Powering Weakened and Stressed Cells in ALS to Function Better with Nanocrystal Therapies

In neurodegenerative diseases like ALS, cells in the brain suffer a decline in their ability to produce energy. These impairments help to drive the progression of these diseases. Clene Nanomedicine is developing a nanocrystal suspension of gold atoms that are small enough to enter mitochondria—the cellular organelles that power activity—to increase two critical energy metabolites to fuel cellular function and counter the disease. The company believes this has the potential to provide functional change to people with ALS and other neurodegenerative conditions. We spoke to Rob Etherington, president and CEO of Clene Nanomedicine, about ALS, the role that the compromised ability of cells to produce energy play in the disorder, and why the company believes its gold nanocrystal therapy has the potential to improve function in people with the condition.

Daniel Levine: Rob, thanks for joining us.

Rob Etherington: Danny, it’s a pleasure to be here. Thanks for inviting me.

Daniel Levine: We’re going to talk about Clene Nanomedicine, nanotherapeutics, and your lead therapy designed to treat ALS and other neurodegenerative diseases. Let’s start with ALS. For listeners not familiar with the condition, what is it?

Rob Etherington: ALS, or amyotrophic lateral sclerosis, is a progressive neurogenerative disease that’s really affecting the way the nerve cells in our bodies talk to our brain and spinal cord.  Amyotrophic basically is a Greek word that means the muscle doesn’t get nourishment, and when a muscle doesn’t get nourishment and can’t actually talk to the muscle from the brain, then we have a series of degeneration that occurs and patients lose the ability to walk and talk and move and chew and swallow and even breathe—a remarkably devastating condition that you and I can appreciate because we count on our very life, our ability to move and walk and talk and eat, and chew and breathe, and patients, very tragically, die within three to five years. Thankfully, we’re in the middle of a renaissance of drug discovery in ALS.

Daniel Levine: How does the condition manifest itself and progress?

Rob Etherington: There’s two types of ALS. Patients either can have a brainstem onset, which would manifest in their inability to start forming words or to talk or to chew or swallow. In other words, kind of a neck up compromise, or patients could have a limb onset disease, which manifests in the ability of the body to talk to the muscles of the hands, the arms, the legs. So, I might be walking or using my hands in a certain manner that I’ve become accustomed to for decades, and all of a sudden I start losing that ability.

Daniel Levine: You mentioned patients generally have a prognosis of living three to five years after diagnosis. You mentioned also that we’re in this renaissance. We’ve had certainly an important new ALS drug approved this year. Is there any indication that that prognosis is changing for patients today?

Rob Etherington: I think it is actually. So, Lou Gehrig was first diagnosed in the thirties when he was in his thirties. So this is the 1930s when he was in his thirties. And Lou Gehrig famously gave his name to this disease. Many people of many generations have called ALS Lou Gehrig’s disease. We call it a little bit less that now. But the point I’m getting at is for decades, for 50-60 years, there was no drug then. There was a drug called Riluzole approved in the 80s, and then there was another drug approved in the last 20 years called Edaravone. And then only just recently, actually six weeks ago, roughly, a new drug was approved in the United States and in Canada. So we have now three drugs that patients could be prescribed. All three of them work in different ways, but there are multiple drugs presently in clinical studies that are working their way down different paths, mechanisms, and timelines to help the patients.

Daniel Levine: You’re working to develop treatments for a number of neurodegenerative diseases. Why start with ALS as your lead indication?

Rob Etherington: What our drug does, called CNM-Au8, it’s a new pioneering drug class called nanotherapeutics. And we’re actually using the active gold to be the active ingredient in our CNM-Au8. And why that is relevant, because at nanoscale, which is to say for your listeners, super small, our drug is able to target energy metabolism. And energy metabolism is in fact the root problem in ALS. Certainly, one of the big challenges in this disease is that the neurons that talk to our muscles require a fair amount of energy. And our drug, CNM-Au8, improves cellular energy production and its utilization. So, ALS, to your question, was the perfect starting point.

Daniel Levine: Clene believes that that’s a commonality between several neurodegenerative conditions, including not only ALS, but Parkinson’s and MS. What happens within the cell that renders its energy producing capabilities less than full?

