E86: Taking a Customized and Collaborative Approach to Therapeutic Development

Mary (00:09):
I'm Mary Parker and welcome to this episode of Sounds of Science. I'm here today with Hugh Hempel, executive Director at the N=1 Collaborative who will talk about how the N=1 C is helping advance therapies in the personalized medicine space to get [00:00:30] the right treatments to patients as quickly as possible. Welcome, Hugh. 

Hugh (00:35):
Thank you very much for having me. Pleasure to be here. 

Mary (00:37):
We're really grateful to have you here. So, congratulations on your new position as executive director of the N=1 Collaborative. Can you tell us more about your new role?

Hugh (00:50):
So, in my new role, which I'm so honored to have, I'm leading a group of folks, both full-time employees as well as a large group of volunteers and an effort to bring individualized [00:01:30] medicine to the marketplace more effectively, affordably and timely.

Mary (01:37):
For anybody listening who hasn't heard the phrase before, can you explain what N= 1 or N of 1 means?

Hugh (01:44):
Sure. N=1 is shorthand for individualized medicine. It comes essentially from the world of science and development where N is essentially the size of a cohort [00:02:00] or the number of patients that are involved in a clinical trial. And in this case, N=1 refers to simply one patient in this particular effort.

Mary (02:12):
So can we go back to the beginning of your journey to the diagnosis of your twin daughters, Addie and Cassie, with Neimann Pick type C deficiency. Can you tell us about that journey for you and your family?

Hugh (02:26):
Sure. Addie and Cassie are identical [00:02:30] twins. They were born in 2004, January 23rd, 2004. I like to say 1, 2, 3, 4 is the date. I love that they developed normally until they were about three years old, and then we began to see some developmental issues. Ultimately, after about a year and a half of diagnostics involving the Mayo Clinic and Stanford University and sort of all the best and brightest physicians we [00:03:00] could find, we unfortunately found that they were discovered with Niemann Pick type C, which a degenerative neurological condition caused by the recessive genetics of my wife and myself. It's typically, well, almost universally fatal and it's quite a heterogeneous disease actually. There are children who [00:03:30] pass away very, very young, and there are actually adult-onset versions of this condition as well, largely defined by the genetic profile of the individual.

Mary (03:45):
So can you tell us about Addie and Cassie? What was their relationship like?

Hugh (03:51):
That's a really difficult, it's both difficult from the painful point of it, given that we lost [00:04:00] them five years ago. But it's also difficult because they really only had three or four years of what I would call normal development to interact with each other. And once the condition started to set in, they fairly quickly became nonverbal and immobile and so forth. So, the interaction between them was difficult to characterize other than when they were little kids. I will say that [00:04:30] they, with the exception of a couple of months when Cassie was in the intensive care unit as a result of a stroke she had from the implantation of an AYA reservoir in her brain, the twins were together from the day they were born until the day they passed away. They passed away on the same, same day. They came into this world within minutes of each other and became angels within minutes of each other. So, I can [00:05:00] say for sure that they were connected, very deeply connected, and they spent their entire lives side by side.

Mary (05:08):
So, what is their legacy and how do you want to bring that into your new role at the N=1 C?

Hugh (05:16):
Well, I suppose their legacy is yet to be determined, and that's why I decided to dedicate my working career to this organization and in particular [00:05:30] to the development of individualized medicine. So, my hope is that Addie and Cassie are the driving force and therefore their legacy will be the evolution of the ecosystem required, the new ecosystem required to build out the capability to deliver individualized medicine, as I said a moment ago, timely, affordable, and accessible to all.

Mary (05:58):
I think that must be the hardest part is [00:06:00] the affordability and of course the timeliness because medicine takes so much time to develop, and it costs so many dollars to pay the scientists. Can you talk about some of the programs that N=1 C has to help counterbalance that?

Hugh (06:15):
Yeah. So yes, it is today, it's extremely expensive and very time consuming to develop an individualized medicine for many, many different reasons. [00:06:30] But the technology is evolving so rapidly that we believe that over time we can put in place systems that facilitate the development of the drug, the approval and necessary testing of the drugs or the therapies to happen much, much more quickly. Because as they say, time is money. So, the more quickly we can get the drugs development developed, the more likely it is to be increasingly more affordable. [00:07:00] Part of that process that we're working on and will require is changes in the regulatory pathway to facilitate this process. So, the current pathway is designed around, for the most part, large scale double-blinded placebo controlled clinical trials for large populations. And so, in collaboration with the FDA, the NIH and other organizations around the world, [00:07:30] we are working to create essentially a new effective pathway for the development, deployment delivery of these individualized medicine.

