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Connecting ALS is a weekly podcast produced by The ALS Association in partnership with CitizenRacecar. We aim to discuss research and technology developments, highlight advocacy efforts, and share the personal stories woven through the community.
Neil Thakur:
What we have in the ALS space is definitely an emotional investment in every drug where we want every drug to work. We handle this like we handle all of our other scientific decisions where we get outside experts to review the data, to ask tough questions, to think about it, and then to make a recommendation. And then we take that recommendation and see how we can translate that into action.
Jeremy Holden:
Hello everyone, and welcome to Connecting ALS, I am your host, Jeremy Holden. Earlier this week, the ALS Association filed comments with the FDA's peripheral and Central Nervous Systems Advisory Committee recommending that it approved Tofersen, a genetic therapy targeting SOD1 gene mutations for use in treating ALS. Association leaders are scheduled to provide oral testimony before the advisory committee on March 22nd. A decision from the FDA on Tofersen is expected by the end of April, and joining me to talk about all this today is Dr. Neil Thakur, Chief Mission Officer at the ALS Association. Dr. Thakur, thanks as always for being with us.
Neil Thakur:
You're welcome, happy to talk with you, Jeremy.
Jeremy Holden:
Neil, how did the association reach the decision it made to support approval of Tofersen under the FDA's accelerated approval authority?
Neil Thakur:
That was a difficult decision, that's something we have to take very carefully. We have complicated relationships with just about every drug that's under study today. We've supported, I think, over 40 drugs that are under study for ALS treatment, including Tofersen as far back as 2004, I think our first grant was. So we're still sorting through all of the different studies that have contributed to the science that has led to this spot, and it looks like it's at least six different grants. We're not even clear on what our financial interest is in this drug, if any, if there is some, we would handle it in the same way we did with Relyvrio in that, if there is any royalty or incentive that comes back to the association, it would go into our research program directly.
The second thing, of course, is a lot of the bigger pharmaceutical partners in the space are sponsors of the association and many other ALS groups. And Biogen, which is the sponsor of Tofersen, has been a partner with us on many different things for a number of years. But I think the biggest issue that we have as staff and volunteer leaders in the ALS space, is that we have very personal connections to the disease. I know people who've been in the trial, I know people who've been in most phase three trials, when they tell me they have a personal opinion on whether a drug works or not, I'm trained as part of my academic training to discount that and to look at the data. And I can do that, I'm pretty confident in my ability to be dispassionate in that respect, but it's hard when I think about how serious ALS is and how much I personally want this disease to go away and how much I want every drug to work.
And so what we have in the ALS space is definitely an emotional investment in every drug where we want every drug to work. And that's not something that we can go to the FDA with, that's not something that can influence their decision. So we developed a policy and we put it online where we handled this like we handle all of our other scientific decisions where we get outside experts to review the data, to ask tough questions, to think about it, and then to make a recommendation. And then we take that recommendation and see how we can translate that into action.
And so that's what we did here, and we did that with permission and support of Biogen, they gave us information that we could use. And this is the same process that we did with Amylyx and Relyvrio where we had independent reviewers look at that drug before we took a stance. And there have been drugs that have come up for review where we haven't gone through this process and so we just never took a position. And in some cases, it wasn't necessary, in some cases, the company didn't take us up on our offer, but we did ask for Biogen because we know it's important and it's a little bit unusual of a drug. And so we did have independent review and we went over the reviews carefully, we went over the evidence carefully, we talked with our volunteer scientific board, and we came up with this decision to support approval of the drug.
And we're doing that, it's complicated because the drug did not meet its primary endpoints, its initial goals of the study. But as you go forward and you look at how people fare on the drug after a long time out, it appears that they're doing better than people who didn't get the drug as quickly, and so that's really important information. And then the other really important consideration for this drug is that it only applies to a small percentage of people who have ALS, only folks who carry the SOD1 mutation, and so this becomes an ultra-rare form of ALS, an ultra-rare disease. And so to conduct another full-length trial to start over again, to conduct a longer study is really difficult. And so that has to be another consideration and the accelerated approval pathway is an appropriate way to resolve that issue. There's an ongoing study, a prevention study that's going to be able to give more information but enough for some time. And so that could provide the FDA with some certainty after it goes through this accelerated approval.
