is what we should be looking at, and these are the different ways that we could look at it.”
If, for example, you need to look at motor function or cognition, what are the good tools for being able to do that? Then, if you do set up your prospective natural history study, you’re using tools that we know are the ones that are going to be relevant for clinical development. I love your idea, of Al’s, starting with the retrospective. Maybe that’s the next step, then, where there’s really pre-competitive, collaborative work, and understanding what we need to be doing in clinical trials.

MARK: Some of that data comes in the form of patient experience. I have had the privilege of working with folks in the ALS community. One of the conferences that I recently attended culminated in a patient presentation from their perspective, really suing for patient-centric trials, and in particular, helping to determine what the salient end points would be. The patients really fully appreciating their disease and their experience, and giving better insight to the trial design, for what to look for and what the end points are that would be most meritorious.
I want to move a little bit into the prevalence consideration. Samantha, you talked about, thankfully, the global market size was not the highest on the list. However, it’s a fact of rare disease that the smaller number of patients is related to the dearth of evidence, the challenge in finding these patients for study, even. I wonder if we can talk as a group about the different ways to determine what the prevalence is, but also, what that prevalence means or doesn’t mean.
For instance, Sam, when you say you’re glad that it’s not the overriding consideration, well, if there’s a smaller number of patients, the price point can go higher to make a salable drug program, but obviously there’s a limit there, and who is the cost sort of pushed onto? That’s a something of highest concern, so methods to calculate prevalence and the factors that go into the use of prevalence in determining which drug programs or diseases to pursue. Either or both of you, just not at the same time.

AL: I have to say, I am surprised that it didn’t come higher up the list. Mark sort of laid out the calculation, patience price equals revenue, right? Sometimes, price can be as dirty as it is. That’s a tricky bit, especially outside of the U.S. The more volume you have is very often going to be part of a consideration set for a company. I am surprised it didn’t come higher. In terms of calculating it, Mark, you are by far more expert, especially in genetic disease about that than I am, but one thing I did want to pick up on, what Sam said, we do have a myopic focus on the U.S. and EU five. That is where the dollars end up coming from.
The shame of it is, there is the rest of the globe which needs to be addressed, especially for genetic disease. Very often in countries, when consanguinity is higher, you’re actually going to have an increased prevalence there, but countries aren’t, industries aren’t. It’s harder to get attraction there. The value for the effort you put in could be lower. I do think mapping epidemiology, beyond just, you know, what gnomAD tries to do but only within the context of the U.S., I do think the more that we can do to shed light on the epidemiology, the prevalence within other countries, then maybe companies start to say, “well, that volume could come from a distributed territory space,” rather than, “I need it here in the U.S. and EU.” That’s where it’s easy to balance the equation.

MARK: Sam, any response?

SAM: I’m like Al. I think it really is an important factor, and as you rightly said, there’s a ceiling to prices. We’ve already seen two gene therapies that have come off the market in Europe because of pricing issues, so we know it’s important. The reason that troubles me so much is because, if you look at the 7,000 or 10,000 — I never know how many it is now — rare diseases, and you look at the prevalence or incidence, you’ll have a very few that are very common, or very common in the rare disease area. The vast majority are just terribly, terribly, rare, one in a million or something. Trying to find solutions for people is absolutely challenging. That’s why I think it’s something that’s so important, how to get that data. Modern times are going to allow us to get better data, but I think there’s an element, when we talk about incidence, we should probably always talk about minimum incidence, because I’m not sure that we’re ever really going to get the full value.
I think it is easier in Europe than the U.S., where you have very centralized care and you have read of these reference centers. Then, if you go to those reference centers and you say, let’s take a time period, and tell me genetically…” Number one, you need a country where they do genetics. You can actually go back and say, how many have you diagnosed in the last X number of years? and it’s probably very, very good data. That’s a way of doing it.I still have trouble in a lot of the rare diseases that I work in, notably, because of issues around nomenclature and ICD coding. It’s really, really difficult to identify, because you need to cross it over with other presentational symptoms of the disease, and it’s really difficult to d. I struggle getting really good incidence/prevalence data, other than working in very centralized countries, where you can start to get an idea.

