NDA late last year. What was the outcome, and what is the path to filing an NDA for accelerated approval?
The meeting was actually two last year, one in July and one in November. We announced it in December. The July one, the agency was like, "Look, we don't think you have enough data to go back and analyze more." In November, that flipped. Now, to be fair, the November meeting, we had three experts with us. We presented more survival data. The agency also said a very interesting path that's been laid out that we're in the middle of pursuing now, which is simply this: that yes, we were regulatorily flexible with Tofersen. Qalsody, the brand name, Biogen's asset for SOD1 ALS. We did so in a very small patient population. Qalsody is 300 or 400 individuals. We knew that there was a demonstrable neurofilament change.
Now, yes, you were significant in your pre-specified serum and plasma data in the HEALEY program, but your change is much more modest than is Tofersen's. What we need to do is we need to see if you can leverage other data to increase the persuasiveness of your findings. The recommendation from the agency, and that was exactly their word, including the word leverage, I'm quoting directly from their communications to Clene, that we announced publicly in December, is to look at the real-world experience that we have presently underway in the NIH-sponsored Expanded Access Protocol. What happened there, just to give your listeners context, is that the NIH gave us a $45 million four-year grant.
That $45 million four-year grant enabled Clene to roughly expand the number of people struggling with ALS who were unable to get into clinical studies and enabled them to come onto CNM-Au8, our asset, for compassionate use in such an Expanded Access Protocol. The third such Expanded Access Protocol that the FDA has approved. The difference, though, with this NIH one, the third one, is that neurofilament is being captured quite comprehensively. It is being done in a very innovative way. We are having the neurofilament captured by home-based phlebotomist pulls. For an ALS patient, a person struggling with ALS and their caregiver, rather than having to go to the clinic to have their blood taken, the phlebotomist comes on site to their home. This is done at baseline and every up to 12 weeks, 6-12 weeks, through the entire time that they are on the study.
We fully enrolled that NIH program in its initial incarnation, up to 180 subjects by December. This summer, we'll have all of those subjects complete at least six months, replicating, therefore, the six-month study in HEALEY. What's interesting is we started enrolling these individuals with ALS into the NIH-sponsored EAP last summer. By this summer, we'll have some people at a year. We'll have a good measure at nine months, which is very relevant for Clene. We've talked about this before. It takes six months to get to steady state. We'll have everybody at six months.
What that's effectively doing is, yes, it's not placebo-controlled, but it does give us, and I'll get to the statistical analysis plan in a second, it does give us a pretty good sense of neurofilament from all of those individuals, which in the aggregate is about 3x the number from the HEALEY platform study itself. Back to the point of the agency's recommendation, you've got this safe asset. You are studying it presently in the open-label experience, but you've now, in that case, compared actives to actives. Let's have you prepare a statistical analysis plan with pre-specified structure, analysis, data, et cetera, because what happens in neurofilament's case is all of that blood is frozen. All of that blood is sent to a central laboratory.
One analyzes neurofilament by the design of present technology at the same time for not just the baseline, but every serial collection through the entire course. Literally, all that blood is presently frozen, sitting in a laboratory, and continually is added to with each of these 6-12 assessments. The key is to see if that biomarker data from the neurofilament assessment that we'll be capturing this summer from a 3x larger analysis data pool is concordant effectively with what we saw originally with HEALEY. If that is the case, the agency said, as they always do, this will be a matter of review. That data could be a possible avenue to the accelerated approval path based upon a biomarker.
Now, in parallel, we're continuing to track all of the survival data that Clene has captured for now nearly four years, not just from natural history controls. One can dispute if that's the right approach. The agency themselves is getting their head around whether or not natural history controls are effective. What's also interesting is we have the survival as people continue to mature in the open-label extension. Just recently, a week ago, in fact, we announced data from the entire Regimen A population. I don't know if that'd be helpful to explain the context there. Just to remind listeners, HEALEY was a platform program. Initially, there were three regimens. There was subsequently a fourth, a fifth, a sixth, seventh, and eighth. All of the regimens have thus far read out negative on the primary endpoint.
