Declining ALS Patients Are Waiting On The FDA's Next Move

So the thought of it, trying of medication through expanded access was simply a no brainer for us. That's Cassandra. She asked us not to use her full name, and she is far too familiar with the devastating effects of a LS often called Luke Garrig's disease. Many members of Cassandra's family have died from a l S because of a rare gene that's passed down through generations. Will hear Cassandra's story later in the program for her family and

thousands of others. A new treatment still in development from the company Biogen, shows some early promise of possibly slowing the rapid progress of the disease. The U S Food and Drug Administration is moving cautiously. It's wary of approving the drug before Moore is known about how effective it

is and possible side effects. But als, activists and people afflicted are pressing the FDA for rapid approval of the drug, or, like you heard Cassandra say, just now, early expanded access to the treatment before approval for those who may have no other hope. Bloomberg's chief medical writer, Robert langerth joins me now to explain what's happening. Robert Langer, thanks so much for joining me today. It's great to be here. But can you talk a bit about a l S

the disease itself, what actually does it do? A LS is one of the most devastating diseases. Basically, the nerves, the control all the voluntary muscles slowly die, and that includes those responsible for breathing, chewing, swallowing. Most people die within three to five years is a typical, and if you choose to go on a respirator and a feeding tube, you can get a new condition that's called locked in, where you're essentially fully paralyzed, unable to communicate with the

rest of the outside world. Your mind and sensors are fully intact about how many people in the US, around the world are afflicted by a L S. Yeah, so in the US figures very about twenty to thirty thousand afflicted with LS. Approximately ten percent of them cases are running families. And then you know the cases roughly uh, the causes are are unknown, so it's you're, not a

common disease, but it is just totally devastating. So that's a lot of people in numbers, and yet not a lot of people when it comes to a drug company spending a lot of money that it takes to develop a drug, and that's been one of the problems associated with trying to find treatments or cures for the disease. It's been very little known about the cause. It's just been a graveyard for drugmakers with numerous failed trials. And one of the problems the disease it's not actually straightforward

to diagnose. There's no like simple blood tests for LS, so it's a kind of a diagnosis of exclusion. So they basically rule everything else out until they can say, you know, the only cause we have we know for the reasons you're progressively getting paralyzed is a LS. We've ruled out everything else, so that means people like often don't get diagnosed until late. That's, you know, another issue for for drugmakers, because you want to try to treat

as early as possible. If you've been online in the last few weeks, there's a good chance you've seen someone taking the ALS ice bucket challenge, people dumping ice cold water on their heads and nominating others to do the same.

I think we all remember about nine years ago now the ice Bucket Challenge where people were pouring cold buckets of ice over their heads as a way to raise awareness and money for a l S. That's certainly raised awareness, we were all talking about it, but in the almost decades since that happened, did it do anything to jump

start both funding and research for cures. Yeah. So one of the historical issues with a LS is that because people die so quickly, it doesn't have that kind of constituency of survivors at some diseases have that can really a lobby and push and attention and money for treatment and research into new treatments. So the ice bucket Challenge kind of did like bring a lot of attention and a lot of new funding to it, and that did appear to result in, you know, more drugs and trials

now that than ever before. And in your latest story about a l S, you write about a new therapy from Biogen which they're trying to get accelerated approval from the FDA, and there's been a bit of back and forth. Can you tell us about that? So in the story, we write about a drug called Toeferson from Biogen, which would be the first drug to attack a known genetic cause of a LS, one of these handful of rare

genes that causes rare, familiar forms of a LS. It's a complicated controversy, but Biologen conducted a small Phase three trial of the drug. I did not succeed on the main goal of its trial and slowing the disease, though it did show promising signs. But what it does do is that it does very clearly lower levels of this blood protein called neurofillment, which is a protein that's released when nerve cells are dying. It's a sign of nerves

cell damage. So that sign is clearly decreased. So it's applied for accelerated approval for TOPS and basically approval of a drug, you know, based on a kind of a bio marker alone without proof that it slows the clinical decline. You mentioned that it was based on a bio marker. What is that. Yeah, so bio markers that's kind of basically a fancy word for blood tests or scans or some other kind of lab or testing value that might kind of show what's kind of going on in the

underlying process of disease. So, so it shows promise, but it hasn't been shown effective yet. It hasn't been proven yet to show clinical effectives. Now, this experimental drug that Biogenna is working on and seeking approval for it is for a subset of a LS that runs in families. So this is not for overall a list, but especially

devastating form of the disease where entire families can be affected. Yeah, this is for people with ALS due to a bad gene called s O D one or sod one, and people with this bad gene that run in their family. If you have just one copy of this gene, you're almost certain to get a l S in your lifetime.

