UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
FORM
10-K
(Mark
One)
☒ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For
the fiscal year ended December 31, 2023
or
☐TRANSITION
REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For
the transition period from
to
Commission
File Number: 001-40060
LONGEVERON
INC.
(Exact
name of registrant as specified in its charter)
(Address of Principal Executive Offices) (Zip Code)
(305)909-0840
(Registrant’s
telephone number, including area code)
Securities
registered pursuant to Section 12(b) of the Act:
Title of each class Trading Symbol Name of each exchange on which registered
Common Stock, par value $0.001 LGVN The Nasdaq Capital Market
Indicate
by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒
Indicate
by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐ No ☒
Indicate
by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange
Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2)
has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐
Indicate
by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule
405 of Regulation S-T (§ 232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant
was required to submit such files). Yes ☒ No ☐
Indicate
by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer smaller reporting company,
or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller
reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☐ Accelerated filer
Non-accelerated filer ☒ Smaller reporting company ☒ Emerging growth company ☒
If
an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying
with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act ☐
Indicate
by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness
of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered
public accounting firm that prepared or issued its audit report. ☐
If
securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant
included in the filing reflect the correction of an error to previously issued financial statements. ☐
Indicate
by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation
received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐
Indicate
by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act). Yes ☐ No ☒
The
aggregate market value of the voting and non-voting common equity held by non-affiliates was approximately $19,016,000 as of June 30,
2023 (the last business day of the registrant’s most recently completed second fiscal quarter).
As
of February 23, 2024, the registrant had 10,294,603 shares of Class A common stock, $0.001 par value per share, and 14,839,993 shares
of Class B common stock, $0.001 par value per share, outstanding.
DOCUMENTS
INCORPORATED BY REFERENCE. None
TABLE
OF CONTENTS
PART I 1
Item 1. Business 1
Item 1A. Risk Factors 27
Item 1B. Unresolved Staff Comments 74
Item 1c. Cybersecurity 74
Item 2. Properties 75
Item 3. Legal Proceedings 75
Item 4. Mine Safety Disclosures 75
Item 6. [Reserved] 76
Item 7A. Quantitative and Qualitative Disclosures about Market Risk 89
Item 8. Financial Statements and Supplementary Data 89
Item 9A. Controls and Procedures 89
Item 9B. Other Information 90
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 90
PART III 91
Item 10. Directors, Executive Officers and Corporate Governance 91
Item 11. Executive Compensation 99
Item 14. Principal Accountant Fees and Services 108
Item 15. Exhibits and Financial Statement Schedules 109
i
CAUTIONARY
NOTE REGARDING FORWARD-LOOKING STATEMENTS
In
this document, the terms “Longeveron,” “Company,” “Registrant,” “we,” “us,”
and “our” refer to Longeveron Inc. We have no subsidiaries.
This
Annual Report on Form 10-K (this “10-K”) contains forward-looking statements, within the meaning of the Private Securities
Litigation Reform Act of 1995, that reflect our current expectations about our future results, performance, prospects and opportunities.
This 10-K contains forward-looking statements that can involve substantial risks and uncertainties. All statements other than statements
of historical facts contained in this 10-K, including statements regarding our future results of operations and financial position, business
strategy, prospective products, product approvals, research and development costs, future revenue, timing and likelihood of success,
plans and objectives of management for future operations, future results of anticipated products and prospects, plans and objectives
of management are forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors
that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements
expressed or implied by the forward-looking statements.
In
some cases, you can identify forward-looking statements by terms such as “anticipate,” “believe,” “contemplate,”
“continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,”
“potential,” “predict,” “project,” “should,” “target,” “will,”
or “would” or the negative of these terms or other similar expressions, although not all forward-looking statements contain
these words. Factors that could cause actual results to differ materially from those expressed or implied in any forward-looking statements
contained in this report include, but are not limited to, statements about:
● the success of competing therapies that are or may become available;
ii
We
have based these forward-looking statements largely on our current expectations and projections about our business, the industry in which
we operate and financial trends that we believe may affect our business, financial condition, results of operations and prospects, and
these forward-looking statements are not guarantees of future performance or development. These forward-looking statements speak only
as of the date of this 10-K and are subject to a number of risks, uncertainties and assumptions described in the section titled “Risk
Factors” and elsewhere in this 10-K. Because forward-looking statements are inherently subject to risks and uncertainties, some
of which cannot be predicted or quantified, you should not rely on these forward-looking statements as predictions of future events.
The events and circumstances reflected in our forward-looking statements may not be achieved or occur and actual results could differ
materially from those projected in the forward-looking statements. Except as required by applicable law, we do not plan to publicly update
or revise any forward-looking statements contained herein after we file this 10-K, whether as a result of any new information, future
events or otherwise.
In
addition, statements that “we believe” and similar statements reflect our beliefs and opinions on the relevant subject. These
statements are based upon information available to us as of the date of this 10-K, and while we believe such information forms a reasonable
basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have
conducted an exhaustive inquiry into, or review of, all potentially available relevant information. These statements are inherently uncertain
and you are cautioned not to unduly rely upon these statements.
iii
PART
I
Item
1. Business
Overview
We
are a clinical stage biotechnology company developing regenerative medicines to address unmet medical needs. The Company’s lead
investigational product is Lomecel-BTM, an allogeneic Mesenchymal Stem Cell (“MSC”) formulation sourced from the bone
marrow of young, healthy adult donors. Lomecel-BTM has multiple potential mechanisms of action that promote tissue repair and healing
with broad potential applications across a spectrum of disease areas. The underlying mechanism(s) of action that may lead to the tissue
repair programs include the stimulation of new blood vessel formation, modulation of the immune system, reduction in tissue fibrosis,
and the stimulation of endogenous cells to divide and increase the numbers of certain specialized cells in the body.
