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Biomarkers as Surrogate Endpoints To Modernize Rare Disease Clinical Trials with Mark Dant


We’re speaking today with Mark Dant. Hello, Mark.

Hi, Steve.

Mark, you hear many things. You’re the parent of somebody with a rare disease. You’ve been involved in drug development as a result for, some decades.

You’re the volunteer executive director of the Ryan Foundation, the former chairman of the board of the volunteer group called the EveryLife Foundation for Rare Disorders, and really many other things. So we’re gonna talk about some important discussions happening now that may be, modernizing rare disease drug development, we hope. So first, would you tell us something about your connection with rare diseases and clinical trials in general?

Sure. And and thanks for the setup, Steve.

Like most people in rare disease, it was not chosen by our family. Rare disease chose us. It’s kind of genetic lightning as it’s once put.

Our only child, Ryan, was diagnosed with an ultra rare condition called mucopolysaccharidosis type one, MPS one, way back in nineteen ninety one. We were told that his diagnosis that, Ryan’s lifespan would be shortened to within in a decade. He was three and a half at the time.

And we also were told that there was little research in this ultra rare condition. It’s the first time I ever heard the term orphan disease.

And we were told that there wouldn’t be much research and that there would never be a business model built for ultra rare conditions because their companies cannot invest in drug development for diseases with such few patients.

Therefore, we were told to take Ryan home and be with them while we could because there was nothing we could do. So for a year, we did nothing, but then we started a nonprofit, the Ryan Foundation, with a great idea, something called a bake sale, to raise three hundred forty two dollars.

We got better at fundraising, found a research scientist at UCLA who developed a drug treatment. And now Ryan is the longest treated person in the world on a weekly IV infusion of a drug that puts back in the system what he can’t make himself. He just had his thirty sixth birthday last weekend. So we’re very happy. It’s not a cure, but as all good science does, it bought him time for better science.

And that, the disease Ryan has, like many rare diseases, is, we it’s safe to say very serious and progressive. Does progressive irreversible damage in people who have it when it’s left untreated. Is that right?

Absolutely. That that’s the the other horrible part about such horrific diseases like, MPS and all these other rare, ultra rare conditions is, they don’t get better on their own. They will never get better on their own. They will only go go down a road where they worsen.

And Ryan was on that road for a good number of years. He started his his first, infusion in the trial was on February thirteenth nineteen ninety eight. So he’s been on drug treatment now for twenty six years, doing well with it. It’s bought him time.

But without the drug treatment, I saw many children and went to many funerals, because of this disease, stole their tomorrows and their parents’ future. So, these diseases need help, and help comes through great science.

And I wanna point out Ryan Dent has spoken on this WCG patient forum channel, and, he talked about it from his adult perspective now how, you and his mom, took the risk to be, in a clinical trial, to have him be the first patient dosed, as a matter of fact. And how now, because of that, he’s able to do things he never would have been able to do, including graduate from university and work. But also he’s married, isn’t he?

Yes. It’s you know, all of us on the rare disease journey, we realize our we realize our tomorrows are are counted, which is something we we don’t often think of as as those not on a rare disease journey is the greatest gift we have is not knowing what will happen tomorrow. We knew what would happen tomorrow with Ryan if there weren’t wouldn’t be, some partnerships formed, to bring a treatment forward.

Ryan realized all the dreams we had packed away laying on the floor next to his bed before we started the nonprofit, before we started we we found the scientist who developed the drug. We would lay there and think about all the dreams that left. He would not graduate high school. He would never drive a car.

He wouldn’t graduate college. He would surely would never get married. We would never have grandchildren. All of these dreams were packed away always in the back of our mind because they don’t go away, but it’s too difficult to think about.

Great science brought those dreams back to Ryan. On on July third twenty twenty one, Ryan married the love of his life, a, very sweet fourth grade bilingual teacher teacher in Arlington, Texas, and they bought their home last Thanksgiving. And they’re living living so far happily ever after.

So that’s a a good point to segue. There are, as we all, as you know, we all say there are around ten thousand rare diseases and the vast majority have no such FDA approved treatment, But there’s a lot of drug development going on in rare diseases now. Many biotech firms and big pharma, many university researchers, the FDA is very engaged in interacting with, the community of drug developers to try to make this a better situation so we can have more outcomes like Ryan’s.

So you’ve been involved in something I wanna ask you about, a discussion regarding that that could modernize drug development.

And, you’ve been to an important meeting recently speaking about this and watching it gets discussed at the Reagan Udall Foundation. For those who don’t know, the Reagan Udall Foundation is a not for profit mandated by Congress, so the FDA has a way of interacting with, all stakeholders, industry research, patient groups, and so forth. So you were there when, a recent meeting was held, and the discussion I want to ask you about is the use of biomarkers as surrogate endpoints in clinical trials.

You’ve been speaking about that in at other meetings where it’s being discussed. So I think the discussion is, very lively right now.

You and I know it’s been going on for decades.

Could you tell us what is that issue of the use of biomarkers as a surrogate endpoint in clinical trial decision making?

You use the term surrogate endpoint, and that is key in in this, process of drug development for for such ultra rare conditions. It takes so long sometimes to to see change or or to clinically, measure change. So how can we do that with with through science?

Science now in the past twenty years, it has changed. And I love the term used with Reagan Udall is modernizing, our science, bring bringing our regulatory process to the modern era.

Biomarkers does that quite effectively.

The pathway towards accelerated approval, is through a surrogate biomarker of of something that had has reasonable likelihood to to predict clinical benefit.

