Subscribe
Share
Share
Embed
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.
Kuldip Dave:
The Advisory Committee voted 9-0, in support of accelerated approval. That is amazing news in this day and age, to see that kind of unanimous support for accelerated approval. Oh, which by the way has never been used in ALS before, was really, really great news for our community.
Jeremy Holden:
Hello everyone and welcome to Connecting ALS. I am your host Jeremy Holden. On March 22nd, the FDA's Central and Nervous Systems Advisory Committee paved the way for approval of Tofersen to treat ALS connected to mutations in the SOD1 gene.
The committee voted unanimously that a reduction in plasma neurofilament light concentration, is reasonably likely to predict clinical benefit of Tofersen. Now, on a second question, the committee voted 5-3 with one abstention, that the clinical data surrounding Tofersen does not provide convincing evidence of effectiveness of Tofersen in the treatment of patients with SOD1 ALS.
Ultimately, the committee reached consensus that the benefits of Tofersen outweigh the risks. A final decision on Tofersen's new drug application is expected before April 25th. Now, this has important ramifications beyond the population of people with SOD1 mutations. Ramifications, we will discuss shortly with Dr. Kuldip Dave, Vice President of Research at the ALS Association.
First however, as they considered the data on Tofersen, the Advisory Committee heard from dozens of voices from the ALS community, who spoke in favor of approval including Calaneet Balas, President and CEO of the ALS Association. One of the other voices the committee heard from, was Larry Falivena, a member of the association's board of trustees, who has been living with ALS since 2017 and who has participated in the Tofersen clinical trials. Larry, thanks as always for being with us on Connecting ALS.
Larry Falivena:
Thanks. Yeah, I appreciate being here.
Jeremy Holden:
Well, we talked to you a couple weeks ago and just last week from this recording, but on March 22nd, you did testify before the FDA's Advisory Committee as they consider whether to recommend approval of Tofersen for the treatment of ALS, for people with SOD1 mutations. You of course, have been a participant in the Tofersen clinical trials. When you spoke to the Advisory Committee, what was the message you wanted them to hear as it went into its deliberation?
Larry Falivena:
Yeah, I think there were two things really. One is that there is a real world evidence that Tofersen is effective, despite the fact that the VALOR trial didn't meet its endpoints. Myself and many other of the people who testified in front of the committee, talked about how their ALS had drastically slowed down, in some cases stabilized. There was even the one young woman who said her symptoms had reversed, which is pretty much unheard of in this disease.
I wanted them to understand that there's real world evidence that this works. The open-label extension data, which was over a much longer period of time than the trial, really has some evidence of the effectiveness of this treatment. The second thing that I really wanted them to take away, is that there's a desperate need for this treatment. It affects not just the person with the disease, but there's wide-ranging effects in families who've lost people for generations and there's a higher tolerance for risk in this patient community.
Jeremy Holden:
Larry, you mentioned some of the other testimony that we heard over the course of 90 minutes, two hours of public discussion, more than two dozen people spoke and a lot of the testimony, I found to be incredibly moving. What did you hear from some of the other folks who addressed the committee? What was some of the message? What really resonated with you, hearing so many of those stories?
Larry Falivena:
Yeah honestly, I think one person had mentioned they lost over 30 members of their family over the years, which to me is just, I can't imagine that and even the very first testimony was from a woman from Allison, who's local to the area. I know her personally. I knew her husband, Corey. He helped me when I was first diagnosed and she said many times, that she feels like Tofersen had given him extra time.
They have two boys around the same age as mine. It was very, very moving. I actually commented to her, that I was glad I didn't have to speak after she did, because I was definitely tearing up, but I think it just really illustrated the desperate need for treatment for this disease. It's a small group, but again, the effects are wide-ranging.
When you're talking about families losing multiple members for generations and then being a family member, knowing that you have the potential of getting this disease and I've said it before, it's like an axe hanging over your head and you don't know when it's going to drop. Yeah, it was incredibly moving. I know the folks on the committee are there to look at the science, but they're also human beings and I have to think that moved them and actually, some of them even commented about how they understand that human aspect.
Jeremy Holden:
Yeah, it definitely felt like it had an impact on the follow on discussion and we will of course share a link in the show notes too, the YouTube video. For folks who weren't able to tune in, can go back and listen to some of that testimony and be similarly moved. After the public forum and after a follow on discussion, the committee held two votes on Tofersen.
We talked about this at the top, but the committee held two votes on Tofersen finding unanimously, that Tofersen is likely to predict clinical benefit and narrowly voting that the data did not convincingly demonstrate effectiveness, but in a follow-up discussion, the committee reached unanimous consensus, that the benefits outweigh the risk and all of this essentially paves the way for accelerated approval. Larry, what was your takeaway on the entirety of the day, the final votes from the committee and as we move into FDA consideration, ahead of that PDUFA date at the end of April?
