As our brains age, our neurons shrink and lose energy making it harder for nerve cells to pass the necessary messages that allow us to move, talk, see, eat, and more. This bioenergetic failure in the brain is also a leading cause behind many neurodegenerative disorders such as ALS, multiple sclerosis (MS), and Parkinson’s. But what if we could in fact boost the energy in our brain—and do so using a natural element such as gold?

That is the mission of Clene Nanomedicine, which has combined cell biology, solid state physics, and materials science to pioneer the development of Clean-Surfaced Nanocrystal (CSN) therapeutics. The company’s goal is to use this process to enhance the energetic support in neurons and change the way neurodegenerative diseases are treated. PM360 spoke with President and CEO Rob Etherington about how this science works, how these treatments differ from the current standard of care for these diseases, and what this platform may mean for other therapeutic categories in the future.

Rob Etherington, CEO, Clene

PM360: How did this company get its start?

Rob Etherington: Our founder, Mark Mortenson, is a physicist and materials scientist. He came up with a very clever thesis on how to use and build clean-surfaced metal-based nanotherapeutics. What we mean by that is the ability to build pure crystals out of metal atoms of the therapeutic elemental metals by using a novel electrochemistry platform. We believe that if we are able to successfully avoid the toxicity associated with synthetic chemistries, and bring these assets forward into the clinic, then it would be a game changer for the way neurodegenerative diseases are treated. We started with a lead asset of a nanotherapeutic built around gold (CNM-Au8), but we also now have a zinc-silver antimicrobial solution (CNM-AgZn17) in the clinic as well as one with platinum and gold (CNM-PtAu7)—alongside other therapeutic metals such platinum, copper, titanium, and other composites and alloys of metals—sitting in the background ready to be clinically developed.

How did you get the initial funding for the company?

The funding was originally a $27 million seed round composed of some ultra-high net worth individuals from the financial services, technology, and biotech space who had a passion for making a difference. Our focus are the high medical need neurodegenerative diseases, with the possibility of our first commercialized indication planned for amyotrophic lateral sclerosis (ALS), which is sometimes referred to as Lou Gehrig’s disease.

How do these nanotherapeutics built with elemental metals work? Can you explain the science behind that?

The basic thesis with nanocatalysis is that our neurons require additional energy to deal with the ravages of neurodegenerative diseases that tend to be increasingly prevalent as we get older. And since our neurons, and our central nervous systems in general, naturally slow down bioenergetically as we age, what we are essentially doing is treating what is called bioenergetic failure. This a completely new paradigm of drug discovery, to focus on a bioenergetic approach, which we believe is critical. Bioenergetic failure underlies the pathophysiology of many neurodegenerative disorders, including ALS, MS, and Parkinson’s disease. We do this by driving (or “catalyzing”) critical energy-forming chemical reactions within neurons and support cells without the need for these cells to expend any energy on their own. We call this “nanocatalysis.”

The electrochemistry devices which grow the clean-surfaced nanocrystals of CNM-Au8.

How does this differ from other treatment approaches out there for neurodegenerative diseases? Are there other companies that are also working in this same space?

No one else is capable of doing exactly what we’re doing. In the case of ALS, there are only two drugs approved in any market worldwide. Riluzole, which is generic and has been available for a while but unfortunately does very little. And more recently Mitsubishi’s edaravone which, unfortunately, also has a narrow indication and does not improve neurological function.

Then, in the case of Parkinson’s, the current standard of care is pretty much only dopamine replacement, which has been available for some time, or deep brain stimulation, which is newer and quite invasive. Both of these help to mitigate symptoms, slowing of movement and muscle-shaking, but again, do not improve the function of patient’s neurons.

And then finally, in the case of MS: this is a very large category, the so-called “disease-modifying therapies” (DMTs), with over 20 approved drugs. While tremendous progress has been made, every single one of the available MS DMTs work to tamp down the body’s immune response so the patient’s own immune system stops attacking the brain and spinal cord.  Although these therapies are clearly needed, patients still lose neurological function, including their ability to walk, control the muscles of their hands and arms, and even the ability to think and remember things. Especially as MS patients get older, they begin to worsen (“progress”) despite no longer experiencing these immune-mediated attacks. These patients have entered what is termed a “progressive” phase of the disease and none of the currently approved DMTs are very helpful for them. This is the major unmet medical need in MS and CNM-Au8 promises to be a breakthrough for these patients.