Rob Etherington: You are exactly correct in that neurodegenerative diseases, they all share a common mechanism and that is a decline in your brain and my brain’s ability to produce energy. Now, our brain is a relatively small percentage of our body weight, in fact, only 3 to 5 percent, yet our brain consumes more than a quarter of the energy that you and I require every day to basically undertake all these aspects of living that we count on. Our ability to move and walk and chew and eat and swallow, as I’ve mentioned, is driven by the brain coordinating this massive series of tasks. And so, yes,  many neuronal populations are vulnerable to energetic failure. And so, Parkinson’s, multiple sclerosis, ALS, and I could continue, there’s many where energetic impairments in the central nervous system in our brain is both predisposing and driving progression in these diseases. And this is a big challenge because we’re living longer, so that’s great that we’re living longer, but as we’re living longer, our brain energy potential is declining with normal aging. And if we couple this decline with normal aging with one of these neurodegenerative diseases, which happens for a whole host of reasons, then things start to go very complicated, very fast.

Daniel Levine: CNM-Au8, your experimental therapy—what is CNM-Au8? I’m sorry, I’m going to do this again. What is CNM-Au8 actually doing once it’s delivered into the body?

Rob Etherington: CNM-Au8 is a nanocrystal suspension of gold atoms. So when I say atoms, that is of course remarkably small. These crystals are so small that they can enter the mitochondria. And the mitochondria are basically the engines of the way our neurons in our brain works. And so, what’s happening is—mechanistically is a word we use in pharmaceuticals—is how the drug is working mechanistically, it’s increasing two key energy metabolites called nicotinamide adenine dinucleotide, very technical, and adenosine triphosphate, very technical. Said less technically, these two are amongst the energy or the gas that the engines of our body, that is to say in this case the central nervous system, is using to drive its function. So, our drug is really increasing energy production and its utilization mechanistically by increasing the amount of gas or energy on hand for the central nervous system to use.

Daniel Levine: The belief is that this would not only be slowing the progression of the disease, but actually disease modifying. Is that correct?

Rob Etherington: Functional change is a good way to express this. We want to improve function. In fact, our clinical studies are designed with function in mind, and by function, again, I’m using purposely and repetitively our abilities to move and walk and talk and eat and chew and breathe because these are functions. These are functions that you and I count upon, and that’s what we’ve designed our clinical studies to assess. So yes.

Daniel Levine: And is this whole approach of dealing with the energy production of the cell validated in these diseases?

Rob Etherington: It’s novel for Clene. Indeed, nobody else is really approaching this in the exact same way that we are, but in large measure because their drugs don’t have the ability to pursue energy improvement to the degree that we have. So, let’s just maybe give you three headlines. So, about 14 months ago, we established brain target engagement and showed that we could improve energy by patients drinking our drug orally and then what we saw with their energy improvement in their brains. We showed that statistically significant in a phase 2 study. And then, about a year ago, we had our first phase 2 data rollout in ALS, and that data showed that we demonstrated a survival benefit that was statistically significant. And then only a couple months ago, we released MS data that showed that we saw neurological improvements in people with stable relapsing MS. And the way we saw that benefit was in the way they saw their vision, the way their eye worked.

Daniel Levine: What’s known about the safety and efficacy of CNM-Au8 from studies that have been done to date?

Rob Etherington: So, we have more than 400 years of subject exposure without any identified safety signals across all three of these diseases—ALS, MS, and Parkinson’s. In other words, we’ve concluded, now, four phase 2 studies, and not only did our animal work result in no adverse effect levels, so that’s important to start these studies, which we had to prove before we started them, but since then with all this people exposure, the 400 years collectively of patients in clinical studies that took our drug—people struggling with these diseases—we don’t have yet a single serious adverse event that has been related to CNM-Au8 that’s been considered severe, life-threatening, or resulting in death. In other words, we have a very solid safety profile for which we are grateful.

Daniel Levine: I wanted to ask you about one of the studies you did, the RESCUE ALS clinical trial. This was reported on about a year ago, and it failed to meet its primary endpoint. This involved the MUNIX biomarker. Can you explain what the Munich biomarker is and why the study failed to meet its endpoint?