We
are currently pursuing three pipeline indications: Hypoplastic Left Heart Syndrome (“HLHS”), Alzheimer’s disease (“AD”)
and Aging-related Frailty. Our mission is to advance Lomecel-BTM and other cell-based product candidates into pivotal or Phase 3
trials, with the goal of achieving regulatory approvals, subsequent commercialization, and broad use by the healthcare community.
In
November of 2023, Longeveron received notice from the World Health Organization (“WHO”) that “laromestrocel”
has been selected as the proposed International Nonproprietary Name for Longeveron’s Lomecel-BTM product. Assuming that
there are no third-party objections to that name, the name will be recommended for adoption by the WHO. Longeveron will adopt that
name if it is recommended by the WHO.
HLHS
Our HLHS program is focused on the potential clinical benefits of Lomecel-BTM
as an adjunct therapeutic to standard-of-care HLHS surgery. HLHS is a rare and devastating congenital heart defect in which the left ventricle
is severely underdeveloped. As such, babies born with this condition die shortly after birth without undergoing a complex series of reconstructive
heart surgeries. Despite the availability of life-saving surgical interventions, clinical studies show that only 50 to 60 percent of affected
individuals survive to adolescence. Early clinical study data shows the potential survival benefit of Lomecel-BTM for HLHS patients
and supports Longeveron’s belief that this data shows the potential to alter the treatment landscape for patients with HLHS. We
have completed a Phase 1 open-label study (“ELPIS I”)1 that supported the safety and tolerability of Lomecel-BTM
for HLHS, when directly injected into the functional right ventricle during the second-stage standard-of-care surgery (adding minimal
additional time to the surgical procedure). Preliminary data revealed that several indices of right ventricular function show suggestions
of either improvement or prevention of deterioration over one year following surgery. Heart transplant-free survival for patients who
received Lomecel-BTM intracardiac injection is favorable as compared to historical controls for survival. The improvement in HLHS
survival following the Phase 1 ELPIS I clinical trial has resulted in acceptance by the American Heart Association (“AHA”)
for a poster presentation at an AHA meeting in November 2023. The ELPIS I trial showed 100 percent survival in children up to 5 years
of age after receiving Lomecel-BTM, compared to a 20 percent mortality rate observed from historical control data. Based on
these findings, the U.S. Food and Drug Administration (the “FDA”) granted Lomecel-BTM both Rare Pediatric Disease (RPD”)
Designation and Orphan Drug Designation (“ODD”) for treatment of infants with HLHS. Longeveron is currently conducting a controlled
Phase 2b trial (“ELPIS II”) to compare the effects of Lomecel-BTM as an adjunct therapeutic versus standard-of-care (HLHS
surgery alone). We hope that a positive outcome could add to the clinical data suggesting the functional and clinical benefit of Lomecel-BTM
as part of standard-of-care treatment in HLHS patients.
1
Alzheimer’s
Disease
In
September 2023, we completed our Phase 2a AD clinical trial, known as the CLEAR MIND trial. This trial enrolled patients with mild Alzheimer’s
disease and was designed as a randomized, double-blind, placebo-controlled study across ten U.S. centers. Our primary objective was to
assess safety, and we tested three distinct Lomecel-BTM dosing regimens against placebo.
The study demonstrated positive results. Notably, all Lomecel-BTM
treatment groups met the safety primary endpoint and showed slowing/prevention of disease worsening relative to placebo. There were statistically
significant improvements in the secondary efficacy endpoint, composite Alzheimer’s disease score (“CADS”) for both the
low-dose Lomecel-BTM group and the pooled treatment groups compared to placebo. Other doses also showed promising results in
slowing/prevention of disease worsening. Additionally, a statistically significant improvement versus placebo was observed in the cognitive
assessment (“MoCA”) and in the activity of daily living observed by a caregiver and measured by Alzheimer’s Disease
Cooperative Study Activities of Daily Living (“ADCS-ADL”). These findings support both the safety and potential therapeutic
benefit of Lomecel-BTM in managing mild Alzheimer’s disease, and we believe lays a strong groundwork for subsequent trials
in this indication.
Aging-related
Frailty
Improvement of the quality of life for the aging population is one
of the strategic directions of the Company. Life expectancy has substantially increased over the past century due to medical and public
health advancements. However, this longevity increase has not been paralleled by health span – the period of time one can expect
to live in relatively good health and independence. For many developed and developing countries, health span lags life-expectancy by over
a decade. This has placed tremendous strain on healthcare systems in the management of aging-related ailments and presents additional
socioeconomic consequences due to patient decreased independence and quality-of-life. Since these strains continue to increase with demographic
shifts towards an increasingly older population, improving health span has become a priority for health agencies, such as the National
Institute on Aging (“NIA”) of the National Institutes of Health (“NIH”), the Japanese Pharmaceuticals and Medical
Devices Agency (“PMDA”), and the European Medicines Agency (“EMA”). As we age, we experience a decline in our
own stem cells, a decrease in immune system function (known as “immunosenescence”), diminished blood vessel functioning, chronic
inflammation (known as “inflammaging”), and other aging-related alterations that affect biological functioning. Our preliminary
clinical data suggest that Lomecel-BTM may potentially address these problems through multiple potential mechanisms of action (“MOAs”)
that simultaneously target key aging-related processes. We are using Lomecel-BTM in registry trials in The Bahamas as part of the
real-world data generation for the aging population.