MARK: That does touch point to the second major topic. Just to close the loop on that, I totally agree with you that there’s an underrecognition of the number of rare disease patients. Very simply, there’s calculations and empirical data, and sometimes both put together, but I think most generally, there’s an underappreciation of how many rare disease individuals there are. You just talked about it. The clinical diagnosis, the clinical heterogeneity, the underappreciation of this being the cause. Up until this point, many patients weren’t subject to genetic sequencing confirmation. There’s just a deflation of the actual number of patients that stand to benefit from developing a drug program.
The other thing that you talked about, Sam, is, depending on the drug mechanism and your drug development thesis, is bundling diseases together. If your drug intervenes at some common touch point, there’s strength in the numbers across multiple different diseases. Obviously, that depends on what the disease is and how your drug works, but that’s a way to get at those one in a million, where otherwise it just wouldn’t be economically feasible to target. I don’t know, Al, if you have anything to comment there.

AL: Yeah, there’s the additivity. You may start in a ultra-rare disease, but if you already know your mechanism is going to play, and they are defined patient populations that you’re going to just lily pad off, like, we’ll start here, we’ll prove the mechanism of the drug, we’ll prove the safety, here’s the next rationalized, scientifically. The only thing that really takes an indication or a disease off the table is when the science can’t be squared. Other than that, it’s just a problem that you have to work around. You can’t fix the problem scientifically with the hammer that you, specifically, have as a company. So if the science doesn’t work, that takes something off the table.
Everything else can sort of be solved. I agree, linking diseases by mechanism, whether that’s biomarkers, whether it’s symptomology of specific disease. Very often in rare disease, we’re trying to actually get at the root cause to try and change the overall progression, but there are a lot of very effective drugs in the rare disease world that address a small subset of what a patient is experiencing. The more we can link symptoms or science/biology targets together into a daisy chain or a string of pearls, then you can create more values. You’ve got to work your way slowly through one pearl to the next. I agree with that, linking things together scientifically, organizationally. Then, the research behind all that, the academic world, the patients, the clinicians, bringing knowledge about why their leukodystrophies are similar, and why there are common themes now mechanisms that you could pull on from a scientific perspective, to affect all of them in the process.

MARK: As I may have mentioned, that came out of some of my experiences with patient advocacy groups for ultra-rare disease that were started by patients’ family members. There’s a distribution of experience and background. Some of the groups that I’ve talked to had actually been working in pharma or the medical field. Others had no touch points into science or medicine or drug development, and everything in between. Outside of being extremely inspired by the efforts of these patient advocacy groups, there’s a great deal of value that they bring, in appreciating the patient journey in organizing, in being motivated.
So I’d like to turn our attention, now, to that topic of collaboration across pharma and patient advocacy groups. That’s a very broad topic. Sam, I don’t know if any of the things that we’ve talked about already is on the tip of your tongue, and if you want to speak to, how do we foster better collaborations across pharma and patients through these advocacy groups?

SAM: Openness, listening. Many companies now, I’d almost like to say all rare disease companies, have somebody that’s called a chief patient officer or patient advocacy or a patient engagement officer, and that’s fabulous. Talking to companies, it’s very important that that role is a strategic role, and it’s fully integrated into the company. It’s not just patient engagement in that somebody goes to patient meetings and they listen to patients — they listen to patients, and they talk about their protocol, and they tell them what they’re doing, and they present whatever. It’s really as early as you can. I say it’s never too late, but really, as early as you can. I’m involved, at the moment, in preclinical, and it has massive value in understanding the needs of the population. When you’re thinking about, what’s the route of administration, what are the volumes that I need to administrate? Even in those very early stages of the design of the construct, it already has value.
But it’s really not about going there and just saying what you’re doing. It’s about, how can we work together, so that I can sit on the fence between inside the company and looking outside. Not every idea, because you’re a patient, not every idea is going to work and it’s going to make a clinical trial successful, but it’s being able to understand how you can collect all that information in different ways and ensure that your company’s thinking about it in every stage of that development. That would be an overall comment that I would say.Then, at every stage you’ve got loads of different things, the collaborative work that you can do with patient engagement and collaboration.

