Longeveron Issues Letter To Shareholders

Dear Fellow Shareholders,

Twenty twenty-four was a year of execution for Longeveron. We made significant progress advancing Longeveron's founding mission - developing cutting-edge cellular therapy research to impact patients' lives for the better by addressing unmet medical needs. We have come a long way pursuing that mission and now have clarity on the pathway to our first potential Biological License Application (BLA) submission.

Today, I am excited to update you on our overall strategy, progress, and key priorities and goals for 2025.

Strategic Overview and 2024 Progress:

Over the past decade, stem cell therapy has seen remarkable strides, transforming from a promising field into one delivering tangible clinical outcomes. We've seen the solidification of cell therapy's role in regenerative medicine and its potential to treat a wide range of conditions, signaling an exciting future for both scientific innovation and patient care.

Longeveron has been at the forefront of this evolution in medicine. Our lead investigational product is laromestrocel (Lomecel-B™), a stem cell therapy derived from culture-expanded mesenchymal stem cells (MSCs) that are sourced from bone marrow of young healthy adult donors. The number of functional MSCs in the body declines as we age, which has driven interest in their use for aging-related conditions. Their unique properties — including the ability to reduce inflammation, promote tissue repair and regeneration, modulate immune responses, and improve vascularization — also support their application in some rare cardiovascular diseases/conditions with high unmet medical need. We believe that by using the same cells that promote tissue repair, organ maintenance, and immune system function, we can develop safe and effective therapies for some of the most difficult diseases and conditions.

A decade ago, our stem cell therapy vision was an academic idea. Today, laromestrocel represents a pipeline in a product opportunity that has delivered positive results from multiple clinical trials: Phase 1 & 2 in Alzheimer's disease, Phase 1 & 2 in Aging-related Frailty, Phase 1 in Hypoplastic Left Heart Syndrome (HLHS), a rare pediatric disease. We are currently conducting a pivotal Phase 2b clinical trial for HLHS. Our development programs for these 3 initial indications address market opportunities of what we estimate to be approximately ~$5+ billion, ~$4+ billion and up to ~$1 billion, respectively. Earlier this year, the World Health Organization's International Nonproprietary Names (INN) Expert Committee approved "laromestrocel" as the non-proprietary name for Lomecel-B™ — a key milestone in the development and future commercialization of our stem cell therapy.

As we did this past year, in 2025, we will continue focusing our efforts on two of our most promising programs: HLHS and Alzheimer's disease.

Hypoplastic Left Heart Syndrome (HLHS):

HLHS is a rare pediatric disease in which the left ventricle (one of the pumping chambers of the heart) is either severely underdeveloped or missing. Because the left ventricle is the chamber that normally pumps blood to the body, infants born with this condition have a profound reduction in blood flow and thus cannot get the normal supply of oxygen to their organs. In order for the children to survive, they must undergo a complicated, three-stage heart reconstruction surgery over the course of the first 5 years of their lives. Despite this surgical reconstruction, only 50% of the affected children survive to age 15 without heart transplantation.

Our program is designed to boost/improve the heart function in these children with the goal of potentially enhancing their survival. In our Phase I clinical trial (ELPIS I) evaluating laromestrocel in 4-month-old infants with HLHS, we observed 100% transplant-free survival up to five years following treatment. This contrasts with an approximately 20% mortality rate observed in historical control data. Five-year post-treatment long-term survival data from the ELPIS I Phase 1 clinical trial was presented at the Congenital Heart Surgeons' Society (CHSS) 51st Annual Meeting in October 2024.

We are currently nearing completion of enrollment for our Phase 2b study, ELPIS II, which is evaluating laromestrocel as a potential adjunct treatment to the standard of care for HLHS. ELPIS II has achieved nearly 95% enrollment, and we expect to complete enrollment in the second quarter of this year.

In September 2024, we completed a Type C meeting with the U.S. FDA regarding our HLHS development program and the pathway toward a potential BLA submission. We reached foundational alignment on the primary endpoint and secondary endpoints for the ELPIS II trial. The FDA confirmed that, contingent on positive results, ELPIS II may be considered a pivotal trial and potentially acceptable for BLA submission seeking full traditional approval. With this regulatory clarity, we are now focused on BLA preparedness and enabling activities for the HLHS program. Notably, because this program has received Rare Pediatric Disease Designation, we may be eligible to receive a Priority Review Voucher (PRV) if our BLA is approved. We may use the PRV internally or sell to a third party. Historically, PRVs have commanded values exceeding $100 million.

Alzheimer's Disease:

The laromestrocel Alzheimer's disease (AD) program continues to garner important recognition and support. In 2024, data from the CLEAR MIND Phase 2a clinical trial evaluating laromestrocel in mild Alzheimer's disease were presented as a featured research oral presentation at the 2024 Alzheimer's Association International Conference held at the end of July and as a late breaking poster presentation at the 17th edition of the Clinical Trials on Alzheimer's Disease Conference (CTAD24) in October. We are very excited about the trial's positive results. The trial met its primary objective of demonstrating safety, with laromestrocel being well-tolerated. In addition, we observed encouraging trends suggesting a potential slowing or prevention of disease progression in patients treated with laromestrocel compared to placebo.

This program has received Regenerative Medicine Advanced Therapy (RMAT) and Fast Track designations, providing us with the opportunity for enhanced and frequent communication with the FDA to facilitate the development and review process.

In March of this year, results from the trial were published in Nature Medicine.