It's so devastating when the people they get it they can they can die within twelve to eighteen months, often an ultra rapid progressing form of LS, and then it can run through families for like generations, like back literally hundreds of years. In your story, you write about a family from Pennsylvania, the Webber family, and they've been afflicted with this form of ALS for generations. You spoke with

Cynthia Weber and her daughter Cassandra. What did they tell you about the family's history with a l S. Yeah, So, in Cynthia Webber's closet for many years, there was a family tree and it was sprawled over two large pages of architecture paper literally detailed three fifty ancestors going back well into the eighteen hundreds, and I gave dates of deaths,

the names, dates of births and deaths and causes. And the reason it was buried away in the closet wasn't that people didn't know it was there, you know, it was because nobody really in the family wanted to look at it because so many people in the family over the years and decades and centuries had died from a LS.

And in fact, more than thirty people on that family tree, on that blueprint, their deaths are marked with the letters A L S, and so in Cynthia Webber's and Cassandra's family, the way they think about it, you know, some people pass on jeans or red hair or green eyes, but they pass on a legacy of death from a LS.

For many years, people in the family were told that before you got married, you had to tell your spouse about the bad genes, about the A L S risk that ran the family, so your potential spouse could have a chance to back out and they would know kind of what they were getting into. For a few years, though, Cynthia Webber's generation, her generation themselves were beginning to think that the bad gene, the L S gene, had sort of skipped their generation because none of Cynthia Webber's siblings

had gotten a LS. But then in two thou nineteen, Cynthia Weber's brother Dwayne started developing symptoms of LS, and he quickly got worse. Bobbing your story, you write how the Webber family sought recent therapies and really had a

difficult time and mixed results. Can you describe their experience with trying to get these drugs that potentially could have prolonged life so because the s a D one or sod one gene runs in the Webber family, that is, the a LS causing gene in their family, they are ideal candidates for this experimental drug from Biologen called Toferson that targets that specific gene that runs in their family.

So Cynthia Webber's brother, Dwayne lindsay he was the first in the recent generation of the family to be diagnosed with a L S, and he in fact managed to get into bao Jen's main phase three trial of it's drug. Toverson, that's the drug that targets a specific gene that runs in the Cynthia Weber family. The family does not know whether he got placebo or the active drug. They believed that when he was on the injections that his LS appeared to progress much more slowly, and then the minute

some of the injections were stopped, he declined rapidly. And the reason they suspect this was because he was in the trial during the beginning of the pandemic and so he missed three treatments because the trial sites shut down during the pandemic temporarily, and during that period when the trial sites shut down, his condition just declined markedly, and the family suspects that he was on the active drug during that period. When we come back, what it's like

when a l S runs in the family. Cynthia Weber's daughter Cassandra, who we heard at the beginning of the episode, has seen the devastating effects of a l S in her own family. Robert Langrith talked about how Cynthia Weber's brother, Cassandra's uncle was diagnosed. Robert spoke to Cassandra and she described the experience and what has happened since. My mom called us and said, girls, I have bad news. Your uncle Dwayne has a l S. And that was I

believe in twenty nineteen. It was pre COVID. At first, the results looked promising. Cassandra's uncle Dwayne appeared to be responding to the treatment, and then COVID came and unfortunately, his experimental trial site decided to stop giving him the to Pherson injections, so he missed three injections and started to rapidly decline. He was able to resume and he got two more, but he had begun progressing quite quickly. After my uncle was diagnosed, he asked his siblings to

please get tested. My mom went to her family doctor in January and requested to have testing done. In June, she called the family doctor's office and asked where her results were. It's easy to get distracted. We were busy. She was here with the grandkids all the time. So finally they got back in contact with the genetic testing company and my mom called me a few days later and said, Honey, I have to go into the office. And I said, Mom, if you have to go into

the office, I have to go with you. And she never wanted to bother anybody, so she said, no, don't take time off from work. But I knew in my heart what the results were. Cynthia became the thirty third person in her family to test positive for the A L S gene, but she wasn't showing signs of the disease. A month later, in July, Cynthia's brother, Dwayne died of a LS. Not long after that, Cassandra noticed small changes

