Join 30-year industry veteran Pepper Landson, Co-founder and CEO of  Praetego as she shares her inspiring journey that led her to tackle Alzheimer’s and dementia through the innovative use of amadorins. Pepper’s intriguing narrative not only highlights her commitment to the public health crisis surrounding these neurodegenerative diseases, but also the collateral damage they inflict on families and caregivers.

Emma Moran: [00:00:00] I’m Emma Moran, VP of CNS at Vial, and I’m really excited to be joined today by Pepper Landson. Pepper, would you like to briefly introduce yourself?

Pepper Landson: Thank you, Emma. My name is Pepper Landson. I’m a 30-year industry veteran. I co-founded and lead a company called Praetego, which is developing novel small molecules to change how we age starting with Alzheimer’s and dementia.

Emma Moran: Pepper, you’ve been involved in developing therapeutics for healthcare needs for a long time, now. What initially drew you to a career in healthcare and pharmaceuticals?

Pepper Landson: I am, by nature, curious. I love problem solving. These two drivers are welcome and, in fact, encouraged in our industry. But, like most folks who find themselves at an opportune moment in time, it’s never a linear process. 30 years ago, I was fortunate enough to stumble into a job working with the US military to research HIV. 

At that time, there was nothing in treatment. There was just the beginning of clinical trials for what was then AZT. Everybody knows how that story turned out. But the United States military and certainly, Department of Defense funding was in collaboration with the folks at NIAD, when Tony was in charge and Debbie Birx was there, Robert Redfield was there.

This group of federal folk; military; they’re medicine, they’re doctors, the scientists just wonderful people focused on solving a problem. They were working diligently to understand the disease and conduct clinical trials to study possible treatments. Working in that environment with these incredibly talented people was infectious, no pun intended.

 After a few years of being able to have the pleasure of being around that type of folk, I was hooked. I’ve been in medical and clinical research ever since.

Emma Moran: So like you Pepper, I’ve also worked in the Alzheimer’s field for a long time. I’m interested to hear more about your research. Can you give us a glimpse into how Praetego, the innovative small molecules, the Amadorins, worked to safeguard against neurodegenerative diseases and share the fascinating research journey that brought them to life?

Pepper Landson: Again, non-linear stories, but the history of the Amadorin development spans 30 years, four generations of candidates, and the third being Praetego. The one constant is our CSO, Dr. Raja Khalifah. He’s a world-class chemist. He’s also the inventor of the Amadorins. 

He identified the original molecule (gen one) and its unique ability to inhibit a significant chemical reaction related to glucose metabolism. We all use glucose for energy. That’s generally no big deal. However, as glucose is metabolized, it also loves to bind with long-acting proteins, lipids, and bits of DNA. These glycated units are targeted for non-enzymatic oxidation driven by redox metal ions. It’s this event, simply known as glycoxidation, that can become harmful. 

The reaction produces highly reactive byproducts, pathogenic oxidated chemistries to (to put a big net around it). But it produces advanced glycation end products, or AGEs. When we’re young, or otherwise healthy, the body deals with the consequences of glycoxidation, or more simply put, glucotoxicity. As we age, or have other comorbid conditions, those consequences start to add up. What does this mean? It means oxidative stress and it means AGE accumulation. 

So what, right? Why does this matter? It matters because these are two known drivers of neuro inflammation and protein aggregation. This pathology encourages plaques and tangles in Alzheimer’s disease. The Amadorins, all four generations, demonstrate the ability to inhibit glycoxidation. Our mechanism transiently caps the redox metal ions that drive the reaction. 

As a result, the Amadorins limit not one but at least three known promoters of neurodegeneration: redox metal ion toxicity, oxidative stress, and AGE accumulation. We have reason to believe our candidates may also be protective of neuronal cells and by, somehow, protecting maybe the mitochondria. That’s a new phase of research we’re trying to further with these candidates. 

We’ve also known what they do outside of the cells. But now we have better technology to help us understand what they may be doing to benefit the inside of the cell.

While the gen one candidate did this, by gen four, the lead candidate is two orders of magnitude more potent. What we’ve learned along the way and steadily refined were features across each generation. We landed on the ideal for a chronic use drug in an aging [00:05:00] population to treat age-related diseases like neurodegeneration.