Mary (07:45):
Yeah, it seems like as with most things in science, every iteration of something like this will make it easier for the next time and the next time after that, although of course it still takes a long time. So as far as I understand, in 2018, the very first patient [00:08:00] in the whole world to receive a drug tailored to her was a girl named Mila, who is a 7-year-old with a fatal neurologic disease, which was Batten's disease. Can you tell us how the collaboration to create a novel medicine for Mila became the genesis for N=1 C?

Hugh (08:57):
So Mila's mom, Julia worked [00:09:00] very closely with co-founder of N=1 C, Tim Yu at Boston Children's to develop Milasen, which was, as you say, I believe the first individualized treatment. It was ASO based treatment specific to Mila. During the journey of creating Mila and Tim and Julia realized much about what we were talking about with respect to the ecosystem requiring or being in need of change, or [00:09:30] I like to call it a bit of a revolution that the technology was facilitating and that there was no obvious organization within the ecosystem that could be the change agent or the thought leaders and consolidate and catalyze the changes that are required to make this possible. And the N=1 C was born as a result

Mary (10:00):
In order to generate this personalized medicine, the N=1 C partnered with Charles River. What made this partnership so successful?

Hugh (10:09):
Well, I'm going to provide you my secondhand perspective on it because I was not personally there, but from my perspective, Charles River is a crucial part of making it possible in the sense that it really does in this instance, in this time and place, take [00:10:30] a village to deliver an individualized therapy. If you think about it, the skills and the capabilities and capacities required to deliver a drug are profound and wide ranging. So, you have to be able to not only know what drug you want to develop, you have to be able to test it, you have to be able to manufacture it in a safe and effective way. Then you need to be able to do a rigorous testing [00:11:00] on it in animal models in order to prove its safety, safety at least. And then you actually have to begin to deploy it in what is typically a graduated or a facilitated dosing strategy. So ,there's many, many elements of this requiring a lot of different skills, many, many different people manufacturing capacity and facilities in order to build the drug. So, Charles River was an instrumental partner [00:11:30] in all of those component pieces, and I had a similar experience with my twins. We also developed individualized medicines for my daughter. So, I know what's required to do that, and organizations like Charles River are crucial to that capability.

Mary (11:52):
I would imagine that it's pretty rare for a rare disease patient's family to have someone in the family who already works in the pharmaceutical [00:12:00] industry. Those probably don't overlap very often. So, a family coming face-to-face with a diagnosis like that, being paired up with someone with the expertise, I could imagine that would be very valuable. And I think the N=1 C helps facilitate those kinds of introductions. Yes,

Hugh (12:17):
Absolutely. So, it's one of our roles is to help facilitate those introductions, and there are others who are working with us in that capacity. I've been [00:12:30] a part of the Global Genes organization for quite some time, and the Global Genes has its own rare concierge capability where they're helping patients connect with physicians or scientists and researchers in order to make this happen. But N=1 C is taking an active role in making those connections, and we're building out tools and databases and capabilities that will help make that easier. And honestly, right now, there just aren't enough of those resources [00:13:00] out there. So, we're eager to build an accredited group of individuals who are specifically trained and dedicated to the development of individualized medicine over time.

Mary (13:14):
Now, I know you only recently became the executive director, but looking back over N=1 C'S history, what do you think are some of its most impressive achievements?

Hugh (13:26):
Well, yes, you say I'm a newcomer and I'm just honored to be involved. [00:13:30] But as I look back in the four short years that N=1 C has existed, it really has established itself slowly, steadily, but surely as I believe a critical catalyst in this ecosystem change. We've built a network of a thousand scientists, clinicians, patient advocates. We've developed best practices. We hold regular educational [00:14:00] seminars on the subject matter. We're building out informational databases that will capture preclinical as well as clinical data regarding treatments that can help inform the community as to how to proceed, how to develop safety profiles, how to do this with the best possible practices. So, all of that's been done in a very short period of time with an extremely small team. [00:14:30] And it's obvious, I think, out there in the community, if you ask folks who are aware that the N=1 C has really made a very profound difference.