in her mom. Her first symptom was that she couldn't lift her leg up off the floor to get into bed, and she thought it was just a grief reaction that she was upset about her brother and things were kind of in her head, and so she chose to ignore them, and I can't say that I blame her. Within a few months, it became apparent that she wasn't walking very well, and because I knew her genetic test results, I was

watching her pretty closely. She was also sixty nine years old, getting older, and I knew that her risk was going up. Our gene has caught a high penetrance rate, meaning by the time you're seventy years old, you have a chance of getting a l S. Sometime around September, I started to notice that Mom couldn't keep up with us. We'd walked to the park down the street with the kids. We've done that walk hundreds of times, and she was lagging behind a little bit. And then October came with

the kid's birthday and she was doing pretty good. And then she always went trick or treating with us, and she couldn't keep up, even to go around the block. So finally, in a quiet moment, I confronted her and I said, Mom, I'm really worried about your leg. So within a few weeks she called me and she said, honey, I need to see someone. I was at work and I walked out to the parking lot and I screamed

because I knew it was coming. The first thing I did is I called the group I had been working with vir Genetic Counseling, and I said, what can we do? And this was December. She had not been officially diagnosed by anybody, but we knew because Santra tried to get Cynthia enrolled in the trial for the same drug Cynthia's brother had tried with some success, but the trial was full. She pressed for her mother to be placed in Biogen's Expanded Access program, another way to get the treatment. After

some advocacy from her doctor, Cynthia's application was approved. So getting expanded Access was based on your score, which includes things like can you go up and down the stairs? Can you cut your own food? Can you adjust your own sheets? So at that point, my mom was still doing really well. She was actually still walking with a lot of difficulty and not far, but with a walker she could transfer and do most of her own care, but she was starting to progress. At this point, Cassandra

made another decision. So after my mom received her genetic testing results, I realized that I needed to be tested as well, because I had a fifty fifty shot of carrying the gene, and I needed to know so that I could try and be proactive and find anything I could do to try and prevent a LS, even though there isn't anything really, and so that I could know to plan for my family's future and to figure out if my children would need to consider genetic testing at

some point. Because of COVID, everything was over Zoom, So they ship a kit to your home and you do your own cheek swab and send that out to the lab and then it takes about six weeks for your test results to come back. So the results disclosure was on a Zoom call with the geneticist followed by a meeting with a neurologist. They told me I had a time that there wouldn't be any chit chat and as

she would come right out with my results. My husband and I had told ourselves we will be prepared for it to be positive, and that if it was negative, we would just be happy. But you can't prepare. I knew as soon as I saw her face that my results were positive, and when she said it out loud, I collapsed. We were sitting at the dining room table and I felt like someone had punched me right in the heart. I couldn't hear, I couldn't see. I just

collapsed in thinking what about my children? So I knew there was a fifty fifty chance of having a JANEK result come back positive, and even though we had told ourselves to be prepared, we weren't. There really is no way to prepare for hearing this news. I knew all of the numbers. I knew we had a high penetrance rate, that I had a nine chance of getting a last by the age of seventy and you my grandfather died

at sto and his brother at thirty. And the only thing I could think about was that I could have given this gene to my children. Each of my children have a shot of carrying this gene, and we can't test them until they turn eighteen, and they need to make that choice. But as a parent, as mom, to think that you may have passed something like this onto your children is heartbreaking. It's devastating. And I also didn't want them to watch me die of a LS like

I watched my uncle, my grandfather. How many generations of our family have to watch each other die by May of this year, Cynthia's a l S had progressed significantly. She believed to overson the drug had extended her life, but she had lost most mobility in her limbs and decided to stop treatment. She moved into the home of Cassandra's older sister. Three months later, in August this year,

Cynthia passed away. Everyone who knows my mom would tell you that she was the kindest person, always a true friend. She was a registered nurse worked at Harrisburg State Hospital doing inpatient mental health for over twenty five years, loving giving. I found a letter one of the doctors wrote about her, and it was just beautiful. He called her a true nursing professional. He acknowledged her thought process, her compassion, and

that's what everybody would tell you. As a nurse practitioner, I understand the path of physiology of a l S, why the things are happening that are happening, But nothing can prepare you for living through a l S with yourself or a loved one. To see the date by day changes. One night she could use her hand, the next day she couldn't. To lose the use of your thumb means you can't feed yourself. To see someone deteriorate every single day. There's no way to prepare for that.

