Rob Etherington, President and CEO of Clene Nanomedicine

Rob Etherington drives an electric car with a personalized license plate that reads “CLENE,” as in Clene Nanomedicine, the company he leads as President and CEO: “Many people ask me, is it because it’s kind-of clean energy? And I say, yeah, effectively.”

The license plate, like the company name, uses the Anglo-Saxon spelling for “clean.” The company develops treatments for neurodegenerative diseases through a platform that uses electro-crystal-chemistry to produce highly faceted, clean-surfaced (hence the name) nanocrystals. Those nanocrystals consist of pure transition elements—such as metals whose electrons can form chemical bonds in two shells rather than just one.

“We’ve purposely riffed off the word ‘clean,’ because we theorized from the beginning that we would have clean toxicity from the get-go,” Etherington told GEN Edge. “Our now-therapeutic technology does not use synthetic chemistry. What patients are drinking every morning has clean surfaces, which is to say, no chemistry at all. So that’s one of the reasons we call it clean.”

Clene’s lead product, CNM-Au8®, is a gold nanocrystal suspension being developed to treat amyotrophic lateral sclerosis (ALS), Parkinson’s disease—and multiple sclerosis (MS), for which the company recently announced positive topline Phase II data in a modified intent to treat (mITT) population. Each indication represents a potential commercial opportunity of >$1 billion per indication, Clene told investors last month.

In the Phase II VISIONARY-MS trial (NCT03536559), which evaluated CNM-Au8 in participants with stable relapsing remitting multiple sclerosis (RRMS), CNM-Au8 met its primary endpoint of low contrast letter acuity (LCLA) letter change in the clinically affected eye with a least squares [LS] mean difference of 3.13. CNM-Au8 also met its secondary endpoint of a statistically significant modified Multiple Sclerosis Functional Composite (mMSFC) score vs. placebo after 48 weeks.

Those results were generated from a modified intent-to-treat (mITT) population that excluded what Etherington said was invalid data from a nine-patient site for two reasons. One was because the site mistakenly allowed a patient to change how she navigated the 25-foot timed walk test during the study, from using a cane to using a wheeled walker.

The other reason, according to Etherington, was LCLA testing execution errors: “multiple rooms, different light boxes, variant ambient light conditions, different testers who actually tested the patients. Taken together, that confounded some of the data from the single site.”

“Novel and unique”

“We were attempting to look at patients that were fully controlled, and that’s a very important point: Nobody has ever looked at such a study population as novel and unique,” Etherington said.

Nearly all patients in VISIONARY-MS (92%) were on background therapy, with more than half of them (53%) on monoclonal antibodies.

“We are taking our drug on top of very controlled patients who are generally happy with their MS controls, but unhappy with their functional compromise. We showed in this study that in the modified intent-to-treat population, we had a p-value of p=0.056, showing a statistically significant change in low contrast, letter acuity,” Etherington added.

That p value was just above the FDA statistical significance threshold of p=0.05—though well below the pre-specified threshold for significance set at p=0.01 due to limited enrollment. Clene says it set a high significance threshold due to the challenge of recruiting patients during the COVID-19 pandemic. Clene ended the trial early in February, by which time only 73 participants were enrolled in VISIONARY-MS, just under half the planned 150.

“A whole series of COVID compromises meant that we had to close the study down, and we frankly wondered if we’d see anything at all, because a half-enrolled study is remarkably underpowered,” Etherington acknowledged. “But at p=0.056, we just missed the classical statistical significance by 0.006. Indeed, we were thrilled that the study was positive of the pre-specified mark.”

VISIONARY-MS was designed as a proof-of-concept study to establish that treatment of neuronal and glial energetic failure can support remyelination and neuroprotection in people living with MS.

Restoration through remyelination

Clene is among a number of companies and researchers looking to treat MS by using drugs to restore the myelin that forms around nerves.

Last month, investigators at Heinrich-Heine-University in Düsseldorf, Germany, published a study in eBioMedicine showing that medrysone—a previously marketed ophthalmic anti-inflammatory corticosteroid first approved in 1969—enhanced the repair of myelin in a mouse model of chronic demyelination.