Summary
of Clinical Development Strategy
Our
core strategy is to become a world-leading regenerative medicine company through the development, approval, and commercialization of
novel cell therapy products for unmet medical needs, with a focus on HLHS. Key elements of our current business strategy are as follows.
2
Clinical
Development Pipeline in 2024
We
are currently in clinical development of a single product, Lomecel-BTM for three potential indications:
Indication Geography Phase 1 Phase 2 Phase 3
HLHS U.S.
Aging-related Frailty* U.S.
Alzheimer’s disease U.S.
Figure
1: Lomecel-BTM clinical development pipeline
* Not currently active for 2024
Hypoplastic Left Heart Syndrome (HLHS). The FDA granted Lomecel-BTM for the treatment of HLHS a Rare Pediatric Disease (“RPD”) Designation (on November 8, 2021), Orphan Drug Designation (“ODD”) (on December 2, 2021), and Fast Track Designation (on August 24, 2022). HLHS is a rare congenital heart condition affecting approximately 1,000 newborns in the US annually. HLHS is a birth defect that affects normal blood flow through the heart. As the baby develops during pregnancy, the left side of the heart does not form correctly. It is one type of congenital heart defect present at birth. Because a baby with this defect needs surgery or other procedures soon after birth, HLHS is considered a critical congenital heart defect. To prevent certain death shortly after birth, these babies undergo a series of three heart surgeries (staged surgical palliation) that converts the normally 4-chamber heart into a 3-chamber one with a single ventricle (the right ventricle) supporting systemic circulation. Despite these life-saving surgeries, HLHS patients nevertheless still have high early mortality and morbidity rates due primarily to heart failure.
3
We are currently conducting an ongoing Phase 2 clinical trial (ELPIS II) under FDA
IND 017677. ELPIS II is a multi-center, randomized, double-blind, controlled clinical trial designed to evaluate Lomecel-BTM as
an adjunct therapy to the standard-of-care second-stage HLHS heart reconstructive surgery which is typically performed at 4-6 months
after birth. The primary objective is to evaluate change in right ventricular ejection fraction after Lomecel-BTM treatment versus
standard-of-care surgery alone (38 subjects total: 19 per arm). This trial is over 50% enrolled and is funded in part by the NHLBI/NIH.
While we cannot predict a specific time when the trial will be fully enrolled, the current plan is that enrollment will be completed
in 2024.
ELPIS
II is a next-step trial to our completed 10-patient open-label Phase 1 trial (ELPIS I) under the same IND. This Phase 1 trial was designed
to evaluate the safety and tolerability of Lomecel-BTM as an adjunct to the second-stage HLHS surgery, and to obtain preliminary
evidence of Lomecel-BTM effect to support a next-phase trial. The primary safety endpoint was met: no major adverse cardiac events
(“MACE”) or treatment-related infections during the first month post-treatment, and no triggering of stopping rules. Furthermore,
fluid-based and imaging biomarker data supported multiple potentially relevant mechanisms-of-action of Lomecel-BTM, and the potential
to improve post-surgical heart function. In addition to the 12-month follow-up evaluation on ELPIS, we continue to follow these patients
on an annual basis. As of February 2024, all 10 patients have survived (100%), seven of the patients have reached the age of five and
have successfully undergone the third-stage surgery, and two of them have reached the age of six years old, all without the need for
a heart transplantation. Based on historical data, over 15% of patients would be expected to have received a heart transplant or have
died within three years after the second-stage surgery, rising to nearly 20% by five years. We intended to continue to follow-up with
these patients for up to an additional five years, until all patients reach ten years of age.
We
are prosecuting a number of patent applications relating to the administration of mesenchymal stem cells for treating HLHS in Canada,
Japan, Taiwan, the United States and the Bahamas, with applications having also been ordered for filing in Australia, China, South Korea,
and the European Patent Office.
Alzheimer’s disease. AD, a devastating neurologic disease
leading to cognitive decline, currently has very limited therapeutic options. An estimated 6.7 million Americans aged 65 and older have
AD, and this number is projected to more than double by 2060. Lomecel-BTM treated patients showed an overall slowing/prevention
of disease worsening compared to placebo in the completed Phase 2a study (CLEAR MIND) as previously detailed in this report, and met
its primary endpoint of safety. These results are consistent with those of our earlier Phase I study2. As previously
indicated, we are actively in pursuit of a partnership to propel our AD initiative forward.
Aging-related Frailty. Aging-related Frailty is a life-threatening
geriatric condition that disproportionately increases risks for poor clinical outcomes from disease and injury. While the definition
of Aging-related Frailty lacks consensus, would be a new indication from a regulatory standpoint, and has no approved pharmaceutical
or biologic treatments, there are a number of companies now working to develop potential therapeutics for this unmet medical need.