It absolutely changed the way I view A l S because now I've lived through it, I've seen it firsthand. I've watched her die from it. Nothing can prepare you for that. Since her mother's passing and her own positive test for the A l S gene, Cassandra has become an activist for more research and greater access to treatments.

I think as soon as someone in your family or someone you love gets an LS diagnosis, and you see the fight that we're up against, you see the limited options, the lack of hope, it kind of turns everyone into a warrior. I haven't met an A l S patient or family yet who hasn't gotten into advocacy. It's kind of like the all time underdog, and we all just want to fight, fight for our loved ones, fight for ourselves. I don't think there's a decision to become an advocate.

I think it automatically happens when we come back. Robert Langrith talks about the future of treatments for A l S and other uncommon diseases. Bob the Webbers and other families who are suffering from a L S have rallied the FDA for more rapid approval of these experimental drugs, and there's been a lot of tension in back and forth over that. Can you describe what's happening in the f d A when it comes to deciding whether or

not to release a drug earlier than it normally would. Yeah, So what's happening is that a LS activists they want to see lots of new drugs for a LS, just like there in recent years have been just lots of new drugs for various types of cancer. The debate is over like how much should the standards, you know, be a lesson. You don't want to put something that doesn't work on the market. You could actually inhibit the development

of actually effective therapies. Why does the FDA draw this distinction between cancer treatments which can be approved on an accelerated basis, and diseases like a L S, where it can't. What's the difference there from the FDA's perspective, not that drugs and other diseases can't use the accelerator process. It just that the accelerator process is much more controversial and some of these other diseases that much less is known about.

Biogen had a drug for Alzheimer's which they pressed very hard for early approval, and it was approved, and that caused quite a big controversy, didn't it. Yeah, So the Biogen had a drug for Alzheimer's that they did not clearly show i was effective in slowing disease, and two large trials one showed it slowed the disease slightly and

the other showed no effect. But it was able to get the drug approved using the accelerated process because at lower levels of a bad brain protein called brain amyloid. And that was just extraordinarily controversial because of the contradictory results on whether it actually slowed the disease. And even if one of these drugs is approved on an accelerated basis, sometimes insurers don't want to pay for it and some doctors are hesitant to prescribe them. Yeah, that's something that

can happen. Yeah, the situation for neurological diseases is so new that it's not clear, you know, how it's going to play out. Certainly with the case of Biogen's Alzheimer's drug, agile Helm, essentially medicare the program for the elderly declined to cover an a broad basis, citing the lack of proof that it's low clinical decline. What did Biogen say

about the response to it's Alzheimer's drug. Basically, they've vigorously campaigned to get Medicare to cover their Alzheimer's drug, agire Helm, but it ultimately refused and they were very disappointed by that decision. So what now is the status of Toberson, the A L S drug that Biogen is developing. So it has been submitted to the US Food and Drug Administration. We are waiting a decision by the US Food and Drug Administration, and the company has also submit to the

drug to regulators in Europe. So there should be a lot of action on it early in bob in the best case scenario, what can we expect from to person? The Webber family had mixed results. It was unclear whether Cynthia Webber and her brother received a placebo or the actual drug. What do we know about its effectiveness and what people suffering from this form of als can expect

from this drug? And so Biogen's drug to Person and its main trial after six months did not clearly show a difference in slowing functional decline between drug and placebo after six months. However, big and reported continued studying the drug after the official main part of the trial was over, and in June it reported that people who could receive the drug early on had less decline than those who had originally been on placebo and got switched to drug

drug later. And the drug also lowers level of a blood protein called neurofilment that is released when nerve cells are damaged or dying. And it's this lowering of levels of neurofilment the drug is ability to do that. Biologen is seeking approval accelerated approval upon and do you think that that will happen with Toeferson Bolgin has already completed the longer term trial that showed that it failed in its main goal and then showed, you know, more promising

results on the extension of the trial. But it's seeking approval accelerator approval based on the ability to slow bio markers. So it's really hard to predict exactly what's going to happen. Robert Langreth, thanks so much for speaking with me today. Thank you. You can read Robert Langreth reporting on a L S at Bloomberg dot com. Thanks for listening to us here at The Big Take, the daily podcast from

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