“The application of the corticosteroid medrysone induces a robust myelin regeneration response marked by regulated astrocyte polarization and trophic factor expression,” concluded the research team, led by corresponding author Patrick Küry, PhD. “This drug may be of use as a potential treatment for late-stage MS where regenerative processes increasingly fail.”

Another drug recently studied for its remyelination potential in MS is digoxin, a cardiac glycoside used clinically to treat heart failure and arrhythmias. In July, a multi-institution research team led by Stephen D. Miller, PhD, Professor Emeritus of Microbiology-Immunology at Northwestern University Feinberg School of Medicine, published a study in Glia reporting that digoxin “completely ameliorated clinical disease symptoms and stimulated recovery of OL [oligodendrocyte] lineage cell numbers.”

“These findings provide critical pre-clinical evidence supporting future clinical trials of myelin-specific tolerance with myelin repair/regeneration drugs, such as digoxin, in MS patients,” Miller and colleagues added. Digoxin was first approved in 1954 and is now sold as a generic drug as well as under brand names that include Lanoxin® (Covis Pharma).

Capital challenge

Clene says the results from VISIONARY-MS support advancing CNM-Au8 into a Phase III program in people with MS who are experiencing progression independent of relapse activity.

“For a patient that’s controlled with their DMT [disease-modifying therapy], but still has neurological, functional deficit, these results demonstrated that CNM-Au8 may be the first therapy to potentially ever promote global neurological improvement as an adjunct to whatever drug they are on, and that we did that safely as well has led us to be very encouraged to design a Phase III study now,” Etherington said.

To advance into that Phase III program and continue current operations, Clene will need to surmount the challenge of raising additional capital, the company has acknowledged in its Form 10-Q filing for the second quarter. How much capital has yet to be determined pending the design of the pivotal study—a topic the company has discussed with regulators.

“We do know that it will be significant enough that we will indeed need to raise capital,” Etherington said. “That capital timeline will happen at the appropriate time when market conditions are right and when our data supports such.”

Clene finished the second quarter with $7.25 million in cash and cash equivalents, part of a total $26.28 million in cash and investments that the company told investors last month was sufficient to fund “key milestones in 2022.”

However, in its quarterly filing, Clene also projected that within the next 12 months: “We will not have sufficient cash and other resources on hand to sustain our current operations or meet our obligations as they become due, and we must obtain additional financing.”

Under a 42-month, up-to-$30 million term loan with Avenue entered into last year, Clene must maintain unrestricted cash and cash equivalents of at least $5 million to avoid acceleration of the full balance of its loan. “These conditions raise substantial doubt about the company’s ability to continue as a going concern,” Clene acknowledged.

Clene finished the second quarter with a net loss of $4.53 million, up from a net loss of $3.35 million in Q2 2021, on revenue that slid to $35 million from $201 million. For the first six months of 2022, Clene more than halved its net loss to $17.89 million from $43.11 million a year earlier.

Seven clinical trials

VISIONARY-MS is one of seven clinical trials focused on evaluating CNM-Au8, of which three are in MS. Clene has completed the first cohort of its Phase II REPAIR-MS trial (NCT03993171) in stable relapsing MS, and is evaluating a second cohort of non-active, progressive MS patients, with data set to read out in the first half of 2023.

Later this year, Clene expects to release topline data from the Healey ALS Platform Trial (NCT04414345  and NCT04297683), designed to assess CNM-Au8 and at least four other potential ALS treatments—zilucoplan (being developed by UCB), verdiperstat (Biohaven Pharmaceuticals, set to be acquired by Pfizer for $11.6 billion), pridopidine (Prilenia Therapeutics), and SLS-005 (also called trelahose injection; Seelos Therapeutics). The 800-patient Phase II/III trial is led by the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, and being conducted at more than 50 centers nationwide.

Should results from the Healy platform trial prove positive, Etherington said, “It could serve as a new drug application-worthy package that we would take to the FDA and ask for consideration.”