That was a long answer, but it's actually a pretty complicated question. The short answer is, after careful review and consultation with outside experts, we are supporting approval under the accelerated pathway. And we hope the FDA will hear us on that and we plan to reach out to them and speak to them on that issue.
Jeremy Holden:
I'm struck by a word that you used a moment ago, and that's the ultra-rare nature of the SOD1 mutation. It strikes me that dealing with an ultra-rare community has to put additional pressure on a regulatory agency like the FDA, think about some of the flexibilities in terms of approval because knowing what I know about sample sizes, it's got to be difficult to get a representative sample when you're dealing with a really small population.
Neil Thakur:
It is really difficult. And to do this trial, Biogen engaged a significant percentage of people living with that form of ALS, which is remarkable and difficult to do. And what we keep encouraging the FDA to do, is to treat every drug and every disease as its own scientific problem and not to apply a cookie cutter standard across all diseases. And so far, I think they're going to be open to that, I think it's also something the scientific community as a whole needs to keep in mind that every disease is different, every drug is different, and the consideration applied in a way that makes sense for that disease space.
Jeremy Holden:
We're going to be hearing from Dr. Tim Miller momentarily about what we've learned during the clinical trial process of Tofersen. But talking about this treating a mutation that affects a small, it just strikes me that this is a therapy that would be available and impactful for a small percentage of the population. But are there learnings coming out of this that can maybe shine a light on a path forward for other mutations, for other gene therapies that could be coming in development?
Neil Thakur:
Yes, and that's really exciting because what I'm hoping is that this is the start of a really important wave in treatment for people with ALS. You may remember, Jeremy, I certainly do, that the mapping of the human genome was an enormous event in scientific understanding, maybe the biggest scientific breakthrough or growth in our knowledge in our lifetimes, and that happened in the nineties. And now it takes so long to take that fundamental knowledge and translate that into meaningful treatment.
And as I mentioned, we did some of the first work on the method to silence a gene back in 2004, and this drug is one of the drugs that came out of that technology, but there are others that are also in study now as well. So I'm actually very hopeful that there are going to be other forms of ALS that have a strong genetic component that we're going to be able to treat using techniques like the one that's behind this Tofersen drug as well as other ways of interfering with the pathologic process with someone's DNA that are understudy through NIH that we help support through our advocacy program.
There's a lot going on, and I think one of the fundamental things for people with ALS or who have ALS in their families, is to understand what their genetic status is. And so if they're a carrier of a gene, they may be able to enroll in a prevention trial, as I mentioned, there's an ongoing prevention study for SOD1 as well. Or if they have another gene where there isn't a prevention trial, if they should develop ALS, they know what treatment they can get. Or if they have ALS now and this Tofersen drug gets approved, it may turn out that Tofersen could be helpful to them as well. I'll give you a link where we have information on how to get genetic counseling and testing, that is als.org/genetictesting and maybe you can put that in the notes or something so people can see how to get free counseling and testing.
One of the issues people need to consider is that, once they know their genetic status, it might affect their ability to get life insurance or long-term care insurance, and that's why it's really important that people get counseling. One of the things we did a couple of years ago, is we worked with some scientists and genetic counselors to help develop counseling standards, and those are the ones that are being used today that's really important. And we've also been working in several states on anti-discrimination bills, so genetic status can't hurt people's ability to get insurance. And several of us got to testify in Maryland a couple of weeks ago to support a bill there, and we have other efforts around the country.
Jeremy Holden:
And we can share some links in the show notes about that testimony in Maryland, the Genetic Testing Protection Act, and as you mentioned, some resources on how to seek genetic counseling and genetic testing. Dr. Thakur, before I let you go, something else we've talked about on this program, back in December, we shared with listeners some actions that the association was taking making sure that approved drugs are accessible for people living with ALS. I know some letters went out to private insurers, the VA centers for Medicare and Medicaid, and I should say for listeners, you should talk to your healthcare team about approved drugs and what's right for you. But Dr. Thakur, what can you tell us about the work being done to ensure access of drugs once they are approved by the FDA?
Neil Thakur:
It's a really good point, I'm glad you brought that up, Jeremy. People do need to talk to their providers, all of these ALS drugs are very expensive. And typically, the first time you ask for a drug approval, it's going to get denied no matter what and the physician just needs to go through the process and eventually it'll get approved. We have, as you mentioned, been reaching out to lots of the big payers and for the most part, having success in getting Relyvrio or the newer drug on formulary. It's been less of an issue for the new form of Radicava because they already had processes for the older form.