Rob Etherington: Yes, certainly. So MUNIX stands for Motor Unit Index. So that’s an abbreviation: MUNIX, Motor Unit Index. And it is the measure of function, in our case, electrophysiological function of the way the brain is able to talk to the muscles of the arm, hand, and leg, quite precisely. We measured the ability of the arm in the biceps, the ability of the hand in two muscles called the APB and the ADM, and the tibialis anterior in the leg. And we put probes, electrical probes, and the doctor asks the person struggling with ALS to flex those respective muscles. And we measure that flex with the probe. Now, we looked at both types of patients. We looked at, bulbar onset patients that I referenced earlier, those patients that have compromise in their neck and above. And we looked at limb onset patients, the patients that have spinal cord compromise. And we collected all of the data for both types of patients. And what we learned is in early disease, and these were early ALS patients—they’d been diagnosed only recently, within four months—that we did not see progression for the brain stem onset patients into the muscles of their hands, arms, and legs. So we missed the primary endpoint for that reason. If we looked only at the limb patients, we saw a near statistical achievement. When I say near, our p-value there was p 0.07, so we missed classical statistical significance by only 0.02. So, it gets a little bit muddled here, what I’m saying. but just to make it clear, if we’d have looked only at limb onset patients, it’s likely that we would’ve seen a statistical significance. We didn’t, however, because we looked at both types of patients. But what we did see is probably very, very critical. And it’s caused Clene to have good faith in CNM-Au8 to pursue because we saw improved patient function, we saw improved quality of life, we saw improved ALS disease progression. And most importantly, as we continue to evaluate these patients, we saw that CNM-Au8 demonstrated a significant impact on long-term survival because the patients on active drug compared to placebo are not passing away at the same rate.

Daniel Levine: It would seem to me there are lessons here both on clinical trial design and patient selection. Why would you enroll patients who didn’t have limb involvement in a study that used MUNIX biomarker as an endpoint?

Rob Etherington: That is the perfect question that we ourselves have armchair quarterbacked here at Clene. It was presumed by us and the scientific advisors that bulbar—see everybody progresses eventually to both—limb onset patients end up having compromise in the way they speak and breathe and swallow. And patients that start with talking compromise end up having limb compromise eventually. In other words, both type of patients translate eventually to compromise across the whole body on balance. So now, what we’ve learned is that nobody will ever do a study using MUNIX in bulbar onset patients. We’ve now learned scientifically that was a mistake. So, to answer your question, we wouldn’t do it again. The advantage of science is we’ve learned that in early disease you need to focus on just limb onset patients.

Daniel Levine: At the same time, are you able to still follow those patients and see if they don’t progress as would be expected?

Rob Etherington: Yes, and that is actually a very important point. So, our exploratory endpoints proved that it was actually useful that we looked at both types of patients because in both types of patients collectively taken together, in other words, we understood that we have a survival benefit taken together. We understood that we have an ability to improve disease progression. That is, patients on placebo, regardless of whether they were limb or bulbar, still progressed aggressively towards either death or the need for full-time breathing support or gastrostomy tube because they could no longer eat or swallow. And our CNM-Au8 patients didn’t progress at near the same rate. In fact, the p-value there was p 0.01, which basically translates that roughly four fifths of our CNM-Au8 patients were able to not progress into this need for gastrostomy tube, this need for a tracheostomy. So, even though the primary endpoint was compromised by looking at both types of patients, the exploratory endpoint and the survival benefit has been of value because we looked at both bulbar and limb onset patients.

Daniel Levine: What’s the development path forward?

Rob Etherington: Well, the next study that immediately translated from RESCUE was the HEALEY study, the Harvard HEALEY study. And this study just read out last month. And in that respect, let’s just explain what HEALEY is for a minute. This is the most important ALS study probably ever attempted. Multiple drugs are being compared to each other in this program. Clene’s was one of the first drugs chosen. There were four drugs chosen for the first regimens. All of these patients are matched. Effectively, it’s a program where all of the same clinical endpoints are evaluated. Patients are randomized within a platform. It’s a page that has been borrowed from the cancer pharmaceutical drug research program that enables multiple drugs to be evaluated at the same time in effectively the same manner. And it’s designed to accelerate drug development for ALS. Now CNM-Au8, in regimen C, we failed the primary endpoint here as well as did, incidentally, the other two regimens that have been announced thus far, regimen A and B. But the difference with CNM-Au8 is that we saw a survival benefit again. So, we saw a survival signal where 90 percent decreased risk of death occurred for our 30 milligram dose, which is by the way, the same dose used in the RESCUE study we just were referencing. So, the advantage that we have is that we now have two studies that show that there’s a survival benefit for patients on CNM-Au8 compared to placebo. And we are evaluating the patients that continue on active drug in both programs to see if the agency, taken into account our safety that as I mentioned earlier, is pretty solid, will tell us what they’d like to do with next steps. The survival benefit that Amylyx saw is in large measure what drove the approval of Amylyx’s asset. We plan to talk to the agency, the FDA in 2023, to basically work with them to review in the totality, the survival benefit that we’re seeing with our drug across two studies, and to see if the agency concurs that that is a worthy conversation to have.

Daniel Levine: There are many other diseases where there’s mitochondrial implication. The cells lose their ability to produce the energy that they should. Is there any reason to believe that your therapy might have broader application?

