[00:00:02] Speaker A: You know, in some ways, it's. I really feel somewhat cured, and I'm still sure I have Alzheimer's, but it seems to have stopped its growth and maybe even improved a little bit. So that's our hope.
[00:00:28] Speaker B: Welcome to the Age of Aging, a podcast about living well with an aging brain, produced by the Penn Memory center. I'm Jake Johnson.
[00:00:37] Speaker C: And I'm Terrence Casey. Welcome to season two. In season one, we talked about lacanumab, which ushered in a new era of Alzheimer's disease research and clinical care. And while we were producing that episode in early July, a second anti amyloid therapy was approved by the FDA. We have some ideas for creative stories planned for season two, but we know that new treatments are a top priority for older adults, and especially for patients and their loved ones at the Penn memory Center. So dynanimab became our priority kicking off season two. So, Jake, the age of aging is not a science lesson. What was your approach in telling this story?
[00:01:16] Speaker B: I knew when approaching a story about anti amyloid therapies, there was going to be a lot of information, a lot of things that I wasn't going to understand. So I needed to talk to an expert, which is easy to find when you live next to the campus of UPenn. So I reached out to doctor Sanjiv Vashnavi at the Penn memory Center to get a better understanding of dynamab. But we also wanted to make sure that we got a more personal perspective, because ultimately, these drugs are going to go to patients, and that's the whole purpose of it. At the end of the day, the University of Pennsylvania was actually involved in the clinical trials for dynam, which led to it ultimately being approved. So that's how I got in contact with Dan and Susan Henderson. Dan Henderson was diagnosed with mild cognitive impairment a few years ago. He was ultimately recommended to join the study, and he was able to participate in it for the last few years.
[00:02:19] Speaker C: Just a note to our listeners. The interview with the Hendersons, which kicks off this next story, was conducted over a phone call. And so bear with us. The audio quality is not great, we know, but it will improve as we transition to other parts of the story.
[00:02:41] Speaker A: Yeah, hi, this is Dan Henderson. I'm no longer part of the. Part of the program.
[00:02:48] Speaker D: The clinical trial.
[00:02:49] Speaker A: The clinical trial.
[00:02:50] Speaker D: And I am Susan Henderson. I am his wife and caretaker.
[00:02:54] Speaker E: Dan and Susan Henderson are a pretty typical couple enjoying their retirement.
[00:02:58] Speaker D: We met in college. Dan went to Davidson College, and I went to Queens College. And they were kind of like brother, sister, schools. And that is how we met. Weve been married. We are celebrating 48 years next week.
[00:03:11] Speaker E: But for the past three years, Dan Henderson has been involved in a clinical trial with major implications for the world of Alzheimers disease research and treatment. The trailblazer study, as it's called, is sponsored by pharmaceutical company Eli Lilly to test their new Alzheimer's treatment. Dynamab, marketed as Kasunla Dananumab, is a part of a new class of Alzheimer's disease treatments called anti amyloid therapies. In July of 2023, the first of these drugs, lekenumab, marketed as lekemb, was approved by the FDA after being diagnosed with mild cognitive impairment while he and Susan were living in Connecticut, Dan began seeing doctor Carlowish at the Penn Memory center. After moving to the Philadelphia area in 2021, he enrolled in the lottery for the trial at Doctor Carlowish's recommendation and was eventually chosen to participate.
[00:03:58] Speaker D: His mom had had early onset Alzheimer's and so passed away at age 70 from that. And there were quite a few sisters of hers that had Alzheimer's dementia. But, you know, it just, it gave us purpose for trying to find some kind of progress in the process, and we were pleased to do it.
[00:04:20] Speaker E: Doctor Sanjiv Vashnavi leads clinical research at the Penn Memory center, including the trailblazer study.
[00:04:26] Speaker F: Entoamy therapies are the first disease modifying treatment, meaning they're actually targeting the disease pathology.
[00:04:34] Speaker E: Doctors like Vashnavi have been prescribing drugs to patients with Alzheimer's for decades. But while these drugs help treat the symptoms of Alzheimer's, they don't actually treat the disease itself.
[00:04:44] Speaker F: They're actually nonspecific to Alzheimer's disease at all. We use them for a lot of different diseases. In essence, they try to help the brain work a little bit harder to try to compensate for memory loss.