You may have seen a theme there. In all the cases, the available drugs for these neurodegenerative diseases do not improve neurological function; improving neurological function is indeed Clene’s intent. We seek to improve the bioenergetic capacity of the neurons and support cells so patients can experience functional improvement. That’s why our clinical endpoints test the way patients see, move, eat, talk, walk, and breathe amongst our various clinical trials. These are the functional aspects of daily living that you and I take for granted and that, unfortunately, patients afflicted with neurodegenerative diseases lose.

How successful have you been in achieving those results so far?

Just a quick little primer: our neurons are connected by axons, which are covered with a myelin sheath. I often liken them to an insulative layer very similar to the rubber insulative sheath over a wire in the walls of our homes. And if that myelin sheath is compromised, then the neuron cannot send a signal from the brain to the muscles. In our animal models, we have seen extensive remyelination, which is the process by which myelin sheaths are restored. We have also seen positive neuroprotective effects, which is when the therapeutic is protecting nerve cells against damage, degeneration, or impairment of function. In fact, in every animal model we have investigated we’ve seen that our asset CNM-Au8 is able to drive neuroprotection.

Our preclinical animal investigations have led us into the human clinic. Presently, we are in a Phase II proof-of-concept study in MS; a Phase II proof-of-concept study in ALS; and two different Phase II, biomarker target-engagement studies to prove mechanistically that the drug gets into the brain once taken orally and can drive bioenergetic capacity within the brains of Parkinson’s and MS patients. Additionally, we are in a Phase III registration program in ALS that is seeking to preserve or improve neurological function.

Also, I should note our asset, CNM-Au8, is taken on top of standard of care in all of our Phase 2/3 clinical trials. In other words, we ask the physician in our clinical studies to bring the patient to Clene with the most effective, current therapy they can prescribe, and our asset is given in addition to that therapy to see if we can improve neurological function. Importantly, to-date we have not seen any drug-drug interactions.

These programs are all ongoing, so the data have not yet been unblinded. But we’ve presented various blinded data that show neurological functional improvement at the American Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), the Northeast ALS Consortium (NEALS), and the Motor Neuron Disease Association meetings. I repeat that the data are still blinded, so I want to add a caution here. But what we are seeing suggests something remarkably interesting if in fact we have a drug effect, which we will find out in the next two to five quarters as these studies progress to completion.

Do you have a goal for when you expect CNM-Au8 to actually become a treatment on the market?

Yes, our Phase III ALS study is a part of the Healey ALS Platform Trial, being sponsored by Harvard University’s Healey Center for ALS and is one of the most innovative neurodegenerative clinical programs ever initiated. It was funded predominately by philanthropic donors and is the first-ever ALS platform trial. If you are unaware, many platform trials have been completed in oncology and are designed to reduce the trial time and costs, and to increase patient participation because there is less likelihood of a patient being assigned to a placebo.

Clene’s CNM-Au8 was selected as one of the first drugs to be evaluated from among nearly 30 different applicants. Expert ALS clinical sites throughout the U.S. are now recruiting patients, with full enrollment expected later this year, and top line data expected in the first half of next year. What that translates into is; in around one year, we will know whether CNM-Au8 will reach statistical significance in reducing the rate of progression in ALS patients utilizing the ALS Functional Rating Scale. If successful, we will plan to commence writing a new drug application to the FDA, and Clene may see the possibility of commercialization approval from the FDA by mid-2023.

Looking beyond that, what are your goals for the company further down the road after you get a product on the market?

Clene’s vision would be to develop a platform of nanocatalysts around many of the therapeutic elemental metals that may have efficacy, and to bring them forward for both orphan diseases as well as more of the common diseases. As a simple example, we have a zinc-silver orally administered asset—both with well-known antibacterial and antiviral activity—which we accelerated into the clinic this year and are testing in a Phase II proof of concept study in PCR-positive COVID patients. Even though our key focus is on neurodegenerative disease, our platform of drug discovery could have utility in a number of other conditions. Indeed, there could be many such oral therapies that Clene could bring forward for other vexing diseases, with our drug assets potentially additive to other pharmacological approaches.

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