That’s the definition of a surrogate. Now if you can measure something in the blood or in the cerebral spinal fluid that when a disease is present, it it stays. And when that, substrate is gone, then the disease improves or or gets better. That would be something called a biomarker. It’s something objective. It’s not something where if a child has, cognitive decline and you’re asking them to take a two hour Bailey or Kaufman test every six months for five years, seven years, ten years.

Children don’t like doing that. They get bored with it, and so they fail the test. Is it because the drug didn’t work, or is it because the the test is a bit subjective and the child just didn’t wanna take it that day? How do we measure if the if the, drug is actually showing clinical benefit? A biomarker can do that. And an assay can show, specifically, through great science, that this reduction of the substrate is true and valid and therefore can, reasonably predict clinical benefit.

And, there’s also that issue when you’re contrasting this to the use of clinical data that’s basically observing what actually happens to the patient or the person because of the disease.

And if you look at that, you mentioned a five year time span of continuously measuring and finally coming to the conclusion, yes, this person has lost cognitive ability or lost their sight or their heart is much worse, whatever they’re measuring. Often that destroys the person’s life while waiting to be able to measure it.

Isn’t that true?

Yes. And then there’s the other parts with regard to trial design. The the gold standard for for many decades, and and and a good standard, is the double blind placebo controlled trial. Well, if you have a surrogate biomarker, something that can reasonably predict clinical benefit, the double blind placebo control where part of the patients in the trial are receive treatment, and the other part, we stand back and watch and watch to see if they get worse.

Once again, we mentioned earlier that these diseases don’t get better on their own, so they’re going to get worse. And many times, that’s irreversible disease as in brain disease, cognitive decline. They’re not going to get back the ability to speak perhaps or to, use the the toileting. These are all daily issues that really affect quality of life.

A biomarker can reasonably predict clinical benefit would would help us look away from perhaps the double blind placebo control five year, seven year, ten year trial to something very objective to be able to see, is this drug really reducing a substrate? And the substrate then is what causes the disease.

Those two factors can help us speed the trial process for many great reasons. More and most importantly, so the patient improves quickly. And there is we have we don’t have to watch patients decline. We can watch patients improve if the drug is safe and effective.

Can you give us some insight as what the hesitation has been over the years? Why not just say, okay. Let’s use surrogate biomarkers.

Right. That’s a very good question, Steve. The FDA has multiple reasons for the things that they do.

They have a two pronged approach to approving drugs, and they’re only two prongs.

Safe. The drug must first be proven safe and effective efficacious. If if both of those standards are met, the drugs drugs should be approved.

It’s difficult to define specifically what effective is and and what safe is on the long haul. Should the FDA approve a drug that ends up to be not safe or harmful or doesn’t work? Well, that’s not good for this, for the FDA. No. And it’s all, obviously, not good for the patients or or the the biotech industry or the ecosystem of drug development.

So, the conversation twenty years ago where it started, actually started with with the drug that Ryan was on. There was a second trial called for because the first trial did not have a double blind placebo control. The substrate was reduced.

It was quite evident that children were getting better, but we had to do a double blind placebo controlled trial. Twenty years passes, and we still are doing the same thing. The difference is leadership within the FDA are are are are interested in listening to all facets, to to biotech, to the patients, to those who live the life every single day. And and now there is conversation because of entities like the Reagan Udall Foundation who who put together this important conversation, with scientists from around the world.

At that specific meeting, scientists from Australia and England and Canada, across the US, Brazil, were all all present. Japan, having having the conversation about that biomarker. Is it effective? Should it be used? And the conclusion was scientifically, without question, it should be. So the difference in the FDA now is I think they really truly are interested in listening to the patient, listening to the scientists who are experts in metabolic diseases like like these and other very difficult, diseases to understand.

The partnership there begins with listening and moves forward with action. So what we’re looking for now is, continue the conversation, but let’s act upon it and move forward. Modernize the process.

So, I know the as you’ve said, the FDA is also trying to keep us safe.

They’re doing a much better job and very, carefully about listening to the patients, and they have been as various rounds of legislation have even mandated that and brought us things like patient focused drug development, which we’ve seen become more sophisticated, with passing years. So, this discussion that has been that happened at the Reagan Udall meeting was about the research going into one of the, diseases that’s biochemically related to your son’s, MPS three, mucopolysaccharidosis type three, Sanfilippo Syndrome, I believe. And specifically about something we can really do to move the needle, we meaning everybody, to validate the biomarker in question.

And you you’ve talked about substrate in the system. So when an an unwanted mucopolysaccharide is in a person’s system and building and building, they probably have one of those diseases. If they take the experimental drug and that goes down, we patient community people like to say the person’s going to get better.

So what is the, there’s there’s discussion right now about validating that specific biomarker for that specific disease? Where did you see that that stands?

Well, I think it’s in a good spot. And I think the reason why it’s in a good spot is, because of the conversation between the scientists, the academic experts who’ve spent their careers, understanding the the biochemistry and the biology of the disease and the system, of which it’s affecting.

That that’s what was important about the break. And you don’t mean any actually, I just came back from Germany two weeks ago where, academic entities from around the world got together in Wuerzburg and had a great conversation to to move forward on a publication to define the science behind this specific biomarker for brain disease in the MPS disorders.

These these are are are very important conversations to have and and to document so that the FDA then can review, these published peer review articles and say that it is a global conversation, not just a conversation between one academic institution versus another. But all of the experts are on the on the same page. Publications are important. And and, they are time stamped so that, science, they can say, at this point, we were here. Where do we need to go?

So this is this is a good thing to hear that this conversation has, taken on a new life after all these years. Mark Dant, thank you for speaking with us today.

Thank you, Steve, and enjoy the conversation as always.