[00:04:55] Speaker E: What makes leukenimab and dananumab so special is that they target actual changes in the brain due to Alzheimer's, which ultimately seems to slow down the progression of the disease. Amyloid and anti amyloid antibodies refers to beta amyloid proteins, thought to be one of the earliest markers of Alzheimer's disease in the brain. When these proteins over accumulate, they begin to form plaques, which can disrupt brain function. While doctor Vashnavi says that there's a debate in the scientific community as to how big a role these plaques play in the disease, it's become increasingly clear from the clinical trials of these medications that the removal of these plaques does benefit people cognitively.
[00:05:32] Speaker F: The amyloid proteins start depositing. We now know, years before people even have clinical symptoms. Based on imaging data, we know that people start having these plaques even ten or more years before they have significant cognitive symptoms. There are ongoing trials of both lecanumab and didanumab looking earlier, and the idea is, if you remove those plaques even earlier, maybe you have an even stronger effect at slowing down or stopping the progression of the disease. So that part is an open question, whether or not these medicines will work earlier.
[00:06:03] Speaker E: So what makes dananumab different from lekenumab, other than the fact that they're made by different companies? Well, not a lot. According to Vashnavi, they both do effectively the same thing, which is remove amyloid in the brain, but they do that through slightly different mechanisms.
[00:06:17] Speaker F: So amyloid protein starts as a small molecule, which then binds to other small amyloid molecules to become protofibrils and fibrils and eventually plaques. So lacanumab is targeting these protofibrils, which are not quite deposited in the plaque, so they're still somewhat soluble.
Idea that lecanumab, or at least the companies that made lecanumab have suggested, is that those soluble amyloid protofibrils may be the ones that are more toxic. So by getting rid of that, you're able to get rid of some of the toxic effects of the amyloid. Lecanumab also binds to the plaques, so it's able to remove the plaques. But again, the primary target is sort of this intermediate size protofibrils. Dynamab, on the other hand, is really directly targeting the plaques. It actually targets a modification on the plaque, so it actually binds directly to the plaques and removes the plaques. It doesn't do anything to the protofibrils.
[00:07:16] Speaker E: Patients receive both drugs via infusion, meaning a slow injection under the skin. However, dynanumab is a monthly infusion, whereas patients taking lekenumab will get infusions every two weeks.
[00:07:27] Speaker F: Whether one is better than the other isn't clear. In reality, both of these medicines remove plaques. And that really, kind of is the main thing that we've been looking for, is to get rid of those plaques. They both have similar sort of cognitive effects in terms of benefits for patients. But again, there may be some differences based on the targeting.
[00:07:48] Speaker E: A little over 1700 people participated in the clinical trials for dynanumab. Dan was among the five participants. The Penn memory Center contributed to the trial. Here's project manager, Melissa Kelly.
[00:07:59] Speaker G: I think it's really rewarding and special to know that our five subjects here at Penn were a part of that data set that was provided to the FDA and ultimately led to approval of the drug.
[00:08:13] Speaker E: The trailblazer study is whats called a phase three, double blind, placebo controlled clinical trial. Yeah, those words dont mean anything to me either. But what from Melissa explained to me, participants received monthly infusions for 18 months of either dynanumab or placebo. In the next 18 months, they switched to the other, all while getting scans, blood work, and performing cognitive tests. However, none of the patients were ever informed about which infusion they were getting or the results of their tests in order to protect the integrity of the data.
[00:08:43] Speaker G: Around May of 2021 is when we first enrolled our first person. We had a very limited time here at Penn, so we had a very narrow window of time to find subjects. And it is quite a lengthy screening process. And ultimately, our goal was six people. We ended up with five in the trial. And I have been with them all since the day they signed their consent form from the very beginning. So I work with these subjects to make sure they're getting their infusions on schedule, make sure they're getting all the other assessments like cognitive testing, MRi and pet imaging, blood work, all of that, and schedule all the visits, conduct some of the procedures, process the blood. And they've been a very faithful, dedicated group. They have never missed visits, always on time, very motivated to contribute to the research that we're doing, which has been amazing.
[00:09:42] Speaker D: And let me tell you, this guy is a rock star with all this stuff.
[00:09:46] Speaker E: Susan Henderson again, I mean, it does not faze him.