We
have previously completed two U.S. clinical trials under FDA IND 016644. One is a multicenter, randomized, placebo-controlled Phase
2b trial which showed that a single infusion of Lomecel-BTM significantly improved 6-Minute Walk Test (“6MWT”)
distance 9 months after infusion (although results were inconclusive at six months after infusion), and also showed a dose-dependent increase in 6MWT distance 6 months after infusion. The second is
a multicenter, randomized, placebo-controlled Phase 1/2 trial (“HERA Trial”) intended primarily to evaluate safety, and
explore the effect Lomecel-BTM may have on specific biomarkers of immune system function in older, frail individuals receiving
the high dose influenza vaccine, as well as to evaluate the potential effects of Lomecel-BTM on signs and symptoms of Aging
Frailty. Results from this study showed that Lomecel-BTM was generally safe and well tolerated in patients with Aging-related
Frailty. Additionally, hemagglutinin inhibition (“HAI”) assay results in the Lomecel-BTM and placebo groups to
influenza were not statistically different, indicating Lomecel-BTM does not suppress the immune system.
4
We
are prosecuting or have sent filing instructions for a number of patent applications relating to the administration of MSC for Aging-related
Frailty in Australia, Canada, China, the European Patent Office, Hong Kong, Israel, Japan, Singapore, South Korea, New Zealand, Taiwan,
the Bahamas and United States.
Manufacturing
The
manufacture and delivery of cell therapy products to patients involves complex, integrated processes. Commercial success in this area
requires manufacturing processes that are reliable, scalable, and economical. We currently operate a manufacturing facility in Miami,
Florida, which supplies Lomecel-BTM for our clinical trials and also serves as our corporate headquarters. We have devoted and plan
to continue devoting significant resources to optimization of process development and manufacturing to reduce per-unit manufacturing
costs and to enable quick scale-up of production upon approval of any of our candidates in a particular country.
Our
current good manufacturing process (“cGMP”) facility went online in early 2017 and consists of 4,150 ft2 (385.5
m2) with approximately 3,000 ft2 (279 m2) of cGMP space comprised of eight International Organization
for Standardization (“ISO”) 7 cleanrooms, and ISO 8 ancillary areas and 1,150 ft2 (107 m2) of warehouse,
research and development and Quality Control space, including two research and development laboratories. The cGMP cleanrooms are used
exclusively for the manufacture of human cellular therapy products for use in clinical trials. The facility is in compliance with FDA
regulations in the Code of Federal Regulations 21, Parts 210 and 211.
Our
lead product, Lomecel-BTM, consists of human allogeneic bone-marrow derived MSCs as the active ingredient. These cells undergo culture-expansion
using proprietary processes, and are then formulated, packaged and stored frozen (cryopreserved) until shortly before use. Fresh
bone marrow is procured from established, licensed U.S.-based third-party tissue suppliers, which harvest the tissue from young, healthy
consenting adult donors. Lomecel-BTM is produced using processes that FDA has reviewed and authorized as part of our INDs. We currently
have bone marrow supply contracts in place with two suppliers: the Oklahoma Blood Institute and All Cells, with a potential third vendor
in process. These suppliers provide adequate bone marrow for our current and anticipated needs; however, if one or both suppliers were
to no longer provide bone marrow, alternate suppliers would be needed or our ability to produce Lomecel-BTM in the future could
be impacted.
Technology
Capabilities
From
the commencement of operations in 2014, we recognized the potential for a cellular therapy product to be a novel therapeutic candidate
in our chosen indications. We have assembled a team of experts and proprietary technologies that we believe enables us to take a systematic
approach to rapidly develop improved cell therapies. We believe having established manufacturing capabilities and operations within the
U.S. early in the development of our product candidates is a competitive advantage. Over time, as needed and appropriate, we expect to
expand regional manufacturing capacity and potentially add external supply nodes to meet projected product requirements for commercialization.
We believe that anticipated future clinical and commercial demand for Lomecel-BTM and new pipeline programs can be met, as our process
has been designed to meet these demands as milestones are achieved. We believe our scalable robust manufacturing process, along with
our proprietary technologies and our industry experienced team, would be challenging and costly for potential competitors to replicate.
Contract
Development and Manufacturing Services
We
produce all of our product candidates in the ISO 7 cleanrooms of our cGMP facility to satisfy our ongoing clinical studies and The Bahamas
Registry Trial. As a revenue-generating opportunity, occasionally we utilize excess capacity, when available, to provide contract manufacturing
and development services to third parties; however, our business development activity is limited in this area.
5
Commercialization
We
currently have no established sales, marketing or product distribution infrastructure. In order to commercialize any of our product candidates
if approved for commercial sale, we will need a sales and marketing organization with technical expertise and supporting distribution
capabilities or collaborate with third parties that have sales and marketing experience. As we move our product candidates through development
toward regulatory approval, we plan to evaluate several options for each product candidate’s commercialization strategy. These
options include further building an internal sales force, entering into a joint marketing collaboration with another pharmaceutical or
biotechnology company, or out-licensing any future approved product to another pharmaceutical or biotechnology company. All such commercialization
will be undertaken in accordance with applicable law.
Competition
The
field of regenerative medicine, which includes gene therapies, cell therapies (such as Lomecel-BTM), and tissue-engineered products,
is broadly defined as “products intended to repair, replace or regenerate organs, tissues, cells, genes, and metabolic processes
in the body,” per the Alliance for Regenerative Medicine (“ARM”), an international advocacy organization. Regenerative
medicine companies number over 1,550 worldwide as of January 2024.