We had run into problems with Cigna, initially, they just denied coverage of Relyvrio altogether. And so we, and I'm sure other advocates as well engaged with that company. And so they announced a new policy that will take effect in April, but it's still problematic, it still has a lot of limitations and some of them, I think you would agree, are just nonsensical, including not allowing people to be on Riluzole and Relyvrio at the same time, and that's just not how a ALS care works.
We're not done with Cigna yet, we're still fighting for access, and we have a meeting scheduled with some of their leadership where we're going to go over this with them again, and we're going to keep going over it until people have access to the drug, it's important and this is the coverage that people already paid for.
Jeremy Holden:
And we'll keep listeners up to date as those conversations unfold. Dr. Thakur, thanks as always for your time this week.
Neil Thakur:
You're welcome, thank you, Jeremy.
Jeremy Holden:
Well, I recently had the opportunity to sit down with the lead investigator on the Tofersen clinical trial team, Dr. Tim Miller, the David Clayson Professor of Neurology from the Washington University School of Medicine in St. Louis. Let's hear what he had to say. Dr. Miller, thanks so much for being with us this week on Connecting ALS.
Tim Miller:
I'm delighted to be here.
Jeremy Holden:
It's an exciting time in ALS research and in drug therapy. And as listeners are probably well aware, the FDA is currently considering, we talked about this a little bit at the top, considering potential approval of Tofersen. And I want to start with a basic understanding of what Tofersen is and how it works.
Tim Miller:
Sure, I'm happy to do that. The short answer is that mutant SOD1 builds up and is toxic, it's a toxic protein, and Tofersen lowers the level or deletes the instructions for how to make that toxic protein. So that's what it does, it erases those instructions.
Jeremy Holden:
How did we get here? Walk me through what we learned from concept through clinical trials, open-label extension. Where do things currently stand in terms of investigating how Tofersen works, it's efficacy, it's safety?
Tim Miller:
In terms of how we got here is, of course, a long story over the last 20 years now of understanding how to use this class of molecules called antisense oligonucleotides that targets RNA, that's that set of instructions that I was talking about. And this has been in development now, again, for the last 20 years. And one important step was understanding that this drug when put into the cerebral spinal fluid, the fluid that bays the brain and spinal cord, distributes throughout the brain and spinal cord. And then that gives us an opportunity to target the SOD1 gene to lower that gene product, to lower the levels of the toxic protein.
But more specifically, in terms of how we got here more recently to the phase three trial or how we got here to thinking about Tofersen being reviewed by FDA, this drug was tested in a phase one trial, really focused on safety, which then led immediately to the phase two, thinking about dose and range and then phase three, which is to test whether the drug works. And that's where we are now, we finished the phase three trial, there were 72 participants on drug and 36 that got the placebo. They were dosed about once a month with this drug given intrathecally, so this is like a lumbar puncture delivered into the cerebral spinal fluid at the lower level in the back.
And then we did a variety of measurements in people that received a drug versus received placebo. First important point that came up was, did we lower levels of SOD1? SOD1 is the mutant gene that causes disease in this population, did we change that? And the answer to that is, yes, very clearly. And we can see that by measuring the levels of that protein in the cerebral spinal fluid.
The second was, looking at neurofilament, and this is a slightly more complicated, neurofilament is a protein that leaks out of damaged neurons and it shows up in the blood and it shows up in the cerebral spinal fluid. We're able to look at that damage marker and what we found is round about 12 weeks, that level of neurofilament had greatly decreased. And to us, this shows that we've stopped the neurodegenerative disease process. We lowered levels of SOD1, we know that that's causing disease, and now we show with neurofilament that we've stopped that neurodegenerative disease processor or at least greatly slowed it down. You can think of that as putting the fire out, stopping the cause in a way.
Then the next part is a look at the clinical effect. This trial had a primary endpoint, all clinical trials do, that primary endpoint was at 28 weeks, and we looked at the ALS Functional Rating Scale. And at 28 weeks, there was a difference, those on Tofersen doing a little better than those on Placebo, but it was not statistically significant. The trial did not beat its primary endpoint, which at first, this was in October of 2021 when we looked at that data, was a little bit surprising. I think it's become much more clear to interpret that result and this trial as we look out at 52 weeks, so we get 88% of people in the trial decided to go on open label extension.