Larry Falivena:
Yeah, I think the first vote confirmed the biomarker information, which is good for two reasons. One, we've been searching for effective biomarkers for a long time now, so if we've really got the handle on this, that's fantastic for a lot of reasons and I think the second vote, really was influenced by the question being targeted towards full approval, not accelerated approval.
And I think that's why at the end they wrapped up and said, "Hey, the rewards outweigh the risks," and that paved with the way for the accelerated approval and I think if the FDA stands behind what they've said about flexibility and being able to use more latitude for treatments for ALS, then I think it's pretty easy yes for them honestly at this point, to give accelerated approval and the fact that there is the open-label extension ongoing.
Biogen said they're going to continue that through 2024, so that will provide additional data, long-term data. At that point, myself and others will have been two, three years worth of data. I think the FDA has the pathway to provide accelerated approval to say yes and then they'll continue to get the data that they need, to confirm what I think we in the community know, which is that this is an effective treatment.
Jeremy Holden:
Yeah, it strikes me that in the discussion around that second vote, that some of the members of the committee were a little bit, I don't want to say concerned, but they were trying to really figure out what that term convincing evidence meant and in the parlance of our times, March Madness, does it have to be a slam dunk? And it seemed like even two of the members who did vote against the convincing evidence standard, explicitly said, "But, this should not stand in the pathway. This should not stand in the way of accelerated approval." I think that consensus at the end, I think does really open up a path for the FDA to, as you said, do the right thing.
Larry Falivena:
Yet and I forget who the person was, but I think there was even an FDA staffer, who clarified that they're not looking for 100% and that's where I think again, at the end where it was summarized that the benefits outweigh the risk, that's really what we're getting at.
Jeremy Holden:
Well, we've got about five weeks until the deadline for the FDA to make a decision, so we will all be watching closely. Larry, thanks again so much for your time.
Larry Falivena:
Yeah, I appreciate it. Thank you.
Jeremy Holden:
To understand why the FDA's decision on Tofersen is important beyond the population it is intended to treat, I recently sat down with Dr. Kuldip Dave. Dr. Dave, thank you so much as always for being with us on Connecting ALS.
Kuldip Dave:
Thank you for having me, Jeremy.
Jeremy Holden:
Yeah, we talked to Larry Falivena, board member of the ALS Association, a member of the board of trustees, about his experience testifying before the Advisory Committee, but I'm curious, as the Vice President of the association's research arm, what was your take away from the Advisory Committee's discussion of Tofersen?
Kuldip Dave:
Yeah, let's remind ourselves of what happened at the Advisory Committee. There were two questions that the FDA was asking the Advisory Committee. One, the first question was on accelerated approval and that is whether the biomarker change seen in NFL is likely to predict clinical efficacy and in this case, when something is approved through an accelerated approval, a confirmation study is required to follow up.
The second question that the FDA asked was on standard approval, which is as the data stands today, is there enough confirmatory evidence to grant it full approval, IE that no follow up confirmation trial is required? Those were the two questions in front of the Advisory Committee and again, as a reminder, the first one, the Advisory Committee voted 9-0 in support of accelerated approval. That is amazing news in this day and age, to see that kind of unanimous support for accelerated approval. Oh, which by the way has never been used in ALS before, was really, really great news for our community.
They voted 3-5 against or with one abstention, that it is not ready for full approval and one thing it's important to note Jeremy, is that Biogen, the sponsor here, was not asking for standard approval. They're asking for accelerated approval and they got that. My takeaway, is that the Advisory Committee bought into the hypothesis that drugs take some time to work and that the biological effects seen with Tofersen, which were early on SOD1 reduction, NFL reduction, that those changes preceded the clinical effects, which happened to emerge later on.
Jeremy Holden:
And correct me if I'm wrong, Dr. Dave, but there is an ongoing trial of Tofersen, that could provide those confirmatory results, after accelerator approval is granted or regardless.
Kuldip Dave:
That's right and the study that you're mentioning is called the ATLAS trial. It is run by PI Michael Benatar, who also happens to be the chair of our research committee and what Tofersen's results showed us, the VALOR study showed us that which was presented to the Advisory Committee, is that the earlier you get on Tofersen, the better outcomes you had and we saw that in the results that were provided.
The ATLAS study goes even one step further. It is testing whether you can even prevent people with SOD1 mutations, who have the mutations but don't have the disease, from getting the disease in the first place or that you can delay when the disease onset happens. This is a really good confirmatory trial to happen on the heels of the VALOR trial, because it will confirm that the earlier you start Tofersen, the better it is in terms of clinical efficacy.
Jeremy Holden:
And if people want to go back and listen to and understand further about Dr. Benatar's research, go back and listen to our interview with him from a couple weeks ago, we can share a link in the show notes for those who want to go back and revisit that conversation. Dr. Dave, how will the committee and the FDA's decision, impact future drug approval considerations and the drug development pipeline?