In
some of our indications, we face competition from both cellular therapy companies, and pharmaceutical/biotechnology companies. In the following table is a general,
non-comprehensive list of cellular therapy companies that we believe could be considered our primary competition, either because they
also develop MSCs as their primary mode of action, albeit for different indications in most cases or on the basis that these companies
are addressing the same indications as Longeveron.
Name Corporate Headquarters Clinical stage pipeline indication(s)
Athersys, Inc. U.S. Ischemic stroke; ARDS; GvHD; Acute Myocardial Infarction
BioCardia, Inc. U.S. Heart failure; Acute myocardial infarction
BrainStorm Cell Therapeutics U.S. ALS; MS
CorestemChemon South Korea ALS (Commercial in South Korea); Lupus
Cynata Therapeutics Australia GvHD
Healios K.K. Japan Ischemic stroke; ARDS
Medipost South Korea Osteoarthritis (commercial); BPD; AD
Pluri, Inc. Israel CLI; ARDS; ARS; GvHD
ReNeuron U.K. Ischemic stroke; Retinitis pigmentosa
SanBio Co., Ltd. Japan Ischemic stroke; Traumatic brain injury
Stemedica Cell Technologies U.S. Ischemic stroke; heart failure; AD
ARDS
= Acute Respiratory Distress Syndrome; GvHD = Graft versus host disease; ALS = Amyotrophic lateral sclerosis; MS = Multiple sclerosis;
BPD = Bronchopulmonary dysplasia; CLI = Critical limb ischemia; CMD = Coronary microvascular disease; ARS = Acute radiation syndrome.
6
Aging
Frailty Competitive Intelligence Research
Per
ClinicalTrials.gov, as of February 18, 2024, there were 107 clinical trials in Aging Frailty listed on the site including all stages
(ongoing, completed, terminated, withdrawn) and all interventions. Of the 107 listed studies, there were 29 studies listed which are
currently enrolling patients with aging frailty. Among those, allogeneic bone-marrow-derived mesenchymal stem cell were listed as an
intervention in three studies:
Alzheimer’s
Disease Competitive Intelligence Research
Per
ClinicalTrials.gov, as of February 18, 2024, there were 3,334 studies listed on the site studying Alzheimer’s disease, including
all stages (ongoing, completed, terminated, withdrawn) and all interventions. Among those, 401 studies were listed with Alzheimer’s
disease as an indication and stem cells as an intervention. Seventeen of them were listed to conduct clinical studies with mesenchymal
stem cells in all stages and only one of them is currently enrolling patients on the study:
There
are many other pharmaceutical and biotechnology companies that are conducting clinical trials of various therapeutics for the treatment
of AD.
7
Intellectual
Property
We
seek to protect our proprietary technology, inventions, and improvements that are commercially important to the development of our business
by seeking, maintaining, and defending patent rights, whether developed internally, acquired from third parties, or licensed from third
parties. We also intend to seek and rely on any statutory or regulatory protections, including FDA’s expedited review program,
data exclusivity, market exclusivity and patent term extensions where available.
By
letter dated November 20, 2023, Longeveron was informed by the WHO that “laromestrocel” has been selected as the proposed
International Nonproprietary Name for Longeveron’s Lomecel-BTM product. Assuming that there are no third-party objections
to that name, the name will be recommended for adoption by the WHO. Longeveron will adopt that name if it is recommended by the
WHO.
We
have a combination of Company-owned and in-licensed patents and patent applications related to cell-based therapy and its various uses.
This portfolio includes patent applications directed to use of allogeneic MSCs to treat sexual dysfunction. We also have in-licensed
a patent family directed to methods of use of CD271+ MSC precursor cells. Our patent applications contain claims that, if allowed, specifically
protect the use of our product in individuals with Aging-related frailty, immunosenescence, and other age-related diseases. We also rely
on trade secrets that may be important to the development of our business. Trade secrets are difficult to protect and enforce and therefore
provide us with only limited protection.
We
expect to file additional patent applications in support of current and new product candidates, as well as for process and
manufacturing-related improvements or inventions, should these arise. These expected additional patent applications may be related
to existing patent applications or may create new patent families. Our commercial success will depend in part on obtaining and
maintaining patent protection and trade secret protection for our current and future product candidates and the methods used to
develop, manufacture, administer, and use them. Our commercial success will also depend on successfully defending our patents
against third-party challenges and operating without infringing on the proprietary rights of others. We are aware of several U.S.
patents held by third parties covering potentially similar or related products, and their manufacture and use. Generally, conducting
clinical trials and other acts relating to FDA approval are not considered acts of infringement in the U.S. If and when
Lomecel-BTM MSCs are approved by the FDA, third parties may seek to enforce their patents by filing a patent infringement
lawsuit against us. Our ability to deter and, if necessary, to stop third parties from making, using, selling, offering to sell or
importing our products or products that are similar to our products depends on the extent to which we have rights under valid and
enforceable patents or trade secrets that cover these activities. We can neither be sure that patents will be granted with respect
to any of our pending patent applications or with respect to any patent applications filed by us in the future, nor can we be sure
that any patents that may be granted to us in the future will be commercially useful in protecting our product candidates, discovery
programs and processes. Unpublished third-party patent applications may exist that would have an effect on our freedom to operate.