Rob Etherington: Well, the visionary data that we released from our phase 2 multiple sclerosis study in August teaches us that it does indeed have broader application. So, let’s just talk about that study for just a minute. In that case, we used, or rather we enrolled, people struggling with MS though they were stable because their MS drug effectively tamped down their body’s immune response leading to no longer an attack on their nerves. They still were functionally compromised and what we did is we evaluated their vision, we evaluated their fine motor control with their fingers and hand. We evaluated their cognitive thinking ability and we evaluated their walk test, how well they could walk unassisted down a hallway under a stopwatch. And in those cases, the visionary study, we reported out that we demonstrated a global neurological improvement in these stable patients despite the fact that they were already on a disease-modifying therapy. In other words, Clene’s CNM-Au8 was able to improve their low contrast letter acuity, which is a medical term, which basically means using a classical eye chart. We were able to improve their ability to see under certain light conditions. That was the primary endpoint. Under the secondary endpoint, we were able to improve their modified MS functional composite scale, which is a combined endpoint looking at the way they saw, thought, moved, and walked. And so that was pretty exciting to Clene because nobody’s ever shown functional improvement on top of standard of care MS drugs. And if in a phase 3 study that is further demonstrated, that is we can approve global function of the way they move or walk or think, then that is the market need in multiple sclerosis.

Daniel Levine: It’s been a difficult time to be a public biotech. You’ve got an $80 million market cap treading near a 52-week low, about 80 percent below your 52-week high. What’s the conversation like with investors these days?

Rob Etherington: Indeed, the small- and mid-cap biotech companies have been under tremendous pressure in the markets. There are so many companies trading below their enterprise value, which is to say that their cash on hand is actually more than their market cap. That is not the Clene scenario, thankfully. But we’ve still, nonetheless, seen a remarkable fall in our market cap over this last year. Investors, they’re worried about the biotech market generally, and we haven’t seen yet a dam breaking with respect to M&A. The big pharma companies are sitting on billions and billions and billions that they’ve not yet spent to increase their pipelines. So, we expect that to happen at some point. It hasn’t happened yet. Once it does happen, I think we’ll see investor sentiment be more enthusiastic about the biotech market. Clene, though, we’re focused on the primary endpoints of the data. So, in the coming months, we are going to see continued survival data from our patients as we receive more data flow from the HEALEY Harvard study and more data flow from the visionary MS study. We’re continuing to follow patients and assessing their function and assessing their ability to live or die. And as that data matures, we plan to build two things: a conversation with the FDA, as I mentioned earlier, and phase 3 studies that will be able to take us down a regulatory pathway asking for, if positive, commercial approval.

Daniel Levine: And is being a public company today more of a hindrance than a help?

Rob Etherington: It’s certainly difficult to be careful by keeping one eye on the public stock price and the pressure that one is there under because of that and also do the job at hand, which is to help the patients improve, or rather get involved in your clinical studies so you can see as to whether or not they improve. That is certainly challenging. The advantage of the public markets historically is that capital raising is possible. That’s challenged now. And so, the answer is nuanced, I guess purposely. We’re grateful that Clene became public. Investors were thankful when we did. So, the last year has been remarkably challenging for all concerned, but do I expect the biotech markets to revert back and start having upcycles. I do.

Daniel Levine: How far will existing cash take you and what is the plan for raising additional capital?

Rob Etherington: As of September 30th, the last time we announced our cash on hand, we had $32 million. that capital gets us through till basically the end of the second quarter next year [2023]. So, not a long runway, but enough of a runway to understand the totality of our survival signal to see our data from our visionary study for another year of patients that have been followed in open label. And so, these are catalysts that, taken together with biomarker data, we’re expecting could lead to very encouraging regulatory conversations. Indeed, just as an aside, there’s one drug right now in front of the agency awaiting an agency decision in the first quarter of next year [2023] for whether or not they’ll be commercially approved. Well, that drug filed an NDA, they missed their primary endpoint as well, but their subgroup analyses and their biomarker data was compelling sufficiently that the agency said, let’s talk about you in an advisory committee meeting. We also saw that the recently approved Amylyx drug was able really to turn to their approval because of leaning into their survival data they saw released this last summer. So, in Clene’s case, we are expecting the catalyst data to arrive, including our biomarker and increased survival data, over the coming months.

Daniel Levine: Rob Etherington, CEO of Clene Nanomedicine. Rob, thanks so much for your time today.

Rob Etherington: Thank you. It’s a pleasure to talk to you Danny.

This transcript has been edited for clarity and readability.