Emma Moran: Fascinating. Alzheimer’s disease and related dementias are often referred to as a public health crisis. How does Praetego’s approach with these Amadorins uniquely position itself to address this crisis on a systemic level?

Pepper Landson: Let me set the table a bit for the scope of the problem. The collection of diseases that fall under the umbrella of dementia, for which Alzheimer’s has the biggest footprint, is truly a crisis. I’m speaking as a caregiver to a mother with Alzheimer’s. I can honestly say the collateral damage to family members, caregivers is profound. This is not a disease operating in a vacuum. It takes everything it can with it as it progresses.

Children become the parents and parents become unrecognizable. You have to have wealth to afford supportive care or to place your loved ones in a home and then pray that home will keep them safe. That cost is out of reach for so many families. Bed space, in a suitable care facility, is limited. It will not keep up with the pace of the Alzheimer’s epidemic, the dementia epidemic. It’s obvious.

With Praetego’s candidates, we aim to be an early intervention and to limit cognitive decline long before overt Alzheimer’s. That’s now possible because we have tools to identify folks at risk decades prior to having frank cognitive decline, frank Alzheimer’s symptoms. Because we can measure it, we can go in sooner.

\ That makes it possible for our candidate, like the amadorins, to be able to run a clinical program, a series of clinical trials, and ultimately have something we can measure that the agency will say, “Yeah, that’s an approval of functional endpoint. It means clinical benefit.” Now, of course, the challenge becomes, how do you afford a trial that’s a little longer than you’d like it to be? 

Thankfully, again, super smart people, statistics, and some other really cutting edge clinical trial design techniques are coming of age that’ll help those of us who work in the chronic diseases of aging, like Alzheimer’s, to slow things down and have trials we can afford to do.

Back to your original question, as I mentioned, we designed the Amadorins to have ideal features for a chronic use drug. They’re oral. IV infusions are great, but a lot of people can’t access that level of care. We design these candidates to have a wide margin of safety. The room to play between the efficacious dose and the toxicity dose is quite broad. You want that in an aging population.

We also design them to be reasonable in terms of pricing. From the beginning, from the bench, we said, “These drugs have to be easy to make. They have to have good IP around them. But, we don’t want to use every most expensive ingredient in order to price these things out of the hands of most folks.” 

We have been thinking about this problem for a long time. With the current gen four candidates starting the PTG-630, we may have finally found the sweet spot. But the other thing that’s super meaningful as a systemic answer to a systemic problem is our mechanism is beneficial to patients who have excess glucose fueling this oxidative stress and AGE pathology pathway. 

We all do it, but diabetics do it faster. That’s now a known thing: diabetes is an extreme risk for Alzheimer’s and dementia. Our working hypothesis it’s because of this glucose toxicity challenge. If we can affect the beginning of that, then we can protect diabetics from having cognitive decline. We can protect everybody else from getting it, too.

In my mind, with that, hopefully, again, future, forward-thinking. If we are right, then our drugs could benefit as many as one in 10. If we’re able to demonstrate sufficient safety profiles when you talk about pre-diabetics being one in three in the United States, this is like a statin. This could actually protect people from a known, undesirable outcome, and be something they just take with a breakfast and get on with their lives.

Emma Moran: That would be absolutely amazing, wouldn’t it?

Pepper Landson: Yes.

Emma Moran: The biotech industry is continually evolving. What emerging trends or technologies do you foresee as game-changers in shaping the future of healthcare, clinical research, and the broader biotech sector?

Pepper Landson: I’m a bit old school, in some respects. The more things change, the more they stay the same. We have AI and that’s done some amazing things for our industry and for life in general. It’s accelerated discovery. It’s accelerated this concept of patient twinning, which is interesting.

There is a team at Duke, which is right down the road from us, that did,[00:10:00] I will call it an artificial clinical trial, which I also thought was fascinating. There’s a paper around it. Of course, these things are super helpful. But, what would be most meaningful when you’re talking about the chronic diseases of aging and, specifically, Alzheimer’s and related dementia is innovation and clinical trial design.

The late stage trials, as I’ve already mentioned, they’re wildly expensive. Right now, the folks who can afford to do it are big pharma. Last I checked, Praetego is not big pharma. [laughs] We have to have the mindset of partnering in order to have these big ambitions. but what I love hearing. 

