Hey, everybody. My name is Alexa Deemer, and I am one of the biotech analysts here at Cantor, and I am very pleased to be hosting this next fireside chat with Clene. With us today we have Rob Etherington, President and CEO. Rob, thank you for joining us. We only have 30 minutes, unfortunately, so we are going to try to get through as much as we can. Rob, maybe for those less familiar with the Clene story, maybe you can give a brief overview of the company, and highlight some of the most important developments that have brought the company to where it is today.
Thank you, Alexa. Appreciate the invite. Clene is a clinical stage nano biotech company. We have been in existence for 13 years. That entire 13 years has been a big adventure, taking our asset to now, at the final stages of a new drug application that we will soon be submitting to the U.S. FDA for the treatment of ALS on the accelerated approval path. Just a little bit of insight. Our lead asset is a nanotherapeutic. People drink it by mouth orally. If I was blindfolded and took our asset versus this glass of water, I would not know a difference. Tastes like room temperature water. We have now hundreds of people that have had access to this asset. In fact, we have over 1,250 collective patient years of experience.
900 people have been taking this asset and hundreds are presently doing so in a compassionate use expanded access protocol, four of which have been approved by the FDA, three in ALS, one in multiple sclerosis. What our asset does is drive the energy necessary to the failing neuron. You and I are highly bioenergetically needy with respect to the way our neurons control everything that we do, the way we move, walk, talk, eat, chew, breathe. By consequence, what our asset is doing is driving important bioenergetic metabolite nutrients, while also reducing reactive oxygen species and driving neural function through supporting the mitochondria. That is a big mouthful. Effectively, your brain and mine is only a small portion of our body weight, but it is consuming a quarter of our energy.
In a patient that has ALS, of which there are 35,000 in America, and of which there are many other thousands worldwide, they still, once they get this diagnosis, are given a uniformly fatal diagnosis. Clene is now at the final stages of just wrapping up a new drug application, which, as I said a minute ago, we will be soon submitting. We will find out hopefully by the end of the year, whether or not the agency will give us a PDUFA date, commencing thus six months of review, an answer of which we hope to receive from the agency as to the possibility of commercialization, sometime June, July next summer.
Okay. We definitely want to get into a lot of the details regarding the regulatory strategy, but before we do that, let's take a step back and talk about some of the data. Although CNM-Au8 did not demonstrate a benefit on the primary ALSFRS endpoint in HEALEY, what did you learn from this study, and why does the totality of the evidence support continued confidence in this drug?
We've completed two phase IIs in ALS, one called RESCUE, and the one you just mentioned called HEALEY, is with Dr. Marisa Govic and her colleagues at Harvard University, as well as more than 50 clinical sites countrywide. The HEALEY study is really the anchor program by which the agency is considering this. Alexa mentioned that we missed the primary endpoint, ALSFRS, as has every other of the seven remaining programs that are thus concluded in HEALEY. Clene is the only of these 8 different programs, 8 different drugs, that achieved the secondary endpoint of survival. We're the only of the 8 different drugs that achieved the exploratory endpoint of clinical worsening, and we're the only of 8 different drugs that achieved a reduction statistically significant in a phase II double-blind placebo-controlled study of the biomarker neurofilament light.
Why that becomes very relevant is because Biogen received an approval a few years back for their SOD1 ALS asset. Just to distinguish, there's 35,000 Americans with ALS, roughly. A small percentage of these, estimated to be a few hundred, have a genetic component of ALS called a missing SOD1 gene. Biogen developed a wonderful asset called tofersen that enables a replacement for this missing gene. Though they missed the primary, secondary, and exploratory endpoints in their phase II study, they nonetheless achieved demonstrable neurofilament drop. What we've done is gone into the agency for heterogeneous disease, which is the 98% of the rest of the ALS, and asked the agency if they would consider the possibility of a surrogate-based, in other words, neurofilament reduction, approval process in that respect. So HEALEY becomes very much the anchor, and there's some critical pieces here.
The agency came back to Clene, and we'll jump more, Alexa, later to the regulatory strategy, but it's important just to give a sense of design. When HEALEY recruited, there was 3 arms that were recruited all at the same time, and the other two assets in two different regimens were not positive, but the agency asked us to look back at that data and to see if we could use this as a comparable control. Namely, because the agency has not been enthusiastic, and we have lots of different examples and many different drugs on natural history. Since all the assets were randomized with the same inclusion, same exclusion, same trial design, same protocol, and same follow-up for nearly four years, this becomes a very interesting data set to look at, and the agency's asked us to really explore that extensively.
Okay. Maybe we can get into a bit more of the details on how NfL actually emerged as the potential surrogate endpoint, and how you use the expanded access program to address the FDA's request for independent evidence of a reproducible NfL effect.
First, let's maybe give some, if unfamiliar to the audience, what neurofilament is.