ALS-FRS, ALS Functional Rating Scale Revised, more precisely, the primary endpoint for all eight regimens with eight different companies' assets have proven negative at the six-month mark for everybody. Clene remains the only asset of the eight regimens to have a survival benefit, which was a key secondary, to have an exploratory benefit of clinical worsening, a key exploratory, and to have a neurofilament benefit in the six-month double-blind. What we've done just last week is we used Regimen A data, the entire cohort of Regimen A, not just the 120 actives, but the 60 placebo as well, totaling, I'm sorry, the 40 placebo, totaling 161 total subjects. They were randomized. It's a concurrent control. They were randomized at the same time into the regimen as all of the regimen Cs.
Any individual coming into the regimen had to meet the same inclusion criteria, had to meet the same exclusion criteria. They were randomized originally to one of three regimens, A, B, and C. Subsequently, when D came online, Regimen D. Regimen A was stopped for futility. Though the asset was considered safe, there was no benefit of efficacy whatsoever. The built-in HEALEY futility was triggered. All patients were pulled off drug and either left the program or rolled over into other individuals, other regimens.
Were they the worst ALS-FRS result?
Yes, it was. It is also a concurrent control for our assets. It is, if you will, a surrogate for the placebo because those individuals could have been in our regimen save for randomization. What we just showed with that analysis is that we have, again, survival that was significant, not just at six months, less than 0.5, again, concordant with the survival we saw against our own placebo set. We also saw that if you look at how we're building our phase three design, which namely is to look at individuals who have a certain neurofilament at baseline and also a certain compromise with respect to their TRICALS risk score. In other words, we're trying to give an apples-to-apples comparison as we build a phase three.
We found that the statistical significance of survival is by an increased hazard ratio and a higher p-value as well. It helps us build the phase three design as we prep to start those individuals in the summer.
Are you actually looking for a larger neurofilament delta with the patients you're treating and analyzing this summer than you saw, or are you just hoping for the increased n to statistically bring you?
Both. Both. The end.
Explain why you're expecting an increased NFL delta.
They're sicker individuals. We know exactly because they are unable to enter any of the classical clinical programs. Even if it's the same delta, Jonathan, then that would be the first seen as HEALEY was the first seen in a double-blind placebo in such a pre-specified statistical analysis plan assessment if it's statistically significant. It's not so much I think that we're hoping for an extraordinarily better neurofilament result, but we're looking to make sure that the first data that we saw at HEALEY was not a false positive, as it were. There is naturally, I think, a concern of any scientist looking at the data that the neurofilament data that we saw at HEALEY was real.
One way to assess that true effect is to also look at an end that is, yes, larger by 3x, as I mentioned earlier, but also to see if we see concordant statistics in a pre-specified statistical analysis plan to help buttress, build, strengthen the argument that we saw with neurofilament at the beginning. I think it's important for the sake of treating ALS people who've already struggled with this disease immeasurably. Now effectively, there's only two drugs in the United States. There's only one drug most of the rest of the world. That same drug, Riluzole, has been available since 1995. In 100 years, nearly, since Lou Gehrig was diagnosed with ALS, we still have only one therapy that's available worldwide, Riluzole, now long generic. We have had 12 nearly failures on ALS-FRS in the last two years.
Clearly, these people who struggle with ALS have been put through the ringer. This disease remains uniformly fatal. The key question, I think, for Clene and the investment thesis is, will the neurofilament data be concordant sufficiently to add to the robust argument that we felt we already had with HEALEY, but make it more robust, more definitive, more evident? Will such an NDA be able to be written that the agency might accept and take to an advisory committee conversation next year? That is the ALS side. I want to make sure we do not leave time. We have time for, rather, the multiple sclerosis side as well, because I know that has been something that you have been very keen on.
On the ALS side of the equation, this is one drug at one dose, 30 milligrams, that if, in fact, the neurofilament is concordant with the HEALEY program, if, in fact, the survival continues to mature. To your point, we have now people that have been in the Expanded Access Protocol for nearly five and a half years in a disease that's uniformly fatal typically for two to four years, even if you take into account the faster slow progression argument. Something seems to be going on, whether we're in the open-label extension with the people we manage that started on this asset in 2019 or in the Expanded Access Protocol that was initially approved. We are still watching many of these people continue to take CNM-Au8 every morning by mouth orally.