I should explain what that means. At 28 weeks, participants in this study had an opportunity to get on the active drug. Nobody knows who was initially on the active drug versus initially who was on placebo, but everyone had the opportunity to go on the active drug and the vast majority, 88% decided to go on active drug and then continued on that active drug. And then we followed them looking at those who were on early start, did they get to first one from the beginning or delayed start, did they get it at 28 weeks in the open-label extension? And then looked at later time points.
And we look at it 52 weeks, what you see is those on early start Tofersen clearly different than those that are delayed start, you also see doing better. And then you see stabilization of function, if you look at the ALS functional rating scale, you see stabilization of function out of 52 weeks, especially if you look between 28 and 52, you see stabilization of breathing. And I'm not showing you the slides today, we'll have a webinar opportunity to talk about slides, but the data that I really have enjoyed seeing the most are the improvement in strength that you see at 52 weeks in those on the early start. And to me, this is remarkable, this is not something we see routinely in the setting of taking care of people living with ALS. Strength doesn't go up, it typically goes down, in some it goes down thankfully slowly, others it goes down more quickly, but it goes down. And here we saw some increases in strength out at 52 weeks.
There are some other details of the trial that I'd be happy to talk to you about, of course, but that's really where we are and why we're at this point. Now we say, it does look like Tofersen is having a clinical effect benefit in this SOD1 ALS population.
Jeremy Holden:
And Dr. Miller, thanks for mentioning that the webinar, we can share a link in the show notes, so that that's scheduled first March 15th. Yes, we are in March now, so thank you for that. We talked about the Tofersen being in front of the FDA, currently under consideration, under the accelerated approval path. How does accelerated approval work, how is it different from how we normally think of something going through FDA for approval?
Tim Miller:
Sure, and I'm happy to talk about that, I should make it clear I'm not a regulatory expert and, of course, now we're talking about this before the FDA meeting. In general, the FDA accelerator approval is for a product for a serious or life-threatening disease or condition, I think that ALS qualifies for that, everyone listening to this podcast is going to agree. And then they need to make a determination whether the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. And the discussion for the FDA later in March will be based on neurofilament, to the lower levels of neurofilament. I gave you my opinion, that lowering of neurofilament demonstrates a slowing of neurodegenerative disease process, and that will be up for discussion at the FDA and that is the surrogate endpoint.
Jeremy Holden:
So with Tofersen in front of the FDA, the FDA has convened its central and Peripheral Nervous Systems Advisory Committee, that hearing is scheduled for later in March. What would you encourage that advisory committee to ask? What question should they be asking as they weigh whether to suggest Tofersen for approval?
Tim Miller:
Well, it's hard for me to predict what the FDA is going to ask or what they're going to be focused on at the advisory meeting. I think on the FDA website and some of the things I just told you, those are the type of things that they need to consider. I think step one, is it a serious or life threatened disease or condition? They have to consider that formally, I don't think that's the hard part. That will be just ALS and SOD1 ALS. I think 50% of the mutations in the United States are SOD1 A5V and the median disease duration for that particular group is 1.2 years. So for them, it's an extraordinarily serious and awful disease, and SOD1, ALS, and the rest of the group is also relentlessly progressive downhill course, so this is a serious disease.
To think about surrogate endpoints, they'll need to think about the biological plausibility of the relationship between the disease and the endpoint, and then the likelihood to predict the desired effect, the evidence to support that relationship. Those are all the things that they're going to weigh in on and think about. There is a large literature on neurofilament, neurofilaments are structural proteins that come in three different flavors, light, medium, heavy, just exactly like it sounds, one longer than the other, heavier than the other. Each of these have been examined in the setting of ALS, and what's striking about the measurements of these proteins, is that they're clearly linked to progression rate and survival.
And again, these are dozens of studies, not just a few dozens of studies that have focused on that relationship in ALS, higher neurofilaments typically associated with faster progression rate and shorter survival, lower neurofilament the opposite. But those are the kinds of data that FDA will need to look at and review, these are not studies that are necessarily from me, but these are studies that have been done by the ALS research community over the last really 15 years, but a whole lot of studies in the last five to 10 years.
Jeremy Holden:
Tofersen targeting the SOD1 mutation, and we talked at the top with Dr. Neil Thakur about how many people that vex, the math there. So where I want to go next is the question of whether this can translate to other or does this shine a path forward for other research? Can there be applications for what we've learned so far for other types of ALS?