I listened to a town hall by the ADDF earlier this week. Dr. Fillit, who’s the head of ADDF, talks about how innovations in digital biomarkers are going to affect the way we do late stage trials. Innovations in statistical design; I’ve been reading what I can get my hands on around randomized start trial design, which is potentially helpful if you want to demonstrate the value of a disease modifying drug versus a symptom management drug.

Those are the kinds of drugs folks like Praetego are developing, and some of the other, companies in our space. Smarter clinical trial design using higher mathematics, statistical design, things like that. It’s not necessarily the fancy buzz of AI; it’s just recognizing we have to be creative and do it better. 

These are little iterative steps that don’t discount the need for man-years for safety, right? We cannot cut corners on confirming when these drugs are well-tolerated because these patients are already compromised. They’re older. They have other things going on. As long as we recognize that there are ways to be creative and progressive without sacrificing good science, integrity in our research, integrity in our data, and of course honoring the patients who give us their time and, everything else, we can do it better. We just have to do it better.

Emma Moran: Absolutely. Pepper, in your opinion, what key qualities are essential for a biotech company’s sustainable growth and impact in the long term? How do you ensure that Praetego embodies these qualities?

Pepper Landson: It’s a powerful question. It transcends biotech. Integrity. Integrity of process, integrity of people, even integrity of the goal. Are your company’s values in alignment with the way you are developing your candidate?

That matters to me. As I mentioned offline, in addition to 30 years in industry, I’m also a trained executive coach. One of the greatest resources I have as a startup CEO is recognizing the values of the company need to be considered. In the context of how we move forward with developing drugs, right? 

As I mentioned, Dr. Khalifah is a world-class chemist. The integrity of the process by which he considers our candidates and develops our candidates, it’s top drawer. He’s had a huge influence on the way I approach things. Integrity, tenacity, these are big hairy problems that are going to take some strong people who are relentless in their pursuit of an answer. If we wilt at the first sign of trouble, we won’t get very far.

Perseverance, of course, as a feature. Compassion, Why are we doing what we do? Because we want to help people. As a CEO, one of the things I ask anybody we consider hiring or even any vendor we consider working with is: “Do you have a wellness plan for you as a person?” 

Because if we don’t take care of ourselves while we’re doing these hard things, we’ll burn ourselves out. That doesn’t serve the mission. Self-compassion. Compassion for the process, for each other, is meaningful. And certainly, focus. There’s lots of shiny things to get distracted by. We’re all guilty of it, that maintaining certainty and integrity of the mission is also key. But most of all, oddly enough, we need to remember that the best form of healthcare is human connection and kindness. 

 Long before we ever made drugs or needed drugs, being in community, creating community, being there for each other, I think that transcends all biotech and I have an active practice to make sure we do that on a routine basis as a company.

Emma Moran: With all your experience, Pepper, have you got any words of wisdom for young people starting a career in pharmaceuticals and biotech nowadays?

Pepper Landson: Yes, actually. First, let me speak as a caregiver to an Alzheimer’s patient. I’m an APOE4 carrier, too. What we’ve learned as an industry, a community of scientists and clinicians is we can take substantial action now. Especially with those who are younger to [00:15:00] practice good habits that will be brain and health protective.

There’s the obvious stuff: eat well, exercise frequently. The less obvious ones: make time to have fun. Make time for the people you love being around who inspire you, who remind you to laugh. human contact and especially, positive human contact. I mean, the kind that make you laugh until you blow milk bubbles out your nose. That’s its own form of medicine. All work and no play is not a recipe for sustainability as an individual or even a company.

Speaking as a healthcare advocate, not just a CEO, I have a practice I have to give myself in order to do my job. I highly encourage that in the community that I’m really active in, here in RTP, of other CEOs of life science companies. We all have to take care of ourselves in order to do our jobs because these are not easy jobs.

In terms of anybody considering a job in biotech, I love the fact biotech has one of the lowest pay disparities between the sexes. That’s super important. I had the pleasure of traveling the world working in research on somebody else’s dime without having to join the military. That was pretty cool, too.

At the end of the day, find something that really lights you up, work super hard at it, and recognize it’s the long game. Quick solutions do not work. You recognize in the grand scheme of things, that’s okay. The setbacks teach us things. If you really love the work, it’s a great lifetime career. It will have an impact on quality of life of people you’ll never meet, as well as the people you know and love.

Emma Moran: Very wise words. Thanks so much for joining me today.

Pepper Landson: My pleasure. Thank you, Emma.