Can you help us understand, compared to other highly active groups, give us a good sense for your survival data versus what those patients have had for survival data? Just so we can understand what the FDA is looking at for survival.
In the double-blind period for the eight HEALEY regimens, there's none of the assets that achieved in the secondary endpoint, six-month period of.
That same longer-term data where everyone took drug.
And so.
The other patients, what was the survival with those?
Again, there isn't any survival with them during the six-month double-blind. There's one other reported survival benefit that was seen in open label by one other asset. That's actually a very important piece of this, that none of the HEALEY programs, the other drugs, have been able to lean into a key survival argument. There's been other HEALEY regimens that have been able to see some speech benefit. There's other HEALEY regimens that have been able and other drugs that are non-HEALEY that have been able to see neurofilament benefit in the open label. Even the most recently concluded regimens, there was originally some thinking that there might be some neurofilament seen in open label. The full data set of those analyses have just concluded, and that didn't occur either.
Back to your survival question, we saw 90% survival at six months, but that's a relatively small set of folks. There was only a few that died in that six-month period. The key thing is what's actually happening in open label. There's the tricky wrinkle, though, and we've commented about this in previous interfaces together, is that what happens when you move everybody over to active drug, which is something that routinely occurs in ALS and did indeed happen in our case, everybody moved over to active drug because they didn't want to be on placebo, in our case, purple-colored water, any longer than is necessary. We start competing against ourselves in survival. That's where we've leaned into the natural history data set that the ALS community has been collecting for decades. That alone has some compromise. It is post-hoc analyses.
Back to the neurofilament argument that the agency proposed, there's the value, the advantage of that. It's not a post-hoc argument. The agency asks us to provide to them a statistical analysis plan, how we'd approach this, have that modeling fully set before any analysis was looked at in any way, before any of the data had any neurofilament return, ask us to come back to the agency so we can align on such SAP. We're waiting now for this meeting. The agency's had our proposed statistical analysis plan for a piece here. The agency, as we all know from headlines, is still getting their new bearings with new leadership. We're not exactly sure when that meeting will occur.
It is our hope that it will occur within the next 30-60 days based upon the fact that we are just expecting this week a new commissioner and hopefully a new head of CDER. We do not believe there has been any changes that we have heard about publicly in our division, which is Division of Neurology One. Again, we have been, what is the word, sensitive?
Yeah. Is 30-60 days from now consistent with the very first guidance they gave you for when this meeting will happen, or have they pushed it back?
No, it's consistent. They wanted us to send it back, the data, and that we'd have such meeting prior to the analysis plan. As I mentioned a minute ago, the analysis plan is summer. Thirty to sixty days is right within the window. The key is that they want an alignment with Clene, kind of eyeball to eyeball on how this approach is being done previous to any of the analysis, any of the data that we could look at. If that pre-specified statistical analysis plan is robust and seems concordant to what we saw with HEALEY at the six-month period, then that could be potentially written.
Back to one piece that Clene has been doing the entire time is building such NDA so that it's ready for the inclusion of this neurofilament data and then to send it to the agency and see what they think.
It really does sound like they're keen, far keener than they used to be on neurofilament and survival versus sticking you with ALS-FRS.
Yes.
One other question. Like in NPC, they've been entertaining a four-domain instead of a five-domain, the five-domain standard scale. Is there any subset of ALS-FRS that the agency is keen on looking at that might omit one or two parameters?
That's very much an important question. That's a key question that we've asked them for this upcoming meeting. We've not seen such answer of that yet because we've not held the meeting, as I've referenced. There is a question in neurofilament that limb onset versus bulbar onset ALS individuals tend to have some differences in neurofilament. We've asked them if it matters to them if it could be a limb-only patient group, if it could be, or does it need to be both. That's one thing that I think there was a drug that was withdrawn in the last two years. Their phase three study was quite a different patient population than their original phase two. Was that a concern? Is that the reason why we saw different data?
Clene is asking these questions, to your point, to make sure that we could build as much of a like-to-like data set, apples-to-apples as is possible for HEALEY, and to look at also with ALS if we could ascertain any difference in fast progressors versus slow progressors, which is a challenge also in the ALS community. Good question. These are exactly the questions that we're asking the agency in our SAP conversation that's upcoming.