Mary (14:42):
So, from what I understand, the N=1 C was launched in 2021 as the first international hub for individualized medicine for rare disease. Can you tell us what drives this philosophy?

Hugh (15:00):
I like to characterize the philosophy in a single statement of the N=1 C as, and Julia I think coined this phrase, or maybe she didn't, but I'll give her credit, Mila to millions. So, her daughter, Mila, was the first in the space. And the goal that we all share philosophically is to make what happened with Mila available to millions again in that sort of timely, affordable, efficient [00:15:30] process. So, there's our philosophy, pure and simple. It's easy to say and very complex to accomplish, but that's what we're dedicated to do.

Mary (15:40):
And what kind of disease candidates does the N=1 C consider taking on?

Hugh (15:47):
I'd like to think that we are largely disease agnostic, especially over time. We're building out a platform that really is both technology treatment and disease agnostic. [00:16:00] So it really doesn't matter in the long, long haul, in the immediate timeframe as we're working right now, practically speaking, our initial focus is on diseases that are immediately life-threatening, where advanced technologies like gene editing, RNA delivery systems can be a safe and effective option to those who are critically ill and their life [00:16:30] is being threatened in the near term. And there's a whole host of reasons for that, but that's our immediate focus.

Mary (16:38):
I understand collaboration is kind of the key to rare disease drug development. Obviously ,there's no one entity that could do this all by themselves. So, can you walk us through the sort of custom approach to an experimental, individualized drug [00:17:00] development that N=1 C takes to progress their therapeutic pipeline?

Hugh (17:07):
Sure. For the sake of clarity, I want to say that N=1 C is really a facilitator. I like to think of as an enzyme or a catalyst in the process don't, there are organizations similar to N=1 C who actually do treatment of patients. [00:17:30] We are not focused on that piece of the puzzle. We are focused in enabling those who do those treatments to be first accessible. So, knowing where they are and who they are,

But also to provide all of them, including the rest of the ecosystem, as you say, it takes a huge village to do a treatment to help facilitate the interaction between the parts of the ecosystem as well. As I said previously, [00:18:00] build best practices and infrastructure to facilitate the learning. If you want to think about it, it's a learning loop. S,o we're doing the work, we're capturing what we've done, we're capturing the outcomes of that, and then we're feeding that feedback loop back into the learning process. And so we're in that context, I'd like to believe that we are enabling those who want to take [00:18:30] on the challenge of doing an individual treatment. In this day and age, we're helping to facilitate that process on their behalf.

Mary (18:40):
So how has establishing ASOrt of standardized framework for individualized medicine propelled the expansion to other customizable platform technologies that may not have been available when you were looking for treatments for your daughters?

Hugh (18:56):
Yeah, that's a great question. 15 [00:19:00] years ago or so, when my daughters were diagnosed, there really was no infrastructure per se. Global Greens, for example, is just a fledgling organization, and the rare disease community has really come in enormously long way in the last 15 years, both legislatively and regulatorily. And from a funding and awareness point of view, we still have a ton of work to do. So to answer your question a little bit more directly, [00:19:30] we still have a long ways to go in terms of getting to that place, which you can, I think characterize in a single word as scalability. So right now, all of these programs are very, very unique. They're in many cases, one off, they're not built on. They're being done sort of case by case basis. And the goal is, again, to just create that scalability [00:20:00] by building out platforms that facilitate the learning process, facilitate a more streamlined, effective regulatory process. And I think part of the goal of accomplishing that, or part of the solution to it is again, as I mentioned earlier, to build out essentially an accredited network of institutions that can take on individualized treatments, who work together, but who are specifically trained and accredited [00:20:30] by the regulatory bodies throughout the world to make decisions and move quickly with individualized medicine, which is how we accomplish streamlining the entire process and making it more effective and scalable.

Mary (20:47):
So speaking of one's contributions, can you describe the new N of 1 donor resource center? What are its goals?