Last year, CNM-Au8 missed its primary endpoint of slowing disease progression as measured by Motor Unit Number Index (MUNIX) and its secondary endpoint (forced vital capacity or FVC) in the Phase II RESCUE-ALS trial (NCT04098406). But Clene insisted it found an efficacy signal for the MUNIX endpoint at week 12, and cited a pre-specified analysis in the subset of limb onset ALS in which, the company said, CNM-Au8 showed a “significant treatment effect” in MUNIX at week 12 and a “trend” for improvement at week 36.

“Befitting of Lou Gehrig, whose legacy is intertwined with the disease, we swung for the fences and ended with a stand-up triple,” Etherington said in a November 2021 statement.

On September 21, Clene presented positive updated survival results from the RESCUE-ALS trial open-label extension (OLE; NCT05299658) showing that, at up to 137 weeks following randomization, patients treated with CNM-Au8 demonstrated an approximately 70% decreased risk of death compared with patients treated with placebo. Last July, Clene reported 14 patients treated with placebo had died in the OLE, compared with five treated with CNM-Au8.

The updated results also showed a significant observed survival benefit with CNM-Au8 vs. predicted median survival derived from the published European Network for the Cure of ALS (ENCALS) prediction model.

CNM-Au8 is also being assessed in ALS through ongoing expanded access programs at the Healey Center (NCT04081714).

Restoring neuronal health

CNM-Au8 is designed to restore neuronal health and function by increasing the human body’s production and use of energy. Patients drink 60 ml consisting of trillions of gold nanocrystals suspended in water—nanocrystals small enough, according to Clene, to cross the blood-brain barrier and travel inside the cells of the human body, whose mitochondrial capacity is improved in response to cellular stresses induced by numerous disease-relevant neurotoxins.

By transmitting thousands of energy-supportive electrons per second per nanocrystal, CNM-Au8 rapidly catalyzes the oxidized form of nicotinamide adenine dinucleotide (NAD+). Once inside cells, CNM-Au8 stimulates production and use of adenosine triphosphate (ATP) while reducing oxidative stress and lowering levels of misfolded proteins harmful to human health.

Clene reasons that it can apply its approach to a variety of nanotherapeutics with unique energy profiles, generating a pipeline of drug candidates with broad applicability across different diseases.

In addition to CNM-Au8, Clene’s pipeline includes:

  • CNM-ZnAg, an ionic solution of zinc and silver that has shown both antiviral and antimicrobial properties. CNM-ZnAg is under study in a Phase II trial (NCT04610138) in symptomatic participants with acute COVID-19 that are not hospitalized at the time of enrollment, with data anticipated by year’s end.
  • CNM-AgZn17, a preclinical-phase topical gel polymer suspension of silver and zinc ions that is being developed to treat infectious diseases and accelerate wound healing.
  • CNM-PtAu7, a research-phase gold-platinum nanotherapeutic that, based on in vitro research, has shown broad-spectrum efficacy across a variety of tumor cell lines, according to Clene.

Clene was founded in December 2012 to discover and develop drugs for neurological diseases and other disorders. The company was formed to commercialize the research of Mark Mortenson, co-inventor of the technology platform behind Clene’s Clean-Surface Nanocrystal (CSN™) therapeutics. Mortenson developed an electrocrystallization process to build a nanosuspension system that can serve as an electron donor to living cells–a process protected by more than 150 patents.

In 2020, Clene went public through a special purpose acquisition company (SPAC) merger with Tottenham Acquisition I Ltd.. The deal valued Clene at $542.5 million and generated about $31.9 million, including funds held in Tottenham’s trust account and a concurrent private placement investment in public equity (PIPE) financing led by existing Clene shareholders.

Clene’s just over 100 employees are split between its headquarters in Salt Lake City, and its manufacturing and quality operations in the town of North East, MD.

“If CNM-Au8 is positive in the Healy ALA Platform Study, and we’re writing a New Drug Application, and we’re planning for commercialization, and for a manufacturing operation that needs to perfectly scale to supply the drug, then that number will grow quite considerably,” Etherington said.

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