AL: I love that. The engaging early, in particular, is really important. The only thing to say is, patient engagement, as infrastructure built into a company, does tend to come when you are already in the peri-clinical phase, as you’re thinking of engaging with clinical trials. Though it is never too early to start, there is a bit of reticence on the part of scientists. I’m going to talk from personal feeling here: I’m not a rare disease patient, I’m not a patient advocate, but there is apprehension about engaging on the level that I know how to engage with a patient community on. It’s at the scientific level, and I need to learn from them to help inform me about how I can be most productive in driving my drug discovery programs. I’m not yet at the point of being able to give them a drug, I can’t even tell them whether we’re going to get there or not. It’s a Tower of Babel. I really do believe that advocacy is a universal translator for all of the parts that are required to build that tower to the sky, the clinicians, the academic researchers, the discovery people, the development people, the commercial people, it’s a tower of Tower of Babel.
Advocacy brings it all together. We really do need to engage earlier, no matter how uncomfortable it can feel, especially when you can’t promise anything yet. You’re having a conversation about what we’re doing, we’re really hoping, and let us try and draw from you. You don’t want it be transactional, but until you get to the point of them being able to deliver something to return to them, it can sometimes feel that way. We’ve got to get over that. I’ve had a number of conversations that happen because we are so glad that you are talking to us now. We understand, in two years time, you may come back and say, sorry it didn’t work.

MARK: Yeah. It’s a two-way street, and I’ve seen it where pharma knows what disease they’re trying to pursue and wants to get engaged with the patient advocacy groups. I’ve seen it come the other way, where the patient advocacy groups, as motivated as they are to develop drugs around their child’s or their own disease, they’re clamoring for the attention of pharma. They want to prove that this is a salient program to develop, they want to evince some of that data, collect it on their own, publish it, mobilize the scientific community to basically make a package for pharma, to say, this is worthy of attention. Again, some of the advocacy groups I’ve seen have taken that all the way to commercial drug. It’s a long but a beautiful arc from this clear need with personal motivation to a successful launched drug. But that’s hard. I mean, it’s easy to succinctly summarize like that, but it’s very challenging.
One of the things that I wanted to touch on: I think we’ve got a mixed audience here, of both pharma and patient advocacy groups. Sam, if you could speak to being stewards of the data, how to make sure that the data that you are collecting where you do have access points to the patients is going to be useful, is going to be actionable? It’s hard work. This is the work that I do at Genomenon with my team. It’s very hard work. How do you counsel the these patient advocacy groups, and what’s the best way to produce this data?

SAM: So I could get contacted by a patient advocacy group that’s interested in saying what could I do in research, and it might not be a research area that we working in, or is your question more relevant to a natural history study that may be run by a company?

MARK: It’s both, in my mind. When asking the question, I was thinking about the natural history study and the structure of the data, making sure that there aren’t holes missing that are critical to realize the value of collecting each data point. As I said, some of the patient advocacy groups I’ve talked to contract with CROs and test molecules and develop pre-clinical studies. Any recommendation on either side of those equations, in the preclinical experiments or the gathering of the data for natural history studies?

SAM: When designing a natural history study, particularly in a field where there may not be publications or previous natural history studies, I will always convene a clinical advisory board that is mainly made of experts, obviously, but people would probably be your clinical sites for the clinical study. I would also convene a patient advisory board. We would do a massive review of the literature. The end deliverable that you want is a study where you can’t say, “I don’t know what I don’t know,” because “I don’t know what I don’t know” means a massive burden on patients. What you need to do is ensure that I’m going to be able to cover the end points that I know that are most important in this field, but in the least burdensome way.
We’re going back to the conversations that we had earlier in the way. I feel strongly that we should be working, because I believe it’s what will make companies successful in their drug development as well. I do believe that transparency, in this field, it’s just very atypical. Rare diseases, it’s different. We always are custodians of data, we do not own patient data. It’s health, it’s not a commodity like another. When you set up a natural history study, and this is around IRDiRC principles as well, about broad consenting, so that we don’t suddenly get to the end going, oh yes, it would be a good idea to be able to share this with the community, because we’ve used it, we’ve done what we needed to with the data, and then you suddenly realize, oh well, I didn’t have my ICF done properly, I didn’t have my these other things. Really, thinking up front about that.
Then, you have to tackle the different internal problems, about, maybe it’s not what I say, you don’t have to share the crown jewels, you might not have to share everything if it’s difficult for a company, but maybe some of the key end points, or what I call the “core essential data,” you need to think about how you can put that back to the community.