Yeah. Great.
Neurofilament stands for neurofilament light. This is molecular weight, not as in sunlight, molecular weight. As the disease ALS, or for that matter, any other neurodegenerative disease, attacks the neuron, it leaves behind a bit of a debris field, a cytoskeletal protein remainder of the damaged and destroyed neuron. I can measure it in my blood, I can measure it in my CSF, my cerebral spinal fluid. Neurofilament has really emerged as the surrogate to understand and to follow. This has been evolving for some years now. That neurofilament light, as I mentioned earlier, Clene remains the only phase II program to see statistically significant difference in neurofilament.
Now modestly, in heterogeneous disease, we didn't have the same benefit as was seen in the tofersen case, just to be clear. That is really the key question in front of the agency is, does a modest neurofilament light reduction matter? Let's go back to the essence of your question, and I'll come back to that second question, is that we saw a neurofilament drop of about 10%.
To Alexa's point, we received $45 million to pursue a significant expansion of our compassionate use program from the NIH. There was an act that I AM ALS and other patient organizations championed called the ACT for ALS. It was $500 million that Congress provided for research and for compassionate use. Clene received nearly 10% of that. That enabled us to actually give to, let's see, 300+ people, our asset for compassionate use. Neurofilament was tracked through the duration of that program. So when we were in front of the agency asking them if they would consider survival as a surrogate, they said, "That's the definitive endpoint. We would define survival as the essence of your primary for your phase III confirmatory, but really we don't have a path for survival as a surrogate.
The surrogate we count on," and the surrogate which they'd already approved, the tofersen Biogen's asset, "is neurofilament light. So let's see if you can see a consistent benefit in your NIH program, much like you saw it in your phase II, and are those equivalent in two different patient populations?" The answer was yes. It turned out the agency had us give them a pre-specified SAP, statistical analysis plan, that was ahead of opening the data set. We saw that we saw about a 10% improvement in both studies, so concordant data on neurofilament light in two different patient populations.
The double-blind HEALEY folks that were 6-month diagnosed to 12-month diagnosed versus the NIH-sponsored compassionate use program, who were folks that were too sick. They were four or five years, as much as four or five years diagnosed. They'd failed all inclusion criteria. They couldn't get into a Clene program because their ALS disease was so progressed, and yet we saw in both patient populations about a 10% improvement.
Remind us how many patients were in both the phase II HEALEY portion and then the expanded access program.
The HEALEY was a six month double blind, of which we treated 160 total subjects, which was 120 actives and 40 placebo. The reason why this becomes a critical discussion of how these regimens are composed is the way that HEALEY was organized is that 480 total subjects were recruited and then randomized into 160, and 160 for the three arms. So we had 120 actives for all three regimens, 40 placebo. We shared the 40 placebo, 40, 40, 120. So it became this 120 active versus 120 placebo set, and when Clene initiated, we were one of 30-odd drugs chosen to begin, and then there was three that started the program.
Of these three, as I mentioned earlier, the agencies ask us to look at all 480 as a comparable control set, since again, as I noted a second ago, same inclusion, same exclusion, same protocol, same treating sites, and except even for the drug itself, nearly identical treatment in terms of the protocol structure. So what this means is we've got two neurofilament sets in two different programs that had concordant data. The agencies basically ask us to go look at this and understand, does neurofilament reduction tie to survival, tie to clinical benefit?
That's my next question. So how do you know that, or how should we think of this 10% being clinically meaningful or not?
Clene had four meetings in the last two years, the most recent of which we wrapped up in March. We announced it on May 3rd, and that was basically around this thesis, can we submit a new drug application? In March, they said not on survival, as I noted earlier, but yes on neurofilament. We are open to reviewing that NDA and receiving it, and then we will make a review decision. But they asked us to actually give them a bit of more breadcrumb trail. I am holding in my hands, actually, the minutes. I want to explain exactly how they explained this. They said, "The proposed data may be capable of supporting the submission review of an application under the accelerated approval pathway for the treatment of ALS.
However, you need to demonstrate substantial evidence of effectiveness, evaluate on neurofilament light, and that the modest magnitude of change in neurofilament," so modest by this they mean the 10%, "is reasonably likely to predict clinical benefit in patients with ALS to support an approval." We received that origin statement, and then three pages of what they wanted. The last three months, basically since we announced this May 3rd and received these final minutes a few days before that, we have spent May and June, July, and the latter piece of August, giving them what we think is exactly the answer to show the question: Does neurofilament change associate with mortality benefit and/or functional change?
