Executive Summary / Key Takeaways

• Clene Inc. is a clinical-stage biopharmaceutical company focused on neurodegenerative diseases, leveraging its proprietary clean-surfaced nanotechnology (CSN) platform to develop therapeutics targeting cellular energy dysfunction.
• The core investment thesis centers on the potential of its lead candidate, CNM-Au8, particularly following recent positive guidance from the FDA regarding a potential accelerated approval pathway for Amyotrophic Lateral Sclerosis (ALS).
• Recent clinical data from the HEALEY ALS trial showed a significant survival benefit for CNM-Au8, and new analyses from the VISIONARY-MS trial demonstrated evidence of remyelination and neuronal repair in Multiple Sclerosis (MS) patients, supported by objective biomarkers.
• Financially, Clene faces significant liquidity challenges, reporting cash and cash equivalents of $9.8 million as of March 31, 2025, with management concluding there is substantial doubt about the company's ability to continue as a going concern without additional financing.
• Key upcoming catalysts include an FDA meeting in Q2 2025 to finalize the statistical analysis plan for EAP NfL data, EAP NfL data analysis in Q3 2025, a planned NDA submission in Q4 2025, planned commencement of the confirmatory RESTORE-ALS Phase 3 trial in H2 2025, and topline REPAIR-MS data in mid-2025. The company also faces a near-term risk related to maintaining its Nasdaq listing.

A Nanotechnology Play in the Neurodegenerative Arena

Clene Inc. is charting a course in the challenging landscape of neurodegenerative diseases, aiming to revolutionize treatment for conditions like Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Parkinson's Disease (PD). At the heart of Clene's strategy is its pioneering clean-surfaced nanotechnology (CSN) platform, a differentiated approach that sets it apart in a field dominated by traditional small molecules and biologics.

The company's patented electro-crystal-chemistry platform enables the production of concentrated, stable, and highly active nanocrystal suspensions. Unlike many traditional nanoparticle synthesis methods that can leave potentially toxic residues, Clene's process yields "clean-surfaced" nanocrystals of transition elements. These nanocrystals possess unusually high catalytic activities, significantly greater than other commercially available nanoparticles evaluated by the company. The core scientific premise is that these catalytic properties can drive and maintain beneficial metabolic and energetic cellular reactions, thereby supporting and protecting diseased or damaged neurons. This focus on cellular energy impairment, common across many neurological disorders, provides a broad potential application for their technology. For investors, this technological differentiation represents a potential competitive moat, offering a novel mechanism of action that could address underlying disease pathology rather than just symptoms.

Clene's journey to its current clinical-stage focus included an earlier phase marked by the development and commercialization of dietary supplements leveraging its nanotechnology platform. Agreements with partners like 4Life Research LLC established initial, albeit small, revenue streams from products like Zinc Factor and Gold Factor. However, the company's strategic pivot and primary resource allocation have been firmly directed towards the high-unmet-need drug development space since becoming a public entity via a reverse recapitalization in December 2020. This transition, while providing access to public markets, also introduced complex capital structures and the ongoing need for significant financing to fuel its ambitious clinical programs.

The competitive landscape in neurodegenerative diseases is populated by both large pharmaceutical players with established portfolios and pipelines (like Biogen (BIIB) and Novartis (NVS)) and smaller, more focused biotech firms (such as Amylyx Pharmaceuticals (AMLX) and Ionis Pharmaceuticals (IONS)). While larger companies benefit from extensive resources, global reach, and established market access, their innovation speed in niche areas can sometimes be slower. Smaller biotechs often bring focused expertise and novel technologies but face significant challenges in funding, clinical execution, and commercialization. Clene positions itself as an innovator leveraging a unique technological approach. The recent failures of other investigational treatments in the HEALEY ALS Platform Trial, such as those from Calico/AbbVie (ABBV), underscore the difficulty in developing effective therapies in this space and highlight the significant unmet need, potentially creating an opportunity for a differentiated approach like Clene's if successful. Clene's strategy appears to be centered on demonstrating clear clinical benefits, particularly in areas like survival and functional improvement, leveraging its technology's potential to target fundamental cellular processes.