For this and more comprehensive risks related to our intellectual property, please see “Risk Factors—Risks Related to
Intellectual Property.”
8
The
term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most jurisdictions
where we file, including the U.S., the patent term is 20 years from the earliest date of filing a non-provisional patent application.
In the U.S., a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays
by the U.S. Patent and Trademark Office “(USPTO”), in examining and granting a patent. Patent term in the U.S. may be shortened
if a patent is subject to a terminal disclaimer over another patent. Delays on the part of a patentee may decrease patent term adjustment.
In
the U.S., the term of a patent that covers an FDA-approved “active ingredient” or methods of its use may also be eligible
for patent term extension, which permits patent term restoration as compensation for the patent term lost during the FDA regulatory review
process. The Drug Price Competition and Patent Term Restoration Act of 1984, the Hatch-Waxman Amendments, or the Biologics Price Competition
and Innovation Act of 2009 permit a patent term extension of up to five years beyond the expiration of the statutory term of a patent,
including any patent term adjustment to which the patent is entitled. The length of the patent term extension is related to the length
of time the active ingredient or method is under regulatory review. Patent term extension cannot extend the remaining term of a patent
beyond a total of 14 years from the date of product approval, only one patent applicable to an approved drug may be extended and only
those claims covering the approved drug, a method for using it, or a method for manufacturing it may be extended. Similar provisions
are available in Europe and other foreign jurisdictions to extend the term of a patent that covers an approved drug. In the future, if
and when our products receive FDA approval, we expect to apply for patent term extensions on patents covering those products. We plan
to seek patent term extensions for any issued patents we may obtain in any jurisdiction where such patent term extensions are available.
We are not assured that the applicable authorities, including the FDA in the U.S., will agree with our assessment of whether such extensions
should be granted, and if granted, the length of those extensions. For more information regarding the risks related to our intellectual
property, see “Risk Factors—Risks Related to Intellectual Property.”
We
may file patent applications directly with the USPTO as provisional applications. We may file U.S. non-provisional applications, direct
foreign applications under the Paris Convention and the Agreement on Trade Related Aspects of Intellectual Property Rights, and Patent
Cooperation Treaty, or PCT, applications. Those applications may claim the benefit of the priority date of one or more earlier filed
applications, when applicable. The PCT system allows a single application to be filed within 12 months of the original priority date
of the patent application and to designate all of the PCT member states in which national or regional patent applications can later be
pursued based on the PCT application.
For
all patent applications, we determine claim strategy on a case-by-case basis. Advice of counsel and our business model and needs are
considered. We seek to file patents containing claims for protection of all useful applications of our proprietary technologies and any
products, as well as all new applications and/or uses we discover for existing technologies and products, assuming these are strategically
valuable. We routinely reassess the number and type of patent applications, as well as the pending and issued patent claims to pursue
maximum coverage and value for our processes and compositions. Further, we may modify claims during patent prosecution to meet our intellectual
property and business needs.
We
recognize that the ability to obtain patent protection and the degree of such protection depends on a number of factors. These include
the volume and scope of the prior art, the novelty, non-obviousness, and utility of the invention, and the ability to satisfy the written
description and enablement requirements of the patent laws. In addition, the coverage claimed in a patent application can be significantly
narrowed before the patent is issued, and its scope can be reinterpreted or further altered even after patent issuance. Consequently,
we may not obtain or maintain adequate patent protection for any of our future product candidates or for our technology platform. We
cannot predict whether the patent applications we are currently pursuing will be issued as patents in any particular jurisdiction or
whether the claims of any issued patents will provide sufficient protection from copying by competitors. Any patents that we hold may
be challenged, circumvented, or invalidated by third parties. We cannot predict whether, in certain jurisdictions, a third-party will
use a method confidentially that we later independently discover and patent, which may result in a limited grant to the third party of
the ability to continue to practice that method despite our patent.
9
In
addition to patent protection, we rely on trademark registration, trade secrets, know-how, other proprietary information and continuing
technological innovation to develop and maintain our competitive position. We seek to protect and maintain the confidentiality of proprietary
information to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.
Although we take steps to protect our proprietary information and trade secrets, including through contracts with our employees and consultants,
third parties may independently develop substantially equivalent proprietary information and techniques or otherwise gain access to our
trade secrets or disclose our technology. Thus, we may not be able to meaningfully protect our trade secrets indefinitely.
We
require our employees, consultants, outside scientific collaborators, sponsored researchers and other advisors to execute confidentiality
agreements upon the commencement of employment or consulting relationships with us. These agreements provide that all confidential information
concerning our business or financial affairs developed or made known to the individual during the course of the individual’s relationship
with us is to be kept confidential and not disclosed to third parties except under specific circumstances. Our agreements with employees
also provide that all inventions conceived by the employee in the course of employment with us or from the employee’s use of our
confidential information are our exclusive property. However, such confidentiality agreements and invention assignment agreements can
be breached, and we may not have adequate remedies for any such breach. In addition, our trade secrets may otherwise become known or
be independently discovered by competitors. To the extent that our consultants, contractors, or collaborators use intellectual property
owned by others in their work for us, disputes may arise as to the rights in related or resulting trade secrets, know-how and inventions.