MARK: Massive review of the literature. That reminds me of the work that I do, and that, Al, you and I did, on a couple of your programs. Without necessarily focusing on that, I wonder if you can respond to Sam, and then we’ll move on to the diagnostic odyssey component.

AL: One thing Sam said that I’ve experienced is, think ahead in your ICFs. I’ve been in that situation, where identifying patients is the hardest thing. There is a firewall between industry and patients for a reason, and there are systems that need to be in place to enable what is completely appropriate communication. Doing a genetic test and then the patient not knowing that they could be contacted, or not opting into a process that makes the company aware of them, and them aware of the company, almost undoes the value of having the genetic test in the first place. Especially if the genetic test wasn’t completely and utterly confirmatory, which we all know is very often the case. But the company’s doing work to help try and explain that, and to give those patients options. I completely agree with what Sam said about thinking ahead in how you engage the community, how the advocacy can prepare their patients for engaging with industry.
The other thing is, I think we’ve said it, but the most important thing a rare disease community can do is to start a registry. It’s the beginning of everything. It’s organizing your patients, it’s organizing the knowledge that those patients bring, it’s organizing the treaters around those patients. I don’t know if we had said it, but for me, that’s the starting point. The most important thing that a rare disease community can do is start a registry. It will lead to a natural history.

SAM: I’m so pleased you’ve said that. I think, more and more, I’m hearing natural history studies, it’s foundational science. That’s the one thing, to the other question, when Mark was saying, if a patient advocacy group contacts me, that’s the one thing that I always try and help to the best of my ability. Being able to set up, either it’s pooling data that exists, identifying where it exists, and trying to pull data together, or setting up a prospective study.

MARK: Segueing from that into the third topic that we talked about, ending the diagnostic odyssey — Al, you talked about finding patients being the biggest challenge when you’ve settled on which disease you’re targeting, what your drug program looks like. Part of that challenge is in education, educating the patient community, the pre-diagnosed patient community. They’re, as I say, most motivated to figure out what’s going on. They’re often very literate on their clinical circumstance and have ideas about what disease it may be. I’ve seen this in my own clinical training as a resident and fellow, the patients are informed about their circumstance, and in some cases, especially for rare disease, know more about the rare disease than their doctor.
So, in terms of ending the diagnostic odyssey, what are some things that we can do to promote awareness, advocacy, and training, particularly among the front guard, the diagnosing physicians? Ordering tests, getting the confirmatory information to then find these patients, and have people these trials to develop a successful drug.

AL: Was that to one of us in particular?

MARK: It wasn’t, I was taken aback by Lauren joining! I see that we’re coming up on the end of the hour, so we’re going to have to be summarizing. Lauren, I don’t know if we’re going to have time for too many questions from the audience, but Sam and Al, if you can just close out this third section by talking about the value of advocacy and promoting awareness, particularly targeted on the treating and diagnosing physicians.

SAM: Well, Al’s kind of raising his eyebrows. Diagnostics is further away from my field, but I think one of the fields that I see some of the patient organizations working in is AI and facial technology. One of the things I think around it is, once you think that it might be rare, you’re on to a diagnosis. Upon thinking that it’s rare, how can you get people to say, “oh this is odd, maybe it’s not something common, maybe they’re linked?” I think that’s the step before thinking, “I might have something rare.” Once you’ve got rare, you can go to AI technology, you can do a whole load of stuff that might be able to help. I don’t know it’s kind of a question more than it is an answer.

MARK: That’s an interesting perspective. I’ve seen that in the clinic, it’s too easy to say, this is a nebulous constellation of symptomatology, it’s not likely to be definable as a clinical syndrome. It’s a perspective shift that you brought up, well, maybe it is, and maybe it does warrant some more definitive testing. I’ve seen it too often in my training, where it’s just too hard to pin down if the physician isn’t properly educated in the specific syndrome, the nature of rare disease, or the testing modalities to confirm a specific rare disease.
Al, I’ll give you the last word here.