On August 10th, a month ago today, nearly, we announced exactly that we have discovered extensive statistically significant connection to those individuals who have a neurofilament reduction or neurofilament stability, that those are expressly the folks that are having the strongest survival benefit, and announced for the first time in Clene's case, those folks also are the ones that are having an ALSFRS benefit and a CAFS benefit. So the CAFS, clinical assessment function and survival. ALSFRS, functional response, how I move and walk and talk and eat and chew and breathe effectively. So those individuals, which the agency has really anchored ALSFRS historically as a key endpoint and was curious if we would see a neurofilament decline equals an ALSFRS correlation, and we indeed did do that.
I see.
We hadn't seen such before. When we looked at the aggregate patient, that was indeed the primary endpoint for which we missed the HEALEY study. But for those individuals that have neurofilament drop, those are the individuals that are also having a statistically significant ALSFRS change. Seven points, incidentally. Just as an aside, there was another drug approved on ALSFRS alone a few years back that could not replicate in their confirmatory study of the data, but they were originally approved on a 2.3 point change, and we're seeing a seven point change.
So nearly 3x that number. The critical thing that Clene has anchored this on is the survival connection to neurofilament reduction. That is the key, is that for those individuals that take our drug, and for those whose neurofilament drops, those are the individuals that are having the survival benefit.
Okay. Got it. I have a few more questions on the regulatory strategy, but maybe we can take a step back, and you can remind everybody of the safety and tolerability profile of CNM-Au8, including with long-term treatment.
That is a key benefit to our asset. We theorized this from the beginning, that we would have a very strong safety profile. The agency wanted to understand that with totality, as they always do. They actually sent us through our paces originally, because our drug taken orally becomes systemic, and they wanted to make certain that there wasn't any hepatic or renal or any other untoward effects. They had us evaluate multiple animals to understand this with target tissue organ understanding. Thankfully now in the clinic, knock on wood, we have over 1,250 patient years collectively. I mentioned that at the beginning. We've had patients now on drug for six and a half years and counting, and I know some of these people that have started our asset beginning in late 2019.
In ALS, that is a very relevant fact, that people have nearly seven years of consistent drug. We have yet not a single serious adverse event that has been related to drug to date. Not a single serious adverse event that has been related to drug to date. People, if they have a side effect, they complain of headache occasionally. They complain of some GI nausea, diarrhea. These are not showstoppers, and in fact, we do not even know of a reported drug-drug interaction because our drug is not hepatically metabolized. Our drug is taken with other assets. Whatever is their standard of care, we put our drug on top of that. The safety profile is actually quite well established. In fact, we were at an FDA meeting in the fall of last year, and a new person came into the meeting.
As has been the case of the agency, some new folks have been coming on to meeting boards with all of the pharma companies, given what the agency has been dealing with. This individual asked a safety question, and the head of the division leaned over and said, "Safety is not of dispute here, so let us go back to the efficacy discussion." Safety is a strong story.
Very impressive. So going back to the regulatory strategy, maybe you can remind us again of the expected timeline for the NDA submission, and discuss where you see the strongest alignment with the FDA and any areas that you think may require some further dialogue with the FDA.
We announced in August that we will be submitting our NDA to the FDA literally at the top of the fourth quarter, so that soon. Very soon.
A few weeks away.
A few weeks away. We have effectively wrapped up the majority of all of our assessments, and we're now working in the last stages with the regulatory publisher to put those pieces together for submission. We then expect the agency to take their classical 60 days to 73 days on their review, at which point they will then decide whether or not they give us a PDUFA date. By consequence, we're thinking that that PDUFA date could come to Clene by the late fourth quarter. If that is the case, then thus would commence a six-month review. Now critical, and they've been categorical about this, there needs to be a confirmatory phase III study as-
I was just going to ask you to outline the design of that-
Yeah, as all-
You can go into that as well.
Accelerated approvals require. Our phase III, we call RESTORE-ALS, is designed as survival as the endpoint. This actually probably is helpful contextually. Lou Gehrig famously lent his name to ALS, and for decades, most Americans called ALS Lou Gehrig's disease. We have now moved off that generally, but we still have great reverence for the legacy that Lou gave us. But in effect, it was 60 years where survival was the primary endpoint, and really as all the effective, now generic drug that everybody is prescribed, was approved on a survival benefit, two months roughly. Since then, we have had survival kind of fade into the background. It has now emerged again as the key, most definitive endpoint. Clene is planning our phase III on survival as the primary, with ALSFRS, et cetera, secondary.
That is going to be a program that we commence at the top of the year. It will involve nearly 700 individuals. It will be quite exhaustively constructed, therefore phase III. Time to event, survival is the primary, and it will follow patients for two years is the intent. The FDA has been clear, before we would consider an approval decision, you must have your phase III underway. Since the timing of such, as I mentioned a minute ago, is summer, possibly commercialization, we are planning to commence the phase III in the first half of the year so that people are on drug.