For more information regarding the risks related to our intellectual property, see “Risk Factors—Risks Related to Intellectual
Property.”
The
patent positions of biotechnology companies like ours are generally uncertain and involve complex legal, scientific, and factual questions.
Our commercial success will also depend in part on not infringing upon the proprietary rights of third parties. Third-party patents could
require us to alter our development or commercial strategies or our products or processes, to obtain licenses or to cease certain activities.
Our breach of any license agreements or our failure to obtain a license to proprietary rights required to develop or commercialize our
future products may have a material adverse impact on us. If third parties prepare and file patent applications in the U.S. that also
claim technology to which we have rights, we may have to participate in interference or derivation proceedings in the USPTO to determine
priority of invention. If third parties file requests for inter partes review of our patents, then we may have to defend those
patents in the USPTO. For more information, see “Risk Factors—Risks Related to Intellectual Property.”
When
available to expand market exclusivity, our strategy is to obtain, or license additional intellectual property related to current or
contemplated development platforms, core elements of technology and/or clinical candidates.
Company-Owned
Intellectual Property
Mesenchymal
Stem Cells as Vaccine Adjuvants and Methods for Using the Same. The claims within this patent application family are currently directed
to methods of enhancing the immune response to vaccination, which was one of the research objectives of our Phase 1/2 HERA Trial. This
research is relevant to Aging-related Frailty subjects, who are particularly vulnerable to the effects of viral contagion, such as influenza
or COVID-19, and who may be lacking in immunoprotection. Certain claims address the ability to enhance a subject’s immune response
to a vaccine through the administration of a therapeutically effective amount of allogeneic MSCs in a subject that exhibits “inflammaging.”
In this family we own and are continuing to prosecute and maintain one allowed U.S. patent application, one allowed application and one
pending application in Japan, one pending application in Australia, and one pending application in the European Patent Office. Another
European Patent Office application has been allowed, and pending conclusion of the opposition period is planned to be validated in Switzerland,
Germany, Spain, France, Great Britain, Italy, and Sweden. All of the patent applications are national or regional phase applications
based on a Patent Cooperation Treaty (“PCT”) application filed in February 2017 and claiming priority to a U.S. provisional
application filed in February 2016. If issued and assuming all maintenance and annuity fees are paid, patents arising from these applications
are projected to expire in 2037. Longeveron has elected to take no further action and to allow to become abandoned, properties in this
family in Canada, Hong Kong, Israel, Singapore, South Africa, South Korea, and New Zealand.
10
Methods
of Using Human Mesenchymal Stem Cells to Effect Cellular and Humoral Immunity. Certain claims in this family of patent applications
relate to the ability for MSC therapy to improve the immune system function in patients with chronic systemic inflammation, a hallmark
of frailty. It is believed that raising or lowering specific biomarkers after therapeutic intervention by a minimum amount may provide
broad protection from an intellectual property standpoint and reflects clinical goals of treatment and treatment response.
In
this family we received a notice of allowance for our U.S. patent application, and 14 patent applications outside of the U.S. (in 12
jurisdictions). The Chinese counterpart of the application has been allowed. Patents have issued in Japan and Taiwan, and a patent registration
has issued in South Africa. With two exceptions (The Bahamas and Taiwan), all of the applications are national or regional phase applications
based on a PCT application filed in November 2017 and claiming priority to a U.S. provisional application filed in November 2016. The
applications in The Bahamas and Taiwan claim priority to that same provisional application but were not filed using the PCT. In addition
to the applications in Taiwan and The Bahamas, PCT national or regional phase applications were filed in the U.S., Australia, Canada,
China, the European Patent Organization, Israel, Japan, South Korea, New Zealand, Singapore, South Africa, and Hong Kong. If issued and
assuming all maintenance and annuity fees are paid, patents arising from these applications are projected to expire in 2037.
Treatment
of Sexual Dysfunction and Improvement in Sexual Quality of Life. This application family is directed towards increasing libido
and improving sexual function and satisfaction in a female patient through the use of allogeneic or autologous MSC therapy, whether derived
from bone marrow, adipose tissue or induced pluripotent stem cells (iPSCs). In this family we own and we are continuing to prosecute
or maintain applications in the United States and European Patent Office, and we own a patent in Japan. We also won and are continuing
to maintain a patent registration in the Bahamas. The U.S., Japanese, and European properties are a national or regional phase applications
based on a PCT application filed on June 15, 2018 and claiming priority to a U.S. provisional application filed in June 2017. The registration
in the Bahamas claims priority to that same provisional application but was not filed using the PCT. If issued and assuming all maintenance
and annuity fees are paid, patents arising from these applications are projected to expire in June 2038. Longeveron has elected to take
no further action and to allow to become abandoned, properties in the family in Australia, Canada, China, Hong Kong, Israel, Korea, Singapore,
South Africa, South Korea, Taiwan, and New Zealand.
Potency
Assay. This application family is directed towards assessing potency of MSCs to produce anti-inflammatory cytokines in response to
a pro-inflammatory stimulus. In this family we own pending applications in Australia, the Bahamas, Canada, China, the European Patent
Office, Hong Kong, Israel, Japan, New Zealand, the Republic of Korea, Singapore, South Africa, and the United States. These applications
have a filing date in April 2021 and claim priority to a U.S. provisional application filed in April 2020. If issued and assuming that
all maintenance and annuity fees are paid, patents arising from these applications are projected to expire in April 2041.