AL: Oh, I hope it’s not the last word, I’m not used to having that. I come from a very genetic background, I do think trying to introduce genetics higher up the testing or diagnostic funnel would be highly impactful for diagnosis. I think genetics at the moment, and Sam mentioned this earlier, the European physicians are much more comfortable with it than, often, we see in the U.S. I think genetics ends up being the, “I’ve ruled everything out and it’s the last possible thing I can do.” Rather than introducing it far earlier in a way that says, “I don’t need it to make a decision, but I can use it to inform my thinking.” We’re learning that, even within rare disease, individual patients, like the stripes of a zebra — oh, this will be a good ending, good last word — just like the stripes of a zebra, no one rare disease patient with a given disease is the same as another one, especially where genetics is involved.
Especially as you’re now thinking about what therapeutic to use, certain therapeutics are only able to address certain mutations. Think of the cystic fibrosis field. Understanding the genetics and therefore stratifying and understanding the patient further up will both be informative to the diagnosis, but also provide valuable information about what you’re going to do when you finally do get to a diagnosis. That’s my plug for genetics.

MARK: That’s a great plug, it’s a great coda. Lauren, we’ll turn it back over to you, with my apologies for eating into so much of the Q&A time with our discussion.

LAUREN: It’s been a great discussion! We do have a couple audience questions, so we’ll answer those in the last few minutes here, before we turn it back to you guys to give a little bit of perspective on your vision for the future of rare disease drug development. The first is actually more of a perspective than a question, but I think it would be interesting to have all of you comment on it. This is from Leon, and this is a perspective I’ve certainly heard before, and I think I’ve had a conversation with you, Al, about this, which is the importance of studying rare disease in the context of common diseases as well. He brings up, specifically, the example of studying familial hypercholesterolemia, and how that opened up a market for lipid lowering drugs. I don’t know if, Al, you want to comment on that, or if Mark and Sam have any additional comments as well.

AL: Oh, it’s a really good point. I’m going to put my scientist hat on now. Rare diseases, especially of monogenic origin, they do two things: they define a patient population at need, and they validate a target and the biology of the target that now serves for moving biology within the context of whatever that disease is, and any broader context. It works both ways. You can identify genetic disease that now says, this target is important for lipid lowering, for cholesterol metabolism. That defines the treatment population. It also now says, this target is validated for something, that now, if you could design a drug against it, you’d be able to move this biology within the context of these other patients.
Similarly, we define big diseases, like type two diabetes or high cholesterol. Now, we start trying to understand, what’s the root cause of that? That gives rise to an understanding of the genetics that may be playing into it, and then identifies the treatment population that is very much at need because of their genetics. We come at it from both sides. So, yes, we need to think about how smaller diseases give us opportunities in larger, and how what we know of larger diseases and digging into them gives us opportunity to identify smaller, at-need patient populations. It’s a good point.

MARK: I won’t add, that was well said, Al.

AL: The last word again!

MARK: (LAUGHTER) On a roll.

LAUREN: Another question I think would be appropriate, specifically, for Sam: Amber asks, “who within the pharma company should smaller advocacy groups be reaching out to? How do we start the conversation to initiate these alliances and share resources?”

SAM: It depends. I think smaller companies are probably easier to reach out to than large companies. Oftentimes, I will have my CEO that passes me on messages, because there’s not always a patient advocacy or patient officer in the company. I’d say SMEs are pretty easy. You can probably go quite high up through LinkedIn, through through various mechanisms. The larger the company, the little bit more complex it gets. Either they would have somebody working in patient advocacy, or maybe the clinical teams would be the best people to reach out to.

LAUREN: Great, thank you! One other question, I think for you as well, Sam, is: “can you tell us about some of the other initiatives underway at IRDiRC, and how we can contribute to those initiatives?”

SAM: Yes, possibly not within the next two minutes. I’m happy that my email is shared, so if that person could reach out to me via email, if that’s possible, Lauren, to make that connection. I’d love to, because we’re always looking for partners at IRDiRC. It really is a collaborative project. We want to work together to ensure that the tools are designed in the most appropriate way, and that they’re used by the whole rare disease community. I’d love to make that connection. There’s a long list of things that we’re doing at the moment, including understanding n-of-1, understanding platform trials, we’re doing work in smaller populations, etc., so a lot of things.