We have already identified the clinical sites for which we are starting this. We have already had approved by the agency this protocol I have just referenced with survival as the primary, and that becomes therefore kind of the perfect, what other endpoint is there but we live longer in ALS? That is the data that Clene is most focused on helping individuals with this disease live longer. Again, the regulatory path is to prove that to the agency with an extensive NDA showing that in neurofilament reduction or neurofilament stability, those are expressly the individuals that have the strongest survival benefit.
Got it. Let's say you get accelerated approval. What commercial infrastructure would be required for the launch, and how are you evaluating independent commercialization relative to a potential partnership?
We've had a lot of pharma companies poking around the edges, as you can appreciate. Our approach has been we can commercialize an ALS on our own, as Amylyx themselves did, and we know very well the ALS centers of excellence. It is, frankly, quite simple with a relatively modest field force, possibly in the high single digits to teens of key account managers to call on the 50 odd centers of excellence across this country. We also are quite close to the I AM ALS team that has organized Synapticure, which is a virtual clinical treatment arm. We envision a very targeted approach. Just to give you some sense of this, again, this other company was able to bring 4,000 individuals on drug in first year.
That gives us a marker of how effectively to see a number of people that would be possibly on drug within 12 months. They did that also with a targeted approach, with a relatively small field team by themselves. Clene intends to do the same thing. Now, to your point about partnership, the same drug has also been clinically studied in multiple sclerosis and in Parkinson's disease. These two areas require, effectively, a partnership. The number of neurologists and frankly, internists that are required to see an MS and PD, Parkinson's disease, are much larger.
That is also a couple of years down the pike. Clene does envision that eventually and effectively we would require a partnership, but for ALS itself, that commercialization is a targeted initiative. Just as an aside, we do all of our own manufacturing. That happens at a series of four clean rooms, and we're now gearing those clean rooms up for commercialization stock as we prepare for the possibility of launch at the second half of next year.
Okay. Got it. I know we have a few more minutes left. I have two other questions I would love to ask. Maybe you can remind us of your current cash position and runway.
We've announced that we have cash nearly to the end of the year, so we don't have extensive runway. That is something that will be resolved and probably it's affecting our market cap. We will need to have more capital infusion. But the key critical piece there is we've had a number of great investors that hold extensive warrants. That number at a PDUFA date, there's two separate warrants that come into play, and then at an approval, there is two other separate sets of warrants that come into play, all of which are triggered by these two respective endpoints.
The Clene intent has been to really hurry as fast as we can towards those two dates, in which case, less capital is required when the warrants come into the money, and by consequence, could be executed. Again, there will need to be a modest amount of money raised to bridge some of this time as we've announced.
Okay, got it. I wanted to save the last few minutes for this next question. It's a bit of an open-ended question, but what aspects of the Clene story do you believe are still most misunderstood or underappreciated by investors?
Two things. How an asset built around material science and physics could drive neurofilament change, and by consequence, energy metabolite change to drive a failing neuron back to function. That is a concept that is definitely outside the box. How a nanotherapeutic suspension could do this by mouth orally and keep people alive is something that people, I think, are waiting for the proof being in the pudding, whether or not the agency would approve such an asset. That's part A. Part B is the pipeline and the product. The same mechanism by which our asset, taken by mouth orally, drives energetic metabolite response to a failing neuron in the mitochondria that drives that energy response not only applies to ALS but also applies to MS, Parkinson's disease, and multiple other neurodegenerative diseases.
Any of these neurodegenerative diseases that have an attack of the neuron dissolving or affecting diminished function, our asset could benefit from. We've chosen to bet the farm on ALS because that is the fastest road to market. But there's many opportunities in this pipeline and a product thesis that could come forward. Then finally, I think the biggest thing the market doesn't understand is will the agency actually give Clene an opportunity here to review this? That will be a decision that we'll know definitively, as I've said, within months.
Okay, got it. Maybe in the last minute, you can just remind everybody on, in your view, the most important things that the company needs to execute on over the next 12 months to drive shareholder value.
The biggest piece is the execution in the last number of months for this new drug application. That is nearly behind us now, and then it will be a matter of waiting for the agency's answer there. We will have all eyes on. I really envision three catalysts. Catalyst one is the achievement of the PDUFA date, and that the agency does indeed move our new drug application into review, upon which we would get such a PDUFA date. Catalyst two is the approval, and then catalyst three is kind of first 6 to 12 months of sales.
All of that, here we sit in September, all of this will be crystal clear by kind of end of year, top of January, summer, and then that first six months of sales, by fourth quarter next year will be pretty evidential. One can certainly appreciate that if this drug is approved, given a PDUFA date, approved, and then if we successfully bring thousands of people on drug, the market cap that Clene is today will be very different tomorrow.
Got it. Okay. All right, so we are out of time. A lot of great content in the last 30 minutes. Thank you so much, Rob and the Clene team, for joining us today, and thank you for everybody in the audience for attending.
Thank you.
Have a good day.
Thank you.
Thank you.