Use
of Mesenchymal Stem Cells in Treatment of Juvenile Hypoplastic Left Heart Syndrome. This patent family is directed to treatment of
HLHS with allogeneic MSCs. In this family we own pending applications in Taiwan, the Bahamas, and the PCT. These applications share a
common priority date of July 2021. National and regional phase applications based on pending PCT application, have been filed or are
expected to be filed in Australia, Canada, China, the European Patent Office, Japan, South Korea, Taiwan, and the United States. If issued
and assuming all maintenance and annuity fees are paid, patents arising from these applications are projected to expire in July 2042.
Administration
of Mesenchymal Stem Cells for Aging-related frailty. This patent family relates to administration of MSCs for Aging-related frailty.
In this family we own pending applications in Taiwan, the Bahamas, and the PCT. These applications share a common priority date of September
2021. National and regional phase applications, based on the pending PCT application have been filed or are expected to be filed in Australia,
Canada, China, the European Patent Office, Hong Kong, Israel, Japan, New Zealand, South Korea, Singapore, and South Africa. If issued,
and assuming that all maintenance and annuity fees are paid, patents arising from these applications are projected to expire in September
2042.
Treatment
of Alzheimer’s Disease with Allogeneic Mesenchymal Stem Cells. This patent family relates to administration of MSCs to treat
AD. We own pending patent applications in Australia, the Bahamas, South Korea, Singapore, South Africa, Israel, Canada, Hong Kong, New
Zealand, China, Japan, the European Patent Office, and the United States. Those applications claim priority to three separate U.S. provisional
applications, the earliest of which was filed in September 2020. If issued, and assuming that all maintenance and annuity fees are paid,
patents arising from these applications are expected to expire in September 2041.
11
License
Agreements and Strategic Collaborations
The
University of Miami (“UM”)
On
November 20, 2014, we entered into an Exclusive License Agreement with UM (the “UM License”) for the use of certain Aging-related
frailty-related MSC technology rights developed by our Chief Science Officer, Dr. Joshua Hare, at UM. The UM License is a worldwide,
exclusive license, with right to sublicense, with respect to any and all know-how specifically related to the development of the culture-expanded
MSCs for aging-related frailty used at the Interdisciplinary Stem Cell Institute of UM (“IMSCs”), all standard operating
procedures used to create the IMSCs, and all data supporting isolation, culture, expansion, processing, cryopreservation, and management
of the IMSCs. We are required to pay UM (i) a license issue fee of $5,000, (ii) a running royalty in an amount equal to three percent
of annual net sales on products or services developed from the technology, payable on a country-by-country basis beginning on the date
of first commercial sale through termination of the UM License Agreement, and which may be reduced to the extent we are required to pay
royalties to a third party for the same product or process, (iii) escalating annual cash payments of up to fifty thousand dollars, subject
to offset. The agreement extends for up to 20 years from the last date a product or process is commercialized from the technology and
was amended in 2017 to modify certain milestone completion dates as detailed below. In 2021 the license fee was increased by an additional
$100,000, to defray patent costs. In addition, the Company issued 110,387 unregistered shares of Class A common stock to UM.
The
milestone payment amendments shifted the triggering payments to three payments of $500,000, to be paid within six months of: (a) the
completion of the first Phase 3 clinical trial of the products (based upon the final data unblinding); (b) the receipt by the Company
of approval for the first new drug application (“NDA”), biologics application (“BLA”), or other marketing or
licensing application for the product; and (c) the first sale following product approval. “Approval” refers to product approval,
licensure, or other marketing authorization by the U.S. Food and Drug Administration, or any successor agency. The amendments also provided
for the Company’s license of additional technology, to the extent not previously included in the UM License and granted the Company
an exclusive option to obtain an exclusive license for (a) the HLHS IND with ckit+ cells; and (b) UMP-438 titled “Method of Determining
Responsiveness to Cell Therapy in Dilated Cardiomyopathy.”
We
have the right to terminate the UM License upon 60 days’ prior written notice, and either party has the right to terminate upon
a breach of the UM License. To date, the Company has made payments totaling $365,000 to UM, and as of December 31, 2023, we had accrued
$50,000 in milestone fees payable to UM.
CD271
On
December 22, 2016, we entered into a worldwide exclusive license agreement with JMH MD Holdings (“JMHMD”), an affiliate of
our Chief Science Officer, Dr. Joshua Hare, for the use of CD271 cellular therapy technology. We are required to pay JMHMD a running
royalty in an amount equal to one percent of the annual net sales of the licensed product(s) used, leased, or sold by or for us by any
sub-licensees, which amounts are payable on a country-by-country basis beginning on the date of first commercial sale and ending on the
latter of expiration of the last to expire patent rights in such country or ten years from the first commercial sale in such country
(provided that if all claims within the patent rights have expired or been finally deemed invalid then the royalty will be reduced by
50%), and which may also be reduced to the extent we are required to pay royalties to a third party for the same product or process.
We are also required to pay an initial fee and, by the first day of each anniversary of the Agreement, starting with the second anniversary,
a minimum royalty of ten thousand dollars. JMHMD also received an equity grant equal to one-half of one percent of the then outstanding
units of the Company on a fully-diluted basis. If we sublicense the technology, we are also required to pay an amount equal to 10% of
the net sales of the sub-licensees.