Can you describe to a non-career statistician any really, really key points of your proposed SAP, or is that just not something you can talk about?
It's not something we can talk about because I fully expect we wanted to, I think our deference needs to be to the agency. If they align to it, we will be speaking about it. If they want it changed, then we will make the changes they request. I shouldn't state publicly until we know what the agency aligns to.
That sounds very reasonable. Can you talk about the draft guidance, the comments that the FDA has asked for, the draft guidance, expected program for serious conditions, accelerated approval? Can you talk about that?
What's important is they've made.
Why it's relevant to you.
Yeah. They've made it very clear that a phase three study needs to be underway. Many of us had questions about what defined underway because many different companies over the last number of years in many different divisions have interpreted underway separately. Clene believes that this is the way the guidance is, is underway at time of approval. We've decided to go one step much more conservative than this, and that is underway, which we're defining as patients randomized into the phase three study. RESTORE is a phase three study built on time to event on survival. Clene has leaned in to exactly the data that we've already seen, which is that people that struggle with ALS want to continue living.
In that respect, our primary endpoint is not a functional domain of 12, I mean, a functional measure of 12 different domains such as ALS-FRS. We want to actually have a time to event study. We're taking a page out of the playbook from cardiology or oncology and making sure that people stay alive on CNM-Au8. In that respect, looking at people that are either alive or dead or have actually the benefit of not requiring permanently assisted ventilation. In the case of ALS, by FDA standard, this is 22 hours a day or more of mechanical ventilation, safe for which I would pass. Those are the two endpoints the agency appreciated. Those are the same two endpoints, incidentally, as the secondary endpoint in the HEALEY program, time to death or time to PAV, permanently assisted ventilation.
That is the design of the phase three. We will be underway to the point that I just raised by summer.
You mean dosing. You said.
I mean dosing. I mean dosing. People will be randomized and on drug. We'll be dosing in this program by summer previous to the filing of said NDA. That is, in our view, a conservative interpretation of what this means. This, we think, also helps fix a challenge that the agency and others have publicly talked about for companies that did not actually do the phase three and delay such phase three. Clene is not doing that. We're actually working actively now in parallel to get that phase three underway previous to submission.
Okay. We've taken, we got about three minutes left. Can you use that to discuss the status of your MS program? Do you anticipate doing an end of phase two meeting? If so, when? What other MS data do you still have to release?
We released last April, just a month after this meeting at the American Academy of Neurology, that in the three-year follow-up with CNM-Au8, we saw increased cognition and we saw increased remyelination evident in function of the vision. This was done with two paraclinical biomarkers, visual evoked potential. We're actually looking at the vision of the individual's eye and the speed, latency, and the volume amplitude of how much can get back to the visual cortex. We also showed in that same data at American Academy of Neurology that we had improved cognition. This was evident by whole brain white matter change using MRI. We had a number of pharma partners that entered under CDA and asked us to do more of the same. We have done further analysis of the data set.
We'll be presenting that data again in a month at American Academy of Neurology. That gives us, in the aggregate, a full picture of what may be happening with either neuron protection and/or remyelination about why CNM-Au8 in a patient population that is on full DMT. They were completely controlled with their MS lesions, but they were still nonetheless having functional deficit. We will be making a presentation that we've not yet publicly disclosed until we actually have that meeting at the American Academy of Neurology, in an oral presentation.
That will give us a full data set of not just the VISIONARY program that was a 12-month double-blind placebo-controlled, but also its two further years of follow-up with a number of looks at that data fully interrogated with visual evoked potential, with MRI, looking at paraclinical biomarker change and to try to ascertain what is driving such cognition and vision improvement. How do we show this? That then constitutes, to your point a minute ago, a phase two conversation, end of phase two conversation that we'll have with the agency in the later end of this year, preparatory for the possibility of a phase three commencement in MS fully controlled patients next year. Also, as an aside, we continued as well with the REPAIR-MS program, which is a translational program looking at individuals with progressive MS.
They're progressing nonetheless despite full DMT. That primary progressive MS patient has never been assessed with AUA yet. That data will also read out from Clene later this year.
All right, Rob. Thank you very, very much for all that. That's a really nice sense of where the company's at currently.
Thank you, Jonathan. It's a pleasure.