Hugh (20:55):
Sure, sure. The Donor Resource Center, we just recently announced it at our annual conference in Montreal. [00:21:00] We're so excited about it. Our donors are excited about it, the recipients of the resources, they're excited about it. What it is to oversimplify perhaps, is we're acting as essentially a clearinghouse or a curator of critical resources that are required to deliver individualized medicine. Example would be something as simple as whole genome sequencing. So we offer that as a service. We [00:21:30] don't offer it. We offer it as a donated resource. Another good example would be sort of access to folks who are capable of GMP manufacturing of the therapy once it's gotten to that point where it needs to be manufactured. So if you think of the entire chain, the sequence of events that need to take place to develop [00:22:00] on these drugs requires, as we've discussed, specialized capabilities all along that way.

So whether it's animal testing or drug manufacturing or literally sort of the design of the ASO or whatever technologies being used to deliver the therapy, all of those elements require specialized talent. And so our goal is to build out a resource center to make those capabilities available [00:22:30] to whoever may need them in our effort to, again, feed the pipeline of the circular or the feedback loop learning that needs to happen while we collect the data, which will help inform the regulatory folks about what we're doing and how effective it is and how safe it is and so forth.

Mary (22:51):
Yeah, that makes perfect sense. I mean, there's no need to reinvent the wheel. There's no need for N of 1 to set up their own genome sequencing center, [00:23:00] but in order to help patients, you can connect patients that need it with the experts that are willing to offer it, and just creating a directory of resources that people can look to so they don't have to start from scratch.

Hugh (23:15):
Exactly. And so we're both doing both. We're building out a directory of these resources so that folks know where to go to get them in that process. We've developed relationships with the providers of those services,

Hugh (23:30):
They've generously donated those services to whoever needs them. And we're just facilitating essentially the grant making process to make those resources available to patients who reach out to us.

Mary (23:48):
Switching focus to the patient side of things. How has the rare disease community increased disease awareness and help promote advances in treatment?

Hugh (24:00):
The rare disease community is, it's a very exciting community to be involved in. There's a whole bunch of activities, far too many to talk about in detail here, but one of the ones I like to focus on is it's a relatively new thing since I've been in the ecosystem, which is every year, [00:24:30] the last day in February, we do what's called Rare Disease Day, where we build for one day, we try to build awareness around rare diseases. And part of that is many, many, many advocates, literally hundreds of advocates descend on Washington DC and meet with lobbyists and champions in the legislature to help facilitate and build awareness [00:25:00] for the rare disease community in general. And that's been incredibly successful. There's been numerous elements of legislation that have been created to help facilitate development for both individualized medicine, but more accurately for small population rare diseases where traditional drug development is difficult to get funded.

The economic model around rare disease drug development is very challenging. And so we have asked [00:25:30] our government, the US at least, to help facilitate that by giving incentives to drug developers and scientists and researchers to put extra effort into rare diseases. So yeah, that's just one example. There are many, many, many other examples. There are numerous organizations now that have come together to do this. I've mentioned global genes. There's every life, which is based in DC to help facilitate [00:26:00] legislative action. And then of course, there's literally hundreds of little frequently mom and pop foundations that spring up like my own. I started the adding and Cassie fund with my wife Chris, and we raised money for basic research. And ultimately when we discovered a compound that would be effective or that we believe we were effective, we raised money to help facilitate translating that [00:26:30] compound into an actual drug and getting it into Addie and Cassie as first in humans, similar to what Julia did with Mila.

And so we couldn't have done that without a foundation and without the generous support of our community, our friends and our family, everything from 10 K runs to bake sales, we raised the money to do that. And we were just one of now hundreds of small foundations who advocate for their own specific rare [00:27:00] disease. And the N=1 C is kind of an umbrella organization that sits in support of, I like to think of it as sits underneath all of the littler rare foundations and provides a platform in support to those organizations to find individualized treatment. And by the way, it's not uncommon at all that an individualized treatment like Milasen for Mila turns into something broader. So I'm a big believer in [00:27:30] the idea that rare disease informs not so rare disease, and so frequently the technology and the work that's done in an individualized setting or in a small cohort setting translates into much larger population. So that's a part of the answer to the question you asked previously about the legacy of the twins. I firmly believe that rare and forms not so rare,

Mary (27:57):
Absolutely. But it also informs fellow [00:28:00] rares who are out there and haven't gotten to that point yet, where you can search our website on criver.com for information about JC and Alex, who are another couple of twins who had juvenile ALS and a treatment that was developed for them, which was called Jacifusen, was eventually tested in other patients. So it might not have gotten to them in time, but it went on to potentially help other patients. So I do think that that legacy [00:28:30] is important.