CNM-Au8: Pursuing the ALS Accelerated Path and Showing Promise in MS

The narrative for Clene is currently dominated by the clinical progress and regulatory path for its lead asset, CNM-Au8. The focus has intensified on ALS, a devastating disease with limited treatment options. Clene participated in the HEALEY ALS Platform Trial, which provided valuable data, including recent cross-regimen analyses showing a significant survival benefit for CNM-Au8 30 mg treatment. This finding is crucial as survival is a key endpoint in ALS trials.

Following an initial setback in September 2024 where the FDA deemed the data insufficient for an accelerated approval submission, Clene engaged in further dialogue and presented additional analyses. This led to positive written guidance from the FDA in December 2024, outlining a potential accelerated approval pathway. The FDA recommended leveraging data from ongoing compassionate use Expanded Access Programs (EAPs) to substantiate the effect of CNM-Au8 on neurofilament light (NfL) decline, a biomarker associated with neuronal damage. While the FDA noted that NfL's suitability as a surrogate endpoint and the magnitude of observed change would be subject to review, this guidance provides a clear roadmap.

Clene is actively pursuing this path. The company plans to meet with the FDA in the second quarter of 2025 to finalize the statistical analysis plan for the EAP NfL biomarker analyses. The actual collection and analysis of this additional data are scheduled for the third quarter of 2025. Based on the outcome of these analyses and ongoing discussions, Clene plans to submit a New Drug Application (NDA) seeking accelerated approval in the fourth quarter of 2025. To meet the FDA's requirement for an "underway" confirmatory trial at the time of accelerated approval submission, Clene plans to commence its confirmatory Phase 3 trial, RESTORE-ALS, in the second half of 2025. This trial is designed with improved survival as the primary endpoint and delayed time to clinical worsening events as a key secondary endpoint. These concrete steps and timelines represent critical near-term catalysts for the company.

Beyond ALS, CNM-Au8 is also being investigated in MS. Recent analyses from the long-term open-label extension of the VISIONARY-MS trial, announced in April 2025, provided new evidence of remyelination and neuronal repair in MS participants treated with CNM-Au8 30 mg. These post hoc analyses revealed consistent anatomical and physiological effects that correlated with clinically meaningful improvements in cognition (measured by SDMT) and visual function (measured by LCLA). Objective biomarkers, including MRI diffusion tensor imaging (DTI) metrics (AD and MTR) and multi-focal visual evoked potential (mf-VEP) metrics (latency and amplitude), supported these findings. Quantitatively, the company reported that 96% of LCLA responders also showed improvement in MRI DTI metrics, 91% of LCLA visual responders exhibited mf-VEP improvements, and 98% of SDMT responders had corresponding improvements in MRI DTI metrics. These results suggest that CNM-Au8's mechanism, targeting mitochondrial function and reducing oxidative stress, may promote repair processes in the central nervous system. Clene has initiated a second dosing cohort in its REPAIR-MS Phase 2 trial, with topline results expected in mid-2025. An End of Phase 2 meeting with the FDA for MS is planned for the third quarter of 2025.

Financial Realities and the Going Concern Question

Despite the promising clinical developments, Clene's financial position reflects the significant costs inherent in drug development. The company has consistently incurred substantial losses and negative cash flows since its inception, a common characteristic of clinical-stage biopharmaceutical companies that have not yet brought a product to market.

For the three months ended March 31, 2025, Clene reported total revenue of $81,000, primarily from dietary supplement sales, a modest increase from $73,000 in the same period of 2024. Operating expenses totaled $4.157 million, a significant decrease from $9.305 million in the prior-year period. This reduction was largely driven by a substantial decrease in research and development expenses ($1.481 million in Q1 2025 vs. $5.869 million in Q1 2024). The decrease in R&D was attributed to the conclusion of certain clinical program phases (like REPAIR-MS enrollment) and reduced regulatory and general preclinical expenses, partially offset by increased costs associated with the ongoing NIH-funded ACT-EAP and planning for the RESTORE-ALS trial. General and administrative expenses also decreased ($2.656 million vs. $3.420 million), influenced by lower public relations and personnel costs, partially offset by increased legal and finance fees. Notably, grant revenue, recorded as a reduction of R&D and G&A expenses, increased significantly to $4.3 million in Q1 2025, contributing to the lower reported expenses.