Tim Miller:
Sure. So I'm happy to talk about the implications of this for other ALS. I think that one thing that I've learned from this study, is that ALS is a treatable disorder, you'd think that I'd already know that, I've had that belief for the last two decades in ALS research. I firmly believe that ALS is treatable that's why I and many other researchers focus on ALS. And there are drugs that slow it down a bit, but this is a drug, at least in some people, and I think the evidence will continue to emerge, as you mentioned, the research continues. This is a drug that bends the curve, this is the drug that's showing some people getting stronger. If you look at the beginning of the trial, end of the trial, 27% people at start Tofersen are stronger than at the beginning of the trial. To me, that's an amazing number.
I've learned that ALS is treatable, and I think that's a really important concept for people listening to this podcast and a really important concept for the ALS research community. Now, having said that, we need the right drug, so with SOD1 ALS, we've gone all the way upstream. We've changed the set of instructions that make the toxic SOD1 protein, that's all the way upstream. So we do need the right drug if we're going to bend the curve.
The other thing we've learned about ALS from this study, in my opinion, is that it's going to take time to heal. If you look at the data 28 weeks, a neurofilament went down, I think that the neurodegenerative disease process was greatly slowed down, but yet at 28 weeks, there was some difference, but not a lot, it's not until you look way out at 52 weeks that you begin to see that healing process. And so it's going to take time to see these clinical benefits, it's going to take time to heal. So I think those are other learnings from this.
Another maybe neurofilament, because we get asked this question a lot now, there clearly could be drugs that work for ALS that don't change neurofilament. A good example of that might be a drug that's focused on muscle, it could be that stabilizing muscle will stabilize the motor neuron, which will in turn lower neurofilament, that's possible. But I wouldn't expect at first pass that a drug that improves muscle function in the setting of ALS would affect neurofilament or something that hits the junction between the motor nerve and the muscle or the way that the motor nerve conducts electrical properties. All those things could make ALS better, I would not predict would change neurofilament. But if neurofilament moves, I think we've learned something and if it goes up, I think that's probably overall not a good thing. And if it goes down, I think that's probably predictive of success. And so I think that we've learned about using neurofilament as part of that readout, and I anticipate that neurofilament will continue to be incorporated into clinical trials.
And then the last piece, though this has already really been launched, is the blueprint. We've been talking about the SOD1 Tofersen program, SOD1 antisense program as a blueprint for how to treat a number of other neurologic diseases, including non-genetic forms of ALs. And that delivering this molecule called an antisense oligonucleotide in this way that can target a specific set of instructions is now being done in a number of other neurodegenerative diseases and being done in other forms of genetic ALS and being considered also for non-genetic ALS. So it's a blueprint for how to use this type of therapy, and I think we'll continue to have important learnings for this drug.
Maybe there's two other points that I'll bring up. One is, I want to highlight the tremendous effort from the community of people living with ALS with SOD1 mutations. There are many people that have participated in this program from the very beginning, and I just want to highlight their efforts and their commitment. Again, this is not an easy study for them to participate in, so I really want to give a shout-out to the participants and to the families. Also, I want to recognize the site staff that did the work, a tremendous amount of effort from the sites and from a whole lot of people and just to remind the community that this was an enormous team effort. And I'm happy to go through all of the people that were involved, and I think that hopefully those are listed somewhere. But this was an enormous team effort, I'm delighted to have the opportunity to be the spokesperson for this large team, but a large team behind this.
I think it's an incredibly exciting time to be in ALS research, and it goes back to the point that I made earlier, I do think, and this is my opinion, that this shows us that ALS is treatable. That concept is so important for the many people that are focused on ALS research, which is, we really could have an impact if we find the right drug. And also, the people living with ALS, which is, there might be something coming through that could really bend the curve. I don't know know what that next one will be for the next drug coming through, I don't know what that'll be for non-genetic forms of ALS, but I'm confident that it's out there.
Jeremy Holden:
I want to thank my guests this week, Dr. Tim Miller, and Dr. Neil Thakur. If you like this episode, please share it with a friend. And while you're at it, rate and review Connecting ALS wherever you listen to podcasts, it's a great way for us to connect with more listeners. Our production partner for this series is CitizenRacecar, Post-Production by Alex Brower, production Management by Gabriela Montequin, supervised by David Hoffman. That's going to do it for this week, thanks for tuning in, we'll connect with you again soon.