Hugh (28:31):
Yeah, the same happened with the twins. So the treatment that the twins receive first inhuman is now being delivered to last, I checked probably more than a hundred other patients around the world using almost identical protocols. And there's ongoing clinical research to get the FDA to approve that compound. So yeah, I mean, that's a perfect example.

Mary (28:56):
So beyond those specific examples, what does the future [00:29:00] hold for rare disease research and drug discovery?

Hugh (29:04):
Oh man, we'd have to spend all afternoon to answer that question. As I said, this is a marathon. This is not a sprint. We've got a long way to go to make the dream of individualized medicines happen. And I think the work we do in the individualized space, of course, I believe translates into the rare space to small [00:29:30] cohorts as well. Boy, I mean, just looking at genome at whole gene sequencing,

(29:43):
That's just coming an enormously long way. I mean, when Addie and Cassie were diagnosed, it was inconceivable that we would be able to afford to do that or that it was necessarily going to pay off. And today it's a considered a foundational element of any diagnostic effort. So it's gone from [00:30:00] tens of thousands of dollars per sequence to a thousand or so dollars, and that's dropping incredibly rapidly. And once you understand the whole genome, I think it becomes much more possible to apply a variety of technologies. The ones that Mila benefited from were ASO delivered meds, but there's gene therapy. There's [00:30:30] sort of CRISP- based editing technologies that can facilitate, I think, individualized treatments. And so we just have to find ways to deliver those technologies effectively.

Mary (30:42):
So what are some of your goals for the future of N=1 C and for the future of Addie and Cassie's legacy?

Hugh (30:51):
The N=1 C'S goals are, again, simplistically with the dream [00:31:00] of Mila to millions. What we're doing is we're building out helping to facilitate this learning loop initially because the process of getting the regulatory frameworks changed or created as the case may be, new regulatory frameworks created. The process of making that possible is having a fairly sizable amount of data that has to be data driven. And so we are building tools and infrastructure to consolidate individualized treatments that are going on around [00:31:30] the world into a single knowledge base that provides, again, this feedback loop of learning so that we can look at all of the events good and bad, that inform the development of these drugs and provide insights that help accelerate. So, people can answer simple questions like, what is the toxicity profile of a particular ASO in a particular setting? [00:32:00] Can we answer those questions? And with the development of AI and other computing technologies and data technologies, not just the science, the medical science, but we've also got significant evolution in data technologies. We're piggybacking on those technologies and bringing them together to the science side to help facilitate this process. So the dream is to, again, have a scalable process that's [00:32:30] cost effective, timely, and therefore accessible to everyone in the world, not just to those who can afford it today.

Mary (32:40):
And how can our listeners help you achieve those goals?

Hugh (32:45):
Well, listening to this podcast is a good start. I think education and awareness are crucial to our success. Of course, you can get involved. I mean, we're always looking, no [00:33:00] matter what role you may be able to play, we're always looking for volunteers to be involved in our program.

Hugh (37:30):
So those of you who might be interested in donating or learning more or getting involved personally, simply visit us at our website, which is www.N1Collaborative.org. You can also contact us via email at [email protected].

Hugh (00:33:30):
It takes a village and we are in a marathon, and if we start now, we will get there. And so we've now got four years under our belt moving this forward, and we're piggybacking on technology and rare disease advocacy and awareness from several decades now. So, the future is bright, and we just got to keep diligently working to get there.

Mary (33:53):
That's very encouraging to hear. Thank you, Hugh, for being part of the show. It's been a pleasure having you.

Hugh (34:00):
It's my pleasure, my honor. Thank you so much for inviting me.

Mary (34:04):
Hugh Hempel, executive director at the N=1 Collaborative. Stay tuned for the next episode of Sounds of Science. Until then, you can subscribe to Sounds of Science on Apple Podcasts, Spotify, Stitcher, or [00:34:30] wherever you get your podcasts. Thanks for listening.