LAUREN: Great, thanks, Sam. Alright, with about two minutes left, I think it’s time to wrap this up. If we didn’t get a chance to get to your questions, we’ll follow up with you shortly. I want to invite our panelists now to share more about their vision for the future of rare disease drug development and patient advocacy. We’ll start with Sam, if you want to share your thoughts there.

SAM: This is an easy one for me, actually, because I can just sit under the IRDiRC goal, which actually is a five-year goal. I couldn’t ever put it into better words, but the IRDiRC goal for 2027 is to enable all people living with a rare disease to receive an accurate diagnosis, care, and available therapy within one year of coming to medical attention. I think the question was asked, what we’re doing, but I think there’s a number of different strategies that are ongoing, that are stepped towards, that we discussed earlier. Platform technologies, basket trials, there’s a great public/private partnership at the moment that’s been launched called Bespoke on AAV gene therapy, which is helping to ensure that there’s shared expertise around design and manufacturing in order to lower costs, so that we can treat people with a more rare disease.
Also, we’ve gone through a lot about continuing to promote natural history studies, but really, strive to understand and appreciate where we need to work pre- competitively to ensure we get better care, better diagnosis, and better treatments to patients faster. Those would be my last words.

AL: Oh, come on, Mark, we’ve got to end on those last words.

MARK: Lauren, who do you want to point to first?

LAURENL Al is next, if you want to share your thoughts, follow on Sam’s great great answer there.

AL: We’ve talked about prospective and retrospective. I completely agree with everything that Sam said, in terms of continuing to strive for our rare disease communities. If we stop, we stagnate, that’s not an option. Retrospectively, I do think it is worthwhile, every once in a while, just reflecting on where we come from, and why we shouldn’t rest on our laurels. There’s a lot that, as a global multidisciplinary community, and that covers everybody, that I really think that we’ve already moved the ball significantly further down the field, to use a football analogy.
Just in my lifetime alone, it’s relatively short, we’ve sequenced and completely organized a human genome. We’ve developed every omic under the sun, even omics that didn’t really exist when central tenant was conceived of. We’ve started centralizing, digitizing medical records. We’ve developed AIs to read those materials and start to organize them and connect them to that omic data. We’ve developed technologies that enable us to very rapidly develop genetic systems and model animals or model systems, for us to then be able to understand disease and test our drugs in.
And we’ve done all of that before, as I experienced this morning, I haven’t even figured out how to stop a printer from jamming. There is a lot for us to take heart from, that even in my lifetime, you go back to the beginning of it, I don’t know how rare disease was ever addressed or recognized — Okay, I admit it, I’m 43 years old — only 43 years later, and there is a significant amount of infrastructure, a significant amount of understanding, and a significant amount of knowledge about where we need to get to and how to get there. For me, it’s, let’s look back and say we’re doing a good job, but let’s keep going.

LAUREN: Mark, you have the last word on this.

MARK: I’ll be succinct. I’ll pick up on where Sam and Al left off, and say, my perspective at Genomenon is on the data, and the harnessing and annotation and refinement and synthesis of the data, but also, in its application. The future that I see is informed by some of the work that I’m doing with a couple of my collaborators in newborn sequencing: solving that problem of understanding the natural history of disease by associating that with clinical data, by understanding, at a global population level, how common are these rare diseases, after all, and how are we going to find them? This newborn sequencing proposition stands, not to solve, but to mitigate a lot of those challenges.
I also think it stands to be economically cost-effective, which is a key component of that. It’s early days, the studies are ongoing now, but it augurs a promising future for capturing more rare disease patients, promoting a more streamlined mechanism to develop drugs to target those rare diseases, obviously to the betterment of the patients themselves. As we’ve said throughout, this is really a patient-centric endeavor that we’re all embarking on. That’s my final word, Lauren.

LAUREN: Great final word. Alright, we’ve had a fantastic discussion today! We have a lot to think about and work toward in the future. Please join me in thanking today’s panelists, and I want to thank all of you as well for attending today. If you enjoyed today’s program and would like to participate in an upcoming rare perspectives discussion, please don’t hesitate to reach out to me! I would love to hear from you, and I also welcome ideas on future topics. With that, thank you again, and I hope you all have a great rest of your day!

MARK: Thank you, Lauren. Thank you, Al, Sam. Bye!