[00:09:50] Speaker D: You know, I am claustrophobic. I mean, you'd have to before you can do any of this. And, I mean, just, even the infusions, he just, he just takes it with the grain of salt. He does a great job with it.
[00:10:04] Speaker G: Dan is awesome. He has a really good sense of humor, and he just has a lot of wit. And, like, will always keep the nurses on their toes. And when they ask him to verify his name and date of birth, he'll sometimes give a fake name and just to keep them on their toes.
[00:10:27] Speaker B: So Melissa Kelly was telling me that you like to crack a lot of jokes, Dan, and give fake names to the nurses and stuff. How you keep such a positive attitude in the, in that situation?
[00:10:40] Speaker A: Well, I guess it's just kind of the way I'm kind of a positive guy, and I do breath jokes and say different things and, you know, so it's kind of natural. It wasn't stressful for me. I, you know, I didn't feel it was at all stressful. You know, the. So three things are dementia, anxiety, and depression. And there was early on, months and months before we even started this, where I was having brain fog. I was having difficulties with a lot of stuff. But then I got into the trial, and a lot of that improved over time. I didn't have those problems as much anymore. So, you know, in some ways, I really feel somewhat cured, and I'm still sure I have Alzheimer's, but it seems to have stopped its growth and maybe even improved a little bit. So that's our hope.
[00:11:38] Speaker F: The one other difference between the two medications is that in dynanumab, at least in the clinical trial, the way the clinical trial was designed, was that Athenae different time points within the trial, people got repeated amyloid imaging to see if they still had that amyloid plaque in their brain. And if they no longer have the amyloid plaque in the brain, they stop the medication and switch people to placebo. The idea with dynanumab is that you may be able to take this medicine until a point when you no longer have these plaques, and then you may be able to stop. We don't have similar data with lacanumab, so it's unclear whether or not we should stop.
[00:12:21] Speaker E: Moving forward, the biggest challenge for doctor Vashnavi and his colleagues is getting these drugs to the most amount of patients and making sure they're the right candidates for these therapies.
[00:12:30] Speaker F: The next step is actual delivery. So, again, we have a screening process, and then how do we figure out who's the right patients for this? So the idea has been to start sort of within our center and then slowly expand beyond our center. Here at the memory center, we have several thousand patients that we follow as part of clinical care. Again, as we started rolling out these therapies, people who are well known to us, who have already gotten a lot of these tests, were the first people who were able to get these therapies again, because they've already gotten some of those four screening steps, they may have already gotten two or three of them even before we started. Right now, we've built a referral pathway, whereas people can send in a consultant neurology and try to get an expedited evaluation specifically for these anti amyloid therapies. The idea is to try to continue to improve that pathway so that if there are patients, even in primary care, who may be good candidates in the past, they may not have been referred to us, or it may have taken a long time to get them to us. There are a lot of challenges, and we have limited clinical capacity and time. The waitlist for appointments in the memory center has been on the order of months, and it's really hard for us to decrease that. As much as we have continued to hire additional faculty. The demand for expertise in this field is just much greater than our supply. So we're continuing to work on trying to, how to maximize our ability to reach patients. We have a lot of information on the Penn Memory center website. We have several webinars talking about these therapies to provide guidance to patients and families, because this is not an easy decision for a patient as well.
[00:14:14] Speaker G: Working with these couples has kind of shifted my perspective on, like, what it means when you say in sickness and in health, because you think about, you know, getting older and getting sick. But I think dementia is a different type of illness and really can shift relationships a lot. And the love and patience that the caregivers show and. And the way that all these couples are able to, like, keep that love going is just really amazing. I'm getting really cheesy, but that's always how I feel. Like it's. I feel lucky. I get to kind of see an intimate look at their relationships and all.
[00:14:53] Speaker D: We're really, really pleased and happy to have been part of it.
[00:14:59] Speaker A: And the fact that it's moving forward and be really used, perhaps, is great.
[00:15:17] Speaker C: Wow. I love the conclusion to this piece. I think it gets to a lot of what we hear all the time from our colleagues at the Penn memory center, that what's most rewarding about this work is working with our patients and their loved ones. Our research staff and our researchers know that the work they're doing is important for the scientific community and for the population at large. But in a given day, you see how important it is for the Hendersons, and you see how important it is to the spousal dyade and the family members and close friends of the Hendersons. And I know this to be true of Melissa in particular, but it's not a unique perspective that she has. We all are moved by the work being done by our caregivers and the resilience of our research participants.