The loss from operations for the quarter was $4.076 million, a notable improvement from the $9.232 million loss in Q1 2024. However, the net loss for the period was only $0.751 million, a dramatic decrease from $11.080 million in Q1 2024. This substantial improvement in net loss was heavily influenced by non-cash gains totaling $3.657 million from changes in the fair value of common stock warrant liabilities ($2.510 million gain) and derivative liabilities ($1.147 million gain). These fair value adjustments are volatile and dependent on factors like the company's stock price and valuation model inputs.

From a cash flow perspective, the company used $5.011 million in operating activities during the three months ended March 31, 2025, compared to $7.082 million used in the same period of 2024. This continued cash burn is the primary driver of the company's liquidity concerns. As of March 31, 2025, Clene held $9.832 million in cash and cash equivalents, down from $12.155 million at the end of 2024.

Management explicitly states in the 10-Q filing that based on current cash levels and expected future losses, "within the next twelve 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 unless we obtain additional financing." This condition, coupled with a covenant under the 2024 Senior Secured Convertible Promissory Notes requiring a minimum of $2.0 million in unrestricted cash, raises substantial doubt about the company's ability to continue as a going concern beyond one year from the filing date.

Clene has been actively seeking additional funding, utilizing its at-the-market (ATM) facility, which generated $2.7 million in gross proceeds during Q1 2025 and an additional $0.9 million subsequent to the quarter end. The company is exploring various financing options, including equity and debt offerings, and potential licensing or collaboration deals. Cost-saving initiatives, including R&D program delays/reductions and staff cuts, have also been implemented. However, management's conclusion indicates these measures are not sufficient on their own to fully alleviate the going concern doubt.

Adding to the financial pressures, Clene received a notice from Nasdaq on May 6, 2025, indicating non-compliance with the minimum Market Value of Listed Securities (MVLS) requirement of $35 million. The company has until November 3, 2025, to regain compliance. Failure to do so could result in delisting, which would severely impact the stock's liquidity and the company's ability to raise future capital.

Risks and the Path Forward

Investing in Clene involves significant risks, many of which are typical for a clinical-stage biotech, amplified by the company's precarious financial position. The primary risks include the inherent uncertainty of clinical trials – the planned RESTORE-ALS Phase 3 trial and the ongoing REPAIR-MS trial may not yield positive results. Regulatory risk is also substantial; despite the positive guidance, there is no guarantee the FDA will ultimately accept NfL as a surrogate endpoint for accelerated approval or that the submitted data will be deemed sufficient. The reliance on third parties for clinical trials (CROs) and manufacturing also introduces execution risk.

Beyond the clinical and regulatory hurdles, the most pressing risk is the company's liquidity. The need for significant additional financing is immediate and critical. The success of future equity or debt raises is subject to market conditions and investor confidence, which can be volatile, particularly for a company with a going concern warning and Nasdaq listing issues. Dilution from future equity financing is highly probable. The Nasdaq listing issue itself poses a material threat, potentially limiting access to capital markets if not resolved.

The competitive landscape, while offering opportunities due to high unmet needs, also presents challenges. Established players have deeper pockets and existing market infrastructure. While Clene's technology offers a differentiated approach, translating that into clinical success and market share requires overcoming significant barriers.

Conclusion

Clene Inc. stands at a critical juncture, embodying the high-stakes nature of biopharmaceutical investment. The company possesses a potentially disruptive clean-surfaced nanotechnology platform and a lead candidate, CNM-Au8, that has shown intriguing clinical signals in devastating neurodegenerative diseases like ALS and MS. The recent FDA guidance for a potential accelerated approval pathway in ALS, coupled with promising remyelination data in MS, provides a tangible path forward and represents the core of the bullish investment thesis. These developments, if successful, could unlock significant value by addressing large, underserved patient populations.

However, this potential is overshadowed by significant financial headwinds. The company's limited cash runway, ongoing cash burn, explicit going concern warning, and Nasdaq listing challenge highlight the urgent need for successful financing. The ability to secure sufficient capital will be paramount to funding the planned clinical trials, pursuing regulatory submissions, and ultimately bringing CNM-Au8 to market, should the data support it. For investors, Clene represents a binary opportunity heavily dependent on successful clinical execution, favorable regulatory outcomes, and the ability to navigate its immediate liquidity requirements. The coming quarters, with key FDA interactions, data analyses, and financing efforts, will be decisive in determining the company's future trajectory.