Kuldip Dave:
First of all, let's remind everybody the FDA hasn't made a decision yet. The Advisory Committee is a committee that advises the FDA. The decision from the FDA is expected by April 25th. In less than a month, we hope to hear positive news from the FDA that this drug will be approved through accelerated pathway.
In terms of future drug approvals, if this goes through, if the FDA approves it, it will be the first accelerated approval in our space and that opens up a path in the future, for other companies to use a biomarker like NFL, as a way to be able to predict clinical efficacy and this trial and this Ad-Com showed that even if you have a six-month blinded study, that if you follow patients through an open label extension study and can look at a longer time point, that if your drug works in that longer time point, that you may be able to relate it back to a biomarker and then link that biomarker to the clinical benefit that's seen later on.
I always like to say Jeremy, think about ALS, it may be a decade or two decades disease pathology, that is probably happening in the background, until symptoms come up and we expect our drugs to work in six months to reverse that years and years of damage and this and the way the Ad-Com went, could really open up avenues as to how drug sponsors in the future can link a change in biomarker to clinical efficacy.
That I think, is going to be important for the drug development pipeline. I think companies will look at this as a way to say, "We have a standard approval process, by which Relyvrio was approved just a few months ago and now we have an accelerated approval process, by which hopefully Tofersen gets approved and that opens up more avenues for our pipeline to leverage.
Jeremy Holden:
And seeing some of that flexibility from the FDA that the association has long called for perhaps, as many listeners are likely aware, SOD1 mutations represent a small portion of the population of people living with ALS, but it struck me that a couple of folks who testified before the Advisory Committee made clear, that they do not have SOD1 mutations, they have ALS, they don't have SOD1 mutations, still out there speaking on behalf of accelerated approval of moving forward with the NDA. I'm curious your thoughts on how approval of Tofersen could be a win for the entire ALS community.
Kuldip Dave:
Yeah, for this, let me give a little bit of a quick background on why Tofersen is different. Tofersen, it's a gene therapy and we don't have a gene therapy approved in ALS. Relyvrio, Radicava and Riluzole, all of them are small molecules or chemical compounds. Tofersen is different, it's a gene therapy that targets, as you said in this case, a particular type of gene that is linked to ALS, called SOD1 and yes, SOD1 ALS is 2% of all ALS, but the approval of such a therapy could have a tremendous impact on the other 98% and this is how it does that.
One, it is a gene therapy. If this gets approved, it opens a path for other gene therapies, whether they are specifically targeting a particular gene linked to ALS, maybe it's c9orf72, maybe it's FUS, F-U-S gene, maybe it's Ataxin-2 gene or you could use a gene therapy like an antisense oligonucleotide, which is what Tofersen is and you can go against targets, that affect the sporadic component of ALS.
I'll give you an example. There are certain target proteins or genes that we know are linked to sporadic ALS. 98% of people with ALS have TDP-43 aggregates or this protein called TDP-43, which accumulates in the spinal cord and the brain. We could use a gene therapy against TDP-43. Similarly, there is a protein called Stathmin. There's been a lot of research on Stathmin in the last decade and Stathmin regulates TDP-43 levels.
You could have a gene therapy against Stathmin and in fact, we don't even have to think about this, this company called QurAlis, which by the way, we have supported through our ALS Association Barnett program in the past, is currently in the clinic developing a gene therapy against Stathmin and that would be for all of ALS, whether you have genetic ALS, familial ALS or Sporadic ALS and an approval of Tofersen would be a win, because it lays the path for genetic therapies and it lays the path for a genetic therapy potentially be being used for Sporadic ALS.
Jeremy Holden:
It is safe to say we could potentially see proof of concept of genetic therapy, ASO technology and accelerated approval in the ALS space, depending on again what FDA decides, but that's what we're potentially looking at.
Kuldip Dave:
Yeah, there are many firsts in this case and you are right, it will be the first gene therapy, it will be the first antisense oligonucleotide. By the way, not all gene therapies are antisense oligonucleotides. You could have siRNAs, you could have a vector approach, you could have CRISPR/Cas9 approach. There are many approaches of genetic therapies, genetic approaches and this is one of them, but this would be the first and of course accelerated approval. You're right, this really opens up many pathways for drug development pipeline.
Jeremy Holden:
You mentioned a neurofilament light earlier, sometimes referred to as NFL, not the ones with the Super Bowl, a different NFL. The discussion around neurofilament light, what did you come away from that out of the Advisory Committee?