Also in March of this year, we held a Type B meeting with the FDA to discuss the regulatory pathway for a potential BLA for laromestrocel in mild Alzheimer's disease. We reached foundational alignment on the overall study design for a proposed single, pivotal, seamless adaptive Phase 2/3 clinical trial. To support an accelerated path to potential approval, the FDA agreed to consider a BLA submission based on positive interim results from this planned single study.

With this regulatory clarity in hand, we are focused on seeking partnership opportunities and/or non-dilutive funding for the Alzheimer's disease program.

Our Core Business Objectives:

Our strategic plan is built on the strength of the science underlying our stem cell therapy laromestrocel. For 2025, we are focused on four key objectives:

1. Advance HLHS Program as the Main Near-Term Value Driver:
   • Pivotal Phase 2 clinical trial (ELPIS II) is nearing enrollment completion.
   • Regulatory pathway clarified with U.S. FDA.
   • Potential to initiate rolling BLA submission in 2026.
   • Potential to receive a Rare Pediatric Disease priority review voucher associated with HLHS upon BLA approval which could have significant monetary value and further enhance our product's value proposition upon approval.
2. HLHS BLA and Commercialization Readiness:
   • Successful meeting with FDA confirmed ELPIS II could be pivotal.
   • 2025 will see significant focus on organizational readiness for potential BLA filing for HLHS in 2026. Our goal is to accomplish BLA readiness this year ahead of data readout to potentially shorten the timeline to BLA submission.
   • Emphasis on Chemistry, Manufacturing, and Controls (CMC) preparedness.
   • Hired industry veteran Chief Technology Officer to support BLA preparedness.
   • We are committed to helping HLHS patients worldwide. In 2025, we intend to take initial steps connecting with non-U.S. regulatory bodies, including EMA (European Union), MHRA (United Kingdom), PMDA (Japan) and HealthCanada.
   • Recognizing substantial revenue potential from worldwide commercialization, we anticipate capitalizing on recent rare disease pricing trends and the unique aspects of our treatment.
3. Strategic Collaborations for Alzheimer's Disease:
   • We believe our Alzheimer's disease program holds immense potential. Due to the large size of the affected population, it involves larger-scale studies and commercialization requirements. This scale of development effort necessitates significant investment, prompting our focus on potential strategic partnerships with biotech/pharmaceutical companies and/or non-dilutive funding sources.
   • We believe the clarity on the pathway to potential BLA submission and the need for only a single pivotal clinical trial enhance the attractiveness and economic benefits of the program to potential partners.
4. Efficient Resource Management and Capital Allocation:
   • We strive to be prudent stewards of shareholder capital and focus allocating it to the organization's top priorities to effectuate optimal resource utilization and alignment with strategic objectives.
   • We prudently manage expenses. In 2024, we reduced total operating expenses 13% while continuing to effectively advance our development programs.

Financial Position and Capital Strategy:

Longeveron is working diligently to effectively advance our development programs while managing expenses and our capital. We will need additional capital to achieve our business strategy and objectives.

We indicated in our recently filed Annual Report on Form 10K that we anticipated our existing cash and cash equivalents would fund our operating expenses and capital expenditure requirements into the fourth quarter of 2025. However, as we also indicated, as a result of our successful Type C meeting with the FDA in August 2024 with respect to the HLHS regulatory pathway, we have started to ramp up BLA enabling activities to prepare for a potential filing with the FDA in 2026 if the current ELPIS II trial is successful. We expect our operating expenses and capital expenditure requirements to accelerate this year as a result of these activities, including CMC (Chemistry, Manufacturing, and Controls) and manufacturing readiness. We intend to seek additional financing and non-dilutive funding options to support these activities, and additional non-dilutive funding and/or strategic partners to support the AD development program. We anticipate that our current cash projections may be impacted by these ramped up activities and any financing transactions we enter into.

2025 Goals and Priorities

Our goals for 2025 center on efficient, effective execution of our strategic plan with an emphasis on three primary operational goals:

1. ELPIS II Completion: We anticipate completion of ELPIS II enrollment in the second quarter of 2025. We will then focus on supporting our investigative sites through completion of the 12-month primary endpoint follow-up period and preparation for data collection and analysis at the end of the study.
2. HLHS BLA Preparedness: We intend to accomplish the majority of BLA readiness in 2025 to support a potentially shortened time frame from clinical trial readout to BLA submission.
3. Alzheimer's Disease Program Partnering: We plan to leverage the strength of our Phase 2 data and clarity on the clinical pathway to a potential BLA for AD to engage with potential funding/commercialization partners.
   
   
   
    

Outlook

Longeveron has made tremendous progress in two important stem cell development programs over the past 12 months, successfully delivering on our strategic plan. We are now approaching multiple potentially transformational milestones over the next 12 months including completion of enrollment in our pivotal Phase 2b clinical trial in HLHS which may establish the timeline for a potential BLA submission for HLHS, and potential partnering for the Alzheimer's disease program. Our team's expertise and industry experience enable the organization to accomplish so much with a small team and few resources. Generating several positive initial results across five clinical trials in three indications, continues to position Longeveron as a leader in stem cell therapy research and, potentially, commercialization of cellular therapeutics.

We believe Longeveron's demonstrated track record of successful clinical execution, strength of data generated to date and the potential size of addressable markets provide for a compelling investment opportunity.

We deeply appreciate the support of our stakeholders and look forward to continued collaboration and progress in the future.

Sincerely,

Wa'el Hashad

CEO, Longeveron