[00:16:19] Speaker B: I was legitimately tearing up when she was saying that in our interview, because I think it's so true. It's incomprehensible what these couples go through, and yet it's something that could happen to one of our parents or someone we love or to us. And so I think it was really intense to hear it come from somebody that works with these couples. All the time. And a beautiful sentiment.
[00:16:47] Speaker C: Kudos to Melissa for wrapping it up so succinctly. But also, I don't want to move past kudos to, to you, Jake and doctor Vashnavi for your tag team in explaining some pretty complex procedures. Do you feel that you know how phase three double blind study works now?
[00:17:07] Speaker B: I'm still not sure what that means particularly, but I think I have a general sense. But yeah, in terms of the actual learning about these drugs, it's, it's funny. I mean, I approach it almost as a learning experience for me as well. So I like to go into this and try and have as little understanding as possible about these drugs or about the topic that I'm going to talk to an expert about because I know that if I don't understand what's going on, the person listening definitely doesn't understand what's going on. So I try and ask a lot of follow up questions and get a sense of what is happening because I don't have a science background. I like science, I like medicine, but it's not something that I studied. Luckily, Doctor Vashnavi did a great job, I thought, explaining it and I think he really made it legible to everybody listening.
[00:17:58] Speaker C: Yeah, we have a science communications training program here and one of the motifs of that is the phrase ignorance is a blessing. I think that not knowing exactly what we're talking about makes us ask better questions of the experts.
[00:18:15] Speaker B: Putting together this episode, it became really clear to me how many people of different kinds of skills and backgrounds go into this work. So you have the participants who are going through this whole process of getting these tests and theyre regular people. And then theres project managers like Melissa Kelly who have this understanding of the background but also have a certain level of social skills interacting with people, making sure that things move along accordingly. And then you have clinicians like Doctor Vashnavi and researchers that have to know all the technicalities of this and make sure that drugs like this are distributed to the right people and to as many people as possible. So I think just the sheer amount of people and different skill sets required for drugs like lecanumab and danamab to even happen is just kind of mind blowing to me.
[00:19:14] Speaker C: In a lot of ways, clinical research is like starting up a freight train. Once you have momentum, things get going. It's easy to see the progress. But getting to that starting point takes so much infrastructure, so much power, so many individuals. I think about one husband in particular who at a research partner. Thank you. Breakfast that we had maybe seven or eight years ago during a Q and a session, he stood up in the back of the room and was clearly extremely frustrated. And he said, nothing has happened. There has been no progress. And it was an important moment, I think, the vulnerability of the caregiver and the transparency of the research team. Doctor Jason Carlois, who not only the co director of the center, but our executive producer in this show, also the doctor of the Hendersons, he responded to say that, in fact, there had been incremental progress with all of these smaller studies, all these things that would eventually get us to this point where we could have approved treatments that are being prescribed by Penn memory center doctors.
But what he understood Washington, how frustrating it was for that caregiver, particularly a spouse or any loved one who would never benefit from those drugs that were being studied. It's a slow process, studying all of these drugs. Doctor Vashnavi spoke about the debate within the scientific community about whether amyloid is even the right track for this freight train to be on. And not everyone is 100% settled on these things. Importantly, we're not done. Now that we've gotten to this point with dynamab, we are studying other avenues of treatment development. We're studying other ways to use these treatments. And for those who won't benefit from dynanumab and the Kanumab, we're working on how we can improve quality of life until there is a treatment available.
If anybody is looking for more information about Danatimab or Lekembe, they can find all of
[email protected]. dot that's Penn p Dash e Dash n Dash Memorycenter.org Dot thanks for listening to this episode of the Age of Aging. The Age of Aging podcast is supported by the Penn Memory center, the University of Pennsylvania Alzheimer's Disease Research center, the Institute on Aging, and the Penn FTD center.
[00:21:48] Speaker B: Contributors include myself and Terence Casey, as well as Nicolette Kalkoveckia, Dalia Al said, Marie Engineering, Jason Carlowish, Emily Largent, and Meg McCarthy.
[00:22:00] Speaker C: More information on the stories you heard today can be found in our show notes and on our website, penmemorycenter.org dot.