Kuldip Dave:
Yeah, a little primer on NFL or neurofilament light. Neurofilament light is a protein that makes up axons of our brain cells. Brain cells have three big parts, dendrites, cell body and an axon. An axon is what connects one neuron or one brain cell to another brain cell or it connects one brain cell to the muscle fiber and what we think is happening, is that when these axons are dying like they do in ALS, that the axons degenerate and the NFL protein that makes up these axons, breaks up and then gets into our cerebral spinal fluid and then gets from the cerebral spinal fluid, into our blood and spills over into our blood and NFL is a marker of neuro degeneration.
If cells are dying, it's going to increase both in CSF or cerebral spinal fluid and in blood components like plasma. This type of work has been going on in NFL for the last two decades, I would say and what we know now, is that NFL is linked to the progression. The higher the NFL, the faster your ALS progression. It's also linked to severity of the disease.
The higher the NFL, the more severe clinical outcomes like survival are in play and what Dr. Benatar's studies have showed, is that it may be related to diagnosis. His study showed that in people that have mutations that are linked to ALS, maybe a year before they get symptomatic or they start to show symptoms, their NFL starts to go up and it may also be related to diagnosis in that way and that's exactly what's being leveraged in the ATLAS trial, that we talked about earlier.
This understanding of its linkage to progression, to severity, to diagnosis, is really important. What we need to be clear about, is that not all drugs are going to work through that mechanism. If there are drugs that are not working through preserving neuronal integrity, then they may not show a change in NFL and I think our approach to NFL has to be nuanced.
It's great that we have a biomarker like this available to us, but that there may be therapies and a perfect example of this Relyvrio. We just saw from an Ad-Com few months ago, it did not change neurofilament light levels, because it may work through a mechanism to restore neurons, which is different from restoring neuronal integrity, which is what Tofersen is doing. I think it's a really nuanced approach, Jeremy to think about NFL.
However, having said that, I do think that this opens up future avenues. Drug companies may be worried about entering into the ALS space. They may be worried about, it's too risky, that it's a rare disease. How will FDA see our drug? What if we do see change in NFL or we don't see a change in NFL? They may worry about this and now we have examples with two very different drugs, working on different biological pathways.
One changing NFL, one does not and one getting through via standard approval and one hopefully getting through via accelerated approval. I think it's a really nuanced way to think about NFL. We would love NFL to be the next cholesterol of ALS and what I mean by that, is when you go year after year to a doctor and cholesterol is looked at in your blood and when your cholesterol levels are high, the doctor will tell you, "Hey, do some exercise or eat less fatty food or here, take a cholesterol reducing medication."
You have no heart disease, but your doctor is taking preventative steps from you getting to heart disease in a few years, because cholesterol is linked to heart disease. We would love to get neurofilament light or any other biomarker in the future, to be that cholesterol, that is measured on a yearly basis, after a certain age and that if your NFL or that biomarker level is up, that there may be prevention strategies, that a neurologist can put you on and I think that's the kind of blue sky type opportunity we have in the future.
Jeremy Holden:
You talk about the nuance Dr. Dave and I think this is a good opportunity to remind listeners, that if you are considering what treatment is right for you, have that conversation with your physician, with your multidisciplinary care team. Those are the best folks to help guide you through that decision making process and just pause to reflect on the fact that we're having to say that now, because treatments are coming through the pipeline and it's a good conversation to be having, hopefully more of those down the road. Easy one before I let you go Dr. Dave, just let's look ahead to the future. What impact could all of this have on the future of ALS research?
Kuldip Dave:
This is, I think one of the most exciting times in the ALS space right now. Think about this. In the last year and a half, we've now had three Ad-Coms, two for Relyvrio and one for Tofersen. This is an exciting time. We know that ALS is a complex disease and there may be redundant biological pathways in our body that lead to ALS.
Someone may get ALS, because their inflammation pathway is disrupted and someone else may get ALS, because their autophagy pathway is not functioning well and someone else may have a mitochondrial defect for which they get... Because it's so complex, we know that ALS is probably going to require multiple treatments, just like other diseases have, cancer, HIV and that's okay if it's a maltreatment disease, as long as we're able to make ALS a livable disease.
And the drug development pipeline, has to be more shots on goal, not all eggs in the same basket. I'm using all these different phrases, but we can't afford to have all of our eggs in the inflammation basket or the autophagy basket or the mitochondrial basket, because we don't know what all of those different pathways are going to work, for a particular patient and the more different kinds of approaches get on the market like Relyvrio, which is a small molecule and going after mitochondria and oxidative stress versus Tofersen, which is a gene therapy going after SOD1 protein. The more of these types of approaches get advanced and hopefully get approved, the more avenues our ecosystem will have, to get success.
Jeremy Holden:
Dr. Dave, thanks so much for your time, as always here on Connecting ALS.
Kuldip Dave:
Thank you Jeremy, for having me.
Jeremy Holden:
I want to thank my guests this week, Dr. Kuldip Dave and Larry Falivena. If you liked this episode, share it with